Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017

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Supplementary Online Content

Berríos-Torres SI, Umscheid CA, Bratzler DW, et al; Healthcare Infection Control Practices Advisory Committee. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg. Published online May 3, 2017. doi:10.1001/jamasurg.2017.0904

eAppendix 1. Centers for Disease Control and Prevention, Guideline for the Prevention of Surgical Site Infection 2017 –Background, Methods and Evidence Summaries eAppendix 2. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017: Supplemental Tables

This supplementary material has been provided by the authors to give readers additional information about their work.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eAppendix 1. Centers for Disease Control and Prevention, Guideline for the Prevention of Surgical Site Infection 2017: Background, Methods and Evidence Summaries

TABLE OF CONTENTS 1. BACKGROUND ...... 4 1.1. Prosthetic Joint Arthroplasty ...... 4 2. SCOPE AND PURPOSE ...... 5 3. METHODS ...... 5 3.1Guideline Questions ...... 5 3.1A. CORE SECTION GUIDELINE QUESTIONS ...... 6 3.1B. PROSTHETIC JOINT ARTHROPLASTY SECTION GUIDELINE QUESTIONS ...... 6 3.2. Literature Search ...... 7 3.3. Study Selection ...... 8 3.4. Data Extraction and Synthesis ...... 11 3.5. Formulating Recommendations ...... 11 4. EVIDENCE REVIEW ...... 13 4.1. Core Section Evidence Review ...... 13 4.1A. PARENTERAL ANTIMICROBIAL PROPHYLAXIS (AMP) ...... 13 4.1B. NON-PARENTERAL ANTIMICROBIAL PROPHYLAXIS ...... 16 4.1C. GLYCEMIC CONTROL ...... 20 4.1D. NORMOTHERMIA ...... 21 4.1E. OXYGENATION ...... 22 4.1F. ANTISEPTIC PROPHYLAXIS ...... 25 4.2. Prosthetic Joint Arthroplasty Section Evidence Review ...... 30 4.2A. BLOOD TRANSFUSION ...... 30 4.2B. SYSTEMIC IMMUNOSUPPRESSIVE THERAPY ...... 32 4.2C. INTRA-ARTICULAR CORTICOSTEROID INJECTIONS ...... 34 4.2D. ANTICOAGULATION ...... 36 4.2E. ORTHOPAEDIC SURGICAL SPACE SUIT ...... 38 4.2F. POSTOPERATIVE AMP DURATION IN PROSTHETIC JOINT ARTHROPLASTY WITH THE USE OF A DRAIN ...... 39 4.2G. BIOFILM ...... 39 5. RE-EMPHASIS OF SELECT 1999 CDC AND HICPAC RECOMMENDATIONS FOR PREVENTION OF SURGICAL SITE INFECTIONS ...... 41 5.1. Recommendations ...... 41 © 2017 American Medical Association. All rights reserved. 2

Downloaded From: https://jamanetwork.com/ on 09/30/2021 1. PREPARATION OF THE PATIENT ...... 41 2. HAND/FOREARM ANTISEPSIS FOR SURGICAL TEAM...... 41 3. OPERATING ROOM VENTILATION ...... 41 4. CLEANING AND DISINFECTION OF ENVIRONMENTAL SURFACES ...... 41 5. REPROCESSING OF SURGICAL INSTRUMENTS ...... 41 6. SURGICAL ATTIRE AND DRAPES ...... 41 7. STERILE AND SURGICAL TECHNIQUE ...... 42 8. POST-OP INCISION CARE ...... 42 6. REFERENCES ...... 43

LIST OF FIGURES eFIGURE 1. Results of the Study Selection Process ...... 10 LIST OF TABLES eTABLE A. Inclusion and Exclusion Criteria for Study Selection ...... 9 eTABLE B. CDC and HICPAC Categorization Scheme for Recommendations ...... 12

Downloaded From: https://jamanetwork.com/ on 09/30/2021 1. BACKGROUND

In 2006, approximately 80 million surgical procedures were performed in the United States at inpatient hospitals (46 million)1 and ambulatory hospital-affiliated or free-standing (32 million) settings.2 Between 2006 and 2009, surgical site infections (SSIs) complicated approximately 1.9% of surgical procedures in the U.S.3 However, the number of SSIs is likely to be underestimated for several reasons including poor case ascertainment after hospital discharge (given that approximately 50% of SSIs become evident after discharge) and exclusion of some high-risk procedures from estimates (e.g., non-closed incisions).4National approaches to SSI surveillance have produced varied estimates of risk in the scientific literature,5 which in combination with inconsistencies in coding and a lack of standardization of post-discharge surveillance, has made it challenging to evaluate or compare interventions and track SSIs over time.6 Multiple patient co-morbidities and risk factors, in addition to procedure-related risk factors, can impact the risk of SSI.6 SSIs result in increased morbidity and mortality. Direct and indirect costs from SSIs include increased hospital length of stay, readmissions for treatment including repeat surgical procedures, outpatient and emergency care visits, use of ancillary services, additional medications (including prolonged antimicrobial therapy), lost productivity, and temporary or permanent disability.7 Actual attributable costs of SSIs are difficult to determine. Cost estimates are commonly restricted to hospital charges and vary according to surgical procedure, depth of infection, facility, region, country, publication year, study design, and accounting method.7-9 Estimated average attributable costs of SSIs range from $10,443 to $25,546 per infection (2005 and 2002 dollars, respectively).10-13 Staphylococcus aureus and coagulase negative staphylococci are the organisms most commonly associated with SSIs, but pathogens can vary by procedure.5 Costs can exceed $90,000 per infection when the SSI involves a prosthetic joint implant14,15 or antimicrobial resistant organism.16 Approximately 55% of SSIs are deemed preventable by application of evidence-based strategies.13 In 2002, the Centers for Disease Control and Prevention (CDC) and Centers for Medicare & Medicaid Services (CMS) instituted the Surgical Infection Prevention (SIP) project with the goal of reducing SSIs and developing effective prevention programs.17 In 2006, SIP became the Surgical Care Improvement Program (SCIP) and expanded to include patient hair removal at the surgical site, glycemic control, and normothermia process measures.18 With the Deficit Reduction Act of 2005, the U.S. Congress set forth a mandate for hospital reporting of process, outcome, and other quality improvement measures, and for making this information available to the public and CMS.19 This act required CMS to adjust payments downward for healthcare-associated infections that could have been prevented through the application of evidence-based strategies. In 2009, the U.S. Department of Health and Human Services' (HHS) National Action Plan to Prevent Health Care-Associated Infections: Road Map to Elimination set a 5-year target goal of a 25% reduction in SSIs detected on admission and readmission, or a 0.75 Standardized Infection Ratio (SIR).20 Since January of 2012, CMS’s Hospital Inpatient Quality Reporting Program has required facilities to report SSI outcome data through CDC’s National Healthcare Safety Network (NHSN).21 These data provide some national estimates of SSI prevention progress (http://www.cdc.gov/hai/surveillance/progress-reports).22

1.1. Prosthetic Joint Arthroplasty Prevention efforts should target all surgical procedures, but especially those in which both the human and financial burden is greatest. In 2011, primary total knee arthroplasty (TKA) accounted for over half of the 1.2 million prosthetic joint arthroplasty procedures (primary and revision) performed in the U.S., followed by total hip arthroplasty (THA), and hip hemi-arthroplasty.23 Primary shoulder, elbow, and ankle arthroplasties are much less common. By 2030, prosthetic joint arthroplasties are projected to increase to 3.8 million procedures per year.24-26 Infection is the most common indication for revision in TKA27 and the third most common indication in THA,28 following instability/dislocation and mechanical loosening, S. aureus and coagulase negative staphylococci are the most common pathogens associated with orthopaedic SSIs.5 Between 2001 and 2009, there was a significant increase in the risk of infection following hip and knee arthroplasties (from 1.99% to 2.18% and from 2.05% to 2.18%, respectively).15 By 2030 the infection risk for hip and knee arthroplasty is expected to increase to 6.5% and 6.8%, respectively.29 Owing to both increasing risk and the number of individuals undergoing prosthetic joint arthroplasty procedures, by 2020 the total number of hip and knee prosthetic joint infection (PJI) cases is projected to increase to 70,000 (from 25,000 in 2010) and up to 221,500 cases per year by 2030.15,29 Treatment of PJI commonly involves a 2-stage procedure, with 4-to-8 weeks of parenteral antimicrobial therapy between stages. When eradication of the infection is not possible, treatment can include arthrodesis or even amputation.30 In 2009, the average hospital cost for the revision of an infected hip or knee arthroplasty was $93,600 and $24,200, respectively.15 Between 2001 and 2009, estimated total hospital costs for treating PJI increased from $320 million to $566 million; costs reached $1 billion in 2014 and are projected to reach $1.62 billion by 2020.15

Any indwelling medical device or prosthetic implant has the potential to become colonized by organisms and embedded in biofilm.31,32 In the U.S., as many as 13 million people experience a biofilm-related infection every year.33 Biofilm is defined as “a microbially derived sessile community characterized by cells that are irreversibly attached to a substratum or interface or to each other, are embedded in a matrix of extracellular polymeric substances that they have produced, and exhibit an altered phenotype with respect to growth rate and gene transcription.”32 Biofilm embedded organisms exhibit significant resistance to antimicrobial agents (10 to 1,000 times the minimum inhibitory concentration [MIC]) as compared with their free floating, planktonic counterparts.32 Between 7% and 39% of PJIs are culture negative,34,35 which is often attributed to previous antimicrobial therapy36 or the presence of difficult-to-culture biofilm embedded organisms, making diagnosis, treatment, and the identification of prevention measures difficult to assess. © 2017 American Medical Association. All rights reserved. 4

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Evidence-based guidelines have provided recommendations for the diagnosis of PJI using conventional testing techniques including serologic and synovial fluid markers, tissue histopathology, traditional culture-based techniques, and imaging studies.37 Recently published studies further support or add to these recommendations.35,36,38-40 Potential future strategies for the diagnosis of PJI include the use of novel serologic41-45 and synovial fluid46 markers. In addition, novel strategies to improve the recovery of biofilm organisms may enhance detection of organisms present in lower numbers or species present as a minority.31 Sonication of the explanted prosthesis35,47-50 or cement spacer49 produces a diluent of released biofilm sonicate. Culture of sonicate effluent may have improved culture sensitivity as compared with standard synovial fluid or tissue culture techniques. Different growth media35,51 and microscopic35,51-55 techniques to better grow and characterize biofilm and the embedded organisms are also being explored. Adjunct molecular techniques hold the potential to improve the sensitivity and specificity of traditional culture-based techniques.51-53,55-61 However, only culture-based techniques provide information on antimicrobial susceptibility, which drives PJI treatment. Therefore exploring ways to enhance culturing techniques continues to be important.62 Multidisciplinary work to standardize the clinical diagnosis of PJI is ongoing. 63

2. SCOPE AND PURPOSE

The Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infections, 2017 provides updated and new recommendations for the prevention of surgical site infection (SSI). This Guideline does not provide comprehensive infection control recommendations for prevention of SSIs; the exceptions are mentioned below. In 2014, the Healthcare Infection Control Practices Advisory Committee (HICPAC), a federal advisory committee of the Centers for Disease Control and Prevention (CDC), reviewed the strong recommendations found in the Guideline for Prevention of Surgical Site Infection, 1999.64 HICPAC determined many of the 1999 recommendations to be accepted practices for the prevention of SSI. HICPAC recommended to CDC that these recommendations be considered core surgical infection prevention practices. These recommendations are located in Section 5 of this Guideline. The 1999 recommendations not updated in this Guideline are considered archived.

The specific areas of focus for the 2017 Guideline were informed by feedback received from clinical experts and input from HICPAC. As in the Guideline for Prevention of Surgical Site Infection, 1999,64 the 2017 Guideline does not address SSI prevention issues unique to: burns; trauma; surgical incisions allowed to heal by secondary intention; transplant procedures; transmission of bloodborne pathogens from healthcare personnel to the patient; pediatric surgical practice; minimally invasive procedures; procedures performed outside of the operating room (e.g., endoscopic procedures); non-surgical invasive procedures (e.g., cardiac catheterization, interventional radiology); and other procedures or conditions not specifically mentioned.64 In general, SSI prevention measures deemed effective in adults are also indicated in the pediatric surgical population, and those effective in the operating room can be adapted or modified for other settings. In addition, this update does not address SSI surveillance or public reporting.65 Recommendations on infection control in healthcare personnel,4,66 environmental infection control,67 and disinfection and sterilization of medical devices68 in healthcare settings are addressed by other guidelines.

To evaluate the evidence on SSI prevention, questions addressing 13 intervention categories were examined. The Core Section of the 2017 Guideline encompasses literature across all surgical procedures and is comprised of 6 topics: parenteral antimicrobial prophylaxis, non-parenteral antimicrobial prophylaxis, glycemic control, normothermia, oxygenation, and antiseptic prophylaxis. The literature for 7 topics related specifically to prosthetic joint arthroplasty procedures was evaluated in the Prosthetic Joint Arthroplasty section of the Guideline. These 7 topics include: blood transfusions, systemic immunosuppressive therapy, intra-articular corticosteroid injections, anticoagulation, orthopaedic surgical space suit, postoperative antimicrobial prophylaxis, and biofilm.

The 2017 Guideline is intended for use by surgeons; physician assistants; perioperative nurses and other allied perioperative assistive personnel; anesthesia providers; postoperative inpatient and clinic nurses; infection prevention staff; healthcare epidemiologists; healthcare administrators; other healthcare providers; and persons responsible for developing, implementing, delivering, and evaluating infection prevention and control programs for surgical procedures performed in an operating room (inpatient or ambulatory setting). The Guideline can also be used as a resource for professional societies or organizations that wish to develop more detailed implementation guidance or to identify future research priorities where there are evidence gaps for the prevention of SSI.

3. METHODS

The 2017 Guideline was based on a targeted systematic review of the best available evidence on SSI prevention. An adapted approach to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the quality of the available evidence and the strength of the resulting recommendations, and to provide explicit links between them.69-72 The Guideline development process has been previously described.73 Methods and details that were unique to this Guideline are included below.

3.1Guideline Questions A preliminary list of questions was developed from a review of the 1999 CDC SSI Guideline.64 The current guideline does not re- evaluate several strong recommendations (Section 5) offered by the 1999 CDC SSI guideline which are now considered to be accepted

Downloaded From: https://jamanetwork.com/ on 09/30/2021 practice for the prevention of SSI. Content experts were surveyed to provide feedback on the questions and to identify additional topics of interest. Guideline questions were put in final form after they were vetted by the co-authors and HICPAC.

3.1A. Core Section Guideline Questions Parenteral Antimicrobial Prophylaxis (AMP) Q1. What are the most effective strategies for administering parenteral AMP to reduce the risk of SSI? What is the optimal timing of preoperative AMP? What is the optimal timing of AMP in cesarean section: prior to skin incision or at cord clamping? How safe and effective is weight-adjusted AMP dosing? How safe and effective is intraoperative redosing of AMP? How safe and effective is postoperative AMP and what is the optimal duration? Non-Parenteral Antimicrobial Prophylaxis Q2. What are the most effective strategies for administering non-parenteral antimicrobial prophylaxis at the surgical incision to reduce the risk of SSI? A. How safe and effective is antimicrobial irrigation? B. How safe and effective are antimicrobial agents applied to the surgical incision? C. How safe and effective are antimicrobial-coated sutures; when and how should they be used? D. How safe and effective are antimicrobial dressings applied to surgical incisions following primary closure in the operating room? Glycemic Control Q3. How do perioperative blood glucose and hemoglobin A1c levels impact the risk of SSI, and what are their optimal perioperative target levels in diabetic and non-diabetic patients?

Normothermia Q4. How safe and effective is the maintenance of perioperative normothermia in reducing the risk of SSI?

Q5. What are the most effective strategies for achieving and maintaining perioperative normothermia?

Oxygenation Q6. In patients with normal pulmonary function, how safe and effective is the perioperative use of increased fraction of inspired oxygen (FiO2) in reducing the risk of SSI?

Q7. What is the optimal target FiO2 to reduce the risk of SSI; how and when should it be administered?

Antiseptic Prophylaxis Q8. What are the most effective strategies for preparing the patient’s skin prior to surgery to reduce the risk of SSI? A. How safe and effective is preoperative antiseptic bathing or showering? B. How safe and effective are antiseptic skin preparation agents individually and in combination? C. How safe and effective is the application of a microbial sealant immediately following skin preparation? D. How safe and effective are plastic adhesive drapes?

Q9. How safe and effective is antiseptic irrigation prior to closing the surgical incision?

Q10. How safe and effective is repeat application of an antiseptic skin preparation agent to the surgical site immediately prior to closing the surgical incision?

3.1B. Prosthetic Joint Arthroplasty Section Guideline Questions Blood Transfusion Q11. How do perioperative blood transfusions impact the risk of SSI in prosthetic joint arthroplasty patients? A. Are specific blood products associated with a risk of SSI? B. If the risk of SSI is increased, can this effect be isolated from the risk associated with more complex cases? C. How does the volume of transfused blood product impact the risk of SSI? D. How safe and effective is withholding blood transfusion to reduce the risk of SSI? Systemic Immunosuppressive Therapy Q12. How does systemic corticosteroid or other immunosuppressive therapy impact the risk of SSI in prosthetic joint arthroplasty patients? A. Does the type of agent impact the risk of SSI? B. Does the preoperative duration of the therapy impact the risk of SSI? C. Does the agent dose impact the risk of SSI? Q13. What are the most effective strategies in managing systemic corticosteroid or other immunosuppressive therapy perioperatively to reduce the risk of SSI in prosthetic joint arthroplasty patients? © 2017 American Medical Association. All rights reserved. 6

Downloaded From: https://jamanetwork.com/ on 09/30/2021 A. How safe and effective is the discontinuation of these agents preoperatively, and when should they be resumed? B. Should the agent dose be adjusted, and if so, for how long? Q14. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty patients who are on systemic corticosteroid or other immunosuppressive therapy?

Intra-articular Corticosteroid Injections Q15. How do preoperative intra-articular corticosteroid injections impact the risk of SSI in prosthetic joint arthroplasty patients?

Q16. What are the most effective strategies for managing the preoperative use of intra-articular corticosteroid injections to reduce the risk of SSI in prosthetic joint arthroplasty patients? A. Does the length of time between intra-articular corticosteroid injection and prosthetic joint arthroplasty impact the risk of SSI? B. Does the corticosteroid injection dose impact the risk of SSI? Anticoagulation Q17. What are the most effective strategies for managing perioperative venous thromboembolism (VTE) prophylaxis to reduce the risk of SSI? A. Does the risk of SSI differ by individual VTE prophylaxis agent? B. What is the optimal timing and duration of perioperative VTE prophylaxis that also reduces the risk of SSI? C. How safe and effective is modifying the dose of the perioperative VTE prophylaxis agent to reduce the risk of SSI? Orthopaedic Space Suit Q18. How safe and effective are orthopaedic space suits in reducing the risk of SSI in prosthetic joint arthroplasty patients, and which healthcare personnel should wear them?

Antimicrobial Prophylaxis Duration with Drain Use Q19. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty in the presence of a drain?

Biofilm Q20. What are the most effective strategies to reduce the risk of biofilm formation and SSI in prosthetic joint arthroplasty patients? A. How effective are cement modifications (i.e., antimicrobial and nanoparticle loading)? B. How effective are prosthesis surface modifications (i.e., antimicrobial coating, galvanic couples, “printing” technologies, and nanotechnology)? C. How effective are vaccines? D. How effective are other biofilm control agents (e.g., biofilm dispersants, quorum-sensing inhibitors, novel antimicrobial agents)?

3.2. Literature Search Following the development of Guideline questions, search terms were developed for identifying literature most relevant to those questions. For the purposes of quality assurance, these terms were compared to those used in relevant seminal studies and guidelines. These search terms were then incorporated into search strategies for the relevant databases. Searches were performed in MEDLINE, EMBASE, CINAHL, and the Cochrane Library. All databases were searched from 1998, when the previous guideline searches ended, through April 2014 for the Core Section and December 2011 for the Prosthetic Joint Arthroplasty Section. Literature published since these dates could affect one or more of the recommendations in this Guideline. References were imported into a reference manager where duplicates were resolved. The detailed search strategy and results for the Core Section and the Prosthetic Joint Arthroplasty Section can be found in eAppendix 2 of this Supplement.

Initial searches were designed to identify systematic reviews (SRs) and randomized controlled trials (RCTs). SRs that included non- randomized trials and observational studies (OBS) were eligible for inclusion. Three factors influenced the decision to limit literature searches to RCTs and SRs:

1. RCTs control for confounding more effectively than OBS and thus provide higher quality evidence on the efficacy of therapies; 2. the broad scope of the Guideline; and 3. the value of providing updated recommendations in a timely manner.

When Guideline questions in the Prosthetic Joint Arthroplasty Section were not adequately addressed in the studies identified by the initial searches, additional searches were performed. The additional searches used keywords that were more specific to each relevant question and were not limited to SRs and RCTs.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 3.3. Study Selection Titles and abstracts were screened by one independent reviewer (S.I.B.T., D.B., R.R.K., or C.E.R.). A random sample of 10% of titles and abstracts had a second independent review to ensure consistency in screening. Kappa scores, used to measure agreement between the two independent reviewers beyond chance, ranged from 0.4–0.5, indicating “moderate agreement” between reviewers.74 Full text articles were retrieved if they were:

1. relevant to one or more Guideline questions; 2. clinical practice guidelines, SRs, or primary study designs meeting the inclusion criteria (RCT for the Core and Prosthetic Joint Arthroplasty sections and OBS for the Prosthetic Joint Arthroplasty section); 3. written in English; and 4. available as full text studies (meeting abstracts were excluded). Animal studies and in vitro basic science studies were excluded from all topics except biofilm. Pediatric patient studies were included. Although the literature databases were searched from 1998 to 2014, studies published earlier than 1998 were eligible for inclusion (e.g., studies suggested by the expert panel, included in the 1999 guideline, or identified in published SRs).

Full-text articles were screened by two independent reviewers (S.I.B.T and R.R.K.; S.I.B.T. and C.E.R.; S.I.B.T and D.B., or D.B and E.C.S.) and disagreements were resolved by discussion. Full-text articles were excluded if:

1. SSI was not reported as an outcome; 2. all patients included had “dirty” surgical procedures (except for Q2 addressing the use of aqueous iodophor irrigation); 3. the study only included oral or dental health procedures; 4. the surgical procedures did not include primary closure of the incision in the operating room (e.g., orthopedic pin sites, thoracotomies, or percutaneous endoscopic gastrostomy [PEG] procedures, or wounds healing by secondary intention); 5. the study evaluated wound protectors used post-incision.

In the Core Section for Q1, parenteral antimicrobial prophylaxis studies comparing the efficacy of antimicrobial prophylaxis to no prophylaxis (placebo-controlled studies) and studies comparing the efficacy of different prophylactic antimicrobial agents were excluded. Also for Q2, non-parenteral antimicrobial prophylaxis, use of gentamicin collagen sponge studies were excluded because they are not approved by the U.S. Food and Drug Administration (FDA). For Q8-10 antiseptic prophylaxis, studies evaluating vaginal antisepsis in combination with abdominal antisepsis were excluded. In addition, studies using electrolyzed ionized solution (not approved by the FDA for intraoperative irrigation of the surgical site) and dry povidone iodine powder spray studies were excluded.

For the Prosthetic Joint Arthroplasty section, studies were excluded if they did not specifically examine prosthetic joint arthroplasties. Questions from 4 topics in the Prosthetic Joint Arthroplasty section were excluded from a targeted search when both:

1. the initial broad search identified very few or no RCTs or SRs that fit the inclusion criteria, and 2. the content experts excluded them as lower-priority topics for guideline questions (i.e., surgical attire [specifically gloves], surgical techniques, anesthesia, and environmental factors).

Also, questions and related studies addressing diagnosis of periprosthetic joint infection (PJI) or biofilm were excluded because they did not address SSI prevention. eTable 74 provides a list of inclusion and exclusion criteria used by reviewers.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eTABLE A. Inclusion and Exclusion Criteria for Study Selection Section 1 Section 2 General Exclusion Criteria (all key (all key questions) questions) Not relevant to key questions   Not RCT or SR  Not in English   Not available as full text article   Surgical site infection not included as outcome   Oral medicine / dental health procedures   Not primary closure   Wound protector used post incision   Animal studies  Basic science studies  Not a prosthetic joint arthroplasty  Specific Exclusion Criteria Topic Placebo-controlled studies Antimicrobial prophylaxis Comparison of different antibiotics Antimicrobial prophylaxis Vaginal antisepsis Skin Preparation Epoeitin administration Blood transfusion Specific Inclusion Criteria Topic “Dirty” procedures Antimicrobial prophylaxis Timing of AMP in high-risk Cesarean sections Antimicrobial prophylaxis Non-AMP irrigation / topical application prior to wound closure Antimicrobial prophylaxis (povidone iodine, electrolyzed/ionized solutions) Platelet gel prior to skin closure Skin preparation

A draft bibliography was shared with a panel of content experts, and the additional suggested references then progressed through title and abstract screening and full text review as described above. Results of the entire study selection process are depicted in eFigure 1.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 eFIGURE 1. Results of the Study Selection Process

5487 Potentially relevant studies 104 Studies suggested by content 168 Studies cited in 1999 CDC identified in literature searches experts SSI guideline

5759 Titles and abstracts screened

4863 Studies excluded

896 Full text review

26 Clinical practice guidelines 719 Studies excluded 592 Not relevant to key questions 117 Study design 19 Additional clinical practice guidelines 6 Not available as full text article identified by writing group 4 Not in English

17 Clinical practice guidelines excluded 44 RCTs identified from excluded SRs

28 Clinical practice guidelines 25 Studies excluded, not cited in present guideline relevant to key questions

170 Studies extracted into evidence and GRADE tables

Downloaded From: https://jamanetwork.com/ on 09/30/2021 3.4. Data Extraction and Synthesis For studies meeting the inclusion criteria, data on the study author, year, design, risk of bias, objective, population, setting, sample size, interventions, and results of clinically relevant outcomes were extracted into standardized evidence tables. From these, evidence tables were developed for each clinical topic represented by the questions. Studies were extracted into the most relevant evidence table. Studies were organized by individual questions and subquestions. Data were extracted by a single author (S.I.B.T., E.C.S., B.L., or R.A.) and cross-checked by another author (S.I.B.T. or E.C.S.). Disagreements were resolved by the remaining authors. Data and analyses were extracted as originally presented in the included studies. Meta-analyses were performed only where their use was deemed critical to a recommendation and only in circumstances in which multiple studies with sufficiently homogenous populations, interventions, and outcomes could be analyzed.

SRs were included if the individual studies fit the inclusion criteria. To avoid duplication of data, primary studies identified by the search were excluded if they were also included in a SR captured in the search, unless:

1. the primary study also addressed a relevant question that was outside the scope of the included SRs, or 2. it was one of a select number of studies in the SR that fit the inclusion criteria and was used to perform a new meta-analysis. SRs of primary studies that were fully captured in a more recent SR were excluded. The only exception was older SRs that addressed a question relevant to the Guideline that was outside the scope of the newer SR.75

Statistical analyses were performed using Review Manager 5.1. For the purposes of this review, statistical significance was defined as p≤0.05.

The risk of bias associated with each study was assessed using scales developed by the ECRI Institute Penn Medicine Center for Evidence-based Practice, and scores were recorded in the evidence tables. eAppendix 2 of this Supplement includes the questions used to assess the risk of bias of the included SRs, RCTs, and OBS. When the risk of bias was rated as “High” for >50% of studies making up the evidence base for a given outcome, one point was deducted for Study Quality in the GRADE tables.

Heterogeneity was assessed using the I2 statistic and by evaluation of forest plots. When the I2 value exceeded 50%, and the source of heterogeneity could not be explained by characteristics of the included studies, subgroup analysis, or examination of the forest plots, one point was deducted for consistency in the GRADE tables.

Publication bias was evaluated for questions that addressed commercial products if there was a reasonable expectation that bias in the publication of studies or the reporting of outcomes might be influenced by the sources of study funding. Additionally, funnel plots were examined for patterns suggestive of publication bias. Disclosures of study authors’ reported conflicts of interest were also reviewed, and relevant information is included in the evidence tables. When these analyses indicated the likely presence of publication or reporting bias, 1 point was deducted for publication bias in the GRADE tables. All GRADE Tables, Evidence Tables, and Risk of Bias Tables can be found in eAppendix 2 of the Supplement.

Evidence-based recommendations were cross-checked with those from other guidelines identified in an initial systematic search.

For all other methods, please refer to the Guideline Methods supplement.73

3.5. Formulating Recommendations Recommendations were formulated based on current evidence that addressed Guideline questions at the time the literature searches were conducted. Explicit associations between the evidence and recommendations are mentioned in the Evidence Review of the Guideline (eAppendix 1 of the Supplement) as well as in the evidence tables and GRADE tables (eAppendix 2 of the Supplement). Evidence-based recommendations were cross-checked with those from other guidelines identified in an initial systematic search.

Category I (levels A, B, and C) recommendations are ALL considered strong and should be equally implemented; only the quality of the evidence underlying the recommendation(s) distinguishes levels A and B. Category IC recommendations are required by state or federal regulation without regard to level of supporting evidence. Category II recommendations are considered weak recommendations to be implemented at the discretion of individual institutions as supplementary procedures -- never in place of Category I recommendations -- and are not intended to be systematically and routinely enforced. The categorization scheme used in this Guideline is presented in eTable 2.

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eTABLE B. CDC and HICPAC Categorization Scheme for Recommendations 73,76 Recommendation Category Category Description Category IA A strong recommendation supported by high-to-moderate quality evidence suggesting net clinical benefits or harms. Category IB A strong recommendation supported by low-quality evidence suggesting net clinical benefits or harms, or an accepted practice (e.g., aseptic technique) supported by low-to-very low-quality evidence. Category IC A strong recommendation required by state or federal regulation. Category II A weak recommendation supported by any quality evidence suggesting a tradeoff between clinical benefits and harms. No recommendation/ An unresolved issue for which there is either low-to-very low-quality evidence unresolved issue with uncertain tradeoffs between benefits and harms or no published evidence on outcomes deemed critical to weighing the risks and benefits of a given intervention.

The wording of each recommendation reflects the recommendation's strength. Active voice is used for Category I recommendations - the strong recommendations. For example, phrases such as “do” or “do not” are used to convey certainty. Passive voice is used for Category II recommendations - the weak recommendations. Words such as "consider” or “is not necessary” are used to reflect lesser certainty about an intervention. Additionally, some interventions described in this guideline may have clinical utility beyond the prevention of SSIs, but these other uses were not evaluated and are outside the scope of this guideline. To recognize the possibility that other uses may exist, these recommendations specified “for the prevention of SSI.”

Readers who wish to examine the evidence underlying the recommendations are referred to the Evidence Review in eAppendix 1 of the Supplement and the evidence tables and GRADE tables in eAppendix 2 of the Supplement. The Evidence Review includes narrative summaries of the data presented in the evidence tables and GRADE tables. The evidence tables include all study-level data used in the Guideline, and the GRADE tables assess the overall quality of the evidence for each question and outcome examined.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 4. EVIDENCE REVIEW

4.1. Core Section Evidence Review

4.1A. PARENTERAL ANTIMICROBIAL PROPHYLAXIS (AMP) Q1. What are the most effective strategies for administering parenteral AMP to reduce the risk of SSI? Q1A. What is the optimal timing of preoperative AMP? The search did not identify RCTs or SRs that evaluated different timings of preoperative AMP administration and its impact on the risk of SSI. The search only identified RCTs that evaluated timing of preoperative AMP administration in surgeries involving tourniquets.

The available data on the optimal timing of antimicrobial prophylactic agent administration in surgeries involving tourniquets examined AMP administered either before or after tourniquet inflation. For this comparison, deep SSI was the critical outcome in decision-making. Length of stay and antimicrobial resistance were also evaluated. The evidence for this comparison consists of 2 RCTs.77,78 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q1 and Evidence Table Q1A.

Low-quality evidence suggested a benefit of AMP administration 1 minute after tourniquet inflation as compared with 5 minutes before limb exsanguination and tourniquet inflation in elective lower limb musculoskeletal procedures. This was based on 1 small RCT77 (N=106, high risk of bias) suggesting significantly fewer deep infections in the post-tourniquet inflation group. Patients had a preoperative admission time of up to 5 days, and limbs were exsanguinated prior to tourniquet inflation. Tourniquet time was longer in the pre-inflation AMP study group, but this difference was not significant.

Moderate-quality evidence suggested no difference in SSI rates based on AMP administration 10 minutes before tourniquet release vs. 10-30 minutes before tourniquet inflation, in total knee arthroplasties. This was based on no difference in deep SSI in 1 large, single- institution RCT78 with 908 total knee arthroplasties and a moderate risk of bias. There were no differences in length of stay and antimicrobial resistance between groups.

Other guidelines The 1999 CDC Guideline for Prevention of Surgical Site Infection and other clinical practice guidelines, based on a review of the evidence and expert opinion, recommend administering by the intravenous route a single dose of prophylactic antimicrobial agent only when indicated. For most prophylactic agents, the 1999 CDC guideline recommended preoperative administration be timed such that a bactericidal concentration of the drug is established in the serum and tissues when the incision is made, and other clinical practice guidelines recommend that administration should be within 60 minutes prior to incision (vancomycin and fluoroquinolones within 60- 120 minutes prior to incision).17,64,79-85 This is considered accepted practice. None of the recommendations address whether it is necessary to administer a complete or a partial infusion of the parenteral AMP dose prior to surgical incision.

Q1B. What is the optimal timing of AMP in cesarean section: prior to skin incision or at cord clamping? The available data on optimal timing of antimicrobial prophylactic agent administration in cesarean section examined AMP administered prior to skin incision versus at cord clamping.

For this comparison, post-partum endometritis was the critical outcome in decision-making. Other outcomes were also evaluated, including incisional SSI, neonatal sepsis, neonatal sepsis workup, neonatal antimicrobial resistance, and neonate admission to higher level of care. In general, endometritis was defined as fever > 100.4°F (38°C) on 2 occasions with uterine tenderness, purulent lochia, tachycardia or leukocytosis. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q1 and Evidence Table Q1B.

High-quality evidence suggested a benefit of AMP administration prior to skin incision as compared with administration immediately after the umbilical cord is clamped in cesarean sections. This was based on a meta-analysis (N=2493) of 7 RCTs86-92 suggesting a 43% reduction in the risk of developing post-partum endometritis and no difference in the odds of developing incisional SSI. High-quality evidence from a meta-analysis (N=1080) of 3 RCTs86,87,92 showed no difference in neonatal sepsis. Moderate-quality evidence consisting of 2 RCTs86,91 evaluating neonatal antimicrobial resistance in cases of sepsis found either no difference in neonatal antimicrobial resistance between groups, or no cases of antimicrobial resistance, respectively. In addition, high-quality evidence from a meta-analysis (N=1604) of 5 RCTs86-88,91,92 suggested no difference in neonatal sepsis workups. Lastly, high-quality evidence from a meta-analysis (N=1694 neonates) of 5 studies86,87,89,91,92 suggested no difference in admissions to higher level of care. One of these studies89 reported being funded by a pharmaceutical company.

Other guidelines Clinical practice guidelines based on a review of the evidence and expert opinion recommend administration of a single preoperative prophylactic antimicrobial agent by the intravenous route, based on the agent pharmacokinetics, commonly beginning within 60

Downloaded From: https://jamanetwork.com/ on 09/30/2021 minutes prior to skin incision in both elective and emergency cesarean section.79-81,83 Administration of AMP after cord clamping is no longer recommended.64

Q1C. How safe and effective is weight-adjusted AMP dosing? Searches of published studies did not identify RCTs or SRs that evaluated weight-adjusted AMP dosing and its impact on the risk of SSI.

Other guidelines Clinical practice guidelines based on a review of the evidence and expert opinion recommend increasing the single preoperative prophylactic antimicrobial agent dose for select prophylactic antimicrobial agents in obese and morbidly obese patients.79-84 For cefazolin, recommendations are to administer 2.0 g80-82,84 for patients weighing >60-80 kg and 3.0 g81,84 if >120 kg. For aminoglycosides, dosing is calculated using the patient’s ideal body weight plus 40% of the difference between the actual and ideal body weight.81,84,93 Vancomycin should be dosed at 15 mg/kg.80-82,84

Q1D. How safe and effective is intraoperative redosing of AMP? The available data examining intraoperative redosing of AMP compared 1 preoperative dose versus 1 preoperative dose plus an additional dose at 2 hours intraoperatively.

For this comparison, abdominal and perineal wound SSI and intra-abdominal abscess were the critical outcomes in decision-making. Antimicrobial resistance was also evaluated as an outcome of interest. The evidence for this question consists of 1 RCT at moderate risk of bias in elective colorectal surgery.94 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q1 and Evidence Table Q1D.

Moderate-quality evidence suggested no benefit of intraoperative AMP redosing. This was based on no difference in abdominal or perineal wound infection, intra-abdominal abscess, or antimicrobial resistance in 1 elective colorectal surgery study from 1991.94 However, procedures with durations >3 hours had a significantly higher risk of SSI and 22% of patients with procedure durations ≥2 hours were not redosed. Fecal contamination almost doubled the SSI rate at every level of contamination (of note, patients underwent mechanical bowel prep). Procedure duration and fecal contamination were not reported by study group. Limited power of the study could result in a false negative finding.

Other guidelines Clinical practice guidelines based on a review of the evidence and expert opinion recommend prophylactic antimicrobial agent redosing in cases of prolonged procedures (when the procedure exceeds the half-life of the prophylactic antimicrobial agent or is longer than 3-4 hours) and in patients with major blood loss (>1,500 ml) or extensive burns.80-84,95 Redosing should also be performed at intervals of 1-2 times the prophylactic antimicrobial agent half-life, starting at the beginning of the preoperative dose.80-84,95 No recommendations are provided for optimal prophylactic antimicrobial agent dosing in obese and morbidly obese patients when redosing.

Q1E. How safe and effective is postoperative AMP and what is the optimal duration? Administration of postoperative AMP was evaluated, both with all surgical procedures combined and by select surgical specialties. Analysis focused on studies that used the same prophylactic antimicrobial agent in both arms. Studies that compared different prophylactic antimicrobial agents or those administering only oral AMP were excluded. Postoperative AMP was defined as any parenteral prophylactic antimicrobial agent administered after intraoperative closure of the surgical incision. Therefore, postoperative AMP (in hours or days) does not include any AMP administered as a single preoperative dose and/or any intraoperative redosing.

The available data examined the following comparisons for different postoperative AMP durations:

1. All surgeries—No post-op AMP vs. ≤24 hours 2. Cardiac a. No post-op AMP vs. ≤24 hours b. No post-op AMP vs. <96 hours c. No post-op AMP vs. 72–96 hours d. ≤24 vs. 72 hours 3. Thoracic—No post-op AMP vs. 2 days 4. Vascular a. No post-op AMP vs. ≤24 hours b. <24 hours vs. 3–5 days c. No post-op AMP vs. 5 days 5. Ear, nose, and throat - ≤24 hours vs. 3–5 days 6. Gynecologic a. No post-op AMP vs. ≤24 hours © 2017 American Medical Association. All rights reserved. 14

Downloaded From: https://jamanetwork.com/ on 09/30/2021 b. b. <24 hours vs. <2.5 days 7. Orthopaedic a. Fracture—No post-op AMP vs. ≤24 hours b. Prosthetic Joint Arthroplasty—No post-op AMP vs. ≤24 hours 8. Colorectal: Bowel preparation with oral antimicrobials a. No post-op AMP vs. 3 days b. ≤24 hours vs. 5 days 9. Colorectal: Bowel preparation only a. No post-op AMP vs. ≤24 hours b. b. No post-op AMP vs. <2-3 days 10. Colorectal: Bowel preparation not reported a. No post-op AMP vs. ≤24 hours b. ≤24 hours vs. 2–3 days 11. Colorectal: No bowel preparation a. No post-op AMP vs. ≤24 hours b. No post-op AMP vs. <2–3 days 12. Appendectomy a. No post-op AMP vs. ≤24 hours b. No post-op AMP vs. 2 days 13. Rectal surgery—No post-op AMP vs. ≤24 hours 14. Gastric surgery a. No post-op AMP vs. ≤24 hours b. No post-op AMP vs. 2 days c. None vs. 4 days 15. Hepatectomy—2 days vs. 5 days

For all comparisons, SSI (superficial, deep incisional, and organ/space) and trocar wound infection were the critical outcomes for decision-making. Antimicrobial resistance, adverse events, length of stay, mortality, and other outcomes were also evaluated. The evidence for this question consists of 45 RCTs in cardiac;96-100 thoracic;101 vascular; 102-104 ear, nose and throat;105,106 gynecologic;107-112 orthopaedic;113-118 and general surgical119-140 procedures. Twenty-eight (62%) studies were published between 1972 and 1998; 17 (38%) studies were published between 2003 and 2013. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q1 and Evidence Table Q1E.

Q1E.1. All surgeries - none vs. ≤24 hours High-quality evidence suggested no benefit of continuing AMP after intraoperative closure of the surgical incisions. This was based on no difference in SSI in 1 large meta-analysis (N=14,285) of 21 RCTs in cardiac; thoracic; vascular; ear, nose and throat; gynecologic; orthopaedic; and general surgical procedures.99,102,108-120,122-124,128,133,137 Fourteen (67%) studies were published between 1984 and 1995; 7 were published between 2005 and 2013. Thirteen studies97,98,108,111,115,118,120-122,125,127-129 reported funding of the study and/or receipt of study supplies from pharmaceutical companies.

Moderate-quality evidence suggested no benefit of continuing AMP after intraoperative closure of the surgical incision in cardiac surgery. This is based on a meta-analysis (N=1746) of sternal organ/space infections in cardiac surgeries in 3 RCTs.97-99 Two studies97,98 reported the authors received funding from pharmaceutical companies.

Results by select surgical specialties or procedures and individual comparators are available in eAppendix 2 of the Supplement: GRADE Table Q1.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q1. Recommendations 1A. Administer preoperative antimicrobial agent(s) only when indicated, based on published clinical practice guidelines and timed such that a bactericidal concentration of the agent(s) is established in the serum and tissues when the incision is made. (Category IB – strong recommendation; accepted practice) 64 (Guideline Question 1A)

1A1. No further refinement of timing can be made for preoperative antimicrobial agents based on clinical outcomes. (No recommendation/unresolved issue) 77,78 (Guideline Question 1A)

1B. Administer the appropriate parenteral prophylactic antimicrobial agent(s) prior to skin incision in all cesarean section procedures. (Category IA – strong recommendation; high-quality evidence) 86-92 (Guideline Question 1B)

1C. The search did not identify randomized controlled trials evaluating the harms and benefits of weight-adjusted AMP dosing and its affect on the risk of SSI. Other organizations have made recommendations based on observational and pharmacokinetic data and a summary of these recommendations can be found in the Other guidelines section of the narrative summary for this question. (No recommendation/unresolved issue) (Guideline Question 1C)

1D. The search did not identify sufficient randomized controlled trial evidence to evaluate the harms and benefits of intraoperative redosing of parenteral prophylactic antimicrobial agents for the prevention of SSI. Other organizations have made recommendations based on observational data and a summary of these recommendations can be found in the Other guidelines section of the narrative summary for this question. (No recommendation/unresolved issue) 94 (Guideline Question 1D)

1E. In clean and clean-contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain. (Category IA – strong recommendation; high-quality evidence) 96-140 (Guideline Question 1E)

4.1B. NON-PARENTERAL ANTIMICROBIAL PROPHYLAXIS Q2. What are the most effective strategies for administering non-parenteral antimicrobial prophylaxis at the surgical incision to reduce the risk of SSI? Q2A. How safe and effective is antimicrobial irrigation? The search identified 2 RCTs examining the impact of antimicrobial irrigation on SSI. For this comparison, SSI was the critical outcome for decision-making. Product-related adverse events and antimicrobial resistance were also evaluated.

In elective colorectal surgeries, moderate-quality evidence suggests a reduction in SSI with intraperitoneal lavage using clindamycin- gentamicin solution that is allowed to rest in the abdominal cavity for 3 minutes. This was based on 1 small RCT141 at low risk of bias in 103 surgeries. In this study, both groups received preoperative AMP followed by an intraoperative bolus at 4 hours if the surgery exceeded this time. Post-irrigation microbiologic samples were only taken from the group irrigated with clindamycin-gentamicin solution. Post-irrigation cultures were positive in 2 patients (4%) in this group and both the Klebsiella spp. and Streptococcus salivarius recovered were resistant to clindamycin and gentamicin. Product-related adverse events were not assessed.

In acute appendectomies, low-quality evidence suggested a reduction in SSI with wound irrigation using ampicillin solution when compared with normal saline irrigation. This was based on 1 RCT142 (N=249) at moderate risk of bias in adult and pediatric patients undergoing appendectomies for suspected acute appendicitis. Both groups received AMP, which was continued for 5 days postoperatively if the appendix was found to be gangrenous or perforated. Almost all Streptococcus and Enterococcus isolates cultured from intraoperative peritoneal and wound swabs were sensitive to ampicillin except for 30% of E. coli isolates. Postoperative complications were infrequent and not associated with the intervention.

The search did not identify RCTs or SRs that evaluated the safety and effectiveness of soaking of surgical implants (e.g., meshes, neurosurgical ventricular shunts) in antimicrobial solution prior to insertion (in combination with parenteral AMP) and its impact on SSI.

Other guidelines Two clinical practice guidelines, based on a review of the evidence, recommend against antimicrobial wound irrigation or intra-cavity lavage to reduce the risk of SSI.85,95 © 2017 American Medical Association. All rights reserved. 16

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q2B. How safe and effective are antimicrobial agents applied to the surgical incision? The available data examined the following comparisons:

1. Ampicillin solution vs. no topical antimicrobial agent 2. Ampicillin powder vs. no topical antimicrobial agent 3. Chloramphenicol vs. no topical antimicrobial agent 4. Rifampin vs. no topical antimicrobial agent 5. Vancomycin powder in hemostatic paste vs. hemostatic paste 6. Autologous platelet-rich plasma (APRP) (spray or gel) vs. no APRP

For all comparisons, SSI was the critical outcome for decision-making. Wound dehiscence, wound closure, and product-related adverse event outcomes were also evaluated. The evidence for the pharmacologic antimicrobial prophylactic agent comparators consists of 6 RCTs,143-148 and for the APRP comparator the evidence consists of 4 RCTs.149-152 APRP provides a platelet concentrate commonly used to enhance both wound hemostasis (formation of a fibrin clot) and wound healing (clot provides a matrix for the migration of tissue-forming cells and endothelial cells involved in angiogenesis and thus the remodeling of the clot into repair tissue).153,154 These characteristics have led to a significant increase in the use of APRP therapies for the treatment of chronic wounds and multiple orthopaedic conditions including bone repair, tendon, and soft tissue injuries.155,156 In addition, in vitro studies have demonstrated that APRP holds strong bactericidal activity and suggest its potential value as an adjunct topical antimicrobial prophylactic agent for use at the time of surgical incision closure.157,158 In all studies, both groups received parenteral AMP. The findings of the evidence review and grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q2 and Evidence Table Q2B.

Q2B.1. Ampicillin solution vs. no topical antimicrobial agent In elective colorectal surgeries, low-quality evidence suggests no benefit to application of ampicillin solution to the subcutaneous and subfascial layers when combined with bowel prep and AMP for 3 days postoperatively. This was based on 1 RCT145 (N=203) at moderate risk of bias. This RCT included patients with previously known infections, including 1 patient with Fournier’s Gangrene. This study noted no adverse events associated with the intervention.

In acute appendectomies, moderate-quality evidence suggested a benefit to cleaning the subcutaneous tissues with ampicillin solution- soaked gauze. This was based on 1 RCT146 (N=246) at moderate risk of bias. This reduction in SSI was not present in the simple, acute appendicitis cases, but was significant in the perforated and gangrenous appendicitis cases. Both groups received preoperative intramuscular AMP.

Q2B.2. Ampicillin powder vs. no topical antimicrobial agent In elective colorectal surgeries, moderate-quality evidence suggested no benefit to ampicillin powder applied to the subfascial and subcutaneous layers when compared with no topical antimicrobial. This is based on 1 RCT147 in (N=170) at moderate risk of bias. AMP was administered preoperatively and was continued postoperatively for 2 doses over 12 hours for both groups.

Q2B.3. Chloramphenicol vs. no topical antimicrobial agent Moderate-quality evidence suggested no benefit of topical chloramphenicol ointment in combination with parenteral AMP. This was based on no difference in SSI in 1 small study at low risk of bias in 92 hemi-arthroplasty or dynamic hip screw fixation procedures for hip fractures.143

Q2B.4. Rifampin vs. no topical antimicrobial agent Low-quality evidence suggested a benefit of topical rifampin in combination with parenteral AMP. This was based on a reduced risk of wound leakage, fewer local signs of inflammation, and reduced risk of wound dehiscence at the umbilical port site in 1 very small (N=48) laparoscopic cholecystectomy study at moderate risk of bias.144 Umbilical port-site infection was defined as “purulent wound leakage.” Based on results reported in a histogram, at 12 hours postoperatively, 71% of patients had purulent wound leakage including almost half of the rifampin and all of the control groups. By 24 hours, the entire control group remained infected; a week later, only 2 infections remained. It is not clear if any of these were true infections.

Q2B.5. Vancomycin powder in hemostatic paste vs. hemostatic paste alone Low-quality evidence suggested a benefit to applying vancomycin powder mixed with hemostatic paste to the cut sternal edges during heart surgery. This was based on 1 RCT148 (N=416) at high risk of bias evaluating the effectiveness of vancomycin powder mixed with hemostatic paste for the prevention of mediastinal/sternal SSI. This study showed a reduction in mediastinal/sternal SSI when vancomycin powder was mixed with hemostatic paste and applied to cut sternal edges versus hemostatic paste alone applied to cut sternal edges.

Other guidelines Clinical practice guidelines based on a review of the evidence and expert opinion have recommendations both for82 and against95 the use of non-parenteral antimicrobials in the prevention of SSI. There are also strong recommendations against the use of antimicrobial © 2017 American Medical Association. All rights reserved. 17

Downloaded From: https://jamanetwork.com/ on 09/30/2021 ointments or creams on umbilical catheter insertion sites and other insertion sites, because of their potential to promote fungal infections and antimicrobial resistance.159 These recommendations exclude dialysis catheters.

Q2B.6. Autologous platelet-rich plasma (spray or gel) vs. nothing Moderate-quality evidence suggested no benefit of APRP spray or gel in combination with parenteral AMP. This was based on no difference in SSI in a meta-analysis (N=452) of 4 small RCTs: 3 studies in cardiac procedures (low149, moderate151 and high152 risk of bias) and 1 study in total knee arthroplasty (TKA) procedures150 (low risk of bias). Each individual study found no difference. The cardiac studies applied APRP spray149,152 or gel151 (produced using the same type of commercial platelet concentrate system) to the saphenous vein harvest site149,151 and/or the sternum.151,152 The TKA study150 applied APRP spray (produced using a different platelet concentrate system than the cardiac studies) to the femoral and tibial cut bone surfaces and joint capsule followed by platelet poor plasma sprayed on the subcutaneous tissue. Moderate-quality evidence from this latter study150 suggested significantly increased risk of delayed total wound closure at 2 weeks postoperatively. Three of the 4 RCTs150-152 reported either industry support of the study or receiving study supplies from the manufacturer.

Q2C. How safe and effective are antimicrobial-coated sutures, when and how should they be used? The available data examined triclosan-coated sutures (absorbable) versus sutures without triclosan (absorbable) for the prevention of SSI. The evidence for this question consists of 14 RCTs.160-173 For this comparison, overall SSI and deep SSI were the critical outcomes for decision-making. Organ/space SSI, superficial SSI, ASEPSIS score174 (where points are given for Additional treatment, the presence of Serous discharge, Erythema, Purulent exudate, Separation of the deep tissues, the Isolation of bacteria, and the duration of inpatient Stay), antimicrobial resistance, wound dehiscence, and product-related adverse event outcomes were also evaluated.

Moderate-quality evidence suggested tradeoffs in the use of triclosan-coated sutures to reduce overall SSI rates. A meta-analysis (N=5388) of 14 RCTs160-173 in colorectal, abdominal, lower limb revascularization, cardiac, breast, cerebrospinal fluid shunt, and mixed surgeries provided high-quality evidence for the reduction in the incidence of “overall SSI” with the use of triclosan-coated sutures. However, a meta-analysis of 2 RCTs161,163 (N=1285) reporting on the outcome of “deep SSI” provided moderate-quality evidence suggesting no benefit to using triclosan-coated sutures to prevent deep SSI. Given that all 14 RCTs utilized triclosan-coated sutures in the deep and/or fascial layer, it was considered important to identify a benefit in the layer in which they are used. Unfortunately, most of the 14 RCTs evaluating triclosan sutures only examined “overall SSI” and did not stratify analyses by SSI type. Only the 2 aforementioned RCTs actually reported on “deep SSI.” The tradeoff between benefit in “overall SSI” and no benefit in “deep SSI” (the layer most important to the evaluation of these deep antimicrobial sutures) results in a Category II recommendation to consider their use, rather than a Category I recommendation to always use these sutures.

In addition, low-quality evidence based on a meta-analysis of 4 RCTs161,162,165,168 (N=1081) in appendectomies and coronary artery bypass grafts (CABG), elective colorectal, and pediatric cerebrospinal fluid shunt surgeries, with heterogeneous patients and closure types, suggested no difference in organ/space SSI rates when triclosan-coated sutures were used primarily in the deep layer. Moreover, high-quality evidence suggested no benefit to using triclosan-coated sutures for the reduction of superficial SSI when this outcome was specifically reported. This is based on a meta-analysis of 4 RCTs161,163,165,171 (N=1922) in appendectomies and CABG, open abdominal, and breast cancer surgeries, where triclosan-coated sutures were used in deep closure in all 4 RCTs. Only 1 of the 4 RCTs171 with superficial SSI as an outcome utilized triclosan-coated sutures in cutaneous closure.

Moderate-quality evidence suggested no difference in SSI in colorectal surgeries where absorbable triclosan-coated sutures were used to close the deep abdominal and fascial layers. This was based on a meta-analysis (N=1912) of 5 RCTs. 163,167-170,175 Administration of bowel prep, length of postoperative AMP, suture type, length of follow-up, SSI definition, and method of closure were not uniform across studies.

High-quality evidence suggested a benefit to using absorbable triclosan-coated sutures to close the abdominal and fascial layers in abdominal surgeries, laparotomies and appendectomies (excluding colorectal surgeries). This was based on a meta-analysis (N=1208) of 3 RCTs.161,163,167 Administration of postoperative AMP, suture type, length of follow up, SSI definition, and method of closure were not uniform across studies.

High-quality evidence suggested a benefit to using absorbable triclosan-coated sutures in a subgroup of all surgery types excluding colorectal and abdominal surgeries. This was based on a meta-analysis (N=2183) of 8 RCTs.160,162,164-166,171-173 Surgical populations included CABG, lower limb revascularization, breast cancer surgery, pediatric cerebrospinal fluid shunt, and mixed pediatric and adult surgeries. Length of postoperative AMP, suture type, length of follow up, SSI definition, and method of closure were not uniform across studies.

In terms of harms, low-quality evidence suggested no difference between groups in antimicrobial resistance. Eight RCTs161,162,165,167- 169,172,173 reported no difference in cultured antimicrobial resistant bacteria between groups. However, none of the studies evaluated triclosan resistance. This evaluation is limited by the absence of standardized methods for determining triclosan-resistance. Low- quality evidence also suggested no difference in wound dehiscence between groups. This is based on a meta-analysis of 3 © 2017 American Medical Association. All rights reserved. 18

Downloaded From: https://jamanetwork.com/ on 09/30/2021 RCTs163,166,170 (N=1582) in elective colorectal, CABG, and open abdominal surgeries. Moreover, moderate-quality evidence consisting of 2 RCTs166,171 suggested no difference in ASEPSIS scores in breast cancer surgeries and CABG open vein harvesting. Lastly, low- quality evidence suggested no difference in product-related adverse events, based on 4 RCTs160-163 which reported no product-related adverse events for either suture type. The authors of 5 of the 14 RCTs reported receiving funds from and/or being employed by the manufacturer of triclosan-coated sutures.162,163,166,167,171

The findings of the evidence review, results by surgical procedures, and grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q2 and Evidence Table Q2C.

Q2D. How safe and effective are antimicrobial dressings applied to surgical incisions following primary closure in the operating room? The available data examined silver-impregnated dressings versus standard dressing or standard gauze and tape for the prevention of SSI. This data consisted of 2 RCTs. The evidence for this question consists of 1 RCT176 at moderate risk of bias and 1 RCT177 at low risk of bias, both in elective colorectal surgeries. For this comparison, all SSI outcomes were critical outcomes for decision-making. The duration of inpatient stay and product-related adverse event outcomes were also evaluated.

Moderate-quality evidence suggested no benefit to silver impregnated dressings. This was based on no difference in overall, organ/space, deep, or superficial SSI in 1 small RCT177 (N=112). Dressings were removed on the seventh postoperative day in the intervention group and “as necessary” in the control group. Patients received mechanical bowel prep in accordance with predefined protocols. No adverse events related to the study were noted. An additional small RCT176 (N=109) suggested a reduction in superficial SSI related to silver impregnated dressings; however, the SSI definition used in this study included antibiotic treatment for any questionable infection. There was no difference in deep infections in this study. In both studies, authors reported receiving funds from the dressing manufacturer.

The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q2 and Evidence Table Q2D.

The search did not identify RCTs or SRs that evaluated the safety and effectiveness of other antimicrobial dressings (e.g., iodine or other antimicrobial ointment-impregnated dressing) applied to surgical incisions closed primarily in the operating room (i.e., the skin edges are re-approximated at the end of the procedure) and their impact on the risk of SSI.64 The search identified a SR of 16 RCTs evaluating various non-antimicrobial dressings.178 This SR found no evidence to suggest that either covering the wound was effective or that any one non-antimicrobial dressing was more effective than another in reducing the risk of SSI in surgical incisions that were closed primarily in the operating room. This Guideline does not address prevention of SSI in trauma-related procedures, in surgical incisions left open to heal by secondary intention (i.e., left open in the operating room to be closed later, left open to heal by granulation, or which break open postoperatively), or burns.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q2. Recommendations 2A.1. Randomized controlled trial evidence suggests uncertain tradeoffs between the benefits and harms regarding intraoperative antimicrobial irrigation (e.g., intra-abdominal, deep or subcutaneous tissues) for the prevention of SSI. Other organizations have made recommendations based on the existing evidence and a summary of these recommendations can be found in the Other Guideline section of the narrative summary for this question. (No recommendation/unresolved issue) 141,142 (Guideline Question 2A)

2A.2. The search did not identify randomized controlled trials evaluating soaking prosthetic devices in antimicrobial solutions prior to implantation for the prevention of SSI. (No recommendation/unresolved issue) (Guideline Question 2A)

2B.1. Do not apply antimicrobial agents (i.e., ointments, solutions, or powders) to the surgical incision for the prevention of SSI. (Category IB – strong recommendation; low-quality evidence) 143-148 (Guideline Question 2B)

2B.2. Application of autologous platelet-rich plasma is not necessary for the prevention of SSI. (Category II – weak recommendation; moderate-quality evidence suggesting a trade-off between clinical benefits and harms) 149-152 (Guideline Question 2B)

2C. Consider the use of triclosan-coated sutures for the prevention of SSI. (Category II – weak recommendation; moderate-quality evidence suggesting a trade-off between clinical benefits and harms) 160-173,175 (Guideline Question 2C)

2D. Randomized controlled trial evidence suggests uncertain tradeoffs between the benefits and harms regarding antimicrobial dressings applied to surgical incisions following primary closure in the operating room for the prevention of SSI. (No recommendation/unresolved issue)176,177 (Guideline Question 2D)

4.1C. GLYCEMIC CONTROL Q3. How do perioperative blood glucose and hemoglobin A1c levels impact the risk of SSI, and what are their optimal perioperative target levels in diabetic and non-diabetic patients? To answer this question, analysis focused on:

A) Blood glucose B) Hemoglobin A1c C) Optimal perioperative target levels D) Risk of SSI

Q3A. Blood glucose and optimal perioperative target levels The available data examined strict versus standard blood glucose control in the prevention of SSI.

For this comparison, SSI and hypoglycemia were considered the critical outcomes for decision-making. Each study reported a primary composite outcome variable that included SSI. Mortality, length of hospital stay, and surgical intensive care unit (SICU) stays were also evaluated in weighing the risks and benefits of perioperative glycemic control. The evidence for this question consists of 2 RCTs in cardiac surgery patients with glycemic control protocols (intravenous, intensive insulin therapy) instituted intraoperatively and continued in the SICU for 24-36 hours.179,180 In both of these studies, 70-80% of patients were non-diabetics, highlighting the importance of glycemic control in both diabetic and non-diabetic surgical populations. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q3 and Evidence Table Q3.

Moderate-quality evidence suggested no benefit of strict (80–100 mg/dL180 or 80–130 mg/dL179) as compared with standard blood glucose target levels (<200 mg/dL180 or 160–200 mg/dL179) in diabetic and non-diabetic cardiac patients. This was based on no differences between groups for both the composite outcome variable and SSI in both studies. In Gandhi et al.180 (N=371), the composite outcome variable included: death, sternal wound infections, prolonged pulmonary ventilation, cardiac arrhythmias, heart block requiring pacemaker or cardiac arrest, stroke or acute renal failure within 30 days postoperatively. In Chan et al.179 (N=109), the composite infection outcome included pneumonia, urinary tract infection, sepsis, septic shock, wound infection, bloodstream infection, and “catheter” infection (did not specify if venous or urinary).

Downloaded From: https://jamanetwork.com/ on 09/30/2021 High-quality evidence suggested no increased risk of hypoglycemia with strict blood glucose target levels. This was based on no differences between groups for the number of hypoglycemic episodes in the SICU180 or the ratio of hypoglycemic episodes per number of glucose measurements.179 Hypoglycemia definitions differed among studies: <60 mg/dL in Gandhi and <50 mg/dL in Chan. While there was no difference between groups for the number of hypoglycemic episodes in the SICU, in Chan et al., both groups reported a higher proportion of hypoglycemia postoperatively as compared with intraoperatively, suggesting the importance of continued close monitoring of glucose levels and the risk of hypoglycemic episodes in the postoperative period, even with standard glycemic control. No clinical complications resulting from hypoglycemia were reported at 30 days of follow-up. In 1 study, authors reported receiving funds from an insulin manufacturing company. 180

Other guidelines While previous CDC guideline recommendations did not specify a perioperative blood glucose target level, they reported that in diabetics “increased glucose levels (>200 mg/dL) in the immediate postoperative period (≤48 hours) were associated with increased risk of SSI.”64 Blood glucose target level of <200 mg/dL became standard clinical practice. Both studies reviewed in this guideline used <200 mg/dL as the upper blood glucose target level.179,180 Recently published professional society guidelines have recommended a slightly lower absolute serum blood glucose target level of <180 mg/dL in diabetic84,181,182 and non-diabetic,84,181 non-critically ill patients. In critically ill patients, blood glucose target levels <150–180 mg/dL183 and 140–200 mg/dL184 have been recommended. For terminally ill patients, those with limited life expectancy, or those at high risk for hypoglycemia, a blood glucose target level of 200 mg/dL has been recommended.182 Intensive insulin therapy (blood glucose target levels of 80–110 mg/dl) to normalize blood glucose in the intensive care unit setting (surgical and medical) is not recommended in either diabetic or non-diabetic patients.84,184

Q3B. Perioperative hemoglobin A1C and optimal target levels The search did not identify RCTs or SRs examining the association between hemoglobin A1c levels and risk of SSI.

Q3. Recommendations 3A.1. Implement perioperative glycemic control and use blood glucose target levels <200 mg/dL in diabetic and non-diabetic patients. (Category IA – strong recommendation; high to moderate-quality evidence) 179,180 (Guideline Question 3)

3A.2. The search did not identify randomized controlled trials evaluating lower (<200 mg/dL) or narrower blood glucose target levels than recommended in this guideline, nor the optimal timing, duration, or delivery method of perioperative glycemic control for the prevention of SSI. Other organizations have made recommendations based on the existing evidence and a summary of these recommendations can be found in the Other guidelines section of the narrative summary for this question. (No recommendation/unresolved issue) (Guideline Question 3)

3B. The search did not identify randomized controlled trials evaluating the optimal hemoglobin A1c target levels for the prevention of SSI in diabetic and non-diabetic patients. (No recommendation/unresolved issue) (Guideline Question 3)

4.1D. NORMOTHERMIA Q4. How safe and effective is the maintenance of perioperative normothermia in reducing the risk of SSI? The available data examined the following comparisons:

1. Warming vs. no warming 2. Warming: perioperative vs. intraoperative only

For all comparisons, SSI was the critical outcome for decision-making. ASEPSIS score, mortality, blood loss, core temperature, length of hospital stay, and duration of surgery outcomes were also evaluated. The evidence for this question consists of 3 RCTs.185-187 The lower limit of normothermia has been inconsistently defined, ranging from a core temperature of 95.9°F to 96.8°F (35.5°C-36°C). The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q4-5 and Evidence Table Q4.

Q4A.1. Warming vs. no warming High-quality evidence suggested a benefit of patient warming over no warming. This was based on a reduced risk of SSI in a meta- analysis (N=616) of 2 RCTs with warming and maintenance of normothermia using various warming techniques in patients undergoing elective hernia repair, varicose vein surgery, and breast surgery (preoperative warming)186 and elective colorectal surgery (intraoperative warming).185 Normothermia was also associated with reduced risk of ASEPSIS scores >20, lower mean units of blood transfused per patient, fewer patients transfused, and reduced hospital length of stay.185 No difference in mortality was observed.185 Both of these studies reported receiving funds from a warming equipment manufacturer.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q4A.2. Warming: perioperative vs. intraoperative only Moderate-quality evidence suggested a benefit of perioperative warming. This was based on reduced incidence of SSI with perioperative warming in 1 RCT of 103 patients undergoing elective major abdominal surgery.187

Q4. Recommendation 4. Maintain perioperative normothermia. (Category IA – strong recommendation; high to moderate- quality evidence) 185-187 (Guideline Question 4)

Q5. What are the most effective strategies for achieving and maintaining perioperative normothermia? The search did not identify RCTs or SRs that evaluated the most effective strategies for achieving and maintaining perioperative normothermia and their impact on the risk of SSI.

Other guidelines Evidence-based clinical practice guidelines provide recommendations on perioperative management of normothermia including risk factor assessment, temperature monitoring tools, and the safety and effectiveness of warming devices.188-191 Recently published professional society guidelines have recommended a minimum temperature of 95.9°F (35.5°C) during the perioperative period.84

Q5. Recommendation 5. The search did not identify randomized controlled trials evaluating strategies to achieve and maintain normothermia, the lower limit of normothermia, or the optimal timing and duration of normothermia for the prevention of SSI. Other organizations have made recommendations based on observational data and a summary of these recommendations can be found in the Other guidelines section of the narrative summary for this question. (No recommendation/unresolved issue) (Guideline Question 5)

4.1E. OXYGENATION Q6. In patients with normal pulmonary function, how safe and effective is the perioperative use of increased fraction of inspired oxygen (FiO2) in reducing the risk of SSI? To answer this question, 3 settings of oxygen delivery were analyzed:

A) General anesthesia: intraoperative endotracheal intubation and postoperative non-rebreathing mask; B) Neuraxial anesthesia: intraoperative and postoperative non-rebreathing mask; and C) Post-operative only: facemask and/or nasal cannula.

Q6A. General anesthesia: intra-operative only endotracheal intubation, 80% oxygen vs. 30% oxygen – both without nitrous oxide For all comparisons, SSI was the critical outcome for decision-making. Adverse events were also evaluated.

Moderate-quality evidence suggested no benefit to supplemental 80% FiO2 compared with 30% FiO2 administered via endotracheal intubation during the intraoperative period only. In 1 study192 at low risk of bias, 434 patients underwent general anesthesia for abdominal, gynecologic and breast surgeries. Administration of FiO2 commenced after intubation and ended at extubation. In cases where extubation was delayed beyond the end of the surgery, the FiO2 was maintained at the programmed level and oxygen was administered during the postoperative period at the physician’s discretion. There were significantly more protocol deviations in the control group; the reasons for these deviations included desaturation and/or bradycardia. No difference was seen between groups in adverse events, including nausea and vomiting, hypotension, and sternal pain. The authors of this study reported receiving study funding from a medical oxygen supply company.

The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q6-7 and Evidence Table Q6.

Q6B. General anesthesia: intra-operative endotracheal intubation and postoperative non-rebreathing mask The available data examined the following comparisons:

1. 80% oxygen vs. 30% oxygen—both without nitrous oxide

Downloaded From: https://jamanetwork.com/ on 09/30/2021 2. 80% oxygen/20% nitrous oxide vs. 35% oxygen/65% nitrous oxide—both with nitrous oxide started 30 minutes after surgical incision

For all comparisons, SSI was the critical outcome for decision-making. ASEPSIS scores, mortality, respiratory failure, atelectasis, tissue oxygenation, and length of stay were also evaluated. The evidence for this question consists of 7 RCTs.193-199 One study198 represents a subanalysis of a larger study;196 therefore results in the GRADE table reflect solely those of the larger study. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q6-7 and Evidence Table Q6. The authors of 1 of these studies193 reported receiving study funding from a medical oxygen supply company.

Q6B.1. 80% oxygen vs. 30% oxygen—both without nitrous oxide Moderate-quality evidence suggested a benefit of supplemental 80% FiO2 administered via endotracheal intubation intraoperatively and non-rebreathing mask for 2–6 hours postoperatively in patients under general anesthesia. This was based on a meta-analysis (N=2622) of 5 RCTs193-196,198,199 at low risk of bias (2 in 791 elective colorectal surgeries,193,195 1 in 235 open reduction and internal fixation procedures,199 1 in 210 elective open appendectomy194 procedures, and in 1 multicenter, mixed surgical population196,198). There was no significant difference in adverse events.196,198

The 3 studies reporting a significant SSI reduction all optimized perioperative tissue oxygen delivery by maintaining normothermia and avoiding hypo or hypervolemia.193-195 Greif et al.,195 the larger colorectal study (N=500), confirmed optimized tissue oxygen delivery, measuring significantly higher intraoperative and postoperative subcutaneous tissue oxygen tension and higher muscle oxygen tension using 80% oxygen.

Meyhoff et al., 196,198 the large (N=1386), multicenter, mixed population study of emergency or elective laparotomy for a variety of general and gynecologic surgical conditions, found no difference in overall, organ/space, deep, or superficial SSI. However, due to a number of factors, the study failed to optimize tissue oxygen delivery. While the target core temperatures were 96.8°F to 98.6°F (36°C -37°C), the minimum reported temperatures were 95.0°F and 95.2°F (35.0°C and 35.1°C) in each group, respectively. More importantly, fluid replacement was intentionally restricted, limiting postoperative weight gain to less than 1 kg. Mortality at 14–30 days was rare, there was no difference between groups, and it was not associated with use of increased oxygenation.193,195 In a recent follow-up study (median 2.3 years, range 1.3–3.4), administration of 80% oxygen was associated with significantly increased long- term mortality only in patients undergoing cancer surgery. The only gynecologic patients included in this study were those with ovarian cancer.200 It is not clear what other cancer patients were included. One study199 of elective open reduction and internal fixations of 235 tibial fractures in 217 patients also showed no difference. Optimized tissue oxygen delivery, normothermia, and normovolemia were not described. This study identified no treatment-associated adverse events.

Q6B.2. 80% oxygen/20% nitrous oxide vs. 35% oxygen/65% nitrous oxide—both groups started nitrous oxide 30 minutes after incision Moderate-quality evidence suggested no benefit of supplemental 80% FiO2 (20% nitrous oxide added 30 minutes after incision) administered via endotracheal intubation intraoperatively and non-rebreathing mask for 2–6 hours postoperatively in patients under general anesthesia. This was based on increased risk of SSI (all combined) in 1 small (N=160), mixed surgical population study.197 Several factors may account for the increased incidence of total SSIs in the intervention group. Patients in the 80% FiO2 group had significantly increased body mass index (BMI), higher blood loss, and were more crystalloid infused. On multivariate logistic regression analysis, 80% oxygen and remaining intubated postoperatively remained predictive of SSI. Mortality was rare in either group and unrelated to increased supplemental oxygenation.

Q6C. Neuraxial anesthesia: Intraoperative and postoperative non-rebreathing mask The available data on the impact of different levels of supplemental increased FiO2 on SSI in patients under regional anesthesia examined 80% oxygen versus 30% oxygen.

For this comparison, SSI was the critical outcome for decision-making. Length of stay was also evaluated. The evidence for this question consists of 3 RCTs.201-203 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q6-7 and Evidence Table Q6.

Moderate-quality evidence suggested no benefit of supplemental 80% FiO2 administered via non-rebreathing mask intra and postoperatively in patients under neuraxial anesthesia. This was based on no difference in risk of SSI in a meta-analysis of 3 studies201- 203 (N=1559) in cesarean sections. Two studies201,203 (N=728) did not note any protocol used during the study to optimize tissue oxygenation. The largest study202 (N=831) ensured adequate volume replacement and normothermia.

Q6D. Postoperative only: Facemask and/or nasal cannula The data available on the impact of different levels of supplemental increased FiO2used in the postoperative period only examined 28– 30% oxygen versus room air.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 For this comparison, SSI was the critical outcome for decision-making. SSI type (organ/space, superficial and deep SSI), ASEPSIS scores, mortality, adverse events, tissue oxygenation, and length of stay were also evaluated. The evidence for this question consists of 2 RCTs.204,205 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q6-7 and Evidence Table Q6.

Moderate-quality evidence suggested no benefit of supplemental 28–30% FiO2 administered via facemask and/or nasal cannula solely in the postoperative period. This was based on no difference in SSIs from 2 studies.204,205 Turtiainen et al., 204 a lower limb vascular surgery study (N=274) at low risk of bias, used 30% oxygen via facemask in the recovery room and on the first postoperative day on the ward, followed by constant oxygen flow of 5 L/min via nasal cannula during the second postoperative day. A significant reduction in SSI was seen only in isolated groin incisions. Subcutaneous tissue oxygen tension (measured hourly for the first 4 hours, then at 18 and 36 hours) was significantly higher in the supplemental oxygenation group. Whitney et al.,205 a second, smaller study at high risk of bias in 24 cervical spine procedures reported no wound complications in either group (supplemental 28% oxygen administered at 2L/min via nasal cannula for 36 hours after discharge from the post-anesthesia care unit as compared with room air). Mortality204 and adverse events204,205 were rare, did not differ between groups, and were unrelated to use of supplemental oxygenation.

Q6. Recommendations 6A. Randomized controlled trial evidence suggests uncertain tradeoffs between the benefits and harms regarding the administration of increased fraction of inspired oxygen (FiO2) via endotracheal intubation during only the intraoperative period in patients with normal pulmonary function undergoing general anesthesia for the prevention of SSI. (No recommendation/unresolved issue) 192 (Guideline Question 6)

6B. For patients with normal pulmonary function undergoing general anesthesia with endotracheal intubation, administer increased FiO2 intraoperatively and post-extubation in the immediate postoperative period. To optimize tissue oxygen delivery, maintain perioperative normothermia and adequate volume replacement. (Category IA – strong recommendation; moderate quality evidence) 193-199 (Guideline Question 6)

6C. Randomized controlled trial evidence suggests uncertain tradeoffs between the benefits and harms regarding the administration of increased FiO2 via facemask during the perioperative period in patients with normal pulmonary function undergoing general anesthesia without endotracheal intubation or neuraxial anesthesia (i.e., spinal, epidural, or local nerve blocks) for the prevention of SSI. (No recommendation/unresolved issue) 201-203 (Guideline Question 6)

6D. Randomized controlled trial evidence suggests uncertain tradeoffs between the benefits and harms regarding the administration of increased FiO2 via facemask or nasal cannula during only the postoperative period in patients with normal pulmonary function for the prevention of SSI. (No recommendation/unresolved issue) 204,205 (Guideline Question 6)

Q7. What is the optimal target FiO2 to reduce the risk of SSI; how and when should it be administered? The search did not identify RCTs or SRs that evaluated both the optimal FiO2 and how and when it should be administered, and included SSI as an outcome. All studies evaluating the use of supplemental increased oxygenation both intraoperatively and postoperatively used 80% FiO2 as the target level.

Other guidelines Evidence-based clinical practice guidelines recommend maintaining patient homeostasis by optimizing oxygenation during major surgery and in the recovery period (maintaining a >95% hemoglobin saturation) in concert with maintaining both patient temperature to avoid hypothermia, and adequate perfusion during surgery.84,95

Q7. Recommendation 7. The search did not identify randomized controlled trials evaluating the optimal target level, duration, and delivery method of FiO2 for the prevention of SSI. Other organizations have made recommendations based on observational data and a summary of these recommendations can be found in the Other guidelines section of the narrative summary for this question. (No recommendation/ unresolved issue) ( Question 7)

Downloaded From: https://jamanetwork.com/ on 09/30/2021 4.1F. ANTISEPTIC PROPHYLAXIS Q8. What are the most effective strategies for preparing the patient’s skin prior to surgery to reduce the risk of SSI? To answer this question, 4 subquestions were asked:

A) How safe and effective is preoperative antiseptic bathing or showering? B) How safe and effective are antiseptic skin preparation agents individually and in combination? C) How safe and effective is the application of a microbial sealant immediately following intraoperative skin preparation? D) How safe and effective are plastic adhesive drapes? It should be noted that while the recommendations in this section apply to patients known to be colonized with S. aureus, they do not separately address the different antiseptic skin preparations that may be suggested for these patients.

Q8A. How safe and effective is preoperative antiseptic bathing or showering? The available data examined the following comparisons:

1. Chlorhexidine gluconate (CHG) solution vs. placebo solution 2. CHG solution vs. un-medicated bar soap 3. CHG solution vs. no wash 4. CHG whole body wash vs. partial body wash 5. Aqueous iodophor solution vs. control (“routine personal hygiene”) 6. CHG washcloth vs. un-medicated bar soap

For all comparisons, SSI was the critical outcome for decision-making. Product-related adverse reactions were also evaluated. The evidence for this question consists of 1 SR206 (7 RCTs207-213) evaluating CHG solution and 1 RCT214 evaluating povidone iodine solution. The RCTs span a 26-year period, with 6 published between 1983 and 1992, and 2 between 2008214 and 2009.212 The search did not identify RCTs or SRs that evaluated optimal preoperative timing, number of showers/baths, or number of product applications at each shower/bathing episode, and their impact on the risk of SSI. The findings of the evidence review and grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q8-10 and Evidence Table Q8A.

Q8A.1. CHG solution vs. placebo solution High-quality evidence suggested no benefit of preoperative bathing or showering with 4% CHG solution as compared with placebo. This was based on no difference in SSI in both a meta-analysis (N=7791) of 4 RCTs206,207,209,211,212 and a meta-analysis (N=6302) restricted to only the 2 higher-quality studies.206,207,211 Each individual trial found no difference. Five months into 1 large study, the placebo solution was found to have antimicrobial properties and was changed; however, the study did not stratify by or exclude that data.209 Procedures included in the studies were elective or potentially contaminated surgery,207 elective inpatient surgery,209 elective clean surgical procedures including thyroidectomy, inguinal herniorrhaphy, hip and knee surgery, laminectomy, mastectomy, vascular surgery,211 and elective plastic surgery of the trunk.212 Number of preoperative showers/baths, amount of antiseptic used per bath, bathing instructions to each group, intraoperative antiseptic skin preparation agent, use of AMP, and follow-up varied among studies. Three studies instructed patients to shower207,211,212 and 1 instructed them to shower or bathe.209 Product-related adverse reactions (irritation, itching, reddening of the skin) were rare and did not differ between groups.206,207,211,212

Q8A.2. CHG solution vs. un-medicated bar soap High-quality evidence suggested no benefit of preoperative bathing or showering with 4% CHG solution as compared with un- medicated bar soap. This was based on no difference in SSI in a meta-analysis (N=1443) of 3 RCTs.206,208-210 Heterogeneity for this comparison was high. Only the largest study (N=1315) reported a reduction in SSI with 4% CHG; however, no special showering/bathing instructions were given to the un-medicated bar soap group, whereas “great care was taken to ensure that the patients using [CHG]…complied with the instructions.”209 Of the 2 smaller, lesser-quality studies, one208 suggested a higher rate of SSI with CHG, while the other210 suggested no difference. Number of preoperative baths, bathing instructions, intraoperative antiseptic skin preparation agent, AMP use, procedures, and follow up varied among studies. One study instructed patients to bathe,208 1 to shower,210 and 1 to shower or bathe.209

Q8A.3. CHG solution vs. no wash Moderate-quality evidence suggested no benefit of preoperative showering with 4% CHG solution as compared with no wash. This was based on no difference in a meta-analysis (N=1142) of 3 RCTs.206,210,212,213 Despite instructions not to shower, it is unclear whether the “no wash” groups showered. The largest study213 favored 4% CHG, while the other 2210,212 suggested no difference. Heterogeneity for this comparison was significant. Studies included outpatient and inpatient procedures, patients undergoing vasectomy,210 plastic surgery of the trunk,212 and elective, clean biliary tract, inguinal hernia, or breast cancer213 procedures. There were also differences in SSI definitions among studies.

Q8A.4. CHG whole body vs. partial body wash Moderate-quality evidence suggested a benefit of a CHG shower (i.e., a whole body wash including the scalp) as compared with a partial body wash (restricted to the proposed surgical site). This was based on reduced risk of SSI with whole body washing (1 time, 2 © 2017 American Medical Association. All rights reserved. 25

Downloaded From: https://jamanetwork.com/ on 09/30/2021 applications on the afternoon before surgery) in 1 large RCT (N=1093) of elective clean biliary tract, inguinal hernia, and breast cancer procedures.206,213

Q8A.5. Aqueous iodophor solution vs. control (“routine personal hygiene”) Very low-quality evidence suggested no benefit of preoperative shower with 10% aqueous iodophor solution as compared with routine personal hygiene. This was based on no infections reported in either group in 1 small RCT (N=114) in elective, clean plastic surgical procedures (thorax or abdomen) designed to evaluate the product’s efficacy in reducing skin contamination, not SSI.214

Q8A.6. CHG washcloth vs. un-medicated bar soap Moderate-quality evidence suggested no benefit of 2 full body wipes with 2% chlorhexidine washcloths the night before and morning of surgery as compared with a shower with un-medicated bar soap the morning of surgery. This was based on no infections reported in either group in 1 small RCT215 (N=100) in elective, shoulder surgeries designed to evaluate the product’s efficacy in reducing skin contamination, not SSI. In this study, authors reported receiving funds from the CHG washcloth manufacturer.

Other guidelines Clinical practice guidelines recommend that patients shower or bathe with an antiseptic agent or soap on at least the night before surgery.64,85,95 This is considered accepted practice. They do not favor the use of one antiseptic agent over another. There may be contraindications for specific antiseptic-agent use in some patients or surgical procedures.

Q8B. How safe and effective are antiseptic skin preparation agents individually and in combination? The available data examined the following comparisons:

1. Aqueous iodophor: 1-step vs. 2-step 2. Aqueous iodophor (1- or 2-step) vs. iodophor in alcohol (1-step with or without adhesive drape) 3. CHG-alcohol (1- or 2-step) vs. aqueous iodophor (1- or 2-step) 4. CHG-alcohol (1- or 2-step) vs. iodophor-alcohol (1- or 2-step) a. CHG-alcohol (2-step) vs. iodophor-alcohol (2-step) b. CHG-alcohol (1-step) vs. iodophor-alcohol (1-step)

For all comparisons, SSI was the critical outcome for decision-making. Product-related adverse event outcomes were also evaluated. The evidence for this question consists of 14 RCTs.216-229 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q8-10 and Evidence Table Q8B.

Q8B.1. Aqueous iodophor: 1-step vs. 2-step High-quality evidence suggested no benefit of using 2-step as compared with 1-step aqueous iodophor for skin preparation of the surgical site. This was based on no difference in SSI in 2 RCTs at moderate risk of bias.220,227 One study in 234 clean (30%) and clean- contaminated (70%) oncologic, non-laparoscopic abdominal procedures compared povidone iodine paint (1% iodine) to a 5-minute povidone iodine scrub (0.75% iodine) followed by povidone iodine paint (1% iodine).220 Another study in 108 CABG procedures did not report the product concentration or scrub duration.227 In the latter study, patients were also instructed to take antimicrobial showers (unspecified product) the evening before and the morning of surgery.

Q8B.2. Aqueous iodophor (1- or 2-step) vs. iodophor in alcohol (1-step with or without adhesive drape) Low-quality evidence suggested no benefit of iodophor in alcohol as compared with aqueous iodophor. This was based on no difference in SSI in a meta-analysis (N=626) of 5 RCTs including 4 RCTs at moderate risk221,222,226,227 and 1 at low risk225 of bias. Only 1 study at moderate risk of bias in CABG procedures showed a reduced risk of sternal SSI with iodophor in alcohol (with or without plastic adhesive drape).227 A second study (low risk of bias) in CABG procedures using iodophor impregnated plastic adhesive drape at the sternal site showed no difference between groups.225 The remaining studies, at moderate risk of bias, reported no infections in THA and TKA,221 shoulder,226 and foot and ankle222 procedures. However, each was designed to evaluate the products’ efficacy in reducing skin contamination, not SSI.

Q8B.3. CHG-alcohol (1- or 2-step) vs. aqueous iodophor (1- or 2-step) High-quality evidence suggested a benefit of CHG-alcohol as compared with aqueous iodophor. This was based on a reduced risk of SSI in a meta-analysis (N=1976) of 5 RCTs (2 low risk,219,228 1 moderate risk,226 and 2 high risk217,224 of bias) and no difference in product-related adverse events. Only 1 large study showed a reduced risk of SSI in multiple mixed clean-contaminated abdominal and non-abdominal (thoracic, gynecologic, and urologic) procedures.219 CHG-alcohol was specifically associated with reduced risk of superficial and deep incisional SSI, but not organ/space SSI or sepsis. The study in clean hernia repairs (herniotomy, herniorrhaphy, or hernioplasty) showed no difference between groups.228 In both of these studies, authors reported receiving funds from and/or being employed by the manufacturer of the CHG-alcohol product. Of the 3 studies at moderate or high risk of bias, 1 in clean, clean- contaminated or contaminated general surgery224 procedures showed no difference, and the studies in clean elective shoulder226 and foot and ankle217 procedures reported no infections; however, each was designed to evaluate the products’ efficacy in reducing skin contamination, not SSI. © 2017 American Medical Association. All rights reserved. 26

Downloaded From: https://jamanetwork.com/ on 09/30/2021 High-quality evidence from 2 studies suggested no difference in product-related adverse events, including skin irritation or pruritus or erythema around the wound.219,224

Q8B.4. CHG-alcohol (1- or 2-step) vs. iodophor-alcohol (1- or 2-step) High-quality evidence suggested no benefit of CHG-alcohol (1- or 2-step) as compared with iodophor alcohol (1-or 2-step). This was based on no difference in SSI in a meta-analysis (N=1323) of 6 RCTs.216,218,223,226,229,230 Three studies (1 at low risk,216 1 at moderate risk,218 and 1 at high risk229 of bias) compared 2-step application, and 3 studies223,226,230 at moderate risk of bias compared 1-step product application. There was no difference in SSI in individual meta-analyses of “2-step” or “1-step” product application. Details are available under the individual comparators below.

Q8B.4.a. CHG-alcohol (2-step) vs. iodophor-alcohol (2-step) High-quality evidence suggested no benefit of 2-step CHG-alcohol as compared with 2-step iodophor-alcohol. This was based on no difference in SSI in 3 studies that compared 0.5% chlorhexidine gluconate and alcohol with 10% povidone-iodine (1% available iodine) and 23% isopropyl alcohol.216,218,229 No preoperative antiseptic shower protocol was reported in the studies. The large, moderate risk of bias study in a mixed general surgery population reported no difference.216 CHG-alcohol was associated with a significant reduction in SSI in biliary and “other clean procedures.” One study (at high risk of bias) in elective, clean, plastic surgery breast procedures reported no difference between groups.229 The smallest study (at moderate risk of bias) in foot procedures reported no infections in either group.218 However, the study was designed to evaluate the products’ efficacy in reducing skin contamination, not SSI.

Q8B.4.b. CHG-alcohol (1-step) vs. iodophor-alcohol (1-step) High-quality evidence suggested no benefit of 1-step CHG-alcohol as compared with 1-step iodophor-alcohol. This was based on no difference in SSI in 3 studies at moderate risk of bias that compared 2% chlorhexidine gluconate with 70% alcohol (water insoluble film) to 0.7% iodine with 74% alcohol (water insoluble film).223,226,230 One study in shoulder procedures (96 arthroscopies and 4 arthroplasties) reported no infections in either group.226 Patients were instructed to shower the evening prior to surgery (product not reported). Iodophor-impregnated plastic adhesive drapes were applied to the shoulder arthroplasties’ operative site. The second study reported only 1 wound infection following 80 foot and ankle procedures.223 Patients were not instructed to take an antiseptic shower prior to surgery. The third study230 of 100 patients undergoing elective lumbar spine surgery reported no deep or superficial SSI in either group at 6 months follow-up. Patients were instructed to adhere to routine bathing practices. All 3 studies were designed to evaluate the products’ efficacy in reducing skin contamination, not SSI, and all received funding by one or both product manufacturers.

Other guidelines Clinical practice guidelines recommend skin preparation with an antiseptic agent, but do not favor one antiseptic agent over another.64,95,231 Recently published professional society guidelines have recommended skin preparation with alcohol-containing preoperative skin preparatory agents.84 There may be contraindications to the use of specific antiseptic skin preparation agents for specific patients.

Q8C. How safe and effective is the application of a microbial sealant immediately following intraoperative skin preparation? The available data examined the application of a cyanoacrylate-based microbial skin sealant immediately after skin preparation as compared to no sealant.

For this comparison considered SSI was the critical outcome for decision-making. Product-related adverse events were also evaluated. The evidence for this question consists of 4 RCTs.232-235 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q8-10 and Evidence Table Q8C.

Low-quality evidence suggested no benefit of cyanoacrylate-based microbial skin sealant applied immediately following skin preparation. This was based on no difference in SSI in a meta-analysis (N=609) of 4 RCTs evaluating surgical site skin preparation with povidone iodine alcohol232,234,235 or aqueous povidone iodine 233,234 solution followed by application of cyanoacrylate-based skin sealant before skin incision (1 CABG sternal and/or venous harvest site,234 1 CABG leg saphenous vein harvest site,232 1 open inguinal hernia repair233, and 1 pediatric scoliosis correction235). The 2 CABG studies also followed skin sealant application with plastic adhesive drape application. One study at moderate risk of bias235 and 2 studies at low risk of bias232,233 suggested no difference between groups. However, due to the low number of events in the latter study, superiority could not be established and study enrollment ceased once the cyanoacrylate sealant was granted regulatory approval by the FDA (based on porcine data on skin contamination).233 All studies were funded by and/or authors had a financial relationship with the skin sealant manufacturer. Only 1 small study232 (low risk of bias) suggested a reduced risk of SSI; however, the authors acknowledged that the apparent increased risk of SSI in the control legs could be explained by their use of a grading system236 whose stringent criteria included minimal erythema or discharge as SSI. High-quality evidence suggested no significant product-related sensitivity or other adverse events.232-234 In the inguinal hernia repair study, surgeons reported difficulty incising through the clear film (4/166 patients) and 1 reported visible “flaking” of the film at the time of procedure (no report of plastic adhesive drape use).233

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q8D. How safe and effective are plastic adhesive drapes? The available data examined the following comparisons:

1. Non-iodophor impregnated adhesive drape vs. no drape 2. Iodophor-impregnated adhesive drape vs. no drape

For all comparisons, SSI was the critical outcome for decision-making. The evidence for this question consists of 6 RCTs.227,237-241 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q8-10 and Evidence Table Q8D.

Q8D.1. Non-iodophor impregnated drape vs. no drape Moderate-quality evidence suggested no benefit of non-iodophor impregnated plastic adhesive drapes in addition to skin preparation as compared with skin preparation alone. This was based on no difference in SSI in a meta-analysis (N=1742) of 4 RCTs spanning a 30-year period (1971–2001), each reporting no difference.237,239-241 The 2 most recent studies237,241 used polyurethane adhesive drapes; drape material information was not reported in the older239,240 studies. The surgical skin preparation agent applied prior to the application of the adhesive drapes varied among studies and may have impacted drape adhesion. Studies included general surgery,239,240 cesarean section,241 and hip fracture237 surgery.

Q8D.2. Iodophor-impregnated drape vs. no drape High-quality evidence suggested no benefit of iodophor-impregnated plastic adhesive drapes in addition to skin preparation as compared with skin preparation alone. This was based on no difference in SSI in a meta-analysis (N=1113) of 2 RCTs spanning a 15- year period (1987-2002), each reporting no difference.227,238 Both studies used povidone iodine alcohol skin preparation (2-step application in the study at low risk of bias in abdominal procedures238 and 1-step application in the study at moderate risk of bias in CABG227 procedures).

Other guidelines Other evidence-based clinical practice guidelines recommend against the routine use of non-iodophor impregnated plastic adhesive drapes and recommend that if a plastic adhesive drape is required, then an iodophor-impregnated one should be used (unless the patient has an iodine allergy).84,95,242

Q8. Recommendations 8A. Advise patients to shower or bathe (full body) with soap (antimicrobial or non-antimicrobial) or an antiseptic agent on at least the night before the operative day. (Category IB – strong recommendation; accepted practice) 206-214 (Guideline Question 8A)

8A.1. Randomized controlled trial evidence suggests uncertain tradeoffs between the benefits and harms regarding the optimal timing of the preoperative shower or bath, the total number of soap or antiseptic agent applications, or the use of chlorhexidine gluconate washcloths for the prevention of SSI. (No recommendation/unresolved issue) 215 (Guideline Question 8A.1)

8B. Perform intraoperative skin preparation with an alcohol-based antiseptic agent, unless contraindicated. (Category IA – strong recommendation; high-quality evidence) 216-230 (Guideline Question 8B)

8C. Application of a microbial sealant immediately following intraoperative skin preparation is not necessary for the prevention of SSI. (Category II – weak recommendation; low-quality evidence suggesting a trade-off between clinical benefits and harms) 232-235 (Guideline Question 8C)

8D. The use of plastic adhesive drapes with or without antimicrobial properties, is not necessary for the prevention of SSI. (Category II – weak recommendation; high to moderate-quality evidence suggesting a trade-off between clinical benefits and harms) 227,237-241 (Guideline Question 8D)

Q9. How safe and effective is antiseptic irrigation prior to closing the surgical incision? The available data examined aqueous iodophor irrigation versus normal saline for the prevention of SSI.

For this comparison, superficial and deep SSIs and organ/space abscess were the critical outcomes for decision-making. Product- related adverse events including wound healing and iodine toxicity outcomes were also evaluated. The evidence for this question consists of 7 RCTs.243-249 In all studies, both groups received parenteral AMP, but the specific protocol was not necessarily described.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q8-10 and Evidence Table Q9.

Moderate-quality evidence suggested no benefit of aqueous iodophor peritoneal lavage in contaminated and dirty general surgical abdominal cases. This was based on no difference in organ/space abscess formation in meta-analysis (N=268) of 3 RCTs.246,247,249 Aqueous iodophor solution amount, concentration, application, and perioperative AMP regimen varied among studies.

Moderate-quality evidence suggested a benefit of intraoperative aqueous iodophor irrigation of the deep incision, in combination with parenteral AMP, for clean spine procedures. This was based on moderate-quality evidence from a meta-analysis (N=660) of 2 RCTs suggesting a reduced risk of deep SSI when the deep tissues were irrigated and allowed to soak for 3 minutes with 0.35% povidone iodine solution, then irrigated with an additional 2 L of normal saline prior to bone grafting and spinal instrumentation.243,244 All procedures in both studies were performed by the same surgeon. Perioperative AMP included preoperative parenteral dose, postoperative parenteral dosing for 2 days followed by oral prophylaxis for an additional 3 days. Over 80% of the SSIs were caused by Methicillin-resistant Staphylococcus aureus (MRSA).

High-quality evidence suggested a benefit of aqueous iodophor irrigation of the subcutaneous tissue in combination with parenteral AMP for clean-contaminated, contaminated, and dirty open abdominal procedures. This was based on reduced risk of superficial SSI on meta-analysis (N=329) of 2 RCTS that performed 60 seconds of subcutaneous tissue irrigation with 10% aqueous iodophor solution prior to wound closure.245,248 The larger 248 study administered parenteral AMP preoperatively and for 48 hours postoperatively, while the smaller245 study only reported administering perioperative parenteral AMP. Individual meta-analyses of clean-contaminated (N=149) and dirty (N=90) procedures both showed reduced risk of superficial SSI.

High-quality evidence from 3 studies suggested no increased risk of product-related adverse events244,245,247 or iodine toxicity.245-247 Moderate-quality evidence from 2 studies suggested no wound healing problems.243,245

The search did not identify RCTs or SRs that evaluated the safety and effectiveness of soaking surgical implants (e.g., meshes, neurosurgical ventricular shunts) in antiseptic solution prior to insertion (in combination with parenteral AMP) and its impact on SSI.

Q9. Recommendation 9A. Consider intraoperative irrigation of deep or subcutaneous tissues with aqueous iodophor solution for the prevention of SSI. Intra-peritoneal lavage with aqueous iodophor solution in contaminated or dirty abdominal procedures is not necessary. (Category II – weak recommendation; moderate-quality evidence suggesting a trade-off between clinical benefits and harms) 243-249 (Guideline Question 9)

9B. The search did not identify randomized controlled trials evaluating the soaking of prosthetic devices in antiseptic solutions prior to implantation for the prevention of SSI. (No recommendation/unresolved issue) (Guideline Question 9)

Q10. How safe and effective is repeat application of an antiseptic skin preparation agent to the surgical site immediately prior to closing the surgical incision? The available data examined the repeat application of aqueous iodophor solution to the patient’s skin immediately prior to closing the surgical incision versus no additional application of topical antiseptic agent for the prevention of SSI. For this comparison, SSI was considered the critical outcome for decision-making.

Low-quality evidence suggested no benefit of repeat application of aqueous iodophor solution to the patient’s skin immediately prior to closing the surgical incision, in combination with parenteral AMP. This was based on no difference in SSI (combined or individual incisional or organ/space SSI) in a small study at high risk of bias, in 107 gastric and colorectal procedures.250

The search did not identify RCTs or SRs that evaluated repeat application of chlorhexidine, chlorhexidine-alcohol, iodophor alcohol or topical antiseptic agents other than aqueous iodophor solution. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q8-10 and Evidence Table Q10.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q10. Recommendation 10. RCT evidence is insufficient to evaluate the tradeoffs between the benefits and harms of repeat application of antiseptic agents to the patient’s skin immediately prior to closing the surgical incision for the prevention of SSI. (No recommendation/unresolved issue) 250 (Guideline Question 10)

4.2. Prosthetic Joint Arthroplasty Section Evidence Review

4.2A. BLOOD TRANSFUSION Q11. How do perioperative blood transfusions impact the risk of SSI in prosthetic joint arthroplasty patients? For the general question of risk of any blood transfusion on SSI, SSI was the critical outcome for decision-making. The evidence for this question consists of 2 RCTs251,252 and 4 OBS.253-256 All of the studies reflect European transfusion practices between 1999 and 2007. Studies were published between 2001 and 2008; however, only 2 report the study periods (1998–2000).255,256 All studies were at low risk of bias.

When reported, hemoglobin thresholds for blood transfusion ranged between 8 and 11g/dL. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q11 and Evidence Table Q11.

High-quality evidence suggested blood transfusions increased the risk of SSI. This was based on increased risk of SSI in a meta- analysis (N=8493) of 6 studies, 2 RCTs251,252 and 4 OBS,253-256 and a separate meta-analysis (N=7484) of the 4 OBS. Analysis combined allogeneic, autologous, and autologous plus allogeneic blood transfusion data. Data in both of these meta-analyses may be driven by 2 OBS with a large number of patients who received allogeneic-only blood transfusion and the possibility of selection bias inherent in OBS.254,256 In contrast, meta-analysis of the 2 RCTs (N=1009) does not suggest an increased risk of SSI with autologous and autologous plus additional allogeneic blood transfusions.

Q11A. Are specific blood products associated with a risk of SSI? The available data examined the following comparisons:

1. Allogeneic blood (any) vs. no transfusion a. Allogeneic not WBC depleted vs. no transfusion b. Allogeneic WBC depleted vs. no transfusion c. Allogeneic “buffy coat depleted” vs. no transfusion d. Allogeneic WBC filtered vs. no transfusion e. Allogeneic “lower WBC content” vs. allogeneic “higher WBC content” 2. Autologous blood (any) vs. no transfusion a. Autologous ±WBC filtration vs. no transfusion b. Autologous whole blood vs. no transfusion c. Autologous “not WBC depleted” vs. no transfusion d. Autologous buffy coat depleted vs. no transfusion e. Autologous “lower WBC content” vs. autologous “higher WBC content” f. Post-operative salvage only vs. autologous donated blood 3. Allogeneic blood (any) vs. autologous blood (any) a. Allogeneic WBC± WBC depleted vs. autologous not WBC depleted b. Allogeneic WBC filtered vs. autologous buffy coat depleted. 4. Combined autologous and allogeneic (any) vs. no transfusion a. Combined autologous and allogeneic vs. autologous only

For all comparisons, SSI, PJI, or reoperation due to wound infection were the critical outcomes for decision-making. Wound disturbance was also evaluated. The evidence for this question consists of 2 RCTs251,252 and 7 OBS253-259 studies. There were differences among studies, including: surgical procedures; definition of SSI; blood product white blood cell (WBC) content; length of blood product storage; hemoglobin transfusion trigger levels and other criteria for transfusion; as well as follow-up. In several studies, missing data resulted in discrepancies in the numbers. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q11 and Evidence Table 11A.

Q11A.1. Allogeneic blood (any) vs. no transfusion Low-quality evidence suggested that allogeneic blood transfusions increased the risk of SSI. This was based on increased risk of SSI in a meta-analysis (N=5737) of 4 OBS253-256 studies in primary and revision THA and TKA and no difference in reoperation due to wound infection in another OBS.259 See individual comparators in eAppendix 2 of the Supplement: GRADE Table 11 for specific study findings. © 2017 American Medical Association. All rights reserved. 30

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q11A.2 Autologous blood (any) vs. no transfusion Moderate-quality evidence suggested that autologous blood transfusions did not increase the risk of SSI. This was based on no difference in a meta-analysis (N=970) of 2 RCTs.251,252 One large RCT in THA suggested no difference at 90 days of follow-up.251 The second small RCT in THA reported no infections in either group; however, this study was designed to evaluate transfusion induced immunomodulation, not SSI, and follow-up was limited to 7 days.252 In contrast, 1 large254 (N=912) prospective OBS in primary and revision THA and TKA suggested reduced risk of SSI and a smaller253 study in primary THA and TKA reported only 1 infection in the transfused group. One RCT reported receiving study supplies from a blood bag manufacturer.251 See individual comparators in eAppendix 2 of the Supplement: GRADE Table 11 for specific study findings.

Q11A.3. Allogeneic blood (any) vs. autologous blood (any) Moderate-quality evidence suggested that allogeneic blood transfusions increased the risk of SSI when compared with autologous transfusions. This was based on a greater than 4-fold increase in risk in a meta-analysis (N=2592) of 3 OBS.253,254,258 Allogeneic blood products included whole blood, WBC depleted, WBC filtered and not filtered; autologous products included whole blood, buffy coat depleted, and perioperative cell salvage-washed blood. See individual comparators in eAppendix 2 of the Supplement: GRADE Table Q11 for specific study findings.

Q11A.4. Combined autologous and allogeneic blood (any) vs. no transfusion Moderate-quality evidence suggested that combined autologous and additional allogeneic blood transfusions did not increase the risk of SSI. This was based on no difference in subanalysis in 1 RCT251 (N=470) and 2 OBS253,254 (N=1632). In each study, patients received allogeneic blood transfusion only after all (2–3 units) of the autologous donated blood (with or without additional salvage blood) had been transfused. Autologous blood products included autologous whole blood, packed red blood cells, salvage blood,254 “buffy coat depleted,”253 or “WBC filtered.”251 Allogeneic blood products included “WBC depleted or not depleted”254 or “WBC filtered (WBCF).”253,256 Transfusion triggers included: hemoglobin levels of 8-9 g/dL,251,254 <11g/dL for autologous transfusions and <6 g/dL for allogeneic transfusions or <10 g/dL in patients with cardiovascular or cerebrovascular disease, or symptomatic anemia in another257 study. See individual comparators in eAppendix 2 of the Supplement: GRADE Table Q11 for specific study findings.

Other guidelines Recent blood transfusion practice guidelines recommend more restrictive transfusion strategies than those used in these studies.260 In hemodynamically stable postoperative surgical patients, transfusion is recommended for hemoglobin levels of 8 g/dL or less for those with symptoms (e.g., chest pain, orthostatic hypotension or tachycardia unresponsive to fluid resuscitation, or congestive heart failure). In adult and pediatric intensive care unit patients, the recommended hemoglobin level for transfusion is 7 g/dL or less.

Q11B. If the risk of SSI is increased, can this effect be isolated from the risk associated with more complex cases? The search did not identify data that directly evaluated the association between increasing blood transfusion requirements, more complex cases, and the risk of SSI in prosthetic joint arthroplasty patients. However, data from 3 OBS254,256,257 stratified blood transfusion requirements and 1 OBS254 reported blood loss, both by procedure type. See individual comparators in eAppendix 2 of the Supplement: GRADE Table Q11 for specific study findings.

Q11C. How does the volume of transfused blood product impact the risk of SSI? The search did not identify data that evaluated differences in the volume of transfused blood product and their impact on the risk of SSI in prosthetic joint arthroplasty patients.

Q11D. How safe and effective is withholding blood transfusions to reduce the risk of SSI? The search did not identify data that both evaluated the safety and effectiveness of withholding blood transfusions and its impact on the risk of SSI in prosthetic joint arthroplasty patients.

Other guidelines Clinical practice guidelines recommend against withholding transfusion of necessary blood products from surgical patients as a means to prevent SSI.64 This is considered accepted practice.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q11. Recommendation 11A. Available evidence suggests uncertain tradeoffs between the benefits and harms of blood transfusions on the risk of SSI in prosthetic joint arthroplasty. Other organizations have made recommendations on this topic and a summary of these recommendations can be found in the Other guidelines section of the narrative summary for this question. (No recommendation/unresolved issue) 251-259 (Guideline Question 11A-C)

11B. Do not withhold transfusion of necessary blood products from surgical patients as a means to prevent SSI. (Category IB –strong recommendation; accepted practice) 64 (Guideline Question 11D)

4.2B. SYSTEMIC IMMUNOSUPPRESSIVE THERAPY Q12. How does systemic corticosteroid or other immunosuppressive therapy impact the risk of SSI in prosthetic joint arthroplasty patients? Immunosuppressive therapies used to treat rheumatoid arthritis (RA) are divided into disease-modifying antirheumatic drugs (DMARDs) and biologic agents. The most common DMARD is methotrexate, but these drugs can also include hydroxychloriquine, leflunomide, minocycline, sulfasazaline, azathioprine, cyclosporine and gold. DMARD combination therapy includes 2 or 3 drugs, most of which are methotrexate-based. Biologic agents are commonly divided into “non-tumor necrosis factor (TNF)” agents (e.g., anakinra, abatacept, rituximab, and tocilizumab) and “anti-TNF” agents (e.g., adalimumab, etanercept, infliximab, certolizumab pegol, and golimumab). Systemic corticosteroids most commonly refer to oral prednisone use.

To answer this question, the following subquestions were asked:

A) Does the type of agent impact the risk of SSI? B) Does the preoperative duration of therapy impact the risk of SSI? and C) Does the agent dose impact the risk of SSI?

Q12A. Does the type of agent impact the risk of SSI? The available data examined the following comparisons:

1. Biologic agents (non-TNF and anti-TNF) vs. DMARDs 2. DMARDs: methotrexate vs. no DMARD therapy

For all comparisons, SSI, PJI, superficial SSI, deep wound abscess, and infected hematoma were the critical outcomes for decision- making. Drug-related adverse events, as well as the adverse events of a surgical wound necrotic eschar, and serous drainage were also evaluated. “Adverse events of surgical wound” was a composite variable that included: wound dehiscence (not completely healed 14 days after surgery or needs secondary closure), continued discharge, and culture-positive infection. The evidence for this question consists of 4 OBS in RA patients.261-264 All studies were at low risk of bias. The authors in 2 of these studies reported receiving funds from pharmaceutical companies.261,262 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q12-16 and Evidence Table Q12-16.

Q12.A.1. Biologic agents (non-TNF and anti-TNF) vs. DMARDs Very low-quality evidence suggested biologic agent therapy (non-TNF and anti-TNF) increased the risk of SSI. This was based on greater than 5-fold increase in risk of SSI and superficial SSI, but no difference in PJI in 3 separate meta-analyses (N=528) of 2 OBS.261,262 Multivariate logistic regression analyses in both studies identified biologic agents as a significant risk factor for infection, and in 1 study261 they were also a risk factor for deep venous thrombosis (DVT). Very-low quality evidence also suggested no difference in other adverse events of the surgical wound.263 For superficial SSI, the large262 study in primary or revision THA or TKA RA patients (superficial SSI rate 18.8%) reported a significantly increased risk with biologic agents, while the smaller261 study (superficial SSI rate of 7.4%) reported no difference. The large and small studies each reported no difference in PJI; however, the number of events in both groups (n=3 and 1, respectively) and the number of arthroplasty procedures in the smaller study (N=108) limited the power of the analyses.

Biologic agents included anti-TNFs (etanercept, infliximab, adalimumab) and non-TNFs (anakinra, abatacept and rituximab). In each study, patients had established RA (on average > 10 years). All patients on biologic agent therapy also received prednisone 3-5 mg/day, and the majority also received methotrexate (88%261 to 92%263) and/or another DMARD261 (13%). DMARD patients in all 3 studies were on single or multiple DMARD therapy in addition to daily prednisone (average, 3 mg/day). The most common DMARD was methotrexate, but none of the studies reported average weekly doses, and only 1 reported the DMARD perioperative administration protocol (it was administered continuously).262

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q12.A.2. DMARDs: methotrexate vs. no DMARD therapy Very low-quality evidence suggested methotrexate therapy did not increase the risk of SSI. This was based on no difference in PJI, deep wound abscess, infected hematoma, necrotic eschar, or serous drainage at 6 months of follow-up in 1 OBS.264 For each outcome, both the study size and the total number of events were limited. This 1991 study utilized data collected between 1978 and 1987 with patients on a mean weekly methotrexate dose of 8.7 mg (range: 7.5–12.5 mg) and could be considered sub-therapeutic in current clinical practice.265 The methotrexate group included both patients who had continued and patients who had stopped methotrexate within 4 weeks of surgery. While patients in the no therapy group had never taken methotrexate, some were on daily prednisone (the study does not report how many).

Q12B. Does the preoperative duration of the therapy impact the risk of SSI? The search did not identify data that directly evaluated the length of time that immunosuppressive therapy was used preoperatively and the impact this therapy had on the risk of SSI in prosthetic joint arthroplasty patients. Thus, disease duration was evaluated as a proxy. SSI was the critical outcome for decision-making. The evidence for this question consists of 2 OBS.261,262 The search did not reveal data that evaluated patients with early RA (<6 months). The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table 12-16 and Evidence Table Q12.

Low-quality evidence suggested that in patients with established RA (>6 months), years of disease duration was a risk factor for SSI. This was based on increased risk in 2 OBS that performed multivariate logistic regression analyses comparing infected to non-infected patients on biologic (anti-TNF) agents and DMARDs.261,262

Q12C. Does the agent dose impact the risk of SSI? The search did not identify data that directly evaluated different doses of biologic agents or DMARDs and their impact on the risk of SSI in arthroplasty patients. The available data examined doses of prednisone and risk of SSI in patients on biologic agents (anti-TNF) as compared with those on DMARDs.

For this comparison, SSI was the critical outcome for decision-making. The evidence for this question consists of 2 OBS in RA patients.261,262 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q12-16 and Evidence Table Q12.

Very low-quality evidence suggested higher prednisone dose increased the risk of SSI. This was based on increased risk of SSI on multivariate logistic regression analyses comparing infected and non-infected patients in 2 OBS.261,262 The small study, with the majority of patients on combination biologic/DMARD or dual DMARD therapy, suggested that increasing prednisone dose was a risk factor for SSI.261 Patients in the biologic agent group were on significantly higher daily prednisone doses (5 mg/day; range 2–7) than those in the DMARD group (3 mg/day; range 0–5). The larger study, where none of the patients were on combination biologic and DMARD therapy, suggested prednisone dose was not a risk factor for SSI. Patients in both groups were on an average prednisone dose of 3 mg/day (range, 0–5).262 Results were not stratified by immunosuppressive therapy agent.

Q13. What are the most effective strategies in managing systemic corticosteroids or other immunosuppressive therapy perioperatively to reduce the risk of SSI in prosthetic joint arthroplasty patients? Q13A. How safe and effective is the discontinuation of these agents preoperatively and when should they be resumed? The available data examined the following comparisons:

1. DMARDs: methotrexate stopped vs. continued perioperatively 2. Biologic agents: anti-TNF stopped vs. continued perioperatively

The evidence for this question consists of 4 OBS examining DMARDs264,266-268 and 1 OBS examining biologic agents266 in RA patients. All studies were at low risk of bias. For all comparisons PJI was the critical outcome for decision-making. RA flares, infected hematomas, necrotic eschar, and non-communicating serous drainage outcomes were also evaluated. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q12-16 and Evidence Table Q12-13.

Q13A.1. DMARDs: methotrexate stopped vs. continued perioperatively Low-quality evidence suggested no increased risk of PJI with methotrexate continued throughout the perioperative period. This was based on no difference in PJI in a meta-analysis of 3 small OBS264,267,268 and a separate OBS266 . In the meta-analysis, both the number of procedures (N=180) and events (n=7) were small. The studies were performed between 1991 and 1996, and the methotrexate doses could be considered subtherapeutic in current practice.265 Procedures followed, and length of time during which therapy was stopped varied. In a larger study, stopping DMARD therapy at the time of surgery (not defined) reduced the incidence of subsequent PJI.266 The authors of this larger study reported receiving funds from multiple pharmaceutical companies.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q13A.2. Biologic agents: anti-TNF stopped vs. continued perioperatively Very low-quality evidence suggested no difference in risk of PJI with continuation of biologic (anti-TNF) therapy perioperatively. This was based on no difference in risk of PJI in a small subanalysis in 1 OBS in THA and TKA patients. 266 Both the number of patients (N=50) and events (n=3), all in the group continuing biologic agent therapy perioperatively, were very small.

Q13B. Should the agent dose be adjusted, and if so, for how long? The search did not identify data that evaluated perioperative immunosuppressive therapy dose adjustment and its impact on the risk of SSI in prosthetic joint arthroplasty patients.

Other guidelines Clinical practice guidelines provide conflicting recommendations regarding the perioperative management of immunosuppressive therapy. In 2008, the American College of Rheumatology (ACR) provided no recommendation for the perioperative management of DMARDs due to the “absence of consistent evidence”.269 The following year, a multinational guideline suggested that methotrexate could be safely continued in the perioperative period in RA patients undergoing elective orthopaedic surgery.265 Their recommendation was based on studies with low methotrexate dosing (4–13 mg/week). For biologic agents, the British Society for Rheumatology recommended in 2005 that treatment with anti-TNF agents be withheld for 2–4 weeks prior to major surgical procedures and restarted postoperatively if there was no evidence of infection and wound healing was satisfactory.270 Recommendations were based solely on information provided by pharmaceutical companies. In 2008, ACR recommended that biologic agents not be used for at least 1 week prior to and 1 week following surgery (based on the pharmacokinetic properties of a given agent).269 The 2012 ACR update does not address perioperative management of immunosuppressive therapy.271

Q12 and Q13. Recommendation 12 and 13. Available evidence suggests uncertain tradeoffs between the benefits and harms of systemic corticosteroid or other immunosuppressive therapy on the risk of SSI in prosthetic joint arthroplasty. Other organizations have made recommendations based on the existing evidence and a summary of these recommendations can be found in the Other guidelines section of the narrative summary for this question. (No recommendation/unresolved issue) 261-264,266-268 (Guideline Questions 12 and 13)

Q14. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty patients who are on systemic corticosteroid or other immunosuppressive therapy? The search did not identify data that specifically evaluated differences in duration of postoperative AMP in prosthetic joint arthroplasty patients who were on systemic corticosteroids or other immunosuppressive agents and its impact on the risk of SSI. However, multiple procedures examined in the Core Section, Q1.E: Postoperative AMP duration that included patients on immunosuppressive therapy showed no benefit of continuing AMP after closing the surgical incision in the operating room. Therefore, the broader recommendation for duration of postoperative AMP should be applied to prosthetic joint arthroplasty procedures irrespective of use of systemic corticosteroid or other immunosuppressive therapies.

Q14. Recommendation 14. For prosthetic joint arthroplasty patients on systemic corticosteroid or other immunosuppressive therapy, Recommendation 1E applies: In clean and clean-contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain. (Category IA – strong recommendation; high- quality evidence) 96-140 (Guideline Question 14)

4.2C. INTRA-ARTICULAR CORTICOSTEROID INJECTIONS Q15. How do preoperative intra-articular corticosteroid injections impact the risk of SSI in prosthetic joint arthroplasty patients? The available data examined the following comparisons:

1. History of corticosteroid injection vs. no injection a. TKA: injection vs. no injection b. THA: injection vs. no injection

Downloaded From: https://jamanetwork.com/ on 09/30/2021 For all comparisons, any SSI, PJI, and superficial SSI were the critical outcomes for decision-making. The evidence for this question consists of 2 OBS in TKA272,273 and 3 OBS in THA274-276 patients. All studies were at low risk of bias. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q12-16 and Evidence Table Q15.

Low-quality evidence suggested that preoperative intra-articular corticosteroid injection did not increase the risk of SSI following total joint arthroplasty. This was based on no difference in a meta-analysis (N=1146) of 5 OBS in TKA272,273 and THA.274-276 See individual comparators below and in eAppendix 2 of the Supplement: GRADE Table Q12-16 for individual TKA and THA findings.

Q15.1.a. TKA: injection vs. no injection Very low-quality evidence suggested that preoperative intra-articular corticosteroid injection did not increase the risk of SSI following TKA. This was based on no difference in SSI, PJI, or superficial SSI in meta-analyses (N=414) of 2 OBS.272,273 Both the total number of patients and events were small. One study in 144 patients273 suggested that a history of preoperative intra-articular injection was significantly associated with PJI after TKA (3 infections, all in the injection group) while another study in 270 TKAs272 reported no PJIs in either group. Both studies had 1 year of follow-up. The majority of infections were superficial SSIs, and no difference was reported at 30 days of follow-up. In the smaller study, patients received injections in the orthopaedic clinic, rheumatology clinic, or general practice setting, while those in the larger study all received their injections in the operating room using strict aseptic technique. Patients had been injected within 11273 and 12272 months of surgery.

Q15.1.b. THA: injection vs. no Injection Very low-quality evidence suggested that a preoperative intra-articular corticosteroid injection did not increase the risk of infection following THA. This was based on no difference in SSI, PJI, or superficial SSI on separate meta-analyses of 3 OBS.274-276 No difference in PJI or superficial SSI was reported in each individual study. In 2 studies, both the number of patients and events was small.274,276 Corticosteroid doses and follow-up periods varied. In each study, corticosteroid injection was administered in a radiology suite using standard protocols for aseptic technique, and 1 study also indicated that the radiologists wore sterile masks and gowns.274

Q16. What are the most effective strategies for managing the preoperative use of intra-articular corticosteroid injections to reduce the risk of SSI in prosthetic joint arthroplasty patients? The search did not identify data that evaluated different intra-articular corticosteroid injection agents and their impact on risk of SSI. To answer this question, 2 subquestions were asked:

A) Does the length of time between corticosteroid injection and prosthetic joint arthroplasty impact the risk of SSI? B) Does the corticosteroid injection dose impact the risk of SSI?

Q16A. Does the length of time between intra-articular corticosteroid injection and prosthetic joint arthroplasty impact the risk of SSI? The available data evaluated different lengths of time between preoperative intra-articular corticosteroid injection and prosthetic joint arthroplasty and the impact on the risk of SSI in THA only, not TKA.

For all comparisons, SSI was the critical outcome for decision-making. The evidence for this question consists of 2 OBS.274,275 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q12-16 and Evidence Table Q16.

Low-quality evidence suggested no association between the length of time between intra-articular corticosteroid injection and THA and the development of SSI. This was based on no difference in the length of time between injection and surgery and the development of SSI in 2 OBS.274,275 The smaller, underpowered study also reported no association between the number of injections and SSI.274 In the larger study, while there was no difference in PJI or superficial SSI (mean time between injection and THA was 112 days), the mean time from injection to surgery for those diagnosed with PJI was less than half as long as those diagnosed with superficial SSI (44 vs. 112 days).275

Q16B. Does the corticosteroid injection dose impact the risk of SSI? The search did not identify data that evaluated different doses of preoperative intra-articular corticosteroid injections and their impact on the risk of SSI.

Other guidelines While clinical practice guidelines include intra-articular corticosteroid injections among their pharmacologic recommendations for the initial management of knee and hip osteoarthritis, they do not provide recommendations on management strategies with regard to SSI prevention.277 Safe injection practices apply to the administration of intra-articular corticosteroid injections.278

Downloaded From: https://jamanetwork.com/ on 09/30/2021 Q15 and Q16. Recommendation 15 & 16. Available evidence suggests uncertain tradeoffs between the benefits and harms of preoperative intra- articular corticosteroid injection on the incidence of SSI in prosthetic joint arthroplasty. Other organizations have made recommendations based on observational data and a summary of these recommendations can be found in the Other guidelines section of the narrative summary for this question. (No recommendation/unresolved issue)272-276 (Guideline Questions 15 and 16)

4.2D. ANTICOAGULATION Q17. What are the most effective strategies for managing perioperative venous thromboembolism (VTE) prophylaxis to reduce the risk of SSI in prosthetic joint arthroplasty patients? To answer this question 3 subquestions were asked:

A) Does the risk of SSI differ by individual VTE prophylaxis agent? B) What is the optimal timing and duration of perioperative VTE prophylaxis for the reduction of SSI in prosthetic joint arthroplasty patients? C) How safe and effective is modifying the dose of the perioperative VTE prophylaxis agent to reduce the risk of SSI?

Q17A. Does the risk of SSI differ by individual VTE prophylaxis agent? The available data examined the following comparisons between different anticoagulation agents:

1. Enoxaparin vs. fondaparinux 2. Enoxaparin vs. rivaroxaban 3. Enoxaparin vs. aspirin (acetylsalicylic acid [ASA]) and mechanical prophylaxis 4. Enoxaparin vs. bemiparin vs. fraxiparin vs. fondaparinux 5. Low molecular weight heparin (LMWHs) or fondaparinux vs. ASA 6. Warfarin vs. no pharmacologic or mechanical prophylaxis 7. Warfarin vs. ASA ± mechanical prophylaxis 8. Higher vs. lower mean International Normalized Ratio (INR)

For all comparisons, SSI and PJI were the critical outcomes in decision-making. Hemorrhagic wound complications, time until wound was dry or persistent wound drainage, drug-related adverse events, and wound hematoma outcomes were also evaluated. The evidence for this question consists of 1 SR,279 4 RCTs,280-283 and 5 OBS28,284-287 in primary and revision, unilateral, THA, TKA, and hip fracture procedures. Injectable agents included LMWHs (Factor Xa and some thrombin inhibition), most commonly enoxaparin or the indirect Factor Xa inhibitor fondaparinux. Oral agents included rivaroxaban (direct Factor Xa inhibitor), warfarin (Vitamin K antagonist, Factors II, VII, IX, X inhibitors), and ASA (cyclooxygenase inhibitor). No reversing agents currently exist for fondaparinux or rivaroxaban. The search did not identify studies that evaluated warfarin as compared to enoxaparin or the impact of unfractionated heparin or clopidogrel on the risk of SSI. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q17 and Evidence Table Q17A-B.

Q17A.1. Enoxaparin vs. fondaparinux Low-quality evidence suggested no difference between perioperative injectable VTE prophylaxis with enoxaparin or fondaparinux and risk of SSI. This was based on no difference in SSI and no drug-related adverse events at the end of VTE prophylaxis (11 days) in a large meta-analysis (N=7237) of 4 RCTs (in primary and revision THA, TKA, and hip fracture procedures (osteosynthesis and hemiarthroplasties).279,288-291 The studies were large, international, multi-center studies evaluating the safety and effectiveness of these agents in reducing the risk of postoperative VTE, not SSI. While fondaparinux administration was standardized (2.5 mg once a day starting postoperatively, except in hip fractures where it was started preoperatively if the case was delayed for >24 hours), enoxaparin dose and timing of administration varied among studies (30 mg twice a day starting postoperatively288,291 or 40 mg once a day starting preoperatively289,290). In all 4 studies, prophylaxis was scheduled to last 5-9 days postoperatively. SSI was a secondary outcome and follow-up was limited (up to 11 days postoperatively). The 4 individual RCTs and the SR meta-analysis were all sponsored by the manufacturer of fondaparinux and authored by the same investigators, in which the lead, senior, and multiple co-authors reported serving as scientific consultants to the manufacturers of both agents evaluated in the studies. Turpie et al., indicated that the sponsor was responsible for data collection and final statistical analysis.291

Q17A.2. Enoxaparin vs. rivaroxaban High-quality evidence suggested no difference between injectable enoxaparin and oral rivaroxaban and risk of SSI. This was based on no difference in SSI in a large meta-analysis (N=12,383) of 4 RCTs in elective primary or revision THA or TKA, and no difference in hemorrhagic wound complications or drug-related adverse events.280-283 These studies were large, international, multi-center studies at © 2017 American Medical Association. All rights reserved. 36

Downloaded From: https://jamanetwork.com/ on 09/30/2021 low risk of bias, evaluating the safety and effectiveness of once daily dosing with enoxaparin or rivaroxaban in reducing the risk of postoperative VTE, not SSI. Eriksson et al.,280 and Kakkar et al.,282 compared enoxaparin 40 mg once-a-day started preoperatively to rivaroxaban 10 mg once-a-day started postoperatively in elective unilateral primary (95%) or revision THA. Rivaroxaban was administered for 35 days in both studies; enoxaparin was administered for 35 days in one280 and 10-14 days in the other.282 Follow up was approximately 2 months. Two other studies evaluated these agents in elective unilateral primary (97%) or revision TKA, administered over 10-14 days.281,283 While rivaroxaban administration was standardized (10 mg once-a-day, started preoperatively), enoxaparin dose and timing varied among studies (40 mg once-a-day, started preoperatively283 or 30 mg twice a day started postoperatively). SSI was a secondary outcome, and follow-up was approximately 6 weeks. All studies were sponsored by the manufacturer of rivaroxaban and authored by investigators who were employees of the manufacturer or who served as scientific consultants to the manufacturers of both agents evaluated in the studies.

Q17A.3 Enoxaparin vs. ASA and mechanical prophylaxis Very low-quality evidence suggested no difference between injectable enoxaparin and combined oral ASA and mechanical prophylaxis and risk of SSI. This was based on no increased risk of SSI on logistic regression analysis in 1 large study in primary THA or TKA.286 Enoxaparin was associated with a longer time until wound was dry in THA, but not TKA. Enoxaparin was started 12-24 hours postoperatively. ASA 325 mg along with pneumatic compression devices was started on the morning after surgery. Analysis was limited to patients with a closed suction drain and normal coagulation profile. Duration of VTE prophylaxis and follow- up period were not reported. Q17A.4. Enoxaparin vs. bemiparin vs. fraxiparin vs. fondaparinux Very low-quality evidence suggested no difference between perioperative injectable LMWHs, ultra LMWH and fondaparinux, and risk of SSI. This was based on no difference in PJI at 6 months of follow-up in a small, nested, case-control study within a larger European multicenter prospective study investigating the independent effects of VTE prophylaxis timing on the risk of PJI in TKA (low risk of bias).284 Of note, logistic regression analysis suggested that hematoma formation increased the risk of PJI 4-fold.

Q17A.5. Enoxaparin, dalterparin, tinzaparin or fondaparinux vs. ASA ± mechanical prophylaxis Very low-quality evidence suggested no difference between perioperative injectable LMWH, fondaparinux, and combined oral ASA (with or without mechanical VTE prophylaxis), and risk of SSI. This was based on no difference in SSI in a subanalysis (n=41,917) of a very large retrospective OBS (low risk of bias) using administrative data from a national sample of primary TKAs.28 Data were collected from 307 facilities over a 2-year period and compared the risk of VTE, bleeding, SSI, and mortality in primary TKA patients, 4,719 (5.0%) of whom were on ASA, 51,923 (55.3%) on oral warfarin, and 37,198 (39.6%) on injectable agents (LMWHs and fondaparinux were combined in the analysis). Pneumatic compression devices were used on the day of surgery or on the first postoperative day in 1,795 (38%), 28,757 (55%), and 17,756 (48%) of the populations, respectively. Patients on ASA had fewer baseline comorbidities, lower baseline risk of VTE, and received care in hospitals with shorter average length of stay that more commonly discharged to the patient’s home after surgery. The study included SSIs detected at the time of admission or upon readmission to the hospital within 30 days of the index procedure using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) wound infection codes. Authors indicated that subtherapeutic dosing and/or inappropriate dose timing of the LMWHs or synthetic Factor Xa inhibitor may have impacted the results. Q17A.6. Warfarin vs. no pharmacologic or mechanical prophylaxis Very low-quality evidence suggested no difference between oral warfarin VTE prophylaxis and no pharmacologic or mechanical prophylaxis, and risk of SSI. This was based on no difference in SSI (deep or superficial) in 1 large retrospective OBS in primary unilateral TKA at 3 months of follow-up (low risk of bias).287 History of anticoagulation prophylaxis for cardiac (arrhythmia or prosthetic valve) or thromboembolic event was not associated with increased risk of SSI or gastrointestinal bleed in patients on 6 weeks of postoperative warfarin VTE prophylaxis. INR levels (target INR: 1.6–2.2) were monitored and medication adjusted twice weekly. Standardized postoperative protocols in both groups included continuous passive motion, physical therapy, weight bearing, and similar pain and nausea medications.

Q17A.7. Warfarin vs. ASA ± mechanical prophylaxis Low-quality evidence suggested no difference between perioperative oral warfarin and ASA (with or without mechanical VTE prophylaxis), and risk of SSI. This was based on no difference in SSI in 2 large retrospective studies at low risk of bias.28,286 In 1 large single institution study, logistic regression analysis suggested that in THA and TKA, warfarin (target INR=2) started on the day of surgery was not associated with an increased risk of SSI or longer time until wound was dry, as compared with ASA 325 mg with pneumatic compression devices started on the morning after surgery.286 Duration of VTE prophylaxis and follow-up period were not reported. Analysis was limited to patients with a closed suction drain and normal coagulation profile. A second, large study using administrative data collected from 307 facilities over a 2-year period, suggested no difference in SSI in primary TKAs.28 Target INR was not reported. Pneumatic compression devices were used on the day of surgery or on the first postoperative day in 55% of patients on warfarin and 38% of patients on ASA. SSIs were detected on admission or readmission to the hospital within 30 days of the index procedure using ICD-9-CM wound infection codes. Authors indicated that subtherapeutic dosing or inappropriate timing may have impacted results.

Q17A.8. Higher vs. lower INR Very low-quality evidence suggested no difference between higher and lower oral warfarin INRs and risk of SSI. This was based on no difference in PJI in a small (N=154) 1:2 case control study in primary and revision THA and TKAs (low risk of bias).285 Low dose © 2017 American Medical Association. All rights reserved. 37

Downloaded From: https://jamanetwork.com/ on 09/30/2021 warfarin (target INR=1.5) was administered on the day of surgery and continued for 6 weeks. Thirteen patients on anticoagulation therapy preoperatively for a chronic condition were heparinized postoperatively until fully anticoagulated on warfarin with a higher target INR=2–3. All of these patients were in the infected cohort. The INR was also significantly higher in patients with wound-related problems who later developed infection. In addition, infected patients and those with wound complications were more likely to have INR > 1.5 at the time of hospital discharge. Infected patients also had a significantly higher incidence of wound hematomas. On multivariate logistic regression analysis, wound hematomas and persistent wound drainage were significant risk factors for PJI. Nine (69%) of the heparinized patients developed wound complications, including: hematomas, persistent wound drainage, or delayed wound healing.

Q17B. What is the optimal timing and duration of perioperative VTE prophylaxis that also reduces the risk of SSI? The available data examined VTE prophylaxis started preoperatively as compared with postoperatively in patients receiving injectable LMWHs (enoxaparin, bemiparin, or fraxiparin) or fondaparinux.

For this comparison, PJI was the critical outcome in decision-making. The evidence for this question consists of 1 OBS in TKA, at low risk of bias.284 The search did not identify data that evaluated optimal timing in THA or in patients taking oral agents. The search did not identify data that evaluated optimal duration of perioperative anticoagulation prophylaxis and its impact on SSI. The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q17 and Evidence Table Q17A-B.

Very low-quality evidence suggested that close perioperative administration of injectable LMWHs or fondaparinux VTE prophylaxis agents did not increase the risk of PJI. This was based on no difference in PJI at 6 months of follow-up, in a small, nested, multicenter, case control study in TKAs.284

Other guidelines Clinical practice guidelines on prevention of VTE in patients undergoing THA, TKA, or hip fracture procedures provide recommendations on choice, timing, and duration of VTE prophylaxis.292,293

Q17C. How safe and effective is modifying the dose of perioperative VTE prophylaxis agent to reduce the risk of SSI? The search did not identify data that evaluated the safety and effectiveness of modifying the dose of perioperative VTE prophylaxis agent and its impact on the risk of SSI.

Q17. Recommendation 17. Available evidence suggests uncertain tradeoffs between the benefits and harms of venous thromboembolism prophylaxis on the incidence of SSI in prosthetic joint arthroplasty. Other organizations have made recommendations based on the existing evidence and these references can be found in the Other guidelines section of the narrative summary for this question. (No recommendation/unresolved issue)28,279-288,290,291 (Guideline Question 17)

4.2E. ORTHOPAEDIC SURGICAL SPACE SUIT Q18. How safe and effective are orthopaedic surgical space suits in reducing the risk of SSI in prosthetic joint arthroplasty patients, and which healthcare personnel should wear them? The available data evaluated the use of a space suit as compared with no space suit.

For this comparison, deep SSI requiring reoperation, deep SSI requiring revision, and deep SSI were the critical outcomes in decision- making. Superficial SSI outcome was also evaluated. The evidence for this question consists of 3 OBS at low risk of bias.294-296 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q18 and Evidence Table Q18.

Very-low quality evidence suggested no benefit to using an orthopaedic space suit to reduce the risk of SSI. This was based on no difference in deep SSI requiring reoperation,295 deep SSI requiring revision surgery,294 or deep or superficial SSI296 in 3 OBS. The number of events for each of these studies was low. The largest national joint registry study with multiple subgroup analyses suggested that use of a space suit was associated with an increased number of deep SSIs requiring revision surgery within 6 months of THA or TKA, but this evidence was limited in size.294 Results did not differ based on the presence or absence of laminar flow. A large multicenter study using administrative data from patients undergoing TKA suggested no difference in deep SSIs requiring reoperation within 90 days.295 Reoperations included incision and drainage and implant removal. The definition of deep SSI in this study may have included PJI. Space suit and laminar flow use varied between groups. A third small study in THA and hip hemiarthroplasties reported only 1 deep SSI in the space suit group and 1 superficial SSI in each group at 24 months of follow-up.296 High-efficiency particulate air (HEPA)/mixed turbulent filtration was used in both groups. © 2017 American Medical Association. All rights reserved. 38

Downloaded From: https://jamanetwork.com/ on 09/30/2021 The search did not identify data that quantified potential complications associated with the use of space suits. In 1 large national joint registry study (N=88,311), comments by surgeons completing a questionnaire (n=35) included “limited spatial awareness and ease of contamination due to an apparent false sense of security” with the use of a space suit.294 The efficacy of the space suit as personal protective equipment was not evaluated.

Also, the search did not identify data that evaluated the association between specific health care personnel wearing a space suit and SSI. One retrospective controlled study included a surgeon questionnaire reporting that the surgeon, assistant, and scrub nurse were the team members wearing a full space suit.294 One prospective controlled study reported those same team members wearing the space suit in the intervention group.296

Q18. Recommendation 18. Available evidence suggests uncertain tradeoffs between the benefits and harms of orthopaedic surgical space suits or the health care personnel who should wear them for the prevention of SSI in prosthetic joint arthroplasty. (No recommendation/unresolved issue) 294-296 (Guideline Question 18)

4.2F. POSTOPERATIVE AMP DURATION IN PROSTHETIC JOINT ARTHROPLASTY WITH THE USE OF A DRAIN Q19. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty in the presence of a drain? The search did not identify data that directly evaluated optimal postoperative AMP duration in the presence of a drain and its impact on the risk of SSI in prosthetic joint arthroplasty patients. However, multiple procedures examined in the Core Section, Q1.E: Postoperative AMP duration that included use of a drain (including prosthetic joint arthroplasty procedures) showed no benefit of continuing AMP after closing the incision in the operating room. Therefore, the broader recommendation for postoperative AMP duration should be applied to prosthetic joint arthroplasty procedures irrespective of drain use.

Q19. Recommendation 19. In prosthetic joint arthroplasty, Recommendation 1E applies: In clean and clean-contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain. (Category IA – - strong recommendation; high- quality evidence) 96-140 (Guideline Question 19)

4.2G. BIOFILM Q20. What are the most effective strategies to reduce the risk of biofilm formation and SSI in prosthetic joint arthroplasty patients? To answer this question 4 subquestions were asked:

A) How effective are cement modifications (i.e., antimicrobial and nanoparticle loading)? B) How effective are prosthesis modifications (i.e., antimicrobial coating, galvanic couples, “printing” technologies, and nanotechnology)? C) How effective are vaccines? D) How effective are other biofilm control agents (e.g., biofilm dispersants, quorum-sensing inhibitors, novel antimicrobial agents)?

Q20A. How effective are cement modifications (i.e., antimicrobial and nanoparticle loading)? The search did not identify data that evaluated the safety and effectiveness of cement modifications in THA and the risk of SSI. In vitro studies and studies that evaluated antimicrobial loaded cement in the absence of perioperative parenteral AMP were excluded from the analysis. The available data examined cefuroxime loaded cement vs. plain cement in primary TKA patient receiving perioperative AMP. For this comparison, deep SSI was the critical outcome in decision-making. In these studies, deep SSI likely refers to or includes PJI. The evidence for this question consists of 2 RCTs.297,298 The findings of the evidence review and the grades for all important outcomes are shown in eAppendix 2 of the Supplement: GRADE Table Q20 and Evidence Table Q20.

Moderate-quality evidence suggested a benefit of cefuroxime loaded cement. This was based on a reduced risk of deep SSI in a meta- analysis (N=428) of 2 RCTs: 1 large study in non-diabetic297 patients and 1 small study (N=78) in diabetic 298 patients. Both studies were at moderate risk of bias. There were no deep SSIs in the cefuroxime loaded cement groups at an average 49 months of follow-up. A single surgeon performed all TKAs in an operating room without ultraviolet lights, laminar flow, or use of an orthopaedic surgical space suit. Only the tibial and patellar components were cemented. Cefuroxime 2 g in 40 g polymethyl methacrylate cement was used © 2017 American Medical Association. All rights reserved. 39

Downloaded From: https://jamanetwork.com/ on 09/30/2021 in the study groups. AMP included parenteral cefazolin and gentamicin preoperatively then every 6 and 12 hours, respectively, postoperatively for 36 hours followed by cefazolin orally for 7 more days. Data on organisms isolated from the SSIs and antimicrobial resistance were not reported.

Q20B. How effective are prosthesis surface modifications (i.e., antimicrobial coating, galvanic couples, “printing” technologies, and nanotechnology)? The search did not identify in vivo studies that evaluated the safety and effectiveness of prosthesis modifications and their impact on biofilm formation and the risk of SSI.

Q20C. How effective are vaccines? The search did not identify in vivo studies that evaluated the safety and effectiveness of vaccines and their impact on biofilm formation and the risk of SSI.

Q20D. How effective are other biofilm control agents (e.g., biofilm dispersants, quorum-sensing inhibitors, novel antimicrobial agents)? The search did not identify in vivo studies that evaluated the safety and effectiveness of other biofilm control agents and their impact on biofilm formation and the risk of SSI

Q20. Recommendations 20A. Available evidence suggests uncertain tradeoffs between the benefits and harms regarding cement modifications and the prevention of biofilm formation or SSI in prosthetic joint arthroplasty. (No recommendation/unresolved issue) 297,298 (Guideline Question 20A)

20B. The search did not identify studies evaluating prosthesis modifications for the prevention of biofilm formation or SSI in prosthetic joint arthroplasty. (No recommendation/unresolved issue) (Guideline Question 20B)

20C. The search did not identify studies evaluating vaccines for the prevention of biofilm formation or SSI in prosthetic joint arthroplasty. (No recommendation/unresolved issue) (Guideline Question 20C)

20D. The search did not identify studies evaluating biofilm control agents such as biofilm dispersants, quorum- sensing inhibitors, or novel antimicrobial agents for the prevention of biofilm formation or SSI in prosthetic joint arthroplasty. (No recommendation/unresolved issue) (Guideline Question 20D)

Downloaded From: https://jamanetwork.com/ on 09/30/2021 5. RE-EMPHASIS OF SELECT 1999 CDC AND HICPAC RECOMMENDATIONS FOR PREVENTION OF SURGICAL SITE INFECTIONS

The Centers for Disease control and Prevention (CDC), Guideline for Prevention of Surgical Site Infection 2017 addresses new and updated strategies for the prevention of Surgical Site Infections (SSIs) in healthcare settings. The 2017 Guideline focuses on a few select areas, and not all of the recommendations that were made in 1999 were reviewed as a part of the guideline development process. However, CDC and the Healthcare Infection Control Practices Advisory Committee (HICPAC) recognized that many of the recommendations remain important and have become infection control standards for surgical infection prevention. In 2014, HICPAC reviewed the 1999 strong recommendations for which the evidence was not re-assessed as part of the development of the 2017 Guideline. This was to reaffirm them as accepted practices (e.g., standard of care). At the July 2014 HICPAC meeting, HICPAC reviewed and recommended to CDC that many of the 1999 strong recommendations should be re-emphasized as accepted practice for preventing surgical site infections.299 CDC and HICPAC recommend that facilities should continue to follow the recommendations outlined below.

5.1. Recommendations

1. PREPARATION OF THE PATIENT a. Whenever possible, identify and treat all infections remote to the surgical site before elective operations and postpone elective operations on patients with remote site infections until the infection has resolved. b. Do not remove hair preoperatively unless the hair at or around the incision site will interfere with the operation. If hair removal is necessary, remove immediately before the operation, with clippers. c. Encourage tobacco cessation for a minimum of at least 30 days before elective operations. d. Ensure skin around the incision site is free of gross contamination before performing antiseptic skin preparation.

2. HAND/FOREARM ANTISEPSIS FOR SURGICAL TEAM a. Perform preoperative surgical hand/forearm antisepsis according to manufacturer’s recommendations for the product being used. b. See 2002 Guidelines for Hand Hygiene in Healthcare Settings for additional surgical hand antisepsis recommendations.300

3. OPERATING ROOM VENTILATION a. Maintain positive pressure ventilation in the operating room and adjoining spaces. Maintain the number of air exchanges, airflow patterns, temperature, humidity, location of vents, and use of filters in accordance with recommendations from the most recent version of the Facilities Guidelines Institute – Guidelines for Design and Construction of Hospitals and Outpatient Facilities (current version – 2014).301

4. CLEANING AND DISINFECTION OF ENVIRONMENTAL SURFACES a. Do not perform special cleaning or closing of operating rooms after contaminated or dirty operations.

5. REPROCESSING OF SURGICAL INSTRUMENTS a. Sterilize all surgical instruments according to published guidelines and manufacturer’s recommendations. b. Immediate-use steam sterilization should never be used for reasons of convenience, as an alternative to purchasing additional instrument sets, or to save time. This practice should be reserved only for patient care items that will be used immediately in emergency situations when no other options are available. c. Refer to CDC and HICPAC Guideline for Disinfection and Sterilization in Healthcare Facilities, 2008 for additional recommendations.68

6. SURGICAL ATTIRE AND DRAPES a. Wear a surgical mask that fully covers the mouth and nose when entering the operating room if an operation is about to begin or already under way, or if sterile instruments are exposed. Wear the mask throughout the operation. b. Wear a new, disposable, or hospital laundered head covering for each case, when entering the operating room. Ensure it fully covers all hair on the head and all facial hair not covered by the surgical mask. c. Wear sterile gloves if serving as a member of the scrubbed surgical team. Put on sterile gloves after donning a sterile gown. d. Use surgical gowns and drapes that are effective barriers when wet (i.e., materials that resist liquid penetration). e. Change scrub suits that are visibly soiled, contaminated, and/or penetrated by blood or other potentially infectious materials.

Downloaded From: https://jamanetwork.com/ on 09/30/2021 7. STERILE AND SURGICAL TECHNIQUE a. Adhere to principles of sterile technique when performing all invasive surgical procedures. b. If drainage is necessary, use a closed suction drain. Place a drain through a separate incision distant from the operative incision. Remove the drain as soon as possible.

8. POST-OP INCISION CARE a. Protect primarily closed incisions with a sterile dressing for 24-48 hours postoperatively.

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6. REFERENCES

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274. Kaspar S, de Beer JD. Infection in hip arthroplasty after previous injection of steroid. J Bone Joint Surg Br. 2005;87B(4):454-457. 275. McIntosh AL, Hanssen AD, Wenger DE, Osmon DR. Recent intraarticular steroid injection may increase infection rates in primary THA. Clin Orthop Relat Res. 2006;451:50-54. 276. Sreekumar R, Venkiteswaran R, Raut V. Infection in primary hip arthroplasty after previous steroid infiltration. Int Orthop. 2007;31(1):125-128. 277. Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res. 2012;64(4):465-474. 278. Centers for Disease Control and Prevention, Siegel JD, Rhinehart E, Jackson M, Chiarello L, Healthcare Infection Control Practices Advisory Committee. 2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007; Available at: http://www.cdc.gov/hicpac/2007IP/2007isolationPrecautions.html. Accessed January 25, 2017. 279. Turpie AGG, Bauer KA, Eriksson BL, Lassen MR, Steering Committees of the Pentasaccharide Orthopedic Prophylaxis Studies. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery - A meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162(16):1833- 1840. 280. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775. 281. Turpie AG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373(9676):1673-1680. 282. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39. 283. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786. 284. Asensio A, Antolin FJ, Sanchez-Garcia JM, et al. Timing of DVT prophylaxis and risk of postoperative knee prosthesis infection. Orthopedics. 2010;33(11):800. 285. Parvizi J, Ghanem E, Joshi A, Sharkey PF, Hozack WJ, Rothman RH. Does "excessive" anticoagulation predispose to periprosthetic infection? J Arthroplasty. 2007;22(6):24-28. 286. Patel VP, Walsh M, Sehgal B, Preston C, Dewal H, Di Cesare PE. Factors associated with prolonged wound drainage after primary total hip and knee arthroplasty. J Bone Joint Surg Am. 2007;89A(1):33-38. 287. Sachs RA, Smith JH, Kuney M, Paxton L. Does anticoagulation do more harm than good? A comparison of patients treated without prophylaxis and patients treated with low-dose warfarin after total knee arthroplasty. J Arthroplasty. 2003;18(4):389-395. 288. Bauer KA, Eriksson BI, Lassen MR, Turpie AG, Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med. 2001;345(18):1305-1310. 289. Eriksson BI, Bauer KA, Lassen MR, Turpie AG, Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip- fracture surgery. N Engl J Med. 2001;345(18):1298-1304. 290. Lassen MR, Bauer KA, Eriksson BI, Turpie AG, European Pentasaccharide Elective Surgery Study Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet. 2002;359(9319):1715-1720. 291. Turpie AG, Bauer KA, Eriksson BI, Lassen MR, Pentathalon Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip- replacement surgery: a randomised double-blind trial. Lancet. 2002;359(9319):1721-1726. 292. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-325S. © 2017 American Medical Association. All rights reserved. 56

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293. Jacobs JJ, Mont MA, Bozic KJ, et al. American Academy of Orthopaedic Surgeons clinical practice guideline on: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Bone Joint Surg Am. 2012;94(8):746-747. 294. Hooper GJ, Rothwell AG, Frampton C, Wyatt MC. Does the use of laminar flow and space suits reduce early deep infection after total hip and knee replacement? The ten-year results of the New Zealand Joint Registry. J Bone Joint Surg Br. 2011;93B(1):85-90. 295. Miner AL, Losina E, Katz JN, Fossel AH, Platt R. Deep infection after total knee replacement: impact of laminar airflow systems and body exhaust suits in the modern operating room. Infect Control Hosp Epidemiol. 2007;28(2):222-226. 296. Pasquarella C, Pitzurra O, Herren T, Poletti L, Savino A. Lack of influence of body exhaust gowns on aerobic bacterial surface counts in a mixed-ventilation operating theatre. A study of 62 hip arthroplasties. J Hosp Infect. 2003;54(1):2-9. 297. Chiu FY, Chen CM, Lin CF, Lo WH. Cefuroxime-impregnated cement in primary total knee arthroplasty: a prospective, randomized study of three hundred and forty knees. J Bone Joint Surg Am. 2002;84-A(5):759-762. 298. Chiu FY, Lin CF, Chen CM, Lo WH, Chaung TY. Cefuroxime-impregnated cement at primary total knee arthroplasty in diabetes mellitus. A prospective, randomised study. J Bone Joint Surg Br. 2001;83(5):691-695. 299. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention. Meeting Minutes: Healthcare Infection Control Practices Advisory Committee (HICPAC), July 2014. 2014; http://www.cdc.gov/hicpac/pdf/mm/HICPAC_July2014_Summary_With_Liaison_ReportsFINAL.pdf. Accessed January 25, 2017. 300. Centers for Disease Control and Prevention, Healthcare Infection Control Practices Advisory Committee. Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. MMWR. 2002;51(RR-16):1- 56. 301. Facilities Guidelines Institute, American Society for Healthcare Engineering. Guidelines for design and construction of hospitals and outpatient facilities. Chicago, IL: American Hospital Association; 2014.

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eAppendix 2. Centers for Disease Control and Prevention, Guideline for the Prevention of Surgical Site Infection 2017: Supplemental Tables

TABLE OF CONTENTS 1. GUIDELINE SEARCH STRATEGIES ...... 61 1.1. Core Section Search Strategies ...... 62 1.1A. CORE SECTION GENERAL SEARCHES ...... 62 1.2. Prosthetic Joint Arthroplasty Section Search Strategies ...... 64 1.2A. PROSTHETIC JOINT ARTHROPLASTY SECTION GENERAL SEARCHES ...... 64 1.2B. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCHES: TRANSFUSION ...... 66 1.2C. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCHES: IMMUNOSUPPRESSIVE THERAPY ...... 71 1.2D. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCHES: ANTICOAGULATION ...... 76 1.2E. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCHES: ORTHOPAEDIC SPACE SUIT ...... 81 1.2F. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCH: ANTIMICROBIAL PROPHYLAXIS WITH A DRAIN ...... 87 1.2G. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCH: BIOFILM ...... 92 2. EVIDENCE, GRADE and RISK OF BIAS ASSESSMENT TABLES ...... 96 2.1. Core Section GRADE, Evidence, and Risk of Bias Assessment Tables ...... 96 2.1A. Q1 PARENTERAL ANTIMICROBIAL PROPHYLAXIS (AMP) ...... 96 2.1B. Q2 NON-PARENTERAL AMP ...... 226 2.1C. Q3 GLYCEMIC CONTROL ...... 310 2.1D. Q4-5 NORMOTHERMIA ...... 315 2.1E. Q6-7 OXYGENATION ...... 328 2.1F. Q8-10 ANTISEPTIC PROPHYLAXIS ...... 371 2.2. Prosthetic Joint Arthroplasty Section GRADE, Evidence, and Risk of Bias Assessment Tables ...... 446 2.2A. Q11 BLOOD TRANSFUSION ...... 446 2.2B. Q12-16 SYSTEMIC IMMUNOSUPPRESSIVE THERAPY ...... 496 2.2C. Q17 ANTICOAGULATION ...... 531 2.2D. Q18 ORTHOPAEDIC SPACE SUIT ...... 566 2.2E. Q20 BIOFILM ...... 578 3. EVALUATION OF THE RISK OF BIAS OF AN INDIVIDUAL STUDY ...... 586 3.1. Instructions ...... 586 3.2. Checklist for Systematic Reviews ...... 586 © 2017 American Medical Association. All rights reserved. 58

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3.3. Checklist for Randomized Controlled Trials...... 586 3.4. Checklist for Observational Studies ...... 586 3.5. Translating Risk of Bias into GRADE Tables ...... 587 4. EVIDENCE TABLE EXTRACTION TEMPLATES ...... 588 5. STUDY TYPE DETERMINATION ...... 590 6. REFERENCES ...... 591 LIST OF FIGURES eFIGURE A. STUDY TYPE DETERMINATION ALGORITHM (Adapted from: Hartling et. al. 2010) ...... 590 LIST OF TABLES eTABLE 1. MEDLINE Search: Core Section ...... 62 eTABLE 2. EMBASE Search: Core Section ...... 62 eTABLE 3. MEDLINE Search: Ortho Section ...... 64 eTABLE 4. EMBASE Search: Ortho Section ...... 65 eTABLE 5. MEDLINE Targeted Search: Transfusion ...... 66 eTABLE 6. EMBASE Targeted Search: Transfusion ...... 68 eTABLE 7. Cochrane Database of Systematic Reviews Targeted Search: Transfusion ...... 70 eTABLE 8. MEDLINE Targeted Search: Immunosuppressive Therapy ...... 71 eTABLE 9. EMBASE Targeted Search: Immunosuppressive Therapy ...... 74 eTABLE 10. Cochrane Database of Systematic Reviews Targeted Search: Immunosuppressive Therapy...... 75 eTABLE 11. MEDLINE Targeted Search: Anticoagulation ...... 76 eTABLE 12. EMBASE Targeted Search: Anticoagulation ...... 78 eTABLE 13. Cochrane Database of Systematic Reviews Targeted Search: Anticoagulation ...... 80 eTABLE 14. MEDLINE Targeted Search: Orthopaedic Space Suit ...... 81 eTABLE 15. EMBASE Targeted Search: Orthopaedic Space Suit ...... 83 eTABLE 16. Cochrane Database of Systematic Reviews Targeted Search: Orthopaedic Space Suit ...... 85 eTABLE 17. CINAHL Targeted Search: Orthopaedic Space Suit ...... 85 eTABLE 18. MEDLINE Targeted Search: Antimicrobial Prophylaxis with a Drain ...... 87 eTABLE 19. EMBASE Targeted Search: Antimicrobial Prophylaxis with a Drain ...... 89 eTABLE 20. Cochrane Database of Systematic Reviews Targeted Search: Antimicrobial Prophylaxis with a Drain ...... 91 eTABLE 21. MEDLINE Targeted Search: Biofilm ...... 92 © 2017 American Medical Association. All rights reserved. 59

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eTABLE 22. EMBASE Targeted Search: Biofilm ...... 94 eTABLE 23. Cochrane Database of Systematic Reviews Targeted Search: Biofilm ...... 95 eTABLE 24. GRADE Table for Q1 Parenteral AMP ...... 96 eTABLE 25. Evidence Table for Q1A. What is the optimal timing of preoperative AMP in surgeries involving tourniquet inflation? ...... 119 eTABLE 26. Evidence Table for Q1B. What is the optimal timing of AMP in cesarean section: prior to skin incision or at cord clamping? ...... 123 eTABLE 27. Evidence Table for Q1D. How safe and effective is intraoperative redosing of AMP? ...... 142 eTABLE 28. Evidence Table for Q1E. How safe and effective is postoperative AMP and what is the optimal duration? ...... 144 eTABLE 29. Risk of Bias Assessments of Randomized Controlled Trials for Q1 Parenteral AMP ...... 223 eTABLE 30. GRADE Table for Q2 Non-Parenteral AMP ...... 226 eTABLE 31. Evidence Table for Q2A. How safe and effective is antimicrobial irrigation? ...... 242 eTABLE 32. Evidence Table for Q2B. How safe and effective are antimicrobial agents applied to the surgical incision? ...... 246 eTABLE 33. Evidence Table for Q2C. How safe and effective are antimicrobial-coated sutures; when and how should they be used? ...... 267 eTABLE 34. Evidence Table for Q2D. How safe and effective are antimicrobial dressings applied to surgical incisions following primary closure in the operating room? ...... 304 eTABLE 35. Risk of Bias Assessments of Randomized Controlled Trials for Q2 Non-Parenteral AMP ...... 308 eTABLE 36. GRADE Table for Q3 Glycemic Control ...... 310 eTABLE 37. Evidence Table for Q3. How do perioperative blood glucose and hemoglobin A1C levels impact the risk of SSI and what are their optimal perioperative target levels in diabetic and non-diabetic patients? ...... 312 eTABLE 38. Risk of Bias Assessments of Randomized Controlled Trials for Q3 Glycemic Control ...... 314 eTABLE 39. GRADE Table for Q4-5 Normothermia ...... 315 eTABLE 40. Evidence Table for Q4. How safe and effective is the maintenance of perioperative normothermia in reducing the risk of SSI? ...... 318 eTABLE 41. Risk of Bias Assessments of Randomized Controlled Trials for Q4-5 Normothermia ...... 327 eTABLE 42. GRADE Table for Q6-7 Oxygenation ...... 328

eTABLE 43. Evidence Table for Q6. In patients with normal pulmonary function, how safe and effective is the perioperative use of increased fraction of inspired oxygen (FiO2) in reducing the risk of SSI? ...... 337 eTABLE 44. Risk of Bias Assessments of Randomized Controlled Trials for Q6-7 Oxygenation ...... 370 eTABLE 45. GRADE Table for Q8-10 Antiseptic Prophylaxis ...... 371 eTABLE 46. Evidence Table for Q8A. How safe and effective is preoperative antiseptic bathing or showering? ...... 381 eTABLE 47. Evidence Table for Q8B. How safe and effective are antiseptic skin preparation agents individually and in combination? ...... 384 eTABLE 48. Evidence Table for Q8C. How safe and effective is the application of a microbial sealant immediately following skin preparation? ...... 412 eTABLE 49. Evidence Table for Q8D. How safe and effective are plastic adhesive drapes? ...... 424 © 2017 American Medical Association. All rights reserved. 60

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eTABLE 50. Evidence Table for Q9. How safe and effective is antiseptic irrigation prior to closing the surgical incision? ...... 430 eTABLE 51. Evidence Table for Q10. How safe and effective is repeat application of an antiseptic skin preparation agent to the surgical site immediately prior to closing the surgical incision? ...... 439 eTABLE 52. Risk of Bias Assessments of Systematic Reviews for Q8-10 Antiseptic Prophylaxis ...... 443 eTABLE 53. Risk of Bias Assessments of Randomized Controlled Trials for Q8-10 Antiseptic Prophylaxis ...... 443 eTABLE 54. GRADE Table for Q11 Blood Transfusion ...... 446 eTABLE 55. Evidence Table for Q11. How do perioperative blood transfusions impact the risk of SSI in prosthetic joint arthroplasty patients? ...... 458 eTABLE 56. Risk of Bias Assessments of Randomized Controlled Trials for Q11 Blood Transfusion ...... 495 eTABLE 57. Risk of Bias Assessments of Other Controlled Studies for Q11 Blood Transfusion ...... 495 eTABLE 58. GRADE Table for Q12-16 Systemic Immunosuppressive Therapy ...... 496 eTABLE 59. Evidence Table for Q12-13 Systemic Immunosuppressive Therapy ...... 505 eTABLE 60.Evidence Table for Q15. How does preoperative intra-articular corticosteroid injection impact the risk of SSI in prosthetic joint arthroplasty patients?...... 519 eTABLE 61. Risk of Bias Assessments of Other Controlled Studies for Q12-16 Systemic Immunosuppressive Therapy ...... 530 eTABLE 62. GRADE Table for Q17 Anticoagulation ...... 531 eTABLE 63. Evidence Table for Q17. What are the most effective strategies for managing perioperative venous thromboembolism (VTE) prophylaxis to reduce the risk of SSI? ...... 536 eTABLE 64. Risk of Bias Assessment of Systematic Reviews for Q17 Anticoagulation ...... 564 eTABLE 65. Risk of Bias Assessments of Randomized Controlled Trials for Q17 Anticoagulation ...... 564 eTABLE 66. Risk of Bias Assessments of Other Controlled Studies for Q17 Anticoagulation ...... 564 eTABLE 67. GRADE Table for Q18 Orthopaedic Space Suit ...... 566 eTABLE 68. Evidence Table for Q18. How safe and effective are orthopaedic space suits in reducing the risk of SSI in prosthetic joint arthroplasty patients and then which healthcare personnel should wear them? ...... 568 eTABLE 69. Risk of Bias Assessments of Other Controlled Studies for Q18 Orthopaedic Space Suit ...... 577 eTABLE 70. GRADE Table for Q20 Biofilm ...... 578 eTABLE 71. Evidence Table for Q20A. How effective are cement modifications (i.e., antimicrobial and nanoparticle loading)? ...... 580 eTABLE 72. Risk of Bias Assessments of Randomized Controlled Trials for Q20 Biofilm...... 585 eTABLE 73. Systematic Review (SR) Extraction Template ...... 588 eTABLE 74. Randomized Controlled Trial (RCT) Extraction Template ...... 588 eTABLE 75. Other Observational Studies (OBS) Extraction Template ...... 589

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1.1. Core Section Search Strategies

1.1A. CORE SECTION GENERAL SEARCHES eTABLE 1. MEDLINE Search: Core Section # Search History Results 1 exp Surgical Wound Infection/ 25,893 2 "surgical site infection*".af. 2,130 3 1 or 2 26,382 4 limit 3 to English language 19,318 5 limit 4 to yr="1998 -Current" 8,709 6 limit 5 to guideline 19 7 limit 5 to systematic reviews 429 8 limit 5 to practice guideline 27 9 limit 5 to meta analysis 161 10 limit 5 to "reviews (maximizes specificity)" 262 11 6 or 7 or 8 or 9 or 10 469 12 limit 5 to randomized controlled trial 715 13 11 or 12 1,170

eTABLE 2. EMBASE Search: Core Section # Search History Results 1 'surgical infection'/exp or 'surgical site infection' or 'surgical wound infection' 19,658 2 limit 1 to English language 13,666 3 limit 2 to 'randomized controlled trial'/de 749 4 limit 3 [1998-2012]/py 566 5 limit 2 to [review] 1,580 6 limit 2 to ('meta analysis'/de OR 'practice guideline'/de) 639 7 'systematic review'/exp 43,081 8 5 and 7 82 © 2017 American Medical Association. All rights reserved. 62

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# Search History Results 9 6 or 8 679 10 limit 9 to [1998-2012]/py 654 11 4 or 10 1,220

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1.2. Prosthetic Joint Arthroplasty Section Search Strategies

1.2A. PROSTHETIC JOINT ARTHROPLASTY SECTION GENERAL SEARCHES eTABLE 3. MEDLINE Search: Ortho Section # Search History Results 1 (arthroplast* or replac* or replant* or joint* or implant* or reconstruct* or prosthe*).af. 1,052,637 2 exp Arthroplasty, Replacement/ or exp Arthroplasty/ 29,697 3 exp Orthopedic Procedures/ 176,717 4 exp Joints/su [Surgery] 42,769 5 1 or 2 or 3 or 4 1,135,596 6 exp Wound Infection/ 34,108 7 "surgical site infection*".af. 2,130 8 exp Prosthesis-Related Infections/ 6,283 9 exp Bone Diseases, Infectious/ 29,730 10 exp Soft Tissue Infections/ 1,876 11 exp Skin Diseases, Infectious/ 90,359 12 6 or 7 or 8 or 9 or 10 or 11 158,415 13 5 and 12 24,509 14 exp Surgical Procedures, Operative/ 2,113,349 15 (surgical* or surgery* or operati*).af. 2,629,634 16 14 or 15 3,467,669 17 (arthro* or orthop*).af. 316,829 18 16 and 17 206,698 19 12 and 18 9,513 20 13 or 19 26,888 21 limit 20 to (english language and yr="1998 - Current") 11,604 22 limit 21 to systematic reviews 262 23 limit 21 to meta analysis 50

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# Search History Results 24 limit 21 to guideline 14 25 limit 21 to practice guideline 22 26 limit 21 to "reviews (maximizes specificity)" 137 27 limit 21 to randomized controlled trial 294 28 22 or 23 or 24 or 25 or 26 or 27 595

eTABLE 4. EMBASE Search: Ortho Section # Search History Results 'wound infection'/exp or 'surgical infection'/exp or 'prosthesis infection'/exp or 'bone infection'/exp or 'soft tissue infection'/exp or 1 'skin infection'/exp or 'surgical site infection'; limit to English language, EMBASE, and [1998-2012]/py 69,175 'arthroplasty'/exp or 'arthroplasty replacement'/exp or 'orthopedic surgery'/exp or ('joint'/exp and surg*) or arthroplast* or replac* or replant* or (joint* and' surgery'/exp) or implant* or reconstruct* or prosthe* or (('surgery'/exp or surgical* or operativ* and (arthro* or 2 orthop*)) and [1998-2012]/py 856,609 3 1 and 2 14,117 4 ‘meta-analysis’/exp 57,212 5 3 and 4 121 6 limit 3 to ‘systematic review’/de 234 7 limit 3 to ‘practice guideline ‘/de 383 8 limit 3 to ‘randomized controlled trial’/de 430 9 5 or 6 or 7 or 8 1,059

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1.2B. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCHES: TRANSFUSION eTABLE 5. MEDLINE Targeted Search: Transfusion # Search History Results 1 (exp "prostheses and implants"/ or prosthe*.af. or implant*.af. or orthoped*.af. or orthopaed*.af.) and (exp joints/ or joint*.af.) 101,924 2 exp Joints/su [Surgery] 44,456 3 exp Arthroplasty, Replacement/ or exp Arthroplasty/ 32,010 4 arthroplast*.af. 42,928 5 exp "Orthopedic Procedures"/ and exp "Joints"/ 39,956 6 or/1-5 141,563 7 exp Infection/ or infection*.af. or infecting.af. or infected.af. or exp "Prosthesis-Related Infections"/ 1,533,905 8 exp Blood Transfusion/ or (blood and transfus*).af. 114,443 9 exp Blood Platelets/ or platelet*.af. or "blood product*".af. 195,879 10 8 or 9 292,467 11 exp Random Allocation/ 73,596 12 exp Randomized Controlled Trials as Topic/ or exp Randomized Controlled Trial/ 394,924 13 exp Double-Blind Method/ 113,512 14 exp Single-Blind Method/ 15,853 15 exp Clinical Trial/ 667,767 16 exp Clinical Trials as Topic/ 251,205 17 clinical trial.pt. 467,170 18 clinical trial, phase i.pt. 11,868 (clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or 19 multicenter study or clinical trial).pt. 665,448 20 or/11-19 895,443 21 (clinical adj trial$).tw. 164,609 22 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. 111,059 23 placebo$.tw. 133,778 24 randomly allocated.tw. 13,342 © 2017 American Medical Association. All rights reserved. 66

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# Search History Results 25 (allocated adj2 random$).tw. 15,627 26 exp Placebos/ 30,626 27 or/20-26 996,307 28 case report.tw. 164,158 29 letter/ 735,581 30 historical article/ 280,723 31 exp Editorial/ 291,753 32 or/28-31 1,454,788 33 27 not 32 956,341 34 exp "Sensitivity and Specificity"/ 350,527 35 (sensitivity or specificity).tw. 590,136 36 ((pre-test or pretest) adj probability).tw. 980 37 post-test probability.tw. 268 38 predictive value$.tw. 54,259 39 likelihood ratio$.tw. 6,512 40 exp "Predictive Value of Tests"/ 117,980 41 or/33-40 1,740,790 42 exp Meta-Analysis as Topic/ 11,873 43 (meta analy$ or metaanaly$).tw. or exp Meta-analysis/ 48,899 44 (systematic adj (review$1 or overview$1)).tw. 29,904 45 exp Review Literature as Topic/ 6,079 46 or/41-45 1,784,999 47 (embase or cochrane or psyclit* or psychlit* or psycinfo or psychinfo).tw. 27,796 48 (cinahl or cinhal).ab. 5,997 49 (science citation index or bids or cancerlit).ab. 2,135 50 or/46-49 1,792,516

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# Search History Results 51 (reference list$ or bibliograph$ or hand-search$ or relevant journals or manual search$).ab. 18,484 52 (selection criteria or data extraction).ab. 20,349 53 exp Review/ 1,675,847 54 52 and 53 14,038 55 50 or 51 or 54 1,800,552 56 exp Comment/ or exp Editorial/ or exp Letter/ 1,108,385 57 55 not 56 1,770,101 exp Epidemiologic studies/ or exp case control studies/ or exp cohort studies/ or Case control.tw. or (cohort adj (study or studies)).tw. or cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or 58 Longitudinal.tw. or Retrospective.tw. or Cross sectional.tw. or exp Cross-sectional studies/ 1,553,551 59 57 or 58 2,972,690 60 6 and 7 and 10 and 59 150 61 limit 60 to english language 136 62 limit 61 to yr="1998 -Current" 103

eTABLE 6. EMBASE Targeted Search: Transfusion # Search History Results ‘blood transfusion’/exp or (‘blood’/exp and (transfusion’/exp or transfused)) or ‘thrombocyte’/exp or ‘blood’/exp or platelet* or ‘blood 1 product’/exp or ‘blood products’ and [english]/lim and [embse]/lim and [1998-2012]/py 627,207 2 ‘prostheses and orthoses’/exp or prosthe$ or implant$ or orthoped$ or orthopaed$ 399,873 ‘joint’/exp or joint$ or ‘joint surgery’/exp or ‘arthroplasty’/exp or arthroplasty or arthroplasties or ‘arthroplasty replacement’ or 3 (‘orthopedic surgery’/exp and ‘joint’/exp) 603,883 4 2 and 3 69,054 5 ‘infection’/exp 2,328,600 6 infection$ or infecting or infected 2,654,665 7 ‘prosthesis related’ and infections 95 8 ‘prosthesis-related infections’/exp 2,328,600 9 5 or 6 or 7 or 8 2,660,483

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# Search History Results 10 1 and 4 and 9 353 11 ‘clinical study’/exp or ‘case control study’/exp or ‘family study’/exp or ‘longitudinal study’/exp or ‘retrospective study’/exp 5,942,135 12 ‘prospective study’/exp 189,505 13 ‘randomized controlled trial’/exp 307,692 14 12 not 13 165,671 ‘cohort analysis’/exp or (cohort and adj and (study or studies)) or (case and control and adj and (study or studies)) or (follow and up and adj and (study or studies)) or (observational and adj and (study or studies)) or (epidemiologic$ and adj and (study or 15 studies)) or (cross and sectional and adj and (study or studies)) 115,089 16 11 or 12 or 14 or 15 5,986,679 17 ‘meta analysis’/exp or (meta and adj and analy$) or metaanaly$ or (systematic and adj and (review$ or overview$)) 61,427 18 cancerlit or cochrane or ‘embase’/exp or psychlit’/exp or ‘psyclit’/ or ‘science citation index’/exp or bids or scopus 44,494 ‘reference lists’ or bibliograph$ or ‘hand search$’ or ‘manual search$’ or ‘relevant journals’ or ‘data extraction’/exp or ‘selection 19 criteria’ 28,035 20 review.pt. 4 21 ‘review’/exp 1,831,423 22 20 or 21 1,831,427 23 19 and 22 15,584 24 letter.pt. or editorial.pt. 3 25 ‘letter’/exp or ‘editorial’/exp 1,179,933 26 24 or 25 1,179,934 27 17 or 18 or 23 98,049 28 27 not 26 93,355 ‘sensitivity and specificity/exp or sensitivity or specificity or (‘pre test’ or pretest and adj and ‘probability’/exp) or ‘post-test probability’ or predictive and value$ or likelihood and ratio$ or ‘predictive value’/exp or ‘diagnostic accuracy ‘/exp and [english]/lim 29 and [embase]/lim and [1998-2012]/py 144,775 ‘clinical trial’/exp or ‘randomized controlled trial’/exp or ‘randomization’/exp or ‘single blind procedure’/exp or ‘double blind procedure’/exp or ‘crossover procedure’/exp or ‘placebo’/exp or randomi?ed and controlled and trial$ or rct$ or ‘random allocation’ or ‘randomly allocated’ or ‘allocated randomly’ or allocated and adj2 and random$ or single and blind$ or double and blind$ or 30 (treble or triple and adj and blind$) or placebo$ or ‘prospective study’/exp 541,923

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# Search History Results ‘case study’/exp or ‘case study’ or ‘case report’/exp or ‘case report’ or ‘abstract report’/exp or ‘abstract report’ or ‘letter’/exp or letter 31 and [1998-2012]/py 1,237,206 32 30 not 31 529,538 33 16 or 28 or 29 or 32 6,160,948 34 10 and 33 232

eTABLE 7. Cochrane Database of Systematic Reviews Targeted Search: Transfusion # Search History Results (transfus* or platelet* or "blood product*") and (surgery or surgical* or operat*) and (joint* or arthroplast* or prosthe* or implant*) in 1 Title, Abstract or Keywords 6

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1.2C. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCHES: IMMUNOSUPPRESSIVE THERAPY eTABLE 8. MEDLINE Targeted Search: Immunosuppressive Therapy # Search History Results 1 (exp "prostheses and implants"/ or prosthe*.af. or implant*.af. or orthoped*.af. or orthopaed*.af.) and (exp joints/ or joint*.af.) 102,099 2 exp Joints/su [Surgery] 44,522 3 exp Arthroplasty, Replacement/ or exp Arthroplasty/ 32,116 4 arthroplasty*.af. 43,040 5 exp “Orthopedic Procedures”/and exp “Joints”/ 40,017 6 or/1-5 141,821 7 exp Infection/ or infection*.af. or infecting.af. or infected.af. or exp "Prosthesis-Related Infections"/ 1,540,242 8 exp Random Allocation/ 73,745 9 exp Randomized Controlled Trials as Topic/ or exp Randomized Controlled Trial/ 397,784 10 exp Double-Blind Method/ 113,903 11 exp Single-Blind Method/ 15,934 12 exp Clinical Trial/ 670,938 13 exp Clinical Trials as Topic/ 253,167 14 clinical trial.pt. 467,996 15 clinical trial, phase i.pt. 11,949 16 (clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or 668,584 multicenter study or clinical trial).pt. 17 or/8-16 900,674 18 (clinical adj trial$).tw. 165,764 19 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. 111,446 20 placebo$.tw. 134,478 21 randomly allocated.tw. 13,417 22 (allocated adj2 random$).tw. 15,704 23 exp Placebos/ 30,699 24 or/17-23 1,002,057 © 2017 American Medical Association. All rights reserved. 71

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# Search History Results 25 case report.tw. 164,536 26 letter/ 742,239 27 historical article/ 281,301 28 exp Editorial/ 295,205 29 or/25-28 1,465,799 30 24 not 29 961,541 31 exp “Sensitivity and Specificity”/ 351,908 32 (sensitivity or specificity).tw. 592,438 33 ((pre-test or pretest) adj probability).tw. 988 34 post-test probability.tw. 272 35 predictive value$.tw. 54,458 36 likelihood ratio$.tw. 6,573 37 exp "Predictive Value of Tests"/ 118,435 38 or/30-37 1,748,938 39 exp Meta-Analysis as Topic/ 12,009 40 (meta analy$ or metaanaly$).tw. or exp Meta-analysis/ 49,740 41 (systematic adj (review$1 or overview$1)).tw. 30,487 42 exp Review Literature as Topic/ 6,208 43 or/38-42 1,793,694 44 (embase or cochrane or psyclit* or psychlit* or psycinfo or psychinfo).tw. 28,506 45 (cinahl or cinhal).ab. 6,190 46 (science citation index or bids or cancerlit).ab. 2,196 47 or/43-46 1,801,291 48 (reference list$ or bibliograph$ or hand-search$ or relevant journals or manual search$).ab. 18,852 49 (selection criteria or data extraction).ab. 20,813 50 exp Review/ 1,682,836

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# Search History Results 51 49 and 50 14,472 52 47 or 48 or 51 1,809,350 53 exp Comment/ or exp Editorial/ or exp Letter/ 1,119,204 54 52 not 53 1,778,639 55 exp Epidemiologic studies/ or exp case control studies/ or exp cohort studies/ or Case control.tw. or (cohort adj (study or studies)).tw. or cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or 1,560,697 Longitudinal.tw. or Retrospective.tw. or Cross sectional.tw. or exp Cross-sectional studies/ 56 54 or 55 2,986,243 57 exp Immunosuppressive Agents/ 229,191 58 exp Immunosuppression/ 46,654 59 "immunosuppressive therapy".af. 10,624 60 immune*.af. 408,428 61 immunolog*.af. 56 62 exp Adrenal Cortex Hormones/ 315,501 63 exp Steroids/ 657,932 64 exp methotrexate/ or exp cyclophosphamide/ 67,761 65 exp Tumor Necrosis Factor-alpha/ 83,932 66 "systemic corticosteroids".af. 2,228 67 steroid*.af. 244,914 68 “tumor necrosis factor*”.af. 116,734 69 (cyclophosphamide or cytoxan or methotrexate).af. 83,530 70 tnf.af. 90,322 71 exp Injections, Intra-articular/ or intra-articular*.af. 11,059 72 or/57-71 1,544,611 73 6 and 7 and 56 and 72 360 74 limit 73 to english language 312 75 limit 74 to yr="1998 -Current" 250 © 2017 American Medical Association. All rights reserved. 73

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eTABLE 9. EMBASE Targeted Search: Immunosuppressive Therapy # Search History Results 1 ‘prostheses and orthoses’/exp or prosthe$ or implant$ or orthoped$ or orthopaed$ 399,873 2 ‘joint’/exp or joint$ or ‘joint surgery’/exp or ‘arthroplasty’/exp or arthroplasty or arthroplasties or ‘arthroplasty replacement’ or 603,893 (‘orthopedic surgery’/exp and ‘joint’/exp) 3 1 and 2 69,054 4 ‘infection’/exp 2,328,600 5 infection$ or infecting or infected 2,654,665 6 ‘prosthesis related’ and infections 95 7 ‘prosthesis-related infections’/exp 2,328,600 8 4 or 5 or 6 or 7 2,660,483 9 ‘clinical study’/exp or ‘case control study’/exp or ‘family study’/exp or ‘longitudinal study’/exp or ‘retrospective study’/exp 5,942,135 10 ‘prospective study’/exp 188,505 11 ‘randomized controlled trial’/exp 307,692 12 10 not 11 165,671 13 ‘cohort analysis’/exp or (cohort and adj and (study or studies)) or (case and control and adj and (study or studies)) or (follow and up and adj and (study or studies)) or (observational and adj and (study or studies)) or (epidemiologic$ and adj and (study or 115,089 studies)) or (cross and sectional and adj and (study or studies)) 14 9 or 10 or 12 or 13 5,986,679 15 ‘meta analysis’/exp or (meta and adj and analy$) or metaanaly$ or (systematic and adj and (review$ or overview$)) 61,427 16 cancerlit or cochrane or ‘embase’/exp or psychlit’/exp or ‘psyclit’/ or ‘science citation index’/exp or bids or scopus 44,495 17 ‘reference lists’ or bibliograph$ or ‘hand search$’ or ‘manual search$’ or ‘relevant journals’ or ‘data extraction’/exp or ‘selection 28,035 criteria’ 18 review.pt. 4 19 ‘review’/exp 1,831,423 20 18 or 19 1,831,427 21 17 and 20 15,584 22 letter.pt. or editorial.pt. 3

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# Search History Results 23 ‘letter’/exp or ‘editorial’/exp 1,179,933 24 22 or 23 1,179,934 25 15 or 16 or 21 98,049 26 25 not 24 93,355 27 ‘sensitivity and specificity/exp or sensitivity or specificity or (‘pre test’ or pretest and adj and ‘probability’/exp) or ‘post-test probability’ or predictive and value$ or likelihood and ratio$ or ‘predictive value’/exp or ‘diagnostic accuracy ‘/exp and [english]/lim 144,775 and [embase]/lim and [1998-2012]/py 28 ‘clinical trial’/exp or ‘randomized controlled trial’/exp or ‘randomization’/exp or ‘single blind procedure’/exp or ‘double blind procedure’/exp or ‘crossover procedure’/exp or ‘placebo’/exp or randomi?ed and controlled and trial$ or rct$ or ‘random allocation’ 539,487 or ‘randomly allocated’ or ‘allocated randomly’ or allocated and adj2 and random$ or single and blind$ or double and blind$ or (treble or triple and adj and blind$) or placebo$ or ‘prospective study’/exp 29 ‘case study’/exp or ‘case study’ or ‘case report’/exp or ‘case report’ or ‘abstract report’/exp or ‘abstract report’ or ‘letter’/exp or letter 1,237,206 and [1998-2012]/py 30 28 not 29 529,538 31 14 or 26 or 27 or 30 6,160,948 32 ‘immunosuppressive agent’/exp or ‘immunosuppressive treatment’/exp or ‘immunosuppressive therapy’ or ‘immunosuppressive agents’ or immunolog* or methotrexate or cyclophosphamide or ‘adrenal cortex hormones’ or ‘systemic corticosteroids’ or ‘tumor 1,749,571 necrosis factor’ or cytoxan or tnf or ‘intra articular’ or ‘tumor necrosis factor’/exp or ‘intraarticular drug administration’/exp or ‘steroid’/exp or ‘corticosteroid’/exp or ‘methotrexate’/exp or ‘cyclophosphamide’/exp and [1998-2012]/py 33 3 and 8 and 32 697 34 31 and 33 398

eTABLE 10. Cochrane Database of Systematic Reviews Targeted Search: Immunosuppressive Therapy # Search History Results 1 "(immuno* or immunolog* or steroid* or corticosteroid* or "adrenal cortex hormone*" or methotrexate or cyclophosphamide or cytoxan or tnf or "tumor necrosis factor*" or (intra-articular" and inject*)) and (surgery or surgical* or operat*) and (joint* or 21 arthroplast* or prosthe* or implant*) in Title, Abstract or Keywords

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1.2D. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCHES: ANTICOAGULATION eTABLE 11. MEDLINE Targeted Search: Anticoagulation # Search History Results 1 (exp "prostheses and implants"/ or prosthe*.af. or implant*.af. or orthoped*.af. or orthopaed*.af.) and (exp joints/ or joint*.af.) 101,924 2 exp Joints/su [Surgery] 44,456 3 exp Arthroplasty, Replacement/ or exp Arthroplasty/ 32,010 4 arthroplasty*.af. 42,928 5 exp “Orthopedic Procedures”/and exp “Joints”/ 39,956 6 or/1-5 141,563 7 exp Infection/ or infection*.af. or infecting.af. or infected.af. or exp "Prosthesis-Related Infections"/ 1,533,905 8 exp Random Allocation/ 73,596 9 exp Randomized Controlled Trials as Topic/ or exp Randomized Controlled Trial/ 394,924 10 exp Double-Blind Method/ 113,512 11 exp Single-Blind Method/ 15,853 12 exp Clinical Trial/ 667,767 13 exp Clinical Trials as Topic/ 251,205 14 clinical trial.pt. 467,170 15 clinical trial, phase i.pt. 11,868 (clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or 16 multicenter study or clinical trial).pt. 665,448 17 or/8-16 895,443 18 (clinical adj trial$).tw. 164,609 19 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. 111,059 20 placebo$.tw. 133,778 21 randomly allocated.tw. 13,342 22 (allocated adj2 random$).tw. 15,627 23 exp Placebos/ 30,626 24 or/17-23 996,307 © 2017 American Medical Association. All rights reserved. 76

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# Search History Results 25 case report.tw. 164,158 26 letter/ 735,581 27 historical article/ 280,723 28 exp Editorial/ 291,753 29 or/25-28 1,454,788 30 24 not 29 956,341 31 exp “Sensitivity and Specificity”/ 350,527 32 (sensitivity or specificity).tw. 590,136 33 ((pre-test or pretest) adj probability).tw. 980 34 post-test probability.tw. 268 35 predictive value$.tw. 54,259 36 likelihood ratio$.tw. 6,512 37 exp "Predictive Value of Tests"/ 117,980 38 or/30-37 1,740,790 39 exp Meta-Analysis as Topic/ 11,873 40 (meta analy$ or metaanaly$).tw. or exp Meta-analysis/ 48,899 41 (systematic adj (review$1 or overview$1)).tw. 29,904 42 exp Review Literature as Topic/ 6,079 43 or/38-42 1,784,999 44 (embase or cochrane or psyclit* or psychlit* or psycinfo or psychinfo).tw. 27,796 45 (cinahl or cinhal).ab. 5,997 46 (science citation index or bids or cancerlit).ab. 2,135 47 or/43-46 1,792,516 48 (reference list$ or bibliograph$ or hand-search$ or relevant journals or manual search$).ab. 18,484 49 (selection criteria or data extraction).ab. 20,349 50 exp Review/ 1,675,847

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# Search History Results 51 49 and 50 14,038 52 47 or 48 or 51 1,800,552 53 exp Comment/ or exp Editorial/ or exp Letter/ 1,108,385 54 52 not 53 1,770,101 exp Epidemiologic studies/ or exp case control studies/ or exp cohort studies/ or Case control.tw. or (cohort adj (study or studies)).tw. or cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or 55 Longitudinal.tw. or Retrospective.tw. or Cross sectional.tw. or exp Cross-sectional studies/ 1,553,551 56 54 or 55 2,972,690 57 exp Heparin/ 53,476 58 exp warfarin/ 12,695 59 exp aspirin/ 35,444 60 exp Anticoagulants/ or anticoagul*.af. 191,442 61 "low-dose unfractionated".af. 111 62 (clopidogrel or plavix).af. 6,385 63 (warfarin* or aspirin* or heparin*).af. 136,516 64 exp Platelet Aggregation Inhibitors/ 84,124 65 anti-platelet*.af. 2,453 66 or/57-65 299,002 67 6 and 7 and 56 and 66 52 68 limit 67 to english language 45 69 limit 68 to yr-“1998-Current” 28

eTABLE 12. EMBASE Targeted Search: Anticoagulation # Search History Results 1 ‘infection’/exp 2,328,600 2 Infection$ or infecting or infected 2,654,665 3 ‘prosthesis related’ and infections 95

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# Search History Results 4 ‘prosthesis-related infections’/exp 2,328,600 5 1 or 2 or 3 or 4 2,660,483 6 ‘prostheses and orthoses’/exp or prosthe$ or implant$ or orthoped$ or orthopaed$ 399,873 ‘joint’/exp or joint$ or ‘joint surgery’/exp or ‘arthroplasty’/exp or arthroplasty or arthroplasties or ‘arthroplasty replacement’ or 7 (‘orthopedic surgery’/exp and ‘joint’/exp) 603,883 8 6 and 7 69,054 ‘heparin’/exp or ‘warfarin’/exp or ‘acetylsalicylic acid’/exp or ‘anticoagulant agent’/exp or ‘antithrombotic agent’/exp or anticoagul* 9 or ‘low-dose unfractionated’ or clopidogrel or plavix or warfarin* or heparin* or aspirin or ‘anti platelet’ 481,497 10 5 and 8 and 9 374 11 ‘meta analysis’/exp or (meta and adj and analy$) or metaanaly$ or (systematic and adj and (review$ or overview$)) 61,427 12 cancerlit or cochrane or ‘embase’/exp or psychlit’/exp or ‘psyclit’/ or ‘science citation index’/exp or bids or scopus 44,495 ‘reference lists’ or bibliograph$ or ‘hand search$’ or ‘manual search$’ or ‘relevant journals’ or ‘data extraction’/exp or ‘selection 13 criteria’ 28,035 14 review.pt. 4 15 ‘review’/exp 1,831,423 16 14 or 15 1,831,427 17 13 and 16 15,584 18 letter.pt. or editorial.pt. 3 19 ‘letter’/exp or ‘editorial’/exp 1,179,933 20 18 or 19 1,174,934 21 11 or 12 or 17 98,049 22 21 not 20 93,355 ‘clinical trial’/exp or ‘randomized controlled trial’/exp or ‘randomization’/exp or ‘single blind procedure’/exp or ‘double blind procedure’/exp or ‘crossover procedure’/exp or ‘placebo’/exp or randomi?ed and controlled and trial$ or rct$ or ‘random allocation’ or ‘randomly allocated’ or ‘allocated randomly’ or allocated and adj2 and random$ or single and blind$ or double and blind$ or 23 (treble or triple and adj and blind$) or placebo$ or ‘prospective study’/exp 541,923 ‘case study’/exp or ‘case study’ or ‘case report’/exp or ‘case report’ or ‘abstract report’/exp or ‘abstract report’ or ‘letter’/exp or letter 24 and [1998-2012]/py 1,237,206 25 23 not 24 529,538 © 2017 American Medical Association. All rights reserved. 79

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# Search History Results 26 ‘clinical study’/exp or ‘case control study’/exp or ‘family study’/exp or ‘longitudinal study’/exp or ‘retrospective study’/exp 5,942,135 27 ‘prospective study’/exp 189,505 28 ‘randomized controlled trial’/exp 307,692 29 27 not 28 165,671 ‘cohort analysis’/exp or (cohort and adj and (study or studies)) or (case and control and adj and (study or studies)) or (follow and up and adj and (study or studies)) or (observational and adj and (study or studies)) or (epidemiologic$ and adj and (study or 30 studies)) or (cross and sectional and adj and (study or studies)) 115,089 31 26 or 27 or 29 or 30 5,986,679 ‘sensitivity and specificity/exp or sensitivity or specificity or (‘pre test’ or pretest and adj and ‘probability’/exp) or ‘post-test probability’ or predictive and value$ or likelihood and ratio$ or ‘predictive value’/exp or ‘diagnostic accuracy ‘/exp and english]/lim 32 and [embase]/lim and [1998-2012]/py 144,775 33 22 or 25 or 31 or 32 6,160,948 34 10 and 33 and [english]/lim and [embase]/lim and [1998-2012]/py 221

eTABLE 13. Cochrane Database of Systematic Reviews Targeted Search: Anticoagulation # Search History Results ("low molecular weight" or "low-molecular-weight" or anticoag* or heparin or warfarin or aspirin or clopidogrel or plavix or "Platelet Aggregation Inhibit*" or anti platelet* ) and ( surgery or surgical* or operat* ) and (joint* or arthroplast* or prosthe* or implant* ) in 1 Title, Abstract or Keywords 8

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1.2E. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCHES: ORTHOPAEDIC SPACE SUIT eTABLE 14. MEDLINE Targeted Search: Orthopaedic Space Suit # Search History Results 1 (exp “prostheses and implants”/ or prosthe*.af. or implant*.af. or orthoped*.af. or orthpaed*.af.) and (exp joints/ or joint*.af.) 102,254 2 exp Joints/su [Surgery] 44,595 3 exp Arthroplasty, Replacement/ or exp Arthroplasty/ 32,203 4 arthroplasty*.af. 43,132 5 exp “Orthopedic Procedures”/ and exp “Joints”/ 40,095 6 or/ 1-5 142,045 7 exp Infection/ or infection*.af. or infecting.af. or infected.af. or exp “Prosthesis-Related Infections”/ 1,541,705 8 exp Random Allocation/ 73,817 9 exp Randomized Controlled Trials as Topic/ or exp Randomized Controlled Trial/ 398,286 10 exp Double-Blind Method/ 114,004 11 exp Single-Blind Method/ 15,965 12 exp Clinical Trial/ 671,638 13 exp Clinical Trials as Topic/ 253,375 14 clinical trial.pt. 468,127 15 clinical trial, phase i.pt. 11,960 (clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or 16 multicenter study or clinical trial).pt. 669,278 17 or /8-16 901,656 18 (clinical adj trial$).tw. 166,027 19 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. 111,543 20 placebo$.tw. 134,617 21 randomly allocated.tw. 13,439 22 (allocated adj2 random$).tw. 15,726 23 exp Placebos/ 30,724 24 or/17-23 1,003,206 © 2017 American Medical Association. All rights reserved. 81

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# Search History Results 25 case report.tw. 164,737 26 letter/ 742,890 27 historical article/ 281,494 28 exp Editorial/ 295,617 29 or/25-28 1,467,233 30 24 not 29 962,656 31 exp “Sensitivity and Specifity”/ 352,539 32 (sensitivity or specifity).tw. 593,131 33 ((pre-test or pretest) adj probability).tw. 988 34 post-test probability.tw. 273 35 predictive value$.tw. 54,533 36 likelihood ratio$.tw. 6,584 37 exp “Predictive Value of Tests”/ 118,653 38 or/30-27 1,751,101 39 exp Meta-Analysis as Topic/ 12,014 40 (meta analy$ or metaanaly$).tw. or exp Meta-analysis/ 49,880 41 (systematic adj (review$1 or overview$1)).tw. 30,599 42 exp Review Literature as Topic/ 6,214 43 or/38-42 1,795,992 44 (embase or Cochrane or psyclit* or psychlit* or psycinfo or psychinfo).tw. 28,587 45 (cinahl or cinhal).ab. 6,206 46 (science citation index or bids or cancerlit).ab. 2,197 47 or/43-46 1,803,599 48 (reference list$ or bibliograph$ or hand-search$ or relevant journals or manual search$).ab. 18,879 49 (selection criteria or data extraction).ab. 20,833 50 exp Review/ 1,684,812

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# Search History Results 51 49 and 50 14,483 52 47 or 48 or 51 1,811,665 53 exp Comment/ or exp Editorial/ or exp Letter/ 1,120,430 54 52 not 53 1,780,921 exp Epidemiologic studies/ or exp case control studies/ or exp cohort studies/ or Case control.tw. or (cohort adj (study or studies)).tw. or cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or 55 Longitudinal.tw. or Retrospective.tw. or Cross sectional.tw. or exp Cross-sectional studies/ 1,563,211 56 54 or 55 2,990,436 57 exp Protective Clothing/ or exp Space Suits/ 9,233 58 (exhaust* or ‘exhaust suit*”).af. 27,803 59 (“body exhaust suit*” or “body-exhaust suit*” or “space suit*”).af. 254 60 57 or 58 or 59 36,996 61 6 and 7 and 56 and 60 37 62 limit 61 to english language 35 63 limit 62 to yr=”1998-Current” 21

eTABLE 15. EMBASE Targeted Search: Orthopaedic Space Suit # Search History Results 1 ‘meta analysis’/exp or (meta and adj and analy$) or metaanaly$ or (systematic and adj and (review$ or overview$)) 61,427 2 cancerlit or cochrane or ‘embase’/exp or psychlit’/exp or ‘psyclit’/ or ‘science citation index’/exp or bids or scopus 44,494 ‘reference lists’ or bibliograph$ or ‘hand search$’ or ‘manual search$’ or ‘relevant journals’ or ‘data extraction’/exp or ‘selection 3 criteria’ 28,035 4 review.pt. 4 5 ‘review’/exp 1,831,422 6 4 or 5 1,831,427 7 3 and 6 15,584 8 letter.pt. or editorial.pt. 3 9 ‘letter’/exp or ‘editorial’/exp 1,179,933 © 2017 American Medical Association. All rights reserved. 83

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# Search History Results 10 8 or 9 1,179,934 11 1 or 2 or 7 98,049 12 11 not 10 93,355 ‘clinical trial’/exp or ‘randomized controlled trial’/exp or ‘randomization’/exp or ‘single blind procedure’/exp or ‘double blind procedure’/exp or ‘crossover procedure’/exp or ‘placebo’/exp or randomi?ed and controlled and trial$ or rct$ or ‘random allocation’ or ‘randomly allocated’ or ‘allocated randomly’ or allocated and adj2 and random$ or single and blind$ or double and blind$ or 13 (treble or triple and adj and blind$) or placebo$ or ‘prospective study’/exp 541,923 ‘case study’/exp or ‘case study’ or ‘case report’/exp or ‘case report’ or ‘abstract report’/exp or ‘abstract report’ or ‘letter’/exp or letter 14 and [1998-2012]/py 1,237,206 15 13 not 14 529,538 16 ‘clinical study’/exp or ‘case control study’/exp or ‘family study’/exp or ‘longitudinal study’/exp or ‘retrospective study’/exp 5,942,135 17 ‘prospective study’/exp 189,505 18 ‘randomized controlled trial’/exp 307,692 19 17 not 18 165,671 ‘cohort analysis’/exp or (cohort and adj and (study or studies)) or (case and control and adj and (study or studies)) or (follow and up and adj and (study or studies)) or (observational and adj and (study or studies)) or (epidemiologic$ and adj and (study or 20 studies)) or (cross and sectional and adj and (study or studies)) 115,089 21 16 or 19 or 20 5,986,679 ‘sensitivity and specificity/exp or sensitivity or specificity or (‘pre test’ or pretest and adj and ‘probability’/exp) or ‘post-test probability’ or predictive and value$ or likelihood and ratio$ or ‘predictive value’/exp or ‘diagnostic accuracy ‘/exp and english]/lim 22 and [embase]/lim and [1998-2012]/py 144,775 23 12 or 15 or 21 or 22 6,160,948 24 ‘infection’/exp 2,328,600 25 Infection$ or infecting or infected 2,654,665 26 ‘prosthesis related’ and infections 95 27 ‘prosthesis-related infections’/exp 2,328,600 28 24 or 25 or 26 or 27 2,660,483 29 ‘prostheses and orthoses’/exp or prosthe$ or implant$ or orthoped$ or orthopaed$ 399,873 ‘joint’/exp or joint$ or ‘joint surgery’/exp or ‘arthroplasty’/exp or arthroplasty or arthroplasties or ‘arthroplasty replacement’ or 30 (‘orthopedic surgery’/exp and ‘joint’/exp) 603,883 © 2017 American Medical Association. All rights reserved. 84

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# Search History Results 31 29 and 30 69,054 ‘surgical attire’/exp or ‘surgical attire’ or ‘protective clothing’/exp or ‘space suit’ or ‘exhaust suit’ or ‘body exhaust suit’ or ‘body- 32 exhaust suit’ 12,127 33 23 and 28 and 31 and 32 and [english]/lim and [embase]/lim and [1998-2012]/py 7

eTABLE 16. Cochrane Database of Systematic Reviews Targeted Search: Orthopaedic Space Suit # Search History Results (suit* or clothing) and (surgery or surgical* or operat*) and (joint* or arthroplast* or prosthe* or implant*) in Title, Abstract or 1 Keywords 8

eTABLE 17. CINAHL Targeted Search: Orthopaedic Space Suit # Search History Results 1 (MH “Protective Clothing+”) 3,434 2 “exhaust suit*” 4 3 “space suit*” 3 4 1 or 2 or 3 3,438 5 (MH “Arthoplasty+”) or (MH “Arthroplasty, Replacement+”) 10,000 6 (MH “Prostheses and Implants+”) 34,039 7 (MH “Joints/SU”) 111 8 (MH “Surgery, Operative+”) 197,035 9 (MH “Surgery, Operative+”) and orthopedic* or orthopaedic* or joint* 20,595 10 ((prosthe* or implant* or orthopaed* or orthoped*)) and MW joints 196 11 arthroplasty or arthroplasties 10,691 12 5 or 6 or 7 or 10 or 11 62,799 13 11 and 12 22 14 13 and 4 21 15 (MH “Infection+”) 62,911

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# Search History Results 16 (MH “Prosthesis-Related Infections”) 610 17 infection* or infected or infecting 129,848 18 15 or 16 or 17 129,848 19 14 and 18 14 20 (MH “Operating Rooms”) 4,940 21 “operating room*” 8,369 22 20 or 21 8,369 23 19 and 22 7

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1.2F. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCH: ANTIMICROBIAL PROPHYLAXIS WITH A DRAIN eTABLE 18. MEDLINE Targeted Search: Antimicrobial Prophylaxis with a Drain # Search History Results 1 exp Anti-Infective Agents/ 1,155,786 2 exp Antibiotic Prophylaxis/ 7,457 3 (antimicrobial or ("anti-infective" and agents) or “anti-infective agents”).af. 139,832 4 1 or 2 or 3 1,181,549 5 exp Time/ or exp Time Factors/ or timing.af. or time.af. or timed.af. or duration.af. 2,675,015 6 exp Drainage/ 41,403 7 drain*.af. 93,852 8 6 or 7 102,200 9 4 and 5 and 8 1,930 10 (exp "prostheses and implants"/ or prosthe*.af. or implant*.af. or orthoped*.af. or orthopaed*.af.) and (exp joints/ or joint*.af.) 102,254 11 exp Joints/su [Surgery] 44,595 12 exp Arthroplasty, Replacement/ or exp Arthroplasty/ 32,203 13 arthroplasty*.af. 43,132 14 exp “Orthopedic Procedures”/and exp “Joints”/ 40,095 15 or/10-14 142,045 16 exp Infection/ or infection*.af. or infecting.af. or infected.af. or exp "Prosthesis-Related Infections"/ 1,541,705 17 exp Random Allocation/ 73,817 18 exp Randomized Controlled Trials as Topic/ or exp Randomized Controlled Trial/ 398,286 19 exp Double-Blind Method/ 114,001 20 exp Single-Blind Method/ 15,965 21 exp Clinical Trial/ 671,638 22 exp Clinical Trials as Topic/ 253,375 23 clinical trial.pt. 468,127 24 clinical trial, phase i.pt. 11,960 25 (clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or 669,278 © 2017 American Medical Association. All rights reserved. 87

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# Search History Results multicenter study or clinical trial).pt. 26 or/17-25 901,656 27 (clinical adj trial$).tw. 166,027 28 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. 111,543 29 placebo$.tw. 134,617 30 randomly allocated.tw. 13,439 31 (allocated adj2 random$).tw. 15,726 32 exp Placebos/ 30,724 33 or/26-32 1,003,206 34 case report.tw. 164,737 35 letter/ 742,890 36 historical article/ 281,494 37 exp Editorial/ 295,617 38 or/34-37 1,467,233 39 33 not 38 962,656 40 exp “Sensitivity and Specificity”/ 352,539 41 (sensitivity or specificity).tw. 593,131 42 ((pre-test or pretest) adj probability).tw. 988 43 post-test probability.tw. 273 44 predictive value$.tw. 54,533 45 likelihood ratio$.tw. 6,584 46 exp "Predictive Value of Tests"/ 118,653 47 or/39-46 1,751,101 48 exp Meta-Analysis as Topic/ 12,014 49 (meta analy$ or metaanaly$).tw. or exp Meta-analysis/ 49,880 50 (systematic adj (review$1 or overview$1)).tw. 30,599

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# Search History Results 51 exp Review Literature as Topic/ 6,214 52 or/47-51 1,795,992 53 (embase or cochrane or psyclit* or psychlit* or psycinfo or psychinfo).tw. 28,587 54 (cinahl or cinhal).ab. 6,206 55 (science citation index or bids or cancerlit).ab. 2,197 56 or/52-55 1,803,599 57 (reference list$ or bibliograph$ or hand-search$ or relevant journals or manual search$).ab. 18,879 58 (selection criteria or data extraction).ab. 20,833 59 exp Review/ 1,684,812 60 58 and 59 14,483 61 56 or 57 or 60 1,811,665 62 exp Comment/ or exp Editorial/ or exp Letter/ 1,120,430 63 61 not 62 1,780,921 exp Epidemiologic studies/ or exp case control studies/ or exp cohort studies/ or Case control.tw. or (cohort adj (study or studies)).tw. or cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or 64 Longitudinal.tw. or Retrospective.tw. or Cross sectional.tw. or exp Cross-sectional studies/ 1,563,211 65 63 or 64 2,990,436 66 9 and 15 and 16 79 67 65 and 66 46 68 limit 67 to english language 38 69 limit 68 to yr=”1998-Current” 24

eTABLE 19. EMBASE Targeted Search: Antimicrobial Prophylaxis with a Drain # Search History Results ‘antiinfective agent’/exp or ‘antibiotic prophylaxis’/exp or ‘antimicrobial’/exp or ‘anti infective’ or ‘anti-infective agents’/exp and 1 [english]/lim and [embase]/lim and [1998-2012]/py 909,070 2 ‘meta analysis’/exp or (meta and adj and analy$) or metaanaly$ or (systematic and adj and (review$ or overview$)) 61,427 3 cancerlit or cochrane or ‘embase’/exp or psychlit’/exp or ‘psyclit’/ or ‘science citation index’/exp or bids or scopus 44,494 © 2017 American Medical Association. All rights reserved. 89

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# Search History Results ‘reference lists’ or bibliograph$ or ‘hand search$’ or ‘manual search$’ or ‘relevant journals’ or ‘data extraction’/exp or ‘selection 4 criteria’ 28,035 5 review.pt. 4 6 ‘review’/exp 1,831,423 7 5 or 6 1,831,427 8 4 and 7 15,584 9 letter.pt. or editorial.pt. 3 10 ‘letter’/exp or ‘editorial’/exp 1,179,933 11 9 or 10 1,179,934 12 2 or 3 or 8 98,049 13 12 not 11 93,355 ‘clinical trial’/exp or ‘randomized controlled trial’/exp or ‘randomization’/exp or ‘single blind procedure’/exp or ‘double blind procedure’/exp or ‘crossover procedure’/exp or ‘placebo’/exp or randomi?ed and controlled and trial$ or rct$ or ‘random allocation’ or ‘randomly allocated’ or ‘allocated randomly’ or allocated and adj2 and random$ or single and blind$ or double and blind$ or 14 (treble or triple and adj and blind$) or placebo$ or ‘prospective study’/exp 541,923 ‘case study’/exp or ‘case study’ or ‘case report’/exp or ‘case report’ or ‘abstract report’/exp or ‘abstract report’ or ‘letter’/exp or letter 15 and [1998-2012]/py 1,237,206 16 14 not 15 529,538 17 ‘clinical study’/exp or ‘case control study’/exp or ‘family study’/exp or ‘longitudinal study’/exp or ‘retrospective study’/exp 5,942,135 18 ‘prospective study’/exp 189,505 19 ‘randomized controlled trial’/exp 307,692 20 18 not 19 165,671 ‘cohort analysis’/exp or (cohort and adj and (study or studies)) or (case and control and adj and (study or studies)) or (follow and up and adj and (study or studies)) or (observational and adj and (study or studies)) or (epidemiologic$ and adj and (study or 21 studies)) or (cross and sectional and adj and (study or studies)) 115,089 22 17 or 20 or 21 5,987,932 ‘sensitivity and specificity/exp or sensitivity or specificity or (‘pre test’ or pretest and adj and ‘probability’/exp) or ‘post-test probability’ or predictive and value$ or likelihood and ratio$ or ‘predictive value’/exp or ‘diagnostic accuracy ‘/exp and english]/lim 23 and [embase]/lim and [1998-2012]/py 144,775 24 13 or 16 or 22 or 23 6,162,421 © 2017 American Medical Association. All rights reserved. 90

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# Search History Results 25 ‘infection’/exp 2,328,600 26 Infection$ or infecting or infected 2,654,665 27 ‘prosthesis related’ and infections 95 28 ‘prosthesis-related infections’/exp 2,328,600 29 25 or 26 or 27 or 28 2,660,841 30 ‘prostheses and orthoses’/exp or prosthe$ or implant$ or orthoped$ or orthopaed$ 399,873 ‘joint’/exp or joint$ or ‘joint surgery’/exp or ‘arthroplasty’/exp or arthroplasty or arthroplasties or ‘arthroplasty replacement’ or 31 (‘orthopedic surgery’/exp and ‘joint’/exp) 603,883 32 30 and 31 69,062 33 1 and 24 and 29 and 32 and [english]/lim and [embase]/lim and [1998-2012]/lim 1,364 34 ‘drain’/exp or drain* 138,118 35 33 and 34 115

eTABLE 20. Cochrane Database of Systematic Reviews Targeted Search: Antimicrobial Prophylaxis with a Drain # Search History Results (antisept* or antibiotic* or antimicrobial* or anti-infect*) and (surgery or surgical* or operat*) and (joint* or arthroplast* or prosthe* or 1 implant*) in Title, Abstract or Keywords 12

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1.2G. PROSTHETIC JOINT ARTHROPLASTY SECTION TARGETED SEARCH: BIOFILM eTABLE 21. MEDLINE Targeted Search: Biofilm # Search History Results 1 (exp "prostheses and implants"/ or prosthe*.af. or implant*.af. or orthoped*.af. or orthopaed*.af.) and (exp joints/ or joint*.af.) 100,195 2 exp Joints/su [Surgery] 43,624 3 exp Arthroplasty, Replacement/ or exp Arthroplasty/ 30,982 4 arthroplast*.af. 41,886 5 exp "Orthopedic Procedures"/ and exp "Joints"/ 39,075 6 or/1-5 139,184 7 exp Infection/ or infection*.af. or infecting.af. or infected.af. or exp "Prosthesis-Related Infections"/ 1,511,311 8 (adhesin* or biofilm*).af. 22,728 9 exp Adhesins, Bacterial/ 5,227 10 "adhesin, staphylococcus aureus".af. 93 ("bacterial adhesin receptor" or "polysaccharide intercellular adhesin" or "adhesin, Pseudomonas" or "Bap protein, Staphylococcus 11 aureus").af. 322 12 exp Biofilms/ 11,763 13 exp Staphylococcus aureus/ 42,676 14 or/8-13 64,215 15 6 and 7 and 14 515 16 limit 15 to english language 472 17 limit 16 to yr="1998 -Current" 382 18 exp Random Allocation/ 72,622 19 exp Randomized Controlled Trials as Topic/ or exp Randomized Controlled Trial/ 386,853 20 exp Double-Blind Method/ 111,942 21 exp Single-Blind Method/ 15,496 22 exp Clinical Trial/ 656,004 23 exp Clinical Trials as Topic/ 247,358 24 clinical trial.pt. 464,810 © 2017 American Medical Association. All rights reserved. 92

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# Search History Results 25 clinical trial, phase i.pt. 11,518 (clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or 26 multicenter study or clinical trial).pt. 653,827 27 or/18-26 878,988 28 (clinical adj trial$).tw. 160,316 29 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. 109,518 30 placebo$.tw. 131,568 31 randomly allocated.tw. 13,041 32 (allocated adj2 random$).tw. 15,306 33 exp Placebos/ 30,269 34 or/28-33 977,370 35 case report.tw. 161,905 36 letter/ 726,601 37 historical article/ 278,462 38 exp Editorial/ 285,735 39 or/35-38 1,435,636 40 34 not 39 937,867 41 exp "Sensitivity and Specificity"/ 342,804 42 (sensitivity or specificity).tw. 578,788 43 ((pre-test or pretest) adj probability).tw. 953 44 post-test probability.tw. 260 45 predictive value$.tw. 53,070 46 likelihood ratio$.tw. 6,322 47 exp "Predictive Value of Tests"/ 114,791 48 or/41-47 833,451 49 exp Meta-Analysis as Topic/ 11,663 50 (meta analy$ or metaanaly$).tw. or exp Meta-analysis/ 46,882 © 2017 American Medical Association. All rights reserved. 93

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# Search History Results 51 (systematic adj (review$1 or overview$1)).tw. 28,388 52 exp Review Literature as Topic/ 5,925 53 or/49-52 74,728 54 (embase or cochrane or psyclit* or psychlit* or psycinfo or psychinfo).tw. 26,489 55 (cinahl or cinhal).ab. 5,754 56 (science citation index or bids or cancerlit).ab. 2,076 57 or/54-56 28,166 58 (reference list$ or bibliograph$ or hand-search$ or relevant journals or manual search$).ab. 18,009 59 (selection criteria or data extraction).ab. 19,848 60 exp Review/ 1,647,360 61 59 and 60 13,695 62 53 or 57 or 58 or 61 96,348 63 exp Comment/ or exp Editorial/ or exp Letter/ 1,090,861 64 62 not 63 90,596 exp Epidemiologic studies/ or exp case control studies/ or exp cohort studies/ or Case control.tw. or (cohort adj (study or studies)).tw. or cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or 65 Longitudinal.tw. or Retrospective.tw. or Cross sectional.tw. or exp Cross-sectional studies/ 1,518,084 66 17 and 40 14 67 17 and 48 23 68 17 and 64 2 69 17 and 65 88 70 66 or 67 or 68 or 69 107

eTABLE 22. EMBASE Targeted Search: Biofilm # Search History Results 1 ‘biofilm’/exp or ‘adhesin’/exp or biofilm* or adhesion* and [english]/lim and [1998-2012]/py 23,287 2 ‘arthroplasty’/exp and [english]/lim and [1998-2012]/py 37,286

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# Search History Results 3 1 and 2 104 3 and (‘case control study’/de or ‘clinical protocol’/de or ‘clinical study’/de or ‘clinical trial’/de or ‘consensus development’/de or ‘controlled clinical trial’/de or ‘controlled study’/de or ‘culture technique’/de or ‘human’/de or ‘in vitro study’/de or ‘major clinical 4 study’/de or ‘practice guideline’/ de or ‘prospective study’/de) 94 5 ‘infection’/exp and [english]/lim and [1998-2012]/py 1,005,608 6 4 and 5 82 7 4 and [embase]/lim and [1998-2012]/py 83

eTABLE 23. Cochrane Database of Systematic Reviews Targeted Search: Biofilm # Search History Results 1 (biofilm* or adhesin*) in Title, Abstract or Keywords 8

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2. EVIDENCE, GRADE and RISK OF BIAS ASSESSMENT TABLES

2.1. Core Section GRADE, Evidence, and Risk of Bias Assessment Tables

2.1A. Q1 PARENTERAL ANTIMICROBIAL PROPHYLAXIS (AMP) 2.1A1. GRADE TABLE: Q1 PARENTERAL AMP eTABLE 24. GRADE Table for Q1 Parenteral AMP Increase Decrease GRADE GRADE

GRADE Overall

Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Q1. What are the most effective strategies for administering parenteral AMP to reduce the risk of SSI? Q1A. What is the optimal timing of preoperative AMP? Elective Lower Limb Musculoskeletal Procedures (majority fracture repairs with some soft tissue surgeries) • In 1 RCT (N=106) of a mixture of implant AMP 1 surgeries with soft tissue operations, where minute limbs were exsanguinated prior to tourniquet after vs. 5 Deep 1 inflation, Patients in the group who received minutes 1 RCT High -1 0 0 -1 0 0 0 0 Low Low SSI* intravenous antibiotics after tourniquet prior to inflation had significantly fewer deep tourniquet infections: 2/52 (3.9%) vs. 8/54 (14.8%); inflation p=0.03, at 12 month follow up. Primary Total Knee Arthroplasty • In 1 RCT (N=908) of primary knee arthroplasties, patients who received AMP 10 Deep 2 intravenous antibiotics after tourniquet inflation 1 RCT High 0 0 0 -1 0 0 0 0 Moderate minutes SSI* had fewer deep SSI at 12 months follow up: before 12/466 (2.6%) vs. 16/442 (3.6%); p=0.44 but tourniquet this difference was not significant. release vs. • There was no difference in the mean length of Moderate 10-30 Length of 2 1 RCT stay between groups: 6.4±1.6 vs. 6.5±2.1 High 0 0 0 -1 0 0 0 0 Moderate minutes Stay days; p=0.58 before tourniquet Antimicr- • 19/ 31 organisms isolated from 28 SSI were inflation obial 2 Staphylococcus. 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Resista- • MRSA: 1/12 (8.3%) vs. 1/16 (6.25%) nce • Methicillin Resistant-Coagulase Negative

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Increase Decrease GRADE GRADE

GRADE Overall

Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Staphylococcus aureus: 4/12 (25.0%) vs. 2/16 (12.5%)

Q1B. What is the optimal timing of AMP in cesarean section: prior to skin incision or at cord clamping? • N=2493 Mothers from 7 RCTs all undergoing SSI- Cesarean section overall OR: 0.57 (0.34- Endome- 7 RCTs 3-9 0.94); p=0.03; I2=0 indicating a reduction in High 0 0 0 0 0 0 0 0 High tritis* the odds of developing endometritis with administration of AMP prior to skin incision • N=2493 Mothers from 7 RCTs all undergoing SSI 3-9 7 RCTs cesarean section, overall OR: 0.82 (0.52 – High 0 0 0 0 0 0 0 0 High Incisional 2 1.31); p=0.41; I =0; indicating no difference • N=1080 Neonates from 3 RCTs all delivered Cesarean by Cesarean section, administration of AMP to section the mother prior to skin incision did not AMP Neonatal 6-8 significantly affect proven neonatal sepsis- 3 RCTs 2 High 0 0 0 0 0 0 0 0 High timing: Sepsis OR: 0.81 (0.45 – 1.44); p=0.47; I =0 5 Prior to • 1 RCT stated that there was no significant High skin difference in the rate of neonatal sepsis incision vs. between groups but data was not shown. at cord • N=1604 Neonates delivered by cesarean clamping section from 5 RCTs, administration of AMP to Neonatal 5 RCTs the mother prior to skin incision did not Sepsis 4,6-9 High 0 0 0 0 0 0 0 0 High significantly affect suspected sepsis that Workup required workup: OR: 0.92 (0.68 – 1.24); p=0.58; I2=0 • In 1 RCT 8, 13 cases of sepsis among 357 Neonatal neonates did not show increased antimicrobial Antimicr- 4,8 resistance 2/6 vs. 3/7 obial 2 RCTs High 0 0 0 -1 0 0 0 0 Moderate • 4 Resista- In 1 RCT , with 38 cases of suspected sepsis there were no cases of antibiotic resistance in nce the neonates

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Neonate • N=1694 Neonates from 5 RCTs all delivered Admissi- by Cesarean section, administration to the on to 5 RCTs mother prior to skin incision did not 3,4,6-8 High 0 0 0 0 0 0 0 0 High Higher significantly affect admission of neonate to an Level increased infant care unit. OR: 0.92 (0.64 – Care 1.32); p=0.64; I2=0 Q1C. How safe and effective is weight-adjusted AMP dosing? Our search did not identify RCTs or SRs that evaluated weight-adjusted AMP dosing and its impact on the risk of SSI. Q1D. How safe and effective is intraoperative redosing of AMP? • In 1 RCT (N=278) in elective colorectal surgery, 271 patients completed 30 day follow up. No difference: 10/143 (7%) vs. 7/128 (5%); p>0.05 • Patients with procedure duration >3h had a significantly higher probability of infection (5/37 (14%)) as compared to those with 2-3hr 1 (5/127 (4%)) or <2h duration 7/107 (7%); Preoperati- p<0.05. Of note, 36/164 (22%) of patients with ve dose SSI* procedure durations ≥2h were not redosed vs. 10 (Abdomi- 1 RCT intraoperatively (antimicrobial half-life was 68 High 0 0 0 -1 0 0 0 0 Moderate 1 nal) min). Study does not report these infections preoperati- by single dose versus redosed. Moderate ve dose • plus Increasing fecal contamination almost doubled the infection rate at every level from additional 2/67 (3%) in those with no contamination, to dose at 2h intraoperat- 10/162 (6%) in those with moderate, and 5/38 ively (13%) in those with gross contamination, p<0.05 (contamination unknown in 4). Study does not report these infections by single dose versus redosed. Intra- Abdomi- 10 1 RCT • No difference: 8/146 (5%) vs. 10/132 (8%) High 0 0 0 -1 0 0 0 0 Moderate nal Abscess* © 2017 American Medical Association. All rights reserved. 98

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Perineal Wound 1 RCT 10 • No difference: 4/9 vs. 4/9 High 0 0 0 -1 0 0 0 0 Moderate Infection* Antimicr- • No difference: 1 minor SSI in each group obial 10 1 RCT culture positive for MRSA as the sole High 0 0 0 -1 0 0 0 0 Moderate resistan- organism ce Q1E. How safe and effective is postoperative AMP and what is the optimal duration? All Surgeries • In a meta-analysis of 21 RCTs, (N=14,285) no None 11- 21 RCT benefit of continuing AMP after the wound is vs. SSI* 31 High 0 0 0 0 0 0 0 0 High High closed in the operating room: OR: 1.19 (0.94 <24h 2 – 1.50); p=0.15; I =25% Cardiac Surgery Organ- • In a meta-analysis of 3 RCTs12,32,33 (N=1746), None Space 3 RCT there was no benefit of continuing AMP after vs. 12,32,33 High 0 0 0 -1 0 0 0 0 Moderate Moderate Sternal the wound was closed in the operating room: ≤96h 2 SSI* OR: 1.84 (0.82 – 4.14); p= 0.14; I =0 • ≤24h AMP duration reduced the risk of SSI at 12 month follow up in 1 large RCT with N=838 patients undergoing CABG with or without valve replacement: 30 /419 (7.2%) vs. 15/419 (3.6%); p=0.02. Overall rate of SSI was 5.9%. • Patients received their first dose of AMP 20- None 30 min after induction of anesthesia, and vs. 12 SSI* 1 RCT those whose procedures lasted >3h were High 0 0 0 -1 0 0 0 0 Moderate Moderate ≤24h redosed intraoperatively.

• The “no postoperative AMP” group also had statistically higher proportion of patients on intraaortic balloon pump postoperatively (0.03) and received more blood transfusions (0.01).Patients who presented with both osteomyelitis and mediastinitis were reported © 2017 American Medical Association. All rights reserved. 99

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders as both an organ/space and a deep incisional SSI. Between 1 and 3 of 5 deep SSI patients in the “no postoperative AMP group” may have had both. Since the study did not stratify those results, deep SSI data were excluded from this analysis. • No S. aureus decolonization was performed. • No difference: 14/419 (3.3%) vs. 8/419 Organ/ (1.9%); p=0.19 at 12 month follow up. Space 12 1 RCT • No statistically significant differences between High 0 0 0 -1 0 0 0 0 Moderate Sternal groups for osteomyelitis, mediastinitis, or SSI endocarditis individually. • ≤24 AMP reduced the risk of superficial Superfic- 12 incisional SSI:16 (3.8%) vs. 7 (1.7%); p=0.04 1 RCT High 0 0 0 -1 0 0 0 0 Moderate ial SSI • However, it is not clear if incisional SSIs included both sternal and donor site wounds.

12 • No difference at 30d, 90d and 365d (P=0.12, Mortality 1 RCT High 0 0 0 -1 0 0 0 0 Moderate 0.18, and 0.34, respectively) • No differences: (14.75±15.8 vs. 12.2±14.2); p=0.25. Length of 12 • Of note, patients in both groups were 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Stay hospitalized for approximately 10 days before surgery and had long mean ICU stays: 10.3±10.9 vs. 9.1±8.7; p=0.09. • The most frequently isolated organisms were Antimicr- Staphylococcus epidermis and obial 12 Staphylococcus aureus (p≥0.05) and the 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Resista- majority of SSIs were polymicrobial: 57.1% vs. nce 60.0%. • MRSA: 4/35 (11.4%) vs. 9/15 (60%); p<0.01

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Organ/ Space 2 RCT • No difference in meta-analysis (N=908) of 2 32,33 2 High 0 0 0 -1 0 0 0 0 Moderate SSI* RCTs, OR: 4.28 (0.47 – 39.24); p=0.20; I =0 Sternal Superfic- ial 3 RCT 32- • No difference in meta-analysis (N=993) of 3 34 2 High 0 0 0 -1 0 0 0 0 Sternal RCTs: OR: 1.23 (0.44 – 3.45); p=0.69; I =0 Moderate SSI*` • No difference in 1 large RCT where 766 SSI* Leg (91%) of 844 CABG patients underwent leg Graft 33 1 RCT vein harvest. 23/377 (6.1%) vs. 20/389 High 0 0 0 -1 0 0 0 0 Moderate Donor (5.1%); 7 day follow up. Overall donor site SSI Site rate 5.6% (43/766) Leg Graft • No difference: 18 reports of wound Donor None dehiscence in each group (7-day follow up). Site 33 vs. 1 RCT The authors included donor site wound High 0 0 0 -1 0 0 0 0 Moderate Moderate Wound 72-96h dehiscence in their calculation of the overall Dehisce- infection rate. nce Superfic- ial Leg 33 • No difference: 5/377 (1.3%) vs. 2/389 (0.5%); Graft 1 RCT High 0 0 0 -1 0 0 0 0 Moderate p=0.26 (7 day follow up) Donor Site SSI* • Significantly shorter length of stay with Length of 34 postoperative AMP in one small (N=85) RCT 1 RCT High -1 0 0 -1 0 0 0 0 Low Stay with data collected 35 years ago: 12.03±4.2 versus 14.6±7.5 days; P<0.05

Antimicr- 34 • One study both incisional SSIs were obial 2 RCT 32,34 Staphylococcus aureus High -1 0 0 -1 0 0 0 0 Low Resista- • One study 32 incisional SSI: The “no nce © 2017 American Medical Association. All rights reserved. 101

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders postoperative AMP group” had 1 Staphylococcus aureus and 1 Staphylococcus epidermis infection as compared to 1 Serratia marcescens and 1 Enterococcus infection in those with postoperative AMP. The one case of endocarditis in the group with “no postoperative AMP” was a Staphylococcus epidermis.

Sternal 35 • No difference in 30 day SSI (N=231) 13/120 1 RCT High -1 0 0 -1 0 0 0 0 Low SSI* (10.8%) vs. 9/111 (8.1%); p=0.48

Deep 35 • No difference in deep sternal SSI (N=231) Sternal 1 RCT High -1 0 0 -1 0 0 0 0 Low 3/120 (2.5%) vs. 1/111 (0.9%); p=0.62 SSI*

Superfic- • No difference in superficial sternal SSI ial 35 1 RCT (N=231) 3/120 (2.5%) vs. 2/111 (1.8%); High -1 0 0 -1 0 0 0 0 Low Sternal p=1.00 ≤24h SSI* vs. Low 72h • No difference in harvest site SSI (N=231) at Harvest 35 1 RCT 30 days 73/120 (5.8%) vs. 6/111 (5.4%); High -1 0 0 -1 0 0 0 0 Low Site SSI* p=0.89

Total 35 • No difference in length of stay: 15.1±5.2 days Length of 1 RCT High -1 0 0 -1 0 0 0 0 Low versus 16.7±9.1 days; p=0.10 Stay • No difference in rates of MSSA: 3/120 (2.5%) Antimicr- vs. 3/111 (2.7%); p=1.00; or MRSA: 2/120 obial 35 1 RCT (1.7%) vs. 3/111 (2.7%); p=0.67 High -1 0 0 -1 0 0 0 0 Low Resista- • Although not significant, nasal swab screen nce results prior to surgery were higher in 1-day © 2017 American Medical Association. All rights reserved. 102

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders group for both MSSA: 8/120 (7.3%) vs. 16/111 (15.5%); p=0.06; and MRSA: 6/120 (5.5%) vs. 4/111 (3.9%); p=0.75. Thoracic Surgery • No difference in 1 RCT (N=203) of patients undergoing thoracic surgery (thoracotomy SSI* 1 RCT 36 with lung resection): 7/102 (7%) vs. 2/101 High 0 0 0 -1 0 0 0 0 Moderate (2%); p=0.11. • Overall SSI rate was 4.4%. • Significantly more empyema in group without Organ/ postoperative AMP: 6/102 (6%) vs. 1/101 Space 36 (1%); p=0.03. SSI 1 RCT High 0 0 0 -1 0 0 0 0 Moderate • Both groups received AMP at induction of (empye- anesthesia and were redosed intraoperatively ma) (2h). None vs. Incisional 36 • No difference: 1/102 (1%) vs. 1/101 (1%); Moderate 1 RCT High 0 0 0 -1 0 0 0 0 Moderate 2 days SSI p=0.9.

36 • 4 (2%) postoperative deaths; none related to Mortality 1 RCT High 0 0 0 -1 0 0 0 0 Moderate AMP or SSI.

Length of 36 • No differences: 15±1.6 days versus 13±1 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Stay days.

Adverse 36 • No side effects of the antimicrobial 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Events prophylaxis were noted. Vascular Surgery

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • No difference in 1 RCT subanalysis (N=169) None of clean, clean-contaminated, and vs. SSI* 1 RCT 16 contaminated elective and emergency High 0 0 0 -1 0 0 0 0 Moderate Moderate <24 hours vascular surgery procedures: 2/89 (3.8%) vs. 3/80 (2.3%), p>0.05 (1 month follow up). • No difference in 1 RCT, of patients <24h undergoing acute femoral embolectomy or

vs. SSI* 37 thrombectomy, subanalysis (N=121): 2/52 High 0 0 0 -1 0 0 0 0 Moderate Moderate 1 RCT 3 days (3.8%) vs. (3/69) 4.3%; p=0.89 (30 day follow up). • Reduced risk of SSI with postoperative AMP in 1 RCT of emergency and elective open arterial reconstructions (N=302): 28/153 (18%) vs. 15/149 (10%); OR: 2.00 (1.02 – 3.92); p=0.04 (42 day follow up). 38 • Overall SSI rate: 14.2% (43/302). SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate None • Patients received first dose of AMP (over 30 vs. minutes) after induction of anesthesia. Moderate 5 days Patients tended to be “elderly and debilitated”, with a higher proportion of those in the “no postoperative AMP” being current smokers and insulin dependent diabetics. Organ/ Space 1 RCT 38 • No difference: 1 graft infection in each group. High 0 0 0 -1 0 0 0 0 Moderate SSI Ear, nose, and throat (ENT) procedures • No difference on meta-analysis of 2 small RCTs (N=127): OR: 1.54 (0.59 – 4.05); ≤24h p=0.38 ; I2=0 2 RCT 39 vs. SSI* 39,40 • 1 RCT of 53 patients undergoing head and High 0 0 0 -1 0 0 0 0 Moderate Moderate

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders follow up and no difference between groups: 8/26 (30.7%) vs. 5/27 (18.5%); p=0.47. • 1 RCT 40 in 74 patients undergoing head and neck procedures including immediate flap reconstruction reported an overall wound infection rate of 10.8% (8/74) at 7 day follow up and no difference between groups 4/35 (11%) vs. 4/39 (10%); p=0.99

Length of 39 • No difference: 25±18 vs. 22±15 days; 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Stay p=0.627.

Pharyng- • No difference: 3/35 (9%) vs. 3/39 (8%) (7 day ocutane- 40 follow up). 1 RCT High 0 0 0 -1 0 0 0 0 Moderate ous • Overall pharyngocutaneous fistula rate: 6/74 Fistula (8%). Gynecologic Procedures • No difference in SSI in a meta-analysis (N=1917) of 5 RCTs: OR: 0.92 (0.51 – 1.65); p=0.77; I2=0 • In 1 RCT 13 (N=531) of patients undergoing laparoscopic-assisted vaginal hysterectomy (LAVH) or ovarian cystectomy (LAOC), total abdominal or vaginal hysterectomies (TAH or None TVH), 1 trocar site infection was reported in 5 RCT vs. SSI* 13,27-30 each group at 90 day follow up: 1/267 vs. High -1 0 0 -1 0 0 0 0 Low Low

≤24h 1/264. • In 1 RCT 27 (N=66) of patients undergoing radical gynecologic pelvic surgery for malignancy, 1 abdominal wound infection was reported in each group at 8 day follow up: 1/37 vs. 1/29. • In 1 RCT 29 with a subpopulation of 608 patients undergoing unspecified gynecologic © 2017 American Medical Association. All rights reserved. 105

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders procedures, no difference in SSI at minimum 7 day follow up: 12/385 vs.4/223; p=0.53 • In 1 RCT 28 of 112 patients undergoing vaginal hysterectomy, no difference in SSI at 3-6 week follow up: 1/58 vs. 2/54 • In 1 RCT30 of 500 women undergoing cesarean section, No difference in SSI at 30 day follow-up: 12/250 (4.8%) vs. 16/250 (6.4%). • In 1 RCT (N=531) among the 478 who had laparoscopic-assisted vaginal hysterectomy (LAVH), total abdominal or vaginal Organ/ 13 hysterectomies (TAH or TVH), only 1 vaginal space 1 RCT High -1 0 0 -1 0 0 0 0 Low cuff infection with pelvic abscess was reported SSI in a patient who underwent LAVH in the 24 hour group: 0/237 vs. 1/241 (0.41%) at 90 day follow up. • In 1 RCT (N=531), among the 455 (86%) patients who had a laparoscopic-assisted vaginal hysterectomy (LAVH) or ovarian Trocar 13 cystectomy (LAOC), only 1 trocar wound Wound 1 RCT High -1 0 0 -1 0 0 0 0 Low infection was reported in a patient who Infection underwent LAOC in the no postoperative AMP group: 1/226 (0.44%) vs. 0/229. (90 day follow up). • One RCT 13 no difference: 4.02 ±1.51 vs. 3.97±1.27. Length of 3 RCT • One RCT 27 no difference: 18 days (range 12- 13,27,28 High -1 0 0 0 0 0 0 0 Moderate Stay 23) vs. 19 days (range, 12-23 days). • One RCT 28 no difference : days ±SD: 4.4±1.1 vs. 4.7±1.2 days.

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • No difference: 1 RCT (N=156) in patients undergoing a laparoscopic-assisted vaginal SSI* 1 RCT 41 hysterectomy (LAVH) no difference: 2/74 High 0 0 0 -1 0 0 0 0 Moderate (2.7%) vs. 3/82 (3.6%) (7 day follow up) • Overall SSI rate: 3.2% (5/156) <24h vs. Organ/ Moderate 41 • No difference 1 vaginal cuff abscess in each <2.5 days Space 1 RCT High 0 0 0 -1 0 0 0 0 Moderate group. (7 day follow up). SSI Trocar 41 • No difference: 1/74 (1.4%) vs. 3/82 (3.7%); wound 1 RCT High 0 0 0 -1 0 0 0 0 Moderate p=0.38. (7 day follow up) infection Orthopaedic Surgery – Fracture Surgery • No difference on meta-analysis of 4 RCTs (N=1722): OR: 1.87 (0.70 – 4.94); p=0.21 ; I2=44% • 3 RCTs 14, 17, 19 reported no difference between groups for all SSIs combined. • One RCT 14 (N=191) in hip fracture patients reported a total of 4 (2.1%) infections and no difference between groups at 6w follow up: 2/83 (2.4%) vs. 2/108 (1.9%); p=0.79. Both None were superficial SSI. Postop dosing group vs. SSI* 4 RCT High -1 0 0 -1 0 0 0 0 Low Low 14,17-19 received AMP for another 24h. ≤24h • 1 RCT 17 (N=200) in a mix of clean orthopaedic fracture surgeries reported a total of 14(7%) infections, and no difference between groups at 28day follow up: 8% vs. 6%; p=0.27 Postop dosing group received AMP for another 24h. • 1 RCT 19 (N=614) in orthopaedic fracture fixation and arthroplasty patients, no difference: 2/301 (0.66%) vs. 3/313 (1.27%); © 2017 American Medical Association. All rights reserved. 107

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders p=0.45 (10 day follow up); overall SSI rate 0.98%. • 1 RCT 18 (N=717) in a mix of orthopaedic fracture surgeries, reported a total of 23 (3.2%) infections (follow up period not reported) with a significantly higher risk of SSI among the no postoperative AMP group : 20/382 (5.3%) vs. 3/335 (0.89%); p<0.01 This significance was seen for both hemiarthroplasties: 5/76 (6.5%) vs. 0/74 (0%); p=0.03 and all other procedures combined: 15/306 (5%) vs. 3/261 (1%); p<0.01. Postoperative dosing group received AMP for another 20h postop. Patients in both groups were hospitalized for approximately 5 days before surgery. • No difference on meta-analysis of 2 RCTs (N=391): OR: 0.33 (0.03 – 3.19); p=0.34. • One RCT 14 (N=191) in hip fracture patients reported no deep infections in either group 2 RCT Deep 14,17 (0/83 vs. 0/108) at 6 week follow up. High -1 0 0 -1 0 0 0 0 Low SSI • 17 1 RCT (N=200) in a mix of clean orthopedic fracture surgeries reported a total of 4 (2%) deep infections and no difference between groups at 28 day follow up: 1% vs. 3%; p=0.34. • No difference in meta-analysis of 2 RCT (N=391), no difference between groups OR: 1.99 (0.64 – 6.17); p=0.24; I2=0%. Superfic- 2 RCT • 1 RCT 14 (N=191) in hip fracture patients 14,17 High -1 0 0 0 0 0 0 0 Moderate ial SSI reported a total of 4 (2.1%) infections and no difference: 2/83 (2.4%) vs. 2/108 (1.9%); p=0.79 (6 week follow up). • 1 RCT 17 (N=200) in a mix of clean © 2017 American Medical Association. All rights reserved. 108

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders orthopaedic fracture surgeries reported a total of 10 (5%) superficial SSIs and no difference: 7% vs. 3%; p=0.21 (28 days follow up).

• In 1 RCT 14 (N=191), there were 7 (3.4%) deaths. There were no significant differences in mortality between groups 3/121 (2.4%) vs. Mortality 2 RCT 4/83 (4.81%) and no deaths resulted from 14,18 High 0 0 0 0 0 0 0 0 High infections. • In 1 RCT 18 (N=717) there were 30 deaths (4%); 1 patient had an uncontrolled wound infection but the cause of death was a stroke. • In 1 RCT (N=191), there were no anaphylactic Adverse 14 1 RCT reactions, allergies, or renal toxicity related to High 0 0 0 -1 0 0 0 0 Moderate Events antimicrobial prophylaxis administration. • In 1 RCT 14 (N=191), Staphylococcus aureus isolated from all SSIs. No gram negative organisms isolated. No mention of antimicrobial resistance. • In 1 RCT 17 (N=200) Staphylococcus aureus was the commonest organism isolated, followed by E. coli. Eight of the 14 SSIs had a Antimicr- negative wound culture (7 superficial, 1 deep). obial 3 RCT 14,17,18 No mention of resistance. High 0 0 0 0 0 0 0 0 High Resista- • 18 nce In 1 RCT (N=717) 31 organisms isolated from 23 wound infections: 9 Staphylococcus aureus, 4 S. epidermis, and 4 E. coli all sensitive to the AMP. In addition, 4 Pseudomonas aeruginosa, and 3 Streptococcus faecalis all resistant to the AMP and 7 strains of other gram negative bacilli, 2 of them resistant to the AMP. Orthopaedic Surgery - Prosthetic Joint Arthroplasty © 2017 American Medical Association. All rights reserved. 109

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • No difference in a meta-analysis of 2 RCT, (N=2,847) no difference between groups OR: 1.84 (0.68 – 4.98); p=0.23. • In the larger RCT 20 (N=2651) in THA, TKA, and hemiarthroplasty patients, no difference in None 2 RCT PJI between groups at 13 month follow up: vs. SSI* 20,21 11/1327 (0.83%) vs. 6/1324 (0.45%); p=0.17; High 0 0 0 0 0 0 0 0 High High ≤ 24h RR: 1.83, (0.68-4.93). • In the second smaller study 21 (N=196), in unilateral or bilateral THA or TKA patients no infections (including deep wound infections) were reported in either group at 12 month follow up. Colorectal Surgery BOWEL PREPARATION INCLUDED ORAL ANTIMICROBIALS PREOPERATIVELY • No difference in 1 RCT (N=360) in patients SSI* 42 undergoing elective laparotomy for colorectal 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Incisional malignancy: 15/179 (8.4%) vs. 13/181 (7.2%); p=0.67 (30 day follow up). SSI* • No difference: 1/179 (0.6%) vs. 2/181 (1.1%); Organ/ 1 RCT 42 p=0.58 (30 day follow up). High 0 0 0 -1 0 0 0 0 Moderate Space • All 3 caused by anastomotic leak. None vs. • Culture isolates available for 23/28 patients Moderate with incisional SSI: Pseudomonas aeruginosa 3 days Antimicr- most commonly isolated in both groups obial 42 1 RCT followed by Enterococcus faecalis. MRSA High 0 0 0 -1 0 0 0 0 Moderate resistan- isolated from 3 patients all in the groups ce without postoperative administration of AMP (in 2 as part of polymicrobial SSI).

Adverse 42 1 RCT • No Clostridium difficile in either group. High 0 0 0 -1 0 0 0 0 Moderate events

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- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • 1 RCT (N=40) in patients with chronic ulcerative colitis, familial polyposis, or Gardner’s syndrome undergoing colectomy, SSI* 1 RCT 43 mucosal proctectomy with ileal pouch-anal High 0 0 0 -2 0 0 0 0 Low ≤24h anastomosis reported no wound or intra- vs. abdominal infections in either group at 1yr Low 5 days follow up: 0/22 vs. 0/18.

Length of 43 • No difference: (mean±SD) 8.7±0.4 days vs. 1 RCT High 0 0 0 -1 0 0 0 0 Moderate stay 8.4±0.2 days.

BOWEL PREPARATION ONLY • No difference in a meta-analysis of 4 RCTs (N=894), no difference between groups OR: 1.58 (0.76 – 3.28); p=0.22; I2=57%. • 1 RCT 15 (N=377) in elective open and laparoscopic colorectal procedures for colon cancer postoperative AMP was associated with reduced risk of SSI at 30 day follow up: 27/190(14.2%) vs. 8/187(4.3%); p<0.01. On multivariate analysis antimicrobial dose was None the only significant factor associated with 4 RCT vs. SSI* 15,22-24 incisional SSI (p<0.01). High -1 -1 0 0 0 0 0 0 Low Low

<24h • 1 RCT 22 1 subgroup analysis 1 (N=138) in patients undergoing elective colorectal procedures suggests no difference: 12/138 (8.7%); 5/71 (7.0%) vs. 7/67 (10.4%); p =0.48 (28-41 day follow up). • 1 RCT 22 subgroup analysis 2 (N=135) in patients undergoing elective colorectal procedures suggests no difference: 16/135 (11.9%); 8/65 (12.3%) vs. 8/70 (11.4%); p=0.87 (28-41 day follow up). © 2017 American Medical Association. All rights reserved. 111

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • 1 RCT 24 (N=154) in elective colorectal procedures suggests no difference: 40/77 (5.2%) vs. 40/77 (5.2%); Follow up NR. • 1 RCT 23 (N= 90) in elective colorectal procedures, excluding inflammatory bowel disease, suggests no difference for abdominal wounds: 18/90 (20%): 7/22 (31%) vs. 11/68 (16%); p=0.12; or perineal wounds: 1/3 (33.3%) vs. 7/13 (53.8%); p=0.53. (6 week follow up). • No difference in a meta-analysis (N=531) of 2 RCTs OR: 0.73 (0.30 – 1.77); p=0.49; I2=0%. • 1 RCT 15 no difference: 5/190 (2.6%) vs. Organ/ 2 RCT 9/187 (4.8%); p=0.26. (30 day follow up). space 15,24 High -1 0 0 0 0 0 0 0 Moderate • 24 SSI 1 RCT no difference for intra-abdominal abscess 2/77 (2.6%) vs. 1/77 (1.3%); p=0.57 or peritonitis 2/77 (2.6%) vs. 2/77 (2.6%); Follow up NR. • No difference in a meta-analysis of 3 RCTs: OR 1.35 (0.70 – 2.61); p=0.37; I2=0%. • 1 RCT44 with subanalysis in elective colorectal procedures (n=207) suggests no difference between groups at 35 day follow up: 11/102(10.7%) vs. 6/105 (5.6%); p=0.19. None • 1 RCT 45 (N=443) in elective colorectal 44- vs. 3 RCT procedures for cancer, inflammatory bowel All SSI* 46 High 0 0 0 0 0 0 0 0 High Moderate <2 – 3 disease (10%), and other (10%), suggests no days difference between groups for deep wound infections: 17/294 (5.8%); 9/149 (6%) vs. 8/145 (6%) or for intra-abdominal abscess: 3/294 (1.0%); 1/149 (1%) vs. 2/145 (1%) at 30 day follow up. • 1 RCT 46 (N=100) in elective colorectal procedures for cancer or diverticulitis © 2017 American Medical Association. All rights reserved. 112

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders suggests no difference between groups: 3/100 (3.0%); 2/54 (3.7%) vs. 1/46 (2.1%); p=0.66 (Follow up NR).

Organ/ 45 • No difference: 1/149 (1%) vs. 2/145 (1%). 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Space* • Overall Organ/Space SSI rate: 3/294 (1.0%).

Antimicr- obial 2 RCT • No difference in bacterial isolates and no 45,46 High -1 0 0 -1 0 0 0 0 Low Resista- report of antimicrobial resistance. nce BOWEL PREPARATION NOT REPORTED • No difference for colorectal cases in 1 RCT None 25 (N=224) in at-risk abdominal surgery: 40/224 vs. SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate (17.9%); 23/113(20.4%) vs. 17/111 (15.3%); ≤24h p>0.2 (30 day follow up). • No difference in a meta-analysis of 4 RCTs, (N=802) no difference between groups OR: 1.13; (0.75 – 1.70); p=0.57; I2=12%. • 1 RCT 47 (N=87) colorectal surgery suggests no difference: 20/87 (23.0%); 13/45 (28.9%) vs. 7/42 (16.7%); p=0.18 (28 day follow up). • 1 RCT 48 with subanalysis (n=428) in high-risk colorectal procedures suggests no difference: ≤24h 47- 4 RCT 45/428 (11%); 22/209 (11%) vs. 23/219 vs. SSI* 50 High 0 0 0 0 0 0 0 0 High High (11%); p=0.99 (30 day follow up). 2-3 days • 1 RCT 49 (N=60) in elective colon surgery no difference: 6/30 (20%) vs. 10/30 (33.3%); p=0.25. • 1 RCT 50 in elective colorectal surgery subanalysis (n=227) no difference in abdominal wound: 23/113 (19.5%) vs. 22/114 (19.3); p=0.84; perineal wound: 7/113 (6.2%) vs. 3/114 (2.6%);p=0.20. © 2017 American Medical Association. All rights reserved. 113

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • No difference in a meta-analysis (N=715) of 3 RCTs: OR: 0.77 (0.37 – 1.63); p=0.50; I2=0%. • 1RCT 48 Intra-abdominal abscess. No difference: 14/428 (3%) total; 6/209 (3%) vs. 8/219 (4%); p=0.65 (30 day follow up). • 1RCT 49 Intra-abdominal abscess no Organ/ 48- 3 RCTs difference: 2/30 (7%) vs. 2/30 (7%); Peritonitis Space 50 High 0 0 0 0 0 0 0 0 High no difference: 1/30 (3%) vs. 3/30 (10%);

p=0.32 (follow up NR). • 1 RCT 50 Intrapelvic abscess no difference: 2/113 (1.8%) vs. 2/114 (1.8%); Intra- abdominal abscess no difference: 2/113 (1.8%) vs. 1/114 (0.9%); p=0.56; Peritonitis no difference: 0/113 vs. 1/114 (0.9%). • Adverse events possibly related to antimicrobial agent included 2 patients with Adverse 50 phlebitis in the group receiving <24 AMP and 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Events in the group receiving longer AMP, 2 cases of hypotension, 1 phlebitis, 1 erythema, and 1 rash. NO BOWEL PREPARATION • No difference in 1 RCT subpopulation (n=46) None 22 of emergency colorectal procedures: 6/46 vs. SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate (13.0%); 4/21 (19.0%) vs. 2/25 (8.0%); p=0.28 ≤24h (28-42 day follow up). None • No difference in 1 RCT subpopulation (n=38) vs. 44 of emergency colorectal procedures: 1/17 SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate <2 – 3 (5.8%) vs. 4/21 (20.0%); p=0.26 (35 day days follow up). General Surgery - OTHER Appendectomy

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • No difference in a meta-analysis of 4 RCTs (N=1039), OR: 0.85 (0.52 – 1.41); p=0.54; I2=0. • 1 RCT11 of emergency non-perforated open appendectomies reported no difference in incisional wound infections between groups: 6/92 (6.5%) vs. 6/94 (6.4%) at 30 day follow. None No deep incisional or organ/space infections 4 RCT vs. SSI* 11,22,25,31 were reported in either group. High 0 0 0 0 0 0 0 0 High High 31 ≤24h • 1 RCT (N=377) of emergency open appendectomies suggested no difference: 9/195 (4.6%) vs. 8/182 (4.3%); p=0.92. • 1 RCT 25 with subpopulation of appendectomies (n=247): 11/114 (9.6%) vs. 21/133 (15.8%); p=0.16. • Drug regimen 1 22: n=112: 4/54 vs. 4/58. • Drug regimen 2 22: n=117 2/63 vs. 0/54. • Increased risk of SSI with 2 days None 44 postoperative AMP: 1 RCT subpopulation of vs. SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate appendectomies (n=246): 3/127 (2.3%) vs. 2 days 10/119 (8.4%); p<0.05. Rectal surgery • No difference in 1 RCT subanalysis of 48 None 26 elective rectal surgery patients: 2/19 (10.5%) vs. SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate vs. 1/29 (3.4%); p=0.35. (1 month follow up). ≤24h • Number of events is small. Gastric Surgery • No difference in 1 RCT with subanalysis gastric procedures (n=64) including None Organ/ 26 gastrectomy (n=8), gastric banding (n=35) vs. 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate space* and other gastric (n=21) reported deep ≤24h surgical sepsis: 1/24 (4%) vs. 4/40 (10%); p=0.41.

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • No difference in meta-analysis of 2 RCTs (N=683) of elective gastric cancer surgeries both with 30 day follow up and intraoperative AMP bolus administered every 3 hours of surgery. OR: 0.87 (0.28 – 2.65); p=0.80; I2=71% 2 RCT 52 SSI* 51,52 • 1 RCT (N=325) 15/164 (9.1%) vs. 10/161 High -1 -2 0 0 0 0 0 0 Very Low

(6.2%); there was a higher incidence of transfusion in the multiple dose group. • 1 RCT51 (N=355) suggested no difference 8/176 (5%) vs. 16/179 (9%); p=0.138; there was a higher incidence of transfusion in the multiple dose group: 0/176 vs. 4/176 (2.2%). • No difference in metaanalysis of two RCTs. (N=683); OR: 1.08 (0.37 – 3.17); P=0.89; I2=75%. None 52 • In 1 RCT (N=325) there were fewer SSI in vs. Very Low the multiple dose group but this difference 2 days Organ/ 2 RCT was not significant: 11/164 (6.7%) vs. 6/164 Space 51,52 High -1 -2 0 0 0 0 0 0 Very Low (3.7%); p=NS (Note: 9/164 (5.5%) vs. 3/161 SSI (0.9%) patients manifested both organ/space and incisional infections). • 1 RCT51 (N=355) suggested fewer SSI in the single dose group but this was not significant 7/176 (4%) vs. 11/179 (6%); p=0.47. • No difference in metaanalysis of two RCTs. (N=683); 0.79 (0.08 – 7.87); 0.84; I2=75%. • In 1 RCT52 (N=325) there were fewer SSI in the multiple dose group but this difference Incisional 2 RCT 51,52 was not significant: 14/164 (8.5%) vs. 7/164 High -1 -2 0 0 0 0 0 0 Very low SSI (4.3%) (Note: 9/164 (5.5%) vs. 3/161 (19%) patients manifested both organ/space and incisional infections). • 1 RCT51 (N=355) suggested higher SSI in the © 2017 American Medical Association. All rights reserved. 116

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders multiple dose group but this difference was not significant: 1/176 (<1%) vs. 5/179 (3%); p=0.215.

Antimicr- obial 52 • No difference in antimicrobial resistance 1 RCT High -1 0 0 -1 0 0 0 0 Low Resista- between groups: 2/15 vs. 0/10. nce • No difference in 1 RCT of elective gastric surgery for gastric cancer (excluded colorectal SSI* 1 RCT 53 surgery): 23/243 (9.5%) vs. 21/243 (8.6%) High 0 0 0 -1 0 0 0 0 Moderate p=NS. (30 day follow up) • Overall SSI rate of 9.1% (44/486) Organ/ 53 • No difference: 12/243(4.9%). Vs. Space 1 RCT High 0 0 0 -1 0 0 0 0 Moderate None 10/243(4.1%) p=NS vs. SSI Moderate 4 days Incisional 53 • No difference: 14/243 (5.8%) vs. 11/243 1 RCT High 0 0 0 -1 0 0 0 0 Moderate SSI (4.5%); p=NS Antimicr- obial 53 1 RCT • No difference in isolate resistance patterns. High 0 0 0 -1 0 0 0 0 Moderate Resista- nce Hepatectomy • No difference in 1 RCT (N=188) in 54 hepatectomies: 7/94 (7.5%) vs. 13/94 SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate (13.8%); 14 day follow up; p=0.24. None vs. • Overall SSI rate: 10.6% (20/188). Moderate 3 days Organ/ 54 • No difference: 4/94 (4.3%) vs. 11/91 (11.7%); Space 1 RCT High 0 0 0 -1 0 0 0 0 Moderate p=0.10 SSI

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Quantity GRADE Comparis- Outcom- Starting Evidenc and Type of Findings of on e GRADE e for Evidence Evidenc- Outcom- response

- e Base e Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders

Incisional 54 • No difference: 3/94 (3.2%) vs. 3/94 (3.2%); 1 RCT High 0 0 0 -1 0 0 0 0 Moderate SSI p=1.00

• There was a significantly longer length of stay Length of 54 1 RCT in the multiple dose group: 12 (4-91) days vs. High 0 0 0 -1 0 0 0 0 Moderate Stay 14 (5-265) days; p=0.03 • No difference in 1 RCT (N=180) in 55 hepatectomies: 4/89 (4.5%) vs. 4/91 (4.4%); SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate 14 day follow up • Overall SSI rate: 4.4% (8/180) Organ/ 2 days vs. 55 • No difference: 2/89 (2.2%) vs. 3/91 (3.3%); Space 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate 5 days p=0.67 SSI

Incisional 55 • No difference: 2/89 (2.2%) vs. 1/91 (1.1%); 1 RCT High 0 0 0 -1 0 0 0 0 Moderate SSI p=0.56

*Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

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2.1A2. EVIDENCE TABLES: Q1 PARENTERAL AMP Q1. What are the most effective strategies for administering parenteral AMP to reduce the risk of SSI? Q1A. What is the optimal timing of preoperative AMP? Our search did not identify RCTs or SRs that evaluated different timings of preoperative AMP administration and its impact on the risk of SSI. eTABLE 25. Evidence Table Q1A. Q1A. What is the optimal timing of preoperative AMP in surgeries involving tourniquet inflation? Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Akinyoo- RCT To compare Number of patients: Intervention group: n=52 SSI Definitions: la 1, 2 the clinical N=106 Intravenous cefuroxime at Postoperative wound Wound infections: 2011 1 outcomes in Patient a dose appropriate to infection spontaneous (ES) patients Characteristics the patient’s age and Intervention: 2/52 (3.9%) drainage of pus administered ·Age, y: mean±SD body weight was Control: 8/54 (14.8%) after suture prophylactic Intervention: 25.6±2 administered 1 minute P=0.031 removal or in antibiotics 5 SD (17.5) after tourniquet inflation association with minutes Control: 31.2±2 SD followed by 3 doses at Other infections: NR overt wound before (20.6) 8 hour intervals during Topic-specific outcomes dehiscence. If a exsanguinatio p=0.687 the initial postoperative Interval to wound healing, wound infection n and inflation ·Gender: 76/106 period. weeks: mean±SD was identified in of the (71.7%) were male Timing of intervention: Intervention: 3.0±0.5 the tourniquet but not reported intraoperative Control: 4.0 ±2.3 postoperative (Intervention) which group Duration of intervention: P=0.002 period, a swab and those ·Obesity: NR NA Reoperations: NR specimen of administered ·Comorbidities: NR Device/agent: cefuroxime Length of stay: NR exudate was prophylactic Monitoring intervention: Mortality: NR sent for antibiotics 1 Procedures: NA Adverse events: NR microscopy, minute after Open reduction internal Control group: n=54 culture and inflation of the fixation 76/106 Intravenous cefuroxime at sensitivity testing tourniquet (71.7%)) a dose appropriate to to guide (control) in Intervention: 40/52 the patient’s age and subsequent elective lower (74.1%) body weight was antibiotic limb Control: 36/54 (69.2%) administered 5 minutes therapy. orthopedic Soft tissue release: before tourniquet Wound healing: a operations. 23/106 (21.7%) inflation followed by 3 well coated non- Intervention: 11/52 doses at 8 hour tender wound (20.4%) intervals during the with a linear scar Control: 12/54 (23.1%) initial postoperative and no sign of Triple arthrodesis 5/106 period. infection. (4.7%) Perioperative care Intervention: 2/52 Standard preventive Anesthesia: all (3.7%) measures: patients © 2017 American Medical Association. All rights reserved. 119

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Control: 3/54 (5.8%) All operations were underwent Keller’s operation 2/106 performed within 5 days general (1.7%) of admission anesthesia Intervention: 1/52 Tourniquet time (min) except for 2 who (1.9%) mean±SD had spinal Control: 1/54 (1.9%) Intervention: 69.8±32.8 anesthesia Indications: Control: 75.3 ±30.8 Eparch bandage Tibial fracture 54/106 P=0.396 was used for (50.9%) exsanguination Intervention: 26/52 and the (50%) tourniquet was Control: 28/54 (51.9%) applied to the Ankle fracture/ thigh in all cases dislocation 22/106 Other notes: (20.8%) Underpowered to Intervention: 10/52 measure (19.2%) infection rates Control: 12/54 Follow-up: 12 (22.2%) months postop Hallux valgus 2/106 Funding Source (1.9%)) Conflicts: Intervention: 1/52 Authors: NR (1.9%) Institution: NR Control: 1/54 (1.9%) Study: NR Clubfoot 28/106 Supplies: NR (26.4%) Intervention: 15/52 (28.9%) Control: 13/54 (24.1%)

Setting: 1 university hospital Location: Nigeria Dates: February 2005 – January 2006 Inclusion Criteria: Patients who underwent clean, elective orthopedic © 2017 American Medical Association. All rights reserved. 120

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score operations on the lower limbs with the use of a tourniquet hemostasis. Exclusion Criteria: NR Soriano RCT To evaluate Number of patients: Intervention group: SSI Definitions: 2008 2 1, 3, 4, the N=908 n=466 NOTE: when an infection Deep tissue (ES) 5, 10 importance of Patient Placebo administered 10- was suspected, the infection rate: a “tourniquet- Characteristics: no 30 minutes before patient underwent open CDC SSI release” dose, differences in inflation of the debridement Guideline with a characteristics tourniquet and 1.5g of Total Deep SSI at 3 Criteria randomized, between groups cefuroxime was months = 24/908 Perioperative double-blind ·Age, y: mean±SD administered 10 min (2.64%) care: study of Intervention: 70.9±7.2 before release of the Intervention: 9/466 Anesthesia: spinal primary total Control: 71.2±7.6 tourniquet. A (1.9%) Other notes: knee ·Gender: female% postoperative dose of Control: 15/442 (3.4%) Sample size arthroplasty Intervention: 73.6% 1.5g cefuroxime P=0.21 calculated from performed Control: 76.5% administered at 6h after a previous deep during ·Obesity: the end of the Total cumulative Deep SSI tissue infection ischemia. Intervention: 37.8% procedure. at 12 months = 28/908 rate (4%) in the Control: 35.5% (3.08%) institution. ·Comorbidities Timing of intervention: Intervention: 12/466 Follow-up: 12 Diabetes mellitus intraoperative (2.6%) months post Intervention: 14.6% Duration of intervention: Control: 16/442 (3.6%) discharge Control: 18.3% NR P=0.44 Funding Source Device/agent: 1.5g Conflicts: Procedures: Total cefuroxime Other infections: NR Authors: None knee arthroplasty Monitoring intervention Topic-specific Institution: NR Indications: Control group: n=442 outcomes: Study: NR Arthritis 1.5g cefuroxime MSSA SSI at 3 months = Supplies: NR Intervention: 98.8% administered 10-30 9/24 (37.5%) Control: 98.7% minutes before inflation Intervention: 3/9 (33.3%) Rheumatoid arthritis of the tourniquet and Control: 6/15 (40%) Intervention: 1.2% placebo was MSSA SSI between 4-12 Control: 1.3% administered 10 min months = 4/4 (100%) before release of the Intervention: 3/3 (100%) Setting: Single center tourniquet. A Control: 1/1 (100%) Location: Spain postoperative dose of

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Dates: September 1.5g cefuroxime MRSA SSI at 3 months = 2004 – December administered at 6h after 6/24 (25%) 2005. the end of the Intervention: 1/9 (11.1%) Inclusion Criteria: procedure. Control: 1/15 (6.67%) Patients undergoing MSSA SSI between 4-12 a primary total knee Standard preventive months = 0/4 arthroplasty who measures: Intervention: 0/3 signed the informed Laminar Air Flow: not used Control: 0/1 consent. Skin Prep: leg washed Exclusion Criteria: with soap then with COPD with/without deep Patients allergic to 10% povidone iodine tissue infection at 12 penicillin solution. months Cement – All prostheses Uninfected (n=880): 9.5% cemented and none Infected (n=28): 21.4% used antimicrobial P=0.05 impregnated cement. Drains: 1 profound and 1 ASA Score 3-4 at 12 superficial drain tube months left after closing the Uninfected (n=880): 129 wound were removed (14.8%) within the first 48 hours Infected (n=28): 12 after the surgical (42.9%) procedures P<0.001 Transfusion: during the surgical procedure and Low 4th day hematocrit the first 6h after the infection rate at 12 procedure, an RBC months transfusion was given Uninfected (n=880): when the hemoglobin 28.3±3.8 level was <9g/dL. After Infected (n=28): 26.5±4.1 this period, the P=0.02 threshold for RBC transfusion was <8g/dL Reoperations: NR Mean no of transfusions All deep prosthetic joint ±SD infections included an Intervention: 0.9±1.3 open debridement and Control: 0.8±1.3 ≥3 deep cultures of Duration of ischemia: synovial fluid samples (mean±SD, min) and periprosthetic © 2017 American Medical Association. All rights reserved. 122

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 54.1±17.9 tissue samples from Control: 53.9±18.3 different sites. Length of stay, days: mean±SD Intervention: 6.4±1.6 Control: 6.5±2.1 Mortality: NR Adverse events: NR

eTABLE 26. Evidence Table for Q1B. What is the optimal timing of AMP in cesarean section: prior to skin incision or at cord clamping? Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Osman RCT To investigate Number of patients: Intervention group: n=90 SSI: Definitions: 2013 3 1, 2, 3, the timing of N=180 Patients who received a Endometritis Post-operative (ES) 4, 10 prophylactic Patient single intravenous Intervention: 0/90 febrile morbidity: ceftizoxime for Characteristics injection of 1g Control: 0/90 an oral elective ·Age, y, mean (SD) ceftizoxime 40 minutes Superficial wound temperature of cesarean Intervention: 30.5 (7.4) pre-incision infection: ≥38oC on two delivery at the Control: 32.2 (5.2) Timing of intervention: Intervention: 8/90 (6.7%) occasions at study hospital. P=0.08 preoperative Control: 3/90 (3.3%) least 4 hours ·Gender: all female Duration of intervention: P=0.2 (all incidences apart, excluding ·Obesity: BMI, mean NA occurred post- the first 24h. Calculated by Device/agent: 1g discharge) Postoperative extractor from mean ceftizoxime infection height & mean Monitoring intervention: Other infections: NR Endometritis: fever, weight in study NA Topic-specific uterine Intervention: 30.9 Control group: n=90 outcomes: tenderness, and Control: 31.2 Patients who received a Neonatal outcomes abnormal lochia P=0.1 single intravenous Admission to the nursery: Wound infection: ·Comorbidities: NR injection of 1g Intervention: 15/90 fever, cellulitis & © 2017 American Medical Association. All rights reserved. 123

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Gestational age, ceftizoxime post cord (16.7%) exudates weeks: mean (SD) clamping Control: 15/90 (16.7%) Peritonitis: elevated Intervention: 38.2 (1.1) Standard preventive P=0.1 temperature, Control: 38.3 (0.9) measures : NR Jaundice tachycardia, P=0.7 Intervention: 5/90 (5.5%) abdominal Gravidity: mean (SD) Control: 4/90 (4.4%) distension and Intervention: 3.5 (1.6) P=1.0 pain with Control: 36.9 (0.4) Reoperations: NR guarding and P=0.5 Length of stay: NR rigidity Procedures: elective Mortality: NR aggravated by cesarean section Adverse events: moving and Indications: Skin rash breathing with Repeated cesarean Intervention: 0/90 (0) absent bowel delivery: Control: 1/90 (1.1%) sounds at the Intervention: 55/90 P=1.0 onset of paralytic (61.1%) ileus. Control: 61/90 (67.8%) Perioperative P=0.1 care: NR Breech presentation: Other notes: study Intervention: 10/90 was (11.1%) underpowered Control: 8/90 (8.9%) Follow-up: 6 P=0.6 weeks post op at Hypertensive disorder clinic visit. Intervention: 2/90 Funding Source (2.2%) Conflicts: Control: 1/90 (1.1%) Authors: None P=0.5 Institution: NR Bad obstetrics events Study: Industry Intervention: 7/90 Supplies: NR (7.8%) Control: 11/90 (12.2%) P=0.3 Others Intervention: 16/90 (17.8%) Control: 9/90 (10%) P=0.1

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Setting: 1 university hospital Location: Sudan Dates: May 2011 – August 2011 Inclusion Criteria: Patients who were planned for elective cesarean delivery (e.g. repeated scars, breech and low lying placenta) Exclusion Criteria: Severe anemia, twins, diabetes mellitus, impaired glucose test, received antibiotics within 2 weeks prior to the operation, if they had any visible infection at any site or elevated temperature at the time of the operation; if they were allergic to drug used; or refusal to participate in study

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Witt RCT To compare Number of patients: Intervention group: SSI: Definitions: 2011 5 1, 2, 3, the N=741 n=370 Local Wound Infection Wound infection: (ES) 4, 5, 6, effectiveness Patient 2g of cefazolin mixed with (LWI), purulent 7, 8, 9 of cefazolin, a Characteristics 100mL saline Intervention: 9/370 discharge or first- ·Age, y: mean (SD) administered 20-30 (2.4%) erythema (>1cm generation Intervention: 31.3 (6.3) minutes before skin Control: 9/371 (2.4%) in diameter) and cephalosporin, Control: 32.2 (5.8) incision Risk difference: 1.1%, induration of the administered ·Gender: all female Timing of intervention: 95%CI (-1.8%-4.0%); incision site. before skin ·Obesity: BMI (kg/m2), preoperative P=0.60 Urinary tract incision vs. mean (SD) Duration of intervention: infection: if there after umbilical Intervention: 28.3 (5.4) NA LWI during hospital stay were clinical cord clamping Control: 28.3 (5.4) Device/agent: 2g Intervention: 6/370 symptoms (i.e. vs. placebo in ·Comorbidities: cefazolin in 100mL (1.6%) polyuria and a 3-arm Gestational diabetes saline Control: 8/371 (2.2%) dysuria) and a randomized mellitus, Monitoring intervention: LWI at 3 weeks positive urine trial of women Intervention: 39/370 NA postpartum dipstick nitrite undergoing (10.5%) Control group: n=371 Intervention: 3/370 test result. elective Control: 33/371 (8.9%) 2g cefazolin in 100mL (0.8%) Perioperative cesarean History of allergy saline administered at Control: 1/371 (0.3%) care: delivery delivery. Intervention: 27/370 cord clamping performed by (17.3%) Standard preventive Endometritis: resident under Control: 30/371 (8.1%) measures: NR Intervention: 1/370 the supervision Immunosuppression, (0.3%) of fully trained Intervention: 4/370 Control: 1/371 (0.3%) attending (1.1%) Endometritis during physicians using Control: 2/371 (0.5%) hospital stay a modified Anticoagulation: Intervention: 0/370 Misgav Ladach Intervention: 9/370 Control: 1/371 (0.3%) technique. (2.4%) Endometritis at 3 weeks Other notes: Control: 12/371 (3.2%) postpartum power Intervention: 1/370 calculation Procedures: elective (0.3%) demonstrated a cesarean delivery. Control: 0/371 sample size of Indications: NR 360 per arm for Setting: 1 university Other infections: a power of 90% hospital Urinary tract infection to detect an Location: Austria (UTI), absolute Dates: March 1, 2004 – Intervention: 8/370 reduction of 5% January 31, 2010 (2.2%) in primary © 2017 American Medical Association. All rights reserved. 126

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Inclusion Criteria: Control: 4/371 (1.1%) outcome at women undergoing UTI during hospital stay α=0.05 cesarean delivery Intervention: 5/370 Follow-up: 30 with a gestational (1.4%) days postop via age of at least 37 Control: 4/371 (1.1%) telephone weeks and UTI at 3 weeks postpartum survey. If reassuring fetal Intervention: 3/370 patients reported heart traces. Women (0.8%) any of the signs who experienced Control: 0/371 & symptoms of rupture of an outcome membranes and Topic-specific measure, they labor contractions outcomes: were asked to were also included Pelvic Abscesses report to the Exclusion Criteria: Intervention: 1/370 clinic for fever >38oC, (0.3%) confirmation cephalosporin Control: 1/371 (0.3%) Funding Source allergy, age <18 Conflicts: years, and exposure Neonatal Outcomes: Authors: NR to any antibiotic showed no statistically Institution: NR agent within 1 week significant difference Study: NR before delivery. between groups (data Supplies: NR not shown)

Reoperations: NR Length of stay days: mean (SD), Intervention: 5.5 (1.6) Control: 5.5 (1.9)

Mortality: NR Adverse events: NR Macones RCT To compare Number of patients: Intervention group: NOTE: study reported Definitions: 2011 4 1, 2, 3, maternal and N=434 n=217 percentages only. Maternal infectious (ES) 4, 5, 6, neonatal Patient 1 g Cefazolin given <30 Numerators were morbidities: (1) 9 outcomes in Characteristics: minutes prior to skin calculated by postoperative women who both groups were incision. extractor: fever (defined as receive similar with respect Timing of intervention: oral temp >38oC prophylactic to baseline preop SSI: on two separate antibiotics demographics Duration of intervention: Wound infection: occasions more © 2017 American Medical Association. All rights reserved. 127

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score prior to skin ·Age, y: mean NA Intervention: 0.5% than 6h apart, incision with Intervention: 28.9 Device/agent: 1 g (1/217) after the initial those who Control: 28.3 cefazolin Control: 1.4% (3/217) 24h postop receive P=0.27 Monitoring intervention: RR: 2.8 (0.7-4.2), P=0.37 period); (2) antibiotics at ·Gender: all females NA wound infection cord clamping ·Obesity: Control group: n=217 Endometritis (defined as Not reported but cited 1g Cefazolin given at cord Intervention: 2.8% purulent as similar at baseline clamping (6/217) discharge from ·Comorbidities: NR Standard preventive Control: 2.8% (6/217) the incision); (3) African American race: measures: RR: 1.0 (0.7-1.3), P=1.00 endomyometritis Intervention: 65.3% Antimicrobial prophylaxis: (defined as (142/217) patients received 1g fundal Control: 64.7 cefazolin. If allergic to Other infections: tenderness and (140/217) penicillin, they received Urinary Tract Infection: fever); (4) P=0.99 900mg clindamycin. Intervention: 0.9% urinary tract Gravidity: mean Cefazolin: (2/217) infection Intervention: 3.5 Intervention: 90.2% Control: 0.9% (2/217) (defined as Control: 3.3 (196/217) RR: 1.0 (0.3-4.0), P=1.00 fever, positive P=0.17 Control: 92.1% (200/217) urine culture). Gestational Age, P=0.71 Topic-specific weeks: mean outcomes: Perioperative Intervention: 38.7 Fever: care: Control: 38.9 Intervention: 2.3% Patients were P=0.70 (5/217) managed in the Control: 3.7% (8/217) postpartum Procedures: RR: 1.6 (0.8-2.2), P=0.42 period at the Scheduled cesarean discretion of Intervention: 73.4% Neonatal outcomes: treating (159/217) NICU Admission physicians. Control: 71.4% Intervention: 3.5% Regional (155/217) (8/217) Anesthesia P=0.62 Control: 4.0% (9/217) Intervention: Low transverse RR: 1.1 (0.7-1.8) 92.1% (200/217) cesarean Suspected sepsis Control: 90.6% Intervention: 95.4% Intervention: 8.9% (197/217) (207/217) (19/217) P=0.88 Control: 95.4% Control: 8.9% (19/217) (207/217) RR: 1.0 (0.7-1.3) Other notes: 217 P=1.00 subjects per arm © 2017 American Medical Association. All rights reserved. 128

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score was calculated Indications Reoperations: NR to see a Setting: 2 university Length of stay: NR decrease in the hospitals Mortality: NR composite Location: USA Adverse events: NR maternal Dates: NR infectious Inclusion Criteria: morbidity rate of those undergoing 10% in the cord nonemergency clamp group cesarean surgery at (based on pilot 36 weeks’ gestation data), with type I or greater. error of 0.05, (Pregnancies were type II error of dated by best 0.20. obstetric estimate using standard Follow-up: in the criteria.) hospital and Exclusion Criteria: postpartum stay. known fetal Funding Source anomaly, exposure Conflicts: to antibiotics within 7 Authors: NR days of admission Institution: NR (including Study: NR intrapartum Group B Supplies: NR Streptococcus prophylaxis), need for emergency cesarean delivery (i.e. for category III electronic fetal monitoring, maternal distress, obstetric hemorrhage), rupture of membranes >18h, and overt maternal intrapartum infection requiring antibiotics.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Yildirim RCT The aim was Number of patients: Intervention group: SSI: Definitions : 2009 6 1, 7, 8, to determine N=389 n=194 Wound infection: Elective cesarean (ES) 9 whether the Patient Characteristics: 1g cefazolin sodium Intervention: 6/194 section: timing of no significant administered 10-45min (3.1%) Cesarean prophylactic differences in prior to skin incision. Control: 8 (4.1%) section antibiotics at demographics Timing of intervention: P = 0.59 performed cesarean between groups preop RR: 1.34, 95%CI (0.45- before the delivery ·Age, y: mean ± SD Duration of intervention: 3.93) presence of influences Intervention: NA Endometritis: labor maternal and 28.25±4.87 Device/agent: 1g Intervention: 5/194 Wound infection: neonatal Control: 27.53±5.02 cefazolin sodium (2.6%) signs of infectious P=0.15 Monitoring intervention: Control: 7/195 (3.6%) erythema, morbidity. ·Gender: all female NA P = 0.56 swelling, ·Obesity: BMI (kg/m2): Control group: n=195 RR: 1.40, 95%CI (0.43- discharge or mean ±SD 1g cefazolin sodium was 4.51) tenderness Intervention: administered after Urinary tract 31.98±2.89 clamping of the Other infections: infection: clinical Control: 31.96±2.29 umbilical cord. Urinary Tract Infections: signs were P=0.93 Intervention: 3/194 checked and a ·Comorbidities Standard preventive (1.5%) urinalysis was Gravidity: mean±SD measures Control: 5/195 (2.6%) performed. Intervention: Antibiotic prophylaxis: 1 g P = 0.47 Neonatal sepsis: 2.57±1.05 of cefazolin sodium was RR: 1.67, 95%CI (0.39- suspected if Control: 2.45±1.05 used for antibiotic 7.11) tachycardia P=0.25 prophylaxis. No other and/or Parity: mean±SD antimicrobial Topic-specific tachypnea as Intervention: prophylaxis was outcomes: well as an 1.14±0.67 administered unless a Postoperative hematocrit increased white Control: 1.11±0.68 postoperative infection level, %: mean±SD, count with bands P=0.59 was diagnosed. Intervention: 30.17±0.97 was present and Gestational Age at Catheter: a foley catheter Control: 30.04±0.92 was confirmed delivery: mean±SD, was inserted pre- P=0.18 by positive weeks cesarean section and Postoperative hemoglobin culture. Intervention: removed postop. level, (g/l): mean±SD Perioperative 38.32±0.94 Skin prep – the abdomen Intervention: 9.91±0.50 care: NR Control: 38.24±0.69 was cleaned with a Control: 9.78±0.59 Other notes: P=0.31 povidone iodine P=0.02 Prior to this study, solution. Estimated blood loss, (ml): the institution Procedures: elective Incision: Pfannistiel mean±SD had a 20% © 2017 American Medical Association. All rights reserved. 130

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score cesarean section incisions were done on Intervention: postcesarean Indications: indications all patients, followed by 656.29±190.54 endometritis for cesarean section transverse lower uterine Control: 668.92±203.57 rate. were similar when segment incision and P=0.52 Study power. A the two groups were delivery of the fetus and Operative time, (min): sample size of compared placenta. mean±SD 197 was Previous cesarean, Closure: suturing of the Intervention: 36.63±2.66 calculated to Intervention: 168 uterine incision was Control: 37.12±3.89 provide 80% (86.6%) performed without P=0.14 power to detect Control: 173 (88.7%) exteriorization of the a 50% difference Multiple pregnancy uterus. The abdominal Neonatal outcomes: in postoperative Intervention: 5 (2.6%) wall was closed in two Intervention: n=201 infections, with Control: 5 (2.6%) layers then skin Control: n=198 α=0.05 Fetal macrosomia incisions were closed. Birth weight, (g): Follow-up: 6 (>4500g) mean±SD weeks postop Intervention: 8 (4.1%) Intervention: Funding Source Control: 6 (3.1%) 3263.75±505.86 Conflicts: Breech and Control: 3232.92±500.26 Authors: None malpresentation, P=0.53 Institution: None Intervention: 13 5-minute Apgar score: Study: None (6.7%) mean±SD Supplies: None Control: 10 (5.1%) Intervention: 9.08±0.71 Placenta previa Control: 9.06±0.78 Intervention: 0 P=0.79 Control: 1 (0.5%) Neonatal Sepsis: Intervention: 9/201 Setting: 1 tertiary care (4.4%) hospital Control: 13/198 (6.3%) Location: Turkey P = 0.38 Dates: June 2007 – RR: 1.47 (0.61-3.53) December 2007 NICU Admission Inclusion Criteria: Intervention: 4/201 (2%) Women undergoing Control: 7/198 (3.4%) elective cesarean P = 0.35 section at the RR: 1.77 (0.51-6.16) hospital without Sepsis workup: exclusion criteria Intervention: 23/201 Exclusion Criteria: (11.2%) use of antibiotics Control: 30/198 (14.6%) © 2017 American Medical Association. All rights reserved. 131

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score during the last 24h, P = 0.30 pathology that RR: 1.35 (0.75-2.42) should be treated NICU Length of Stay, with antibiotics, pre- days: mean±SD existing maternal Intervention: 8.25±2.62 diseases (such as Control: 5.66±2.58 diabetes, collagen P=0.16 vascular disease, immune system Reoperations: NR problems), Length of stay, days: chorioamnionitis, mean±SD fever on admission, Intervention: 2.30±1.09 need of transfusion Control: 2.39±1.18 before or during the p=0.46 cesarean section, ruptured Mortality: NR membranes, Adverse events: emergency cesarean There were no serious section, and pre- side effects related to term cesarean the use of cefazolin. section. Sullivan RCT To conduct a Number of patients: Intervention group: SSI: (Follow up 6 weeks) Definitions: 2007 8 1, 2, 3, prospective, N=357 n=175 Wound Infections Endomyometritis: (ES) 4, 5, 6, double-blind, Patient Received 1gm cefazolin Intervention: 5/175 (3%) maternal fever 7, 8, 9, randomized Characteristics: No mixed with 50 cc Control: 10/182 (5%) greater than 10 clinical trial to significant normal saline 15-60 Relative Risk (95% CI) 100.4oF on 2 determine differences found minutes prior to 0.52 (0.18-1.5) separate whether between groups. incision. Placebo (50 cc P>0.05 occasions along antibiotic ·Age, y: mean normal saline) Adjusted OR (95% CI) with uterine prophylaxis Intervention: administered at cord 0.4 (0.1-1.3) fundal administered 28.3±6.1 clamp Endomyometritis tenderness, preoperatively Control: 28.3±6.0 Timing of intervention: Intervention: 2/175 (1%) tachycardia or is more ·Gender: All Female Pre and Intraoperative Control: 10/182 (5%) leukocytosis. effective in ·Obesity (Maternal Duration of intervention: Relative Risk (95% CI) Wound Infection: preventing Weight) mean ±SD preoperative 0.2 (0.2-0.94) purulent infectious Intervention: (Intervention) and P<0.05 discharge, morbidity 225.3±144.5 Intraoperative (Control) Adjusted Odds Ratio erythema, and following Control: 228.1±152.9 Device/agent: Cefazolin (95% CI) induration of the cesarean ·Comorbidities: Monitoring intervention: 0.22 (0.05-0.9) incision site. © 2017 American Medical Association. All rights reserved. 132

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score delivery than Diabetes NR Total Infectious Morbidity Hematomas, administration Intervention: 17/175 Control group: n=182 Intervention: 8/175 seromas, or following cord (10%) Received placebo (50 cc (4.5%) wound clamp. Control: 29/182 normal saline) 15-60 Control: 21/182 (11.5%) breakdowns: in (16%) min prior to incision. Relative Risk (95% CI) the absence of Preeclampsia 1gm cefazolin mixed 0.4 (0.18-0.87) previously Intervention: 18/175 with 50 cc normal saline Statistically significant discussed signs (10.3%) administered at the time Adjusted OR (95% CI) were not Control: 25/182 of cord clamping. 0.35 (0.14-0.82) considered (13.7%) Standard preventive wound Operative Time, min: measures: NR Other infections: infections. mean ±SD Pyelonephritis: 1 case in Neonatal Sepsis: Intervention: intervention group. diagnosed by a 43.5±13.6 Pneumonia: 1 case in positive blood Control: 48±14.9 control group culture. Parity: mean Topic-specific Perioperative Intervention: 1.4 outcomes: care: NR Control: 1.2 Neonatal outcomes Other notes: Premature delivery Sepsis Weakness of (<37wks): Intervention: 6/185 (3%) this study is the Intervention: 30/175 Control: 7/194 (3.6%) high-risk nature (17%) Suspected sepsis of the study Control: 46/182 Intervention: 35/185 population. They (25%) (19%) were more Procedures: Cesarean Control: 36/194 (18.5%) obese, more Section Delivery; No difference in causative likely to have Performed by organisms or increased diabetes, resident physicians incidence of antibiotic preterm delivery, as primary surgeons resistant organisms. multiple which resulted in NICU Admission gestation and be increased average Intervention: 25/175 of minority surgery time (14.3%) ethnicity than Control: 33/182 (18.3%) the general Indications: P=0.40 population. The Arrest disorders NICU Days: mean±SD location of the Intervention: 50/175 Intervention: 14.2±15.8 trial was in a (28.6%) Control: 19.7±24.9 tertiary care Control: 53/182 P=0.01 center. (29.1%) No statistical difference in Follow-up: © 2017 American Medical Association. All rights reserved. 133

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Non-reassuring fetal terms of birth weight, Through their status gestational age, septic hospital course Intervention: 36/175 workup, intermediate and up to the 6- (20.6%) admission, NICU week Control: 39/182 admission, length of postpartum visit. (21.4%) stay or pH<7.1 Funding Source Not laboring Reoperations: NA Conflicts: Intervention: 51/175 Length of stay: NR Authors: None (29.1%) (NICU, see above) Institution: None Control: 44/182 Mortality: NR Study: None (23.8%) Adverse events: No Supplies: None Other cases of maternal Intervention: 38/175 anaphylaxis or other (21.7%) adverse events related Control: 45/182 to cefazolin use (24.7%) reported during the trial. Setting: 1 Tertiary Hematomas & Seromas Care Hospital that did not meet Location: USA criteria for wound Dates: NR (26 months infections: 7 cases total total) Inclusion Criteria: Women whose pregnancies were older than 24 weeks estimated gestational age and required cesarean delivery Exclusion Criteria: cephalosporin allergy, gestational age less than 18 weeks, exposure to any antibiotic agent within 1 week of delivery, or the need for emergent cesarean delivery. © 2017 American Medical Association. All rights reserved. 134

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Thigpen RCT To determine Number of patients: Intervention group: SSI: (follow up 6 weeks) Definitions: 2005 7 1, 2, 3, if the N=302 n=153. Received 2g Wound Infection: Endometritis: (ES) 4, 5, 6, administration Patient cefazolin in fluid just Intervention: 6/153 Maternal 7, 8, 9 of prophylactic Characteristics: No before skin incision and (3.9%) temperature antibiotics for significant statistical placebo at cord Control: 8/149 (5.4%) ≥100.4oF on 2 cesarean difference existed in clamping RR (95% CI): 0.84 (0.45- separate section at the baseline Timing of intervention: 1.55) occasions 6 time of cord characteristics pre and intraoperatively Not statistically hours apart clamping, as between groups Duration of intervention: significant exclusive of the opposed to ·Age, y: mean±SD preoperative Endometritis first 12 hours immediately Intervention: 23.5±5.7 (intervention) and Intervention: 12/153 following before the skin Control: 24.3±5.9 intraoperative (at (7.8%) surgery, incision, ·Gender: 100% Female clamping) Control: 22/149 (14.8%) accompanied by influences the ·Obesity: NR Device/agent: Cefazolin RR (95% CI): 0.67 (0.42- uterine incidence of ·Comorbidities: NR Monitoring intervention: 1.07) tenderness and/ maternal Time after ruptured NR Not statistically or purulent or infectious membranes, h: Control group: n=149 significant foul smelling morbidity and/ mean±SD Received placebo just lochia. or negatively Intervention: 7.2±5.8 before skin incision and ITT Analysis Wound infection: impacts upon Control: 8.6±6.4 2g cefazolin in fluid at Maternal infection: with or without the neonatal P=0.045 cord clamping RR (95% CI): 0.81 (0.52- an elevated course. Gestational age at Standard preventive 1.40) maternal delivery, nulliparity measures: temperature, and history of ABX: Other infections: No accompanied by previous cesarean Group B Streptococcal cases of maternal tenderness with delivery, need for ABX Pneumonia or wound cervical ripening, Intervention: 27/153 Pyelonephritis. dehiscence, induction, cervical (17.6%) Topic-specific breakdown of exam on admission, Control: 40/ 149 (26.8%) outcomes: the surgical cervical dilatation RR (95% CI): 0.74 (0.55- Neonatal morbidity edges, and/ or was similar. 1.03) No statistically significant purulent Procedures: Cesarean No other antibiotics were difference between the drainage section delivery given unless a two groups (birth Urinary tract Indications: postoperative infection weight, Apgars, UaPh, infection: Arrest disorder was diagnosed. NICU admissions, Maternal Intervention: 86/153 sepsis or sepsis temperature (56.2%) workup, or maternal ≥100.4oF on 2 Control: 91/149 comorbidities or separate (61.1%) contributing factors. occasions 6 © 2017 American Medical Association. All rights reserved. 135

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Fetal Distress Infection: hours apart Intervention: 17/153 Intervention: 20/153 exclusive of the (11.1%) (13.1%) first 12 hours Control: 18/149 Control: 21/149 (14.1%) following (12.1%) RR (95% CI): 0.96 (0.68- surgery, with a Other 1.34) positive urine Intervention: 50/153 Sepsis culture, (32.7%) Intervention: 7/153 abnormal Control: 40/149 (4.6%) urinalysis, and (26.8%) Control: 7/149 (4.7%) flank pain. P=.541 RR (95% CI): 0.96 (0.58- Pneumonia: 1.69) hyperpyrexia, as Setting: 1 Regional Suspected sepsis well as x-ray and Medical center Intervention: 11/153 physical Location: USA (7.2%) examination Dates: NR (30 month Control: 14/149 (9.4%) findings period) RR (95% CI): 0.76 (0.47- consistent with Inclusion Criteria: 1.22) lung Singleton Pneumonia consolidation. pregnancies if the Intervention: 1/153 Neonatal Sepsis: patient had labored (0.7%) Suspected if and required Viral Syndrome tachycardia and/ cesarean surgery. Intervention: 1/153 or tachypnea, as Group B Strep (0.7%) well as an prophylaxis Pyelonephritis: none increased white (aqueous penicillin) NICU Admission count with was allowed. Intervention: 14/153 bands, was Exclusion Criteria: (9.2%) present and was Multiple Control: 8/149 (5.4%) confirmed by pregnancies, acute RR: 1.28, 95%CI (0.91- positive blood chorioamnionitis, 1.79) cultures. allergy to penicillin or Reoperations: NA Perioperative cephalosporins, Length of stay: NR care: Most cesarean section women had without labor, or the Mortality: NR regional administration of Adverse events: NR anesthesia. systemic antibiotics General Anesthesia within the past 2 Intervention: weeks. 16/153 (10.5%) © 2017 American Medical Association. All rights reserved. 136

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Control: 17/ 149 (11.4%) RR (95% CI): 0.95 (0.66-1.38) Other notes: Prospective power analysis performed for risk of endometritis and wound infection determined that 270 women in each arm were sufficient (power 0.80) to detect 10% difference. (Based on projected 10% risk of infection in post-cesarean population). An interim analysis was planned for the power analysis because the investigation was not concluded near the completion (4 months) of the fellowship of the senior author. The interim power analysis indicated that with the rate of infection being © 2017 American Medical Association. All rights reserved. 137

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score 50% more than expected for the 2 groups, there was an 80% power to detect a difference with a total of 300 randomized women. Follow-up: For 6 weeks postpartum. Funding Source Conflicts: Authors: NR Institution: NR Study: NR Supplies: NR Wax RCT To test the Number of patients: Intervention group: n=49 SSI (follow up 2 & 6 Definitions: 1997 9 1, 2, 3, hypothesis N=90 1g cefazolin in 50 ml 0.9% weeks) Endometritis: Fever (ES) 4, 5, 6, that a single 1 Patient saline administered Wound infection: to 100.4oF on 2 7, 8, 9, g dose of Characteristics: within 5 min of deciding Intervention: 1/49 (2%) occasions at 10 cefazolin Patients were similar to proceed with Control: 2/41 (4.9%) least 6h apart or administered between groups with cesarean delivery. The P=0.35 a single fever preoperatively regards to: placebo of 50 ml 0.9% Endometritis: ≥101oF outside is no more · Maternal Age, y: saline was administered Intervention: 1/49 (2%) the first 24h effective than mean±SD over 5 minutes at cord Control: 1/41 (2.4%) following one Intervention: 24.7±4.5 clamping 1 subject in Intervention delivery administered Control: 25.2±4.8 Timing of intervention: group experienced both associated with after cord ·Gender: 100% Female Pre and intraoperatively endometritis and wound uterine or clamping in ·Obesity: Duration of intervention: infection. parametrial preventing Weight: mean±SD Intra and Other infections: No tenderness, post-cesarean Intervention: 191±26 postoperatively secondary infections malodorous or infections lb. Device/agent: Cefazolin were seen in either purulent lochia, Control: 189±32 lb. Monitoring intervention: group or leukocytosis ·Comorbidities: NR NR Topic-specific Wound infection: Duration of labor Control group: n=41 outcomes: Incisional mean±SD 50 ml 0.9% saline was Neonatal Morbidity: erythema, Intervention: 13.0±7.2 administered within 5 Pneumonia: tenderness, © 2017 American Medical Association. All rights reserved. 138

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score h minutes of deciding to Intervention: 2/49 (4.1%) warmth, with or Control: 9.9±7.3 h proceed with cesarean Control: 0/41 without purulent P=0.03 delivery. The 1.g of Febrile illness drainage. Duration of internal cephazolin in 50 ml readmissions Intra-abdominal monitors mean±SD 0.9% saline was Intervention: 2/49 (4.1%) abscesses, Intervention: 11.1±4.2 administered over 5 Control: 0/41 septic pelvic h minutes at cord No source of infection thrombophlebitis Control: 9.3±4.7 h clamping. was identified in either , or symptomatic P=0.04 Standard preventive neonate Treatment: urinary tract Newborn 1 and 5 measures: Both discharged after infection: ND minute Apgar AMP: Time from first receiving 72h of Neonatal scores<7, umbilical infusion to incision antibiotics and no Outcomes: arterial cord (min) mean ±SD further sequelae Sepsis screen, pH<7.20 and NICU Intervention: 35±31 Suspected Sepsis workup: sepsis, admissions similar Control: 36±26 Intervention: 6/49 pneumonia between two groups (12.2%) (based on Procedures: (not Skin prep: All patients Control: 2/41 (4.9%) clinical and statistically received identical skin P=0.28 radiographic significant between prep of iodophor and Workup was negative in findings), and groups) isopropyl alcohol. all meningitis: ND Primary: 61/90 (67.8%) Surgical Drape: Occlusive Meningitis: none Perioperative Primary w/ tubal adhesive surgical Delayed onset or partially care: ligation: 5/90 (5.6%) drapes were used for treated infections Indwelling catheter: Repeat: 18/90 (20%) each case. 2weeks: 84 infants : placed Repeat with tubal Nonstandard preventive none preoperatively ligation: 6/90 (6.7%) measures: 6 weeks: 76 infants: for bladder All procedures were Technique: Intraoperative none drainage. performed by surgical technique was Other notes: None residents under the determined by surgeon Reoperations: NA Follow-up: supervision of attending Length of stay: NR Mothers were physicians. Mortality: NR counseled Indications: Adverse events: None verbally and Arrest of dilation or reported for mothers or given written descent: infants. instructions Intervention: 30/49 describing signs (61.2%) of infection Control: 20/41 before leaving (48.8%) the hospital and Fetal Distress scheduling © 2017 American Medical Association. All rights reserved. 139

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 3/49 follow-up. (6.1%) Mothers were Control: 9/41 (22.0%) contacted by P=0.03 phone or seen in Malpresentation clinic at 2weeks Intervention: 4/49 (n=83/90; 11 by (8.2%) phone and 72 in Control: 6/41 (14.6%) clinic) and 6 Repeat in labor weeks (n=76/90; Intervention: 4/49 5 by phone and (8.2%) 71 in clinic_ after Control: 5/41 (12.2%) delivery. Other Infants were Intervention: 8/49 examined by a (16.3%) pediatrician 2 Control: 1/41 (2.4%) weeks post- P=0.03 partum. Mothers Setting: 1 Military were interviewed Hospital and infant charts Location: USA reviewed at 6 Dates: NR (12 month weeks of life. period) Funding Source Inclusion Criteria: Conflicts: Singleton subjects Authors: None undergoing Institution: None cesarean delivery at Study: None ≥37 week gestation. Supplies: None Exclusion Criteria: Penicillin or cephalosporin allergy, antibiotic use within 2 weeks of delivery, temperature ≥37.8oC in labor, administration of group B streptococcal or sub- acute bacterial © 2017 American Medical Association. All rights reserved. 140

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score endocarditis prophylaxis during labor, insulin- dependent diabetes mellitus, human immunodeficiency virus infection, chronic glucocorticoid use, or multiple gestation.

Q1C. How safe and effective is weight-adjusted AMP dosing? Our search did not identify RCTs or SRs that evaluated weight-adjusted AMP dosing and its impact on the risk of SSI.

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eTABLE 27. Evidence Table for Q1D. How safe and effective is intraoperative redosing of AMP? Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Cuthbert- RCT To determine Number of patients Intervention group: SSI: Definitions: son 1, 2, 4, whether a N=278 n=132 Intra-abdominal Wound infection: if 1991 10 7 double dose of Patient Patients who received 2 abscess: there was a (ES) intravenous Characteristics: doses of 3.1g of 2doses: 10/132(8%) purulent Timentin there were no timentin. 1 1dose: 8/146 (5%) vs. discharge from provides statistically intravenously just Perineal wound the suture line or superior significant before incision the infection: if there was a prophylaxis differences between other, 2 hours after the 2doses: 4/9 non-purulent with respect to groups. beginning of the 1dose: 4/9 discharge that postoperative Age: NR operation. Antimicrobial contained wound Gender: NR Timing of intervention: Resistance: pathogenic infection Obesity: NR pre and intra/post op No difference: 1 minor SSI bacteria. compared with Comorbidities: NR Duration of intervention: in each group culture a single dose, Procedures: 2h after the beginning positive for MRSA as Perioperative they Abdominal of the operation. the sole organism care: NR performed a operations where the Device/agent: Timentin Other notes: None controlled bowel was opened. 3.1g Follow-up: 30 clinical trial in Setting: 11 hospitals Control group: n=146 days patients Location: Australia Patients received a single Funding Source undergoing Dates: NR dose of timentin of 3.1g Conflicts: elective Inclusion Criteria: intravenously just Authors: NR colorectal patients undergoing before incision. Institution: NR surgery. elective abdominal Standard preventive Study: NR operations in which measures: The bowel Supplies: NR the bowel was was mechanically opened. cleansed preoperatively Exclusion Criteria: and no oral Patients known to be antimicrobials were allergic to penicillin administered. or who had received antimicrobials in the 72 hours before their planned operation. Patients were excluded if the large bowel was not opened at operation, © 2017 American Medical Association. All rights reserved. 142

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score if intra-abdominal pus was found at operation, if a stoma or mucous fistula was brought out through the main abdominal wound and/or if the main abdominal wound was not closed primarily.

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eTABLE 28. Evidence Table for Q1E. How safe and effective is postoperative AMP and what is the optimal duration? Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Hirokawa RCT To evaluate Number of patients: Intervention group: n=94 SSI: Definitions: 2013 54 1, 2, 6, the necessity N=190 Flomoxef sodium (FMOX) SSI: Combined SSI and (ES) 7, 8, 9, of Patient 1.0g was given 30 Intervention: 7/94 (7.5%) remote infection. 10 postoperative Characteristics: the minutes before the Control: 13/94 (13.8%) SS (secondary antibiotic two groups were operation and every 3 P=0.24 outcome): a prophylaxis matched for hours during the Superficial/deep incisional condition in after liver characteristics operation. Intervention: 3/94 (3.2%) which purulent resection ·Age, y: median (range) Timing of intervention: Control: 3/94 (3.2%) discharge was without Intervention: 68 (35- Preoperative P=1.000 observed from reconstruction 82) Duration of intervention: Organ/space any incision or of the intestine Control: 68 (22-88) NA Intervention: 4/94 (4.3%) space that was or biliary tract. ·Gender: m:f Device/agent: 1.0g Control: 11/94 (11.7%) manipulated Intervention: 64:30 flomoxef sodium P=0.10 during operation Control: 30:34 administered <30 days after ·Obesity intravenously Other infections surgery with or ·Comorbidities: Monitoring intervention: Remote site infections without Virus infection: NA Intervention: 2/94 (2.1%) microbiologic Intervention: 42/94 Control group: n=94 Control: 8/94 (8.5%) evidence, per (44.7%) Flomoxef sodium (FMOX) P=0.10 the guidelines Control: 29/94 (30.9%) 1.0g was given 30 Topic-specific issued by the minutes before the outcomes: NA CDC. Procedures: Liver operation and every 3 Reoperations: NR Remote site resection hours during the Length of stay: infection: a Primary hepatectomy: operation then every 12 Postoperative hospital condition in Intervention: 9/94 hours for 3 days after stay, days: median which fever and (9.6%) the operation. (range) leukocytosis Control: 17/94 (22.1%) Standard preventive Intervention: 12 (4-91 were present P-0.14 measures: Control: 14 (5-265) with bacteria in Hemiheptaectomy: Surgery: performed P=0.034 sputum, urine, Intervention: 28/94 according to standard catheter tip, (29.8%) techniques: Mortality: blood, or bile Control: 24/94 (25.5%) Cavity Irrigation: Intervention: 1/94 (1.1%) juice or Segmentectomy: abdominal cavity was Control: 1/94 (1.1%) according to the Intervention: 27/94 irrigated 4L of warm physician’s (28.7%) saline. Adverse events: NR judgment Control: 22/94 (23.4%) Drains: not inserted regardless of Limited resection: Blood transfusion: carried microbiologic Intervention: 39/94 out when surgical evidence. © 2017 American Medical Association. All rights reserved. 144

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (41.5%) bleeding >1000m and Signs of infection Control: 48/94 (51.1%) hemoglobin level (Primary decreased to <8.0 g/dL Outcome): Indications: postoperative Hepatocellular status with ≥1 of Carcinoma: the following Intervention: 44/94 inflammatory (46.8%) findings after Control: 44/94 (46.8%) postoperative Cholangiocellular day (POD) 4: (1) carcinoma: body Intervention: 3/94 temperature (3.2%) ≥38oC; (2) white Control: 4/94 (4.3%) blood cell count Colorectal metastasis: ≥12,000/mm3; Intervention: 42/94 and (3) (44.7%) additional Control: 37/94 (39.4%) increase (>20% Living-donor liver increase from transplantation: the previous Intervention: 1/94 value) in white (1.2%) blood cell count Control: 4/94 (4.3%) and/or C- reactive protein. Setting: 1 University Perioperative Medical Hospital care: NR Location: Japan Other notes: None Dates: April 2008 – Follow-up: NR June 2011 Funding Source Inclusion Criteria: Conflicts: patients from 18-90 Authors: None years and adequate Institution: None organ functional Study: None reserve of important Supplies: None organ systems (heart, lungs, kidneys, and liver [Child-Pugh class A or B]) © 2017 American Medical Association. All rights reserved. 145

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Exclusion Criteria: (1) severe comorbidities, such as preoperative infection, hemodialysis, myocardial infarction, or respiratory disorders requiring oxygen inhalation; (2) concomitant operations on other organs, including biliary or digestive tract anastomosis; (3) proven mental illness; and (4) absences of informed consent. Lyimo RCT To determine Number of patients: Intervention group: SSI: Definitions: 2013 30 1, 4, 7, the N=500 n=250 Total Surgical Site Infection: presence (ES) 8, 9, 10 equivalence of Patient Patients received a single Infection: of fever (temp intravenous Characteristics: intravenous dose of Intervention: 12/250 >38oC at least 4 single dose of patients in both gentamicin(3mg/Kg) (4.8%) [95%CI 2.2-7.4] hours apart on gentamicin groups were similar plus metronidazole Control: 16/250 (6.4%) two or more (3mg/kg) plus at baseline. (500mg) 30 – 60 Absolute difference occasions, metronidazole ·Age minutes before (95%CI): 1.6% (-2.4- excluding the (500mg) given ≤20 y: operation 5.6%) [95%CI 3.4-9.4] first 24h post 30 – 60 min Intervention: 38/250 Timing of intervention: Incidence rates of post cesarean.)and before incision (15.2%) preoperative cesarean infections signs and and multiple Control: 42/250 Duration of intervention: Intervention: 1.7/ 1000 symptoms of doses of (16.8%) NA person days abdominal gentamicin 21-30 y: Device/agent: Gentamicin Control: 2.3 / 1000 wound infection (3mg/kg) and Intervention: 146/250 (3mg/Kg) plus person days or endometritis metronidazole (28.4%) metronidazole (500mg): Incidence rate ratio = Abdominal wound (500mg) given Control: 135/250 Monitoring intervention: 0.74 995%CI 0.32- infection: partial both 30-60 (54.0%) NA 1.65), p=0.2146 or total min before >30 y: Control group: n=250 Other infections: NR dehiscence, © 2017 American Medical Association. All rights reserved. 146

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score incision and Intervention: 66/250 3 doses - Patients Topic-specific presences of followed by (26.4%) received a dose of outcomes: NR purulent or gentamicin Control: 73/250 gentamicin (3mg/Kg) Reoperations: NR serous (3mg/kg) once (29.3%) plus metronidazole Length of stay: NR discharge form a day and ·Gender: 100% female (500mg) 30 – 60 Mortality: NR the wound with metronidazole ·Obesity: minutes before Adverse events: NR indurations, (500mg) every Intervention: 83/250 operation followed by warmth and 8 hours for 24 (33.2%) gentamicin (3mg/Kg) tenderness. hours after Control: 63/250 once a day and Endometritis: the emergency (25.2%) metronidazole (500mg) presence of cesarean ·Comorbidities every 8 hours for 24h fever (38oC or surgery Gravidity: postoperatively above) in Multigravida: Standard preventive association with Intervention: 173/250 measures: one or more of (69.2%) Wound dressing: wound the following: Control: 167/250 was left open. uterine (66.8%) tenderness or Presence of cesarean foul smelling scar, yes lochia. Intervention: 98/250 Perioperative (39.2%) care: Control: 87/250 Bladder catheter (34.8%) was removed Ruptured amniotic after 48h membrane Other notes: Intervention: 129/250 Sample size was (51.6%) calculated to be Control: 158/250 490 based on (63.2%) alpha = 0.05 and P=0.01 beta = 0.20 Duration of operation Follow-up: 30 (>60 min) days postop. Intervention: 99/250 Patients who (39.6%) could not attend Control: 110/250 their follow up (44.0%) appointments Procedures: were contacted emergency cesarean via phone or by section communicating © 2017 American Medical Association. All rights reserved. 147

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Indications: NR with a ten cell Setting: Single leader via teaching hospital physical Location: Tanzania address. Dates: October 2011 – Funding Source May 2012 Conflicts: Inclusion Criteria: Authors: None pregnant women Institution: None admitted to the Study: None institution’s labor Supplies: None ward that needed or had indication for emergency cesarean section (under spinal anesthesia) during the study dates that had consented to the study. Exclusion Criteria: Pregnant women with fever (temp ≥38oC), prolonged obstructed labor, and prolonged and premature rupture of membranes (rupture of membrane >12 hours). Pregnant women presenting with features of chorioamnionitis (i.e., foul smelling lochia, uterine tenderness associated with fever) allergies to the antibiotic used in the study, or those who had used the © 2017 American Medical Association. All rights reserved. 148

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score antibiotics in the 24 hours preceding the operation or unconscious patients who could not provide consent. Haga RCT To confirm the Number of patients: Intervention group: SSI: Definitions: 2012 52 1, 6 validity of N=325 n=164 Overall SSI: SSI – Incision site (ES) single-dose Patient A single dose of 1g Intervention: 15/164 infection and antimicrobial Characteristics cefazolin administered (9.1%) organ/space prophylaxis for ·Age, y: mean (range) intravenously. An Control: 10/161 (6.2%) infection were the prevention Intervention: 68 (33- additional dose Difference (95%CI): -2.9% CDC SSI of SSI and 90) administered when (-5.9-0.00) Guideline examined Control: 68 (39-91) surgery duration >3h. definitions independent ·Gender: male:female Timing of intervention: Superficial/ Incisional Anastomotic risk factors Intervention: 118:46 preop Infections dehiscence: influencing the Control: 117:44 Duration of intervention: Intervention: 14/164 confirmed by development ·Obesity: preop (8.5%) clinical and/or x- of surgical site BMI mean (range), Device/agent: 1g Control: 7/161 (4.3%) ray examination infections kg/m2 cefazolin Difference (95%CI): -4.2 (- Remote infection: following Intervention: 21.7 Monitoring intervention: 6.9- -1.5) an infection elective (15.2-31.6) NA occurring at a gastric cancer Control: 21.9 (15.4- Control group: n=161 Organ/space infections site other than surgery. 31.6) 6 doses - 1g cefazolin Intervention: 11/164 the surgical site, ·Comorbidities: administered (6.7%) such as Diabetes mellitus: intravenously. An Control: 6/161 (3.7%) pneumonia, Intervention: 38/164 additional dose Difference (95%CI): -3.0 (- urinary tract (23.2%) administered when 5.5- -0.6) infection, Control: 36/161 surgery duration >3h. Organ/space infections enteritis, or (22.4%) An additional 5 doses related to anastomic bloodstream were given every 12h dehiscence or (catheter- Procedures: elective postop pancreatic fistula related) gastric surgery Standard preventive Intervention: 10/164 infection. Total gastrectomy: measures: (6.1%) Perioperative proximal/distal Wound covering: surgical Control: 6/161 (3.7%) care: gastrectomy: towels for conventional Other notes: Intervention: 66:98 gastrectomy, wound Both Superficial & power Control: 66:95 protectors for Organ/Space calculation Combined resection: laparoscopic or Intervention: 9/164 based on © 2017 American Medical Association. All rights reserved. 149

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 37/164 laparoscopic-assisted (5.5%) detecting an 8% Control: 36/161 surgeries. Control: 3/161 (1.9%) difference in the Gallbladder: Anastomoses = stapled. incidence of Intervention: 15/164 Rinsing abdominal cavity- SSIs with a CI of Control: 13/161 copiously rinsing with 2- Other infections: 95% and a Spleen: 3L saline before closure All remote infections: power of 80% Intervention: 23/164 Closure – approximated by Intervention: 6/164 resulted in Control: 20/161 staples (3.7%) sample size of Pancreas: Drains – closed suction Control: 5/161 (3.1%) 159 in each arm. Intervention: 3/164 drains were placed sub- P=0.78 Follow-up: 30 Control: 2/161 hepatically and/or Pneumonia: days postop via Liver: subphrenically Intervention: 3/164 inspection at Intervention: 2/164 according to the type of (1.8%) outpatient clinic. Control: 2/161 gastrectomy, brought Control: 2/161 (1.2%) Funding Source Small intestine: out through separate Enterocolitis: Conflicts: Intervention: 0/164 stab wounds. Drains Intervention: 1/164 Authors: NR Control: 1/161 were removed after 7 (0.6%) Institution: NR days. Control: 2/161 (1.2%) Study: NR Indications: gastric Dressing – sterile dressing Urinary Tract Infection: Supplies: NR cancer was removed within Intervention: 1/164 Pathologic stage: 48h (0.6%) 1/II:III/IV Blood Transfusion: Control: 0/161 Intervention: 54:110 Intervention: 10/164 Bloodstream infection: Control: 65:96 (6.1%) Intervention: 1/164 P=0.16 Control: 21/161 (13.0%) (0.6%) P=0.03 Control: 1/161 (0.6%) Setting: one university medical center Topic-specific Location: Japan outcomes: Dates: February 2007 Multivariate regression – November 2010 analysis Inclusion Criteria: Blood Loss (every 100mL) Patients undergoing OR (95%CI): 1.13 (1.05- elective surgery for 1.23), p<0.01 gastric cancer BMI (≥25 kg/m2): Exclusion Criteria: OR (95%CI): 2.76 (1.10- Patients <20 years 6.90), P=0.03 old, those with a Age (every 10 years known allergy to increment: © 2017 American Medical Association. All rights reserved. 150

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score cephalosporins, OR (95%CI): 1.65 (1.01- those with any 2.70), P=0.046 infection within the Reoperations: NR prior 2 weeks, those Length of stay: with synchronous Mortality: NR cancer at any sites Adverse events: NR other than the stomach, and those needing colon resection because of tumor involvement. Hussain RCT To determine Number of patients: Intervention group: SSI Definitions : 2012 31 1, 6, 7, the role of N=377 n=195 Surgical site infection SSI: pus discharge (ES) 8, 10 postoperative Patient A single preoperative dose Intervention: 9/195 from wound that antibiotics in Characteristics: of cefuroxime sodium (4.6%) necessitated reducing the statistically there and metronidazole half Control: 8/182 (4.3%) wound opening surgical site was no difference an hour before surgery. and drainage. infections between group Timing of intervention: Other infections: NR Intra-abdominal (SSIs) and characteristics. Preoperative Topic-specific collection: fluid intra- ·Age, y: mean±SD, Duration of intervention: outcomes: collection inside abdominal Intervention: NA No Intraabdominal the peritoneal abscess 32.78±10.62 Device/agent: cefuroxime collection of fluid cavity confirmed formation after Control: 31.70±9.96 sodium reported by ultrasound or open ·Gender: ratio of m:f Monitoring intervention: Reoperations: NR computed appendectomy Intervention: 1.15:1 NA Length of stay, days: tomography and in patients Control: 1.16:1 Control group: n=182 Intervention: 2.29±0.82 requiring with non- ·Obesity: NR A preoperative dose of Control: 2.35±0.48 drainage. perforated ·Comorbidities: NR cefuroxime sodium and Perioperative appendicitis Exclusionary criteria metronidazole half an Mortality: no perioperative care: NR (NPA), and to Procedures: hour before surgery mortality Other notes: NR define the emergency open plus an additional dose Adverse events: NR Follow-up: 30 uniform appendectomy of cefuroxime sodium days guidelines in Indications: acute and metronidazole at Funding Source the appendicitis 8h postop Conflicts: management Setting: 1 tertiary care Standard preventive Authors: NR of these hospital measures Institution: NR patients in our Location: Saudi Arabia Technique: performed Study: NR institution. Dates: January 2010 – through right lower Supplies: NR July 2011 quadrant incision. © 2017 American Medical Association. All rights reserved. 151

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Inclusion Criteria: Wound closure: primarily Patients admitted in all patients following with the clinical washing with normal diagnosis of acute saline. appendicitis undergoing emergency open appendectomy. Exclusion Criteria: Patients who had received antibiotics within 72 hours of admission or who were diabetics, immunocompromise d, or pregnant. Also, those who were found to have complicated appendicitis (gangrenous, perforated, appendicular mass or abscess) or normal appendix per-operatively were excluded as well. Imamura RCT To assess Number of patients: Intervention group: SSI Definitions: 2012 51 1, 2, 4, non-inferiority N=355 n=176 Total: Superficial, Deep (ES) 10 of the Patient 1g Cefazolin 30 min after Intervention: 8/176 (5%) incisional & omission of Characteristics: anesthesia and before Control: 16/179 (9%) organ/space postoperative patient the surgical incision RR (95%CI) – 0.51 (0.22- infections were antimicrobial characteristics were plus every 3h 1.16) diagnosed by prophylaxis in balanced between intraoperatively. P=0.138 CDC NNIS patients with groups. Timing of intervention: OR for SSI with infection gastric cancer ·Age: y, median (range) preoperative intraoperative antimicrobial definitions. Intervention: 66 (36- Duration of intervention: prophylaxis: Perioperative 84) NA Patients with BMI<25 care: NR Control: 65 (35-84) Device/agent: 1g 0.31 (0.099-0.998), Other notes: © 2017 American Medical Association. All rights reserved. 152

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score ·Gender; Male: female cefazolin p=0.050 power Intervention: 115:61 Monitoring intervention: Patients who with BMI≥25 calculation was Control: 120:59 NA 1.09 (0.25-4.72), P=0.91 conducted for ·Obesity: BMI (kg/m2) Control group: n=179 All 24 SSI in patients who composite SSI. Intervention: 22.3 1 g cefazolin before the underwent distal Follow-up: 30 (16.3-33.0) surgical incision, every gastrectomy without days postop Control: 22.5 (12.4- 3h intraoperatively plus protocol violation. Funding Source 32.9) 1g cefazolin on Superficial incisional: Conflicts: ·Comorbidities: postoperative day 0 (at Intervention: 1/176 (<1%) Authors: None Blood loss, median night) and every 12h Control: 45/179 (3%) Institution: None (range) mL until postoperative day P=0.215 Study: None Intervention: 200 (1- 2 (2g/ day for 2 Deep Incisional: Supplies: None 880) postoperative days) Intervention: 0/176 Control: 210 (1-1700) Standard preventive Control: 0/179 measures: Organ/space Procedures: distal Drainage Tube: Intervention: 7/176 (4%) gastrectomies and Intervention: 157/176 Control: 11/179 (6%) lymphadenectomies. (89.2%) P=0.469 Two patients underwent Control: 153/179 (85.5%) O/S With anastomotic a total gastrectomy Transfusion: leakage because they had a Intervention: 0/176 Intervention: 1/176 positive resection Control: 4/175 (2.3%) (0.6%) margin, and one had Care before and after Control: 4/179 (2.3%) palliative bypass surgery and wound O/S without anastomotic surgery with management were leakage gastrointestinal done according to Intervention: 6/176 anastomosis. respective institutional Control: 7/179 (2.3%) Indications: gastric standards. cancer Other infections: Setting: Seven Remote site infections: hospitals (4 tertiary Overall: care & 3 university Intervention: 5% (CI 2- hospitals) 10) Location: Japan Control: 3% (CI 1-7) Dates: June 2, 2005 – December 6, 2007 Pneumonia or bronchitis:2 Inclusion Criteria: patients (unclear which patients who had group) histologically proven UTI © 2017 American Medical Association. All rights reserved. 153

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score gastric Intervention: 10/176 adenocarcinoma that (0.6%) was deemed curable Control: 1/179 (0.6%) with a distal gastrectomy. Topic-specific Patients with an ASA outcomes: NR score of 1 or 2 Reoperations : NR Exclusion Criteria: If Length of stay: patients had an Intervention: 12 (7-114) active or Control: 12 (7-87) uncontrolled P=0.742 infection, received Mortality: NR neoadjuvant Adverse events: no chemotherapy, or severe reaction to had been given antimicrobial steroids. prophylaxis occurred in either group. Lin RCT To elucidate Number of patients: Intervention group: SSI (30 days): Definitions: 2011 35 1 the effect of N=231 n=120 Sternal Wound infection SSI – CDC 1999 (ES) the duration of Patient Patients received 1g of Intervention: 13/120 Guideline prophylactic Characteristics: cefazolin within 1 hour (10.8%) Definitions antibiotics, a baseline prior to incision, and an Control: 9/111 (8.0%) Perioperative prospective, characteristics were additional dose was P=0.48 care: NR randomized similar in each allowed if it was a Deep infections Other notes: None control study group. prolonged operation (1 Intervention: 3/120 Follow-up: 1 was ·Age, y: mean±SD additional dose for (2.5%) month postop conducted to Intervention: 64.4±9.6 every 3-4 hours of Control: 1/111 (0.9%) Funding Source compare the Control: 65.5±11.5 surgery). Then 1g P=0.62 Conflicts: effectiveness P=0.45 cefazolin every 8 hours Superficial Authors: NR of preventing ·Gender: male, for 3 doses after the Intervention: 3/120 Institution: NR SSI after Intervention: 94/120 operation. (2.5%) Study: NR Coronary (78.3%) Timing of intervention: Control: 2/111 (1.8%) Supplies: NR Artery Bypass Control: 90/111 pre and postoperatively P=1.00 Graft (CABG) (81.1%) Duration of intervention; Harvest Site Infection using1-day or P=0.60 Na Intervention: 7/120 3-day ·Obesity: BMI (kg/m2), Device/agent: Cefazolin (5.8%) antibiotic mean±SD Monitoring intervention: Control: 6/111 (5.4%) prophylaxis. Intervention: 25.0±2.8 NA P=0.89 Control: 25.1±2.9 Control group: n=111 © 2017 American Medical Association. All rights reserved. 154

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score P=0.84 Patients received 1g of Other infections: NR ·Comorbidities cefazolin within 1 hour Topic-specific Hypertension: prior to incision, and an outcomes: Intervention: 80/120 additional dose was Time to SSI, d: (66.7%) allowed if it was a Intervention: 12.8±3.3 Control: 75/111 prolonged operation (1 Control: 18.9±5.3 (67.6%) additional dose for P=0.004 P=0.88 every 3-4 hours of Diabetes Mellitus surgery). Then 1g Reoperations: NR Intervention: 52/120 cefazolin every 8 hours Length of stay: (43.3%) for 9 doses after the Postop ICU Stay, d Control: 43/111 operation. mean±SD (38.7%) Standard preventive Intervention: 2.2±0.9 P=0.48 measures: Control: 2.6±1.6 Smoking MRSA Swab – screening P=0.05 Intervention: 46/120 for MRSA carriage was Postop LOS, d mean±SD (38.3%) conducted 1 day preop. Intervention: 12.1±3.6 Control: 34/111 No decolonizing agents Control: 16.7±9.1 (30.6%) were used. P=0.10 P=0.22 COPD Mortality: Intervention: 3/120 3 patients died (2.5%) immediately after Control: 0/111 surgery but were P=0.60 excluded. Adverse events: NR Nasal Swab Screening S. aureus positive Intervention: 14/120 (12.7%) Control: 20/111 (19.4%) P=0.18 MSSA carrier Intervention: 8/120 (7.3%) Control: 16/111 (15.5%) P=0.06 © 2017 American Medical Association. All rights reserved. 155

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score MRSA carrier Intervention: 6/120 (5.5%) Control: 4/111 (3.9%) P=0.75

Procedures: Coronary Artery Bypass Graft (CABG) Emergency Intervention: 26/120 (21.7%) Control: 30/111 (27.0%) P=0.34

Indications Setting: 1 university hospital Location: Taiwan Dates: June 2002 – April 2004 Inclusion Criteria: Patients who underwent nonemergency CABG surgery and were ≥18 years old. Exclusion Criteria: Patients with existing preoperative infections; those undergoing treatment with antibiotics; hypersensitivity to cefazolin; renal dysfunction (serum creatinine level © 2017 American Medical Association. All rights reserved. 156

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score >2mg/dL or creatinine clearance <35mL/min, or under hemodialysis treatment); left ventricular ejection fraction <30%; obesity (body mass index >31kg/m2); chronic obstructive pulmonary disease (COPD); undergoing combined surgery other than CABG; neutropenia (leukocyte count <1000/cm3); pregnancy or undertaking breastfeeding; or refusal of consent Suzuki RCT To establish Number of patients: Intervention group: SSI: (follow up 4 weeks) Definitions: 2011 42 1, 2, 7, the optimal N=360 n=179 Incisional SSI Postoperative (ES) 8, 9 duration of Patient A single dose of Intervention: 15/179 infection: an perioperative Characteristics: No oxacephem (1g) (8.4%) infection antimicrobial significant difference antimicrobial 11/15: No fever and occurring within administration was observed in prophylaxis was were improved by 30 days after of an baseline patient administered removal of some surgery. oxacephem characteristics intravenously before sutures and abscess SSI: diagnosed by antimicrobial between groups. surgery. The drainage ≥2 physicians in patients ·Age, y, mean±SD antimicrobial was given 2/15: Developed fever Incisional SSI: undergoing Intervention 65±11 from 1 hour before the and were treated by macroscopic elective colon Control: 66±9. incision was made. antimicrobials & abscess or cancer ·Gender m/f When the operative abscess drainage purulent surgery, by Intervention: 101/84 time exceeded 3 hours, Control: 13/181 (7.2%) discharge determining Control: 101/84 an addition al gram of 13/13: No fever and observed on the the incidence ·Obesity: NR antimicrobial was were improved by operative wound of SSIs with ·Comorbidities: administered removal of some Organ/ space SSI: the use of Diabetes Timing of intervention: sutures and abscess An infection in © 2017 American Medical Association. All rights reserved. 157

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score mechanical Intervention: 17/185 Pre and intraoperatively drainage the organ preparation (9.2%) (based on procedure P=0.0008 (Δ=0.10) subjected to and chemical Control: 14/185 duration) Duration of Organ/ space SSI surgery. preparation (7.6%) intervention: Pre and Intervention: 1/179 Remote infection: together with Procedures: Elective intraoperatively (vs. up (0.6%) Evaluated by oral laparotomy for colon to 4 days in controls) Control: 2/181 (1.1%) chest plain films, antimicrobial cancer Device/agent: oxacephem P<0.001 (Δ=0.10) sputum, urine, administration. Indications: colon 1g IV antimicrobial 3/3: anastomic blood, or cancer Monitoring intervention: leakage catheter culture T Category NR (Cultures of after surgery. Tis, T1/ T2-T4 drainage or purulence Other infections: Perioperative Intervention: 21/164 were made) Remote Infection care: NR Control: 29/156 Control group: n=181 Intervention: 8/179 (4.5%) Other notes: Non- TNM Classification: not Oxacephem (1g) 6/8: Catheter infection inferiority margin significant; antimicrobial was Detected Post-OP day is 10% (Δ=0.10). Setting: 1 university administered 3 or later & resolved Based on this, hospital intravenously twice with catheternremoval there were no Location: Japan daily for 4 days from the & antimicrobial differences in Dates: August 2002- day of surgery until administration incidence of October 2007 post-op day 3. The 1/8: Jugular vein SSIs, Inclusion Criteria: antimicrobial was given phlebitis organ/space or Patients undergoing from 1 hour before the 1/8: Pneumonia remote elective laparotomy incision was made. Control: 6/181 (3.3 %) infections for colon cancer When the operative 4/6: Catheter infection between groups Exclusion Criteria: time exceeded 3 hours, Detected Post-OP n (single dose vs. Patients with stoma, an addition al gram of day 5 or later & postop dosing X those who could not antimicrobial resolved with catheter up to 4 days) undergo the normal prophylaxis was removal & abx Follow-up: 4 mechanical administered 1/6: Urinary Tract weeks post- preparation owing to Standard preventive Infection discharge at a stenosis or measures: 1/6: Pneumonia hospital visit. obstruction, and Bowel Prep: All patients P<0.0001 (Δ=0.10) Funding Source those with a underwent mechanical C. difficile Colitis Conflicts: preoperative and chemical Intervention: 0/179 Authors: NR diagnosis of stage IV preparation of the Control: 0/181 Institution: NR and American bowel. Study: NR Society of 1. Mechanical: 10 ml Topic-specific Supplies: NR Anesthesiologists of sodium outcomes: NA score of ≥3. picosulfate was Reoperations: © 2017 American Medical Association. All rights reserved. 158

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score orally 3/3 Organ/ space SSI administered 2 developed fever and days before required reoperation surgery and 2,000 Length of stay: ml of polyethylene Mean Length of stay for glycol-electrolyte patients with colon sodium was orally cancer: 15±4 days administered in (facility data) the morning of the Mortality: NR day before surgery Adverse events: 2. Chemical: 0.5g of Small Bowel Obstruction kanamycin sulfate Intervention: 5/179 and 0.5g of (2.8%) metronidazole Control: 8/181 (4.4 %) were orally P<0.0001 (Δ=0.10) administered at 1, Other 2 and 11pm on the Intervention: 2/179 day before the (1.1%) operation. 1/2: Venous thrombosis of the lower extremities 1/2: Duodenal Stenosis Control: 2/181 (1.1 %) 1/2: Postoperative hemorrhage 1/2: Duodenal Stenosis Tamayo RCT To test the Number of patients: Intervention group: SSI: (Follow up at least 1 Definitions: 2008 12 1, 2, 4, hypothesis N=838 n=419 year) CDC definitions (ES) 7, 8, 9 that single Patient A single dose of 2g Total SSIs: 50/838 (5.9%) were used doses of Characteristics: cefazolin was Intervention: 30/419 throughout. cefazolin are Both groups were administered (8.3%) Superficial SSI – as effective as homogeneous and intravenously between Control: 15/419 (3.6%) The infection a 24-hour comparable in as far 20-30 minutes after the P=0.004 covers the skin regimen of as their demographic induction of anesthesia. Total Incisional SSI and cefazolin in profiles and clinical . For all procedures Intervention: 21 (5.0%) subcutaneous preventing characteristics were lasting more than 3 Control: 7 (1.7%) cellular tissue SSIs in adults concerned except for hours, a new dose of 1g P=0.007 and is © 2017 American Medical Association. All rights reserved. 159

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score undergoing transfusions (below). of cefazolin was Superficial Incisional SSI accompanied by cardiac ·Age, y: mean±SD administered Intervention: 16 (3.8%) one of the procedures Intervention: intraoperatively. Control: 7 (1.7%) following: 67.5±10.5 Timing of intervention: P=0.04 purulent Control: 68.2±10.5 Single dose Deep Incisional SSI drainage ·Gender: m/f preoperatively (re- Intervention: 5 (1.2%) through the Intervention: 272/147 dosed intraoperatively Control: 0 incision, positive Control: 247/172 depending on P=0.03 results of the P=0.07 procedure Organ/Space SSI incisional ·Obesity: NR duration)Duration of Intervention: 14 (3.3%) culture, and ·Comorbidities intervention: Pre and Mediastinitis and classic Diabetes: intraop vs. extended endocarditis were inflammatory Intervention: 111/419 dosing X 24hrs postop documented signs that allow (26.5%) in controls simultaneously in 2 the wound to be Control: 125/419 Device/agent: Cefazolin patients opened by the (29.8%) 2g IV Control: 8 (1.9%) surgeon except Peripheral Vascular Monitoring intervention: P=0.19 in cases in which Disease Wound cultures Osteomyelitis the incisional Intervention: 25/419 Control group: n=419 Intervention: 3 (0.7%) culture was (5.9%) Administered 2g of Control: 2 (0.5%) negative. Control: 38/419 (9%) cefazolin intravenously P=0.5 Deep incisional SSI P=0.08 between 20-30 minutes Mediastinitis – Infection ·Intraoperative values after the induction of Intervention: 8 (1.9%) involves the not statistically anesthesia, followed by Control: 5 (1.2%) deep soft tissues significant except for 1g every 8 hours. For P=0.28 of the incision Intraoperative values: all procedures lasting Endocarditis with at least 1 of Hematocrit after CPB, more than 3 hours, a Intervention: 5 (1.2%) the following: mean±SD: new dose of 1g of Control: 1 (0.2%) purulent cefazolin was P=0.10 drainage, a deep Interventions:27.07± administered Other infections: incision that 4.20 intraoperatively. Sepsis spontaneously Control: 26.48±4.07 Standard preventive Intervention: 17 (4.0%) dehisced or was P=0.05 measures: NR Control: 18 (4.2%) deliberately ·Postoperative values P=0.50 opened by the Intra-aortic balloon Topic-specific surgeon when pump outcomes: patient had a Intervention: 5/419 Antimicrobial resistance: fever (temp (1.1%) Pathogens isolated ≥38oC), or Control: 14/419 were similar distribution localized pain or © 2017 American Medical Association. All rights reserved. 160

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (3.3%) in both groups tenderness P=0.03 (P≥0.05). 43/50 (86%) (unless the Red cell transfusion of SSIs were gram results of an patients positive cocci (S. incisional culture Intervention: 261/419 epidermis (SE) most were negative), (62.3%) common, followed by S. or evidence of Control: 216/419 aureus (SA). deep incision (51.5%) SE-MRSE infection found P=0.01 Intervention: 12/20 SE in a direct Procedures: Elective and 12/35 (34.3%) SSI examination or Coronary artery Control: 5/9 SE and 5/15 second bypass grafting (33%) SSI operation (CABG) or valve SE-MSSE Mediastinitis – operations or both Intervention: 8/20 SE and Organ/space Indications: NR 8/35 (22.8%) SSI SSI Setting: 1 tertiary-level Control: 4/9 se and 4/15 characterized by hospital (26.6%) SSI 1 of the Location: Spain following: Dates: September SA-MRSA positive results 2003 – January Intervention : 4/11 SA of a culture 2007 and 4/35 (11.4)% SSI obtained from Inclusion Criteria: Control: 1/5 SA and 1/15 mediastinal Adult patients (>18 SSI (6.6%) tissue or fluid years of age) SA-MSSA: during a surgical undergoing elective Intervention 7/11 SA and operation, coronary artery 7/35 (20.0%) SSI patient fever bypass grafting Control: 4/5 SA and 4/15 (temp ≥38oC), (CABG), valve (26.6%) SSI sternal pain or operations or both instability, by means of Gram negative bacilli in mediastinal sternotomy. 12/50 (24%) ; involvement Exclusion Criteria: polymicrobial SSI rates suggested by a Presence of active similar between groups computed infection, the Reoperations: NR tomographic administration of Length of stay: scan, or antimicrobial therapy Preoperative organisms in the 48 hours hospitalization d, cultured form the before surgical mean±SD mediastinal area intervention, Intervention: 9.7±7.9 Sternal © 2017 American Medical Association. All rights reserved. 161

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score emergency surgical Control: 10.8±10.3 osteomyelitis – intervention, or P=0.11 An organ/space allergy to Mean ICU Stay d, SSI indicated by betalactams. Also, mean±SD persistent patients with Intervention: 10.3±10.9 purulent transplants or who Control: 9.1±8.7 drainage from did not wish to P=0.09 the sternotomy & participate in the Duration of hospitalization confirmed by study. after operation d, microbiologic mean±SD and Intervention: 14.75±15.8 histopathologic Control: 12.2±14.2 findings. P=0.25 Endocarditis – Organ/space Mortality: SSI 30 day: characterized by Intervention: 22 (5.2%) Duke’s criteria Control: 31 (7.4%) (Durack 1994) P=0.12 Perioperative 90 day: care: NR Intervention: 29 (6.9%) Other notes: Control: 37 (8.8%) SSI Risk P=0.18 Stratification: 365 day NNIS Intervention: 43 (10.3%) Statistical Analysis: Control: 48 (11.5%) Study powered P=0.34 to detect reduction in SSI Adverse events: rate of <5% with Intra-aortic balloon pump a=0.20 and Intervention: 5 (1.1%) β=0.05 (n=419 Control: 14 (3.3%) in each arm) P=0.03 Follow-up: Red cell transfusion Patients were patients examined daily Intervention: 261 while in the (62.3%) hospital. Cardiac Control: 216 (51.5%) surgeons P=0.01 personally © 2017 American Medical Association. All rights reserved. 162

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Arterial Fibrillation followed up with Intervention: 17 (4.0%) patients in the Control: 21 (5.0%) cardiac P=0.30 outpatient clinic Respiratory Failure for at least 1 Intervention: 28 (6.6%) year after Control: 23 (5.4%) discharge from P=0.28 the hospital Acute Renal Failure Funding Source Intervention: 21 (5.0%) Conflicts: Control: 27 (6.4%) Authors: NR P=0.22 Institution: NR Renal replacement Study: NR treatment Supplies: NR Intervention: 12 (2.8%) Control: 13 (3.1%) P=0.50 Liu RCT To investigate Number of patients: Intervention group: n=27 SSI: (follow up 30 days) Definitions: 2008 39 1, 2, 3, the impact of n=53 Received one dose of Surgical wound infection: Surgical wound (ES) 4, 6, 7, the duration of Patient preoperative Total: 13 (24.5%) infection: 8, 10 prophylactic Characteristics: prophylactic Intervention: 5 (18.5%) Purulent antimicrobials There were no antimicrobial Control: 8 (30.7%) discharge either on post- significant (intravascular P=0.473 spontaneously operative differences between clindamycin 300mg) Bivariate analysis of or by incision wound groups according to one hour before incision population based on and drainage infection in basic data and and then at 6 hour infections within 30 days patients laboratory studies. intervals over a period Bivariate analysis of after the undergoing ·Age, y: mean±SD of 72 hours. population based on operation. major head Timing of intervention: infections Perioperative and neck Intervention:56.4±12 Pre and postoperatively Infected n=14 / Uninfected care: NR neoplasm .3 Duration of intervention: n=40 Other notes: operations Control: 56.5±11.1 1 hour before incision to Tumor size, cm: mean±SD Operative and to ·Gender: m/f 24 or 72 hours after Infected: 3.2±1.3 procedures were determine Intervention: 23/4 surgery Uninfected: 2.2±1.1 all performed by associated Control:21/5 Device/agent: P=0.005 one surgeon and factors in post- ·Obesity: BMI, kg/m2, clindamycin Tracheostomy all postoperative average Monitoring intervention: Infected: 13 (100%) operative wound wound Intervention: 23.6 NR Uninfected: 14 (50%) conditions were infection. Control: 23.6 Control group: n=26 P<0.001 evaluated by © 2017 American Medical Association. All rights reserved. 163

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score ·Comorbidities Received one dose of Duration of antimicrobials another doctor Previous radiotherapy: preoperative 24 hours (Control) (Statistical Intervention: 2/27 prophylactic Infected: 8 (61.5%) analysis: sample (14.8%) antimicrobial Uninfected: 18 (45%) size not large Control: 8/26 (30.8%) (intravascular P<0.001 enough and Perioperative data: clindamycin 300mg) 72 hours (Intervention) statistic power Surgical reconstruction one hour before incision Infected: 5 (38.5%) unsatisfied Intervention: 4/27 and then at 6 hour Uninfected: 22 (55%) Follow-up: 30 (14.8%) intervals over a period P<0.001 days Control: 10/26 (38.5%) of 24 hours. Previous radiotherapy postoperatively Perioperative blood Infected: 8 (61.5%) Funding Source loss Standard preventive Uninfected: 4 (10.0%) Conflicts: Intervention: 239±110 measures: NR P<0.001 Authors: None Control: 262±136 Previous chemotherapy Institution: None Perioperative blood Infected: 9 (69.2%) Study: None transfusion: YES Uninfected: 4 (10.0%) Supplies: None Intervention: 4/27 P<0.001 (14.8%) Surgical reconstruction Control: 7/26 (26.9%) Infected: 10 (76.9%) Uninfected: 4 (10%) Procedures: Head and P<0.001 neck surgical Serum Albumin: g/dl±SD procedures Infected: 3.5±0.7 Reconstruction with Uninfected: 4.1±0.4 free flaps or P=0.013 pectoralis major Hemoglobin: g/dl±SD myocutaneous flaps: Infected: 10.8±1.9 14/53 (26.4%) Uninfected: 13.4±1.8 Intervention: 4/27 P<0.001 (14.8%) Perioperative blood loss: Control: 10/26 ml±SD (38.5%) Infected: 380±113 Laryngectomies Uninfected: 208 ±93 accounted for small P<0.001 portion of cases Perioperative blood Indications: Tumor transfusion Sites Infected: 7 (53.8%) Oral cavity/Oropharynx/ Uninfected: 4 (10.0%) Larynx/ P<0.001 © 2017 American Medical Association. All rights reserved. 164

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Hypopharynx/ Logistic regression Others identified preop Intervention: hemoglobin ≤10.5g/dL 18/2/1/2/4 (p=0.025) and surgical Control: reconstruction (P=0.036) 1/7/2/13/3 as independent risk factors Setting: 1 Veterans Other infections: NR Hospital Topic-specific Location: Taiwan outcomes: Dates: January 2004- Antimicrobial Resistance: December 2004 NR Inclusion Criteria: 13/53 (24.5%) total SSIs Patients scheduled 6/13 (46.1%) polymicrobial to receive head and P. aeruginosa (9/13, neck surgical 69.2%) procedures that E. faecalis (4/13, 30.0%) would enter the K. pneumonia (4/13, upper aerodigestive 30.8%) tract. C. koseri (1/13, 7.7%) Exclusion Criteria: A. baumannii (1/13, 7.7%) Those under Reoperations: NR antimicrobial Length of stay, d: treatment, allergic to Intervention: 22±15 clindamycin, with Control: 25±18 diabetes mellitus, or P=0.627 reluctant to join this Mortality: NR protocol. Adverse events: One patient developed an allergic reaction after treatment and was forced to drop out.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Fujita RCT To determine Number of patients: Intervention group: SSI: (follow up NR) Definitions: ND 2007 15 1, 2, 7, the efficacy of N=377 n=190 Total SSI Perioperative (ES) 8, 9, 10 a single-dose Patient Single Dose Group Intervention: 32/190 care: To ensure regimen of Characteristics: Received 1 g cefmetazole (16.8%) High infection that the trial second- Although patient age just before skin incision. rate results were generation was significantly Though additional Control: 17/187 (9.1%) applicable cephalosporin higher in the control doses are generally, cefmetazole group, other patient recommended every 3- Incisional SSI specific without characteristics were 4 hours during Intervention: 27/190 instructions on metronidazole identical. extended surgery, none (14.2%) surgical and oral ·Age, y: mean±SD were given Control: 8/187 (4.3%) techniques and antimicrobials Intervention: Timing of intervention: P=0.009 on postoperative with regards to 59.4±11.1 Preoperatively care were not reduction in Control: 62.1±9.8 Duration of intervention: Organ or Space SSI included incidences of P=0.01 Preoperatively or Intervention: 5 (2.6%) Other notes: surgical site ·Gender: m/f preoperatively and up Control: 9 (4.8%) Trial was designed infections and Intervention: 126/64 to 16 hours P=0.26 as non-inferiority all other Control: 107/80 postoperatively in test to detect 5% infectious ·Obesity: NR controls. Because only incidence of difference in complications ·Comorbidities: NR Device/agent: incisional SSIs differed incidence of following Procedures: cefmetazole 1g significantly between incisional SSI elective Colorectal Surgery Monitoring intervention: groups, subset analysis with CI 95%, colorectal Conventional: NA performed: Multivariate power 90% surgery. Intervention: 129/190 Control group: n=187 analysis revealed assuming (67.9%) 3-Dose Group antimicrobial dose was the incidence of Control: 133/187 Received 1 g cefmetazole only significant factor infection of 5%. (71.1%) just before skin incision associated with incisional Sample size of Colectomy/ anterior plus 2 postoperative 1g SSI (P=0.002). This result 238 required in resection/ doses at 8 and 16 is confusing unless they both arm. After abdominoperineal hours after the first meant to say antimicrobial 1yr interim resection administration. Though duration. analysis Intervention: 73/56/0 additional doses are revealed Control: 77/53/3 recommended every 3- The incidence of incisional significant Laparoscopic: 4 hours during SSI in the control was difference Intervention: 61/190 extended surgery, none lower even in patients between groups (32.1%) were given whose surgery lasted 3hrs and enrollment Control: 54/187 or less than in the was stopped. (28.9%) Standard preventive intervention group. Significance at Colectomy/ Anterior measures: <0.05 © 2017 American Medical Association. All rights reserved. 166

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score resection Bowel Prep: Patients The incidence of incisional Follow-up: Intervention: 49/12 underwent mechanical SSI associated with Wounds were Control: 42/12 bowel prep with 2L laparoscopic surgery was checked daily No gastric or hepatic polyethylene glycol- lower than in conventional until discharge resections included) electrolyte solution 1 although not statistically and at the first Indications: day before surgery. No significant postoperative Colon cancer: 241/377 oral AMP was Other infections: Urinary hospital visit (63.9%) Rectal administered as part of tract infections, (when? NR) cancer: 136/377 the bowel prep pneumonia, septicemia, Funding Source (36.1%) infective diarrhea and Conflicts: Setting: 7 major line sepsis. Authors: None hospitals Other Institution: None Location: Japan Intervention: 12/190 Study: None Dates: May 6, 2004 – (6.3%) Supplies: None April 25, 2005 Control: 9/187 (4.8%) Inclusion Criteria: P=0.52 Patients aged 20-80 Total Infections: (SSI plus years scheduled to other) undergo elective Intervention: 44/190 colorectal surgery. (23.1%) Exclusion Criteria: Control: 26/187 (13.9%) Emergency P=0.03 operations, C. difficile Colitis: obstruction of the Intervention: 0 small bowel, stomal Control: 2/187 (1.1%) surgery or bypass Topic-specific surgery, outcomes: NR preoperative Reoperations: NR infectious diseases, Length of stay, d: penicillin or mean±SD cephalosporin Intervention: 12.5±7.4 allergy, antimicrobial Control: 12.2±5.6 administration before P=0.66 hospitalization, With incisional SSI: n=35 inflammatory bowel 14.6±9.3 diseases, angina or Without incisional SSI: myocardial n=342 infarction, mild or 12.1±6.2 severe renal P=0.03 © 2017 American Medical Association. All rights reserved. 167

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score dysfunction, mild or Mortality: NR severe diabetes Adverse events: mellitus, and steroid Postoperative administration before Complications [Mainly surgery Small Bowel Obstruction] Intervention: 18/190 (9.5%) Control: 18/187 (9.6%) P= 0.96 Mohri RCT To compare Number of patients: Intervention group: SSI: (follow up 6 weeks) Definitions: CDC: 2007 53 1, 4, 6, the efficacy of N= 486 n=243 Overall: 44 (9.1%) Incisional SSI: (ES) 7, 8, 9 single- and Patient Single does prophylaxis Intervention: 23 (9.5%) Infection multiple-dose Characteristics: Cefazolin 1 g IV: n=122 Control: 21 (8.6%) occurring within antimicrobial Baseline (50.2%) Difference %: 0.9 (-4.3, 30 days after prophylaxis for characteristics were Ampicillin-Sulbactam 1.5g: 5.9) operation and the prevention similar between n=121 (49.8%) 3 patients in the involving skin, of surgical-site groups. 30 minutes prior to intervention group had subcutaneous infection in ·Age, y: mean (range) surgery, patients an infection that tissue or deep patients Intervention: 68 (22- received either 1g involved both the soft tissue (e.g. undergoing 91) cefazolin or 1.5 g incisional and deep or fascial and elective Control: 68 (23-90) ampicillin-sulbactam by organ/space sites muscle layers) of gastric cancer ·Gender: no male (%) slow intravenous Incisional the incision site, surgery. Intervention: 174 infusion over 15 Intervention: 14 (5.8%) and at least one (71.6%) minutes. An additional Control: 11 (4.5%) of the following Control: 164 (67.5%) dose was administered Difference %: 1.3 (-2.7, • Purulent 2 ·Obesity, BMI, kg/m , if the operation was 5.2) drainage, with or Mean(range) prolonged beyond 3h. Organ/Space without laboratory

Intervention: 21.6 Timing of intervention: Intervention: 12 (4.9%) confirmation, from (13.4-31.6) Preop and intraop if Control: 10 (4.1%) the incision Control: 21.4 (13.6- procedure lasted >3hrs Difference %: 0.8 (-2.9, • Organisms 34.0) Duration of intervention: 4.5) isolated from an ·Comorbidities Preop and intraop if Other infections: NR aseptically Diabetes Mellitus (no procedure lasted >3hrs Topic-specific obtained culture of Intervention: 17/243 vs. perioperative in outcomes: fluid or soft tissue (7.0%) controls for total 7 AMP Antimicrobial Resistance: from the incision Control: 19/243 doses ( at 12hr intervals 33/47 (70.2%) SSIs had • At least one of (7.8%) ) purulent discharge and the following signs Gastric Cancer: T1/ T2- Device/agent: cefazolin were cultured. or symptoms of © 2017 American Medical Association. All rights reserved. 168

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score 4 1g IV or ampicillin- 13/33 (39.3%) were infection: pain or Intervention: 94/149 sulbactam 1.5g (V culture positive tenderness, Control: 108/135 Monitoring intervention: S. aureus: 3 Intervention; localized swelling, Operative details: Control group: n=243 2 control redness, heat or Blood loss: mean Multiple dose prophylaxis MRSA: 2 intervention 2 fever (38oC) (range) Cefazolin: n=121 (49.8%) control • Spontaneous Intervention: 338 (10- Ampicillin-sulbactam: E. faecium 1 control wound dehiscence 2811) n=122(50.2%) Streptococcus spp. 1 • Abscess or other Control: 405.7 (10- 30 minutes prior to control evidence of 2917) surgery, patients E. coli 1 intervention infection involving P=0.028 received either 1g S. marcescens 1 the fascia or cefazolin or 1.5 g intervention muscle layer found Extent of Lymph node ampicillin-sulbactam by Enterobacter spp 1 on direct resection slow intravenous intervention examination, D0 or D1 infusion over 15 There were no appreciable during reoperation, Intervention: 92/243 minutes. An additional differences between or by (37.9%) dose was administered groups in the resistance histopathological Control: 112/243 if the operation was pattern of isolates. or radiological (46.1%) prolonged beyond 3h. examination. D2 The same dose of Reoperations: NR Organ/space SSI: Intervention 151/243 antibiotics was given at Length of stay: NR Infection occurring (62.1%) 12 hour intervals Mortality: NR within 30 days Control: 131/243 postoperatively to Adverse events: AMP after operation and (53.9%) achieve a total of 7 was not associated with involving the intra- antibiotic doses. any major side effects abdominal cavity Procedures: Elective Standard preventive and at least one of gastric cancer measures: the following: surgery Hair removal: Hair was • Purulent Total or proximal “shaved” using electric discharge from a gastrectomy/ distal clippers after induction drain placed gastrectomy/ wedge of general anesthesia through a stab resection/ Skin prep: surgical site wound into the gastrojejunostomy was wiped with 10% intra-abdominal Intervention: povidone-iodine cavity 78/147/2/16 solution before surgery • Organisms Control: 94/141/1/7 and draped with a isolated form an Indications: gastric disposable towel. aseptically cancer Closure: Absorbable obtained culture of Setting: 10 centers synthetic sutures were fluid or tissue in © 2017 American Medical Association. All rights reserved. 169

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Location: Japan used for closure of the the intra- Dates: May 2001 – fascia and peritoneum. abdominal cavity December 2004 Skin was closed using • Abscess or other Inclusion Criteria: stainless steel staples evidence of Patients undergoing and the wound then infection involving elective gastric wiped with normal the intra- cancer surgery in saline. Staples were abdominal cavity one of ten centers. removed after 7 days. found on direct Exclusion Criteria: Drains: Intra-abdominal examination, Aged<20 years, drainage tubes were during reoperation, pregnant, allergic to passed through a stab or by penicillins or incision separate from histopathological cephalosporins, had the wound. They were or radiographic received removed within 48h of examination. antimicrobial surgery Perioperative treatment in the past Local antimicrobial care: See 2 weeks, had an Irrigation: None standard infection at the time Adhesive dressing: site preventive of surgery, had kept covered with an measures malignant disease of adhesive dressing until Other notes: None another organ, or removal of the staples. Follow-up: had colorectal Non-standard preventive Patients resection at the time measures: assessed daily of surgery. Also, Antimicrobial prophylaxis until discharge moderate or severe choice: choice of cefazolin with liver disease or ampicillin-sulbactam postoperative (alkaline was left to the operating follow-up at 6 phosphatase, surgeon who was blinded weeks by an alanine to treatment schedule. independent aminotransferase, investigator at aspartate each institution. aminotransferase or Funding Source total bilirubin more Conflicts: than 5 times the Authors: NR upper limit of Institution: NR normal) and sever Study: NR renal impairment Supplies: NR (serum creatinine level above 2.0 © 2017 American Medical Association. All rights reserved. 170

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score mg/dl.)

Togo RCT To investigate Number of patients: Intervention group: n= SSI: (follow up 30 days) Definitions: 2007 55 1, 2, 6, two different N=180 89 Total SSI SSI: CDC (ES) 7, 8, 9, postoperative Patient 1g fluorometholone was Intervention: 4/89 (4.5%) Guideline 10 durations of Characteristics: administered 30 Control: 4/91 (4.4%) definitions for antimicrobial There were no minutes before surgery, P=0.033 Prevention of prophylaxis significant followed by 1g every 3 Intra-abdominal infection Surgical Site administration differences in any hours during surgery, (infection at cut surface Infection were (fluorometholo category between 1g 2 hours after of liver= Organ/Space) used. ne) after groups. completion of surgery, Intervention: 2/89 (2.2%) Inflammatory elective ·Age, y: mean ±SD and then 1g every 12 Control: 3/91 (3.3%) findings (fever hepatectomy Intervention: hours)for 2 days Wound infection and flare, and their 62.8±11.2 postoperatively (Incisional) drainage of pus respective Control: 61.6±10.7 Timing of intervention: Intervention: 2/89 (2.2%) from incision, or impact on the ·Gender: m/f Pre-, intra-, and Control: 1/91 (1.1%) drain, detection incidence of Intervention: 55/34 postoperatively Statistically Significant of a pathogen by SSI and Control: 61/30 Duration of intervention: Postoperative infection culture of fluid Systemic ·Obesity: NR Beginning 30 minutes Risk Factors or tissue sample inflammatory ·Comorbidities before surgery and Infected n=13 and fluid response Diabetes Mellitus (-/±/+) continued for 2 days vs. Non-infected: n=167 retention on syndrome Intervention: 70/5/14 5 days in controls Duration of operation, min: imaging (SIRS). Control: 68/5/18 Device/agent: mean±SD indicating Specifically, 2- Operative findings: fluorometholone 1g IV Infected: 494±106 presence of pus day versus 5- No significant Monitoring intervention: Non-infected: 352±107 in a deep region. day difference between Hematological and P<0.001 Cases judged as postoperative groups in terms of biochemical tests were Bile Fistula (+/-) SSI by physician regimens. resection rates, number performed before Infected: 4/9 included even if of liver segments surgery, immediately Non-infected: 4/163 pus drainage resected, prognostic after surgery, and P<0.001 and culture score, operation time, additional tests were negative. © 2017 American Medical Association. All rights reserved. 171

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score blood loss or blood performed as needed. Other infections: Systemic transfusion Control group: n=91 Remote Infections Inflammatory Procedures: Elective 1g fluorometholone was Intervention: 3/89 (3.4%) Response Hepatectomy without administered 30 Control: 2/91 (2.2%) Syndrome the reconstruction of minutes before surgery, P=0.242 (SIRS): the the biliary or followed by 1g every 3 Catheter Infection consensus intestinal tract hours during surgery, Intervention: 2/89 (2.2%) criteria Indications: 1g 2 hours after Control: 2/91 (2.2%) established by Hepatocellular completion of surgery, Pneumonia the American carcinoma/ liver and then 1g every 12 Intervention: 1/89 (1.1%) Thoracic Society metastasis/ donor/ hours for 5 days Control: 0/91 and the Society other postoperatively Postoperative infections of Critical Care Intervention: 33/43/4/9 Standard preventive total (SSI + RI) Medicine were Control: 33/45/5/8 measures: Intervention: 7/89 (7.9%) used. When 2/ 4 Setting: 1 University ABX prophylaxis: No Control: 6/91 (6.6%) of the following Hospital patient received pre- P=0.049 criteria were Location: Japan operative administration SIRS Positive Rate present: Dates: April 2003 – of oral antimicrobial At Postop day 2 • Body March 2006 agents. Intervention: 26/89 temperature of ≤ Inclusion Criteria: (31.7%) 36oC and ≥38oC Patients who Control: 12/91 (14.1%) • A pulse rate of underwent elective P=0.007 ≥90/min liver resection for At Postop day 3 • A respiratory rate hepatic lesions. Intervention: 12/89 of ≥ 20/min or Exclusion Criteria: (14.6%) PaCO2> 32 torr Patients who were Control: 4/91 (4.7%) • White blood cell concomitantly P=0.029 counts of treated with the After Postop day 3 ≥12,000/mm3 and resection of other Intervention: 6/89 (7.3%) ≤4,000/mm3 or organs – resection Control: 5/91 (5.9%) ≥10% immature and anastomosis of P=0.709 cells the bile duct; SIRS Duration all (mean) Biliary drainage and Intervention: 1.34 days Complications: resection and Control: 0.95 days • Drainage of bile anastomosis of the P=0.065 from the digestive tract and abdominal wound patients In whom Topic-specific and drain, showing apparent infection outcomes: a total bilirubin was noted at the Treatment: when post- level of >5mg/mL © 2017 American Medical Association. All rights reserved. 172

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score time of surgery. operative infection was or 3 times the Also, patients with a diagnosed during the serum level in the past medical history study, the treatment discharge fluid. of allergic reaction to was changed to • An intra- β-lactams, a pre- therapeutic abdominal operative serum antimicrobial agents. accumulation of creatinine level of Diarrhea: bile confirmed by ≥1.5 mg/dL, diabetes Intervention: 2/89 (2.2%) percutaneous mellitus under insulin Control: 0/91 drainage control, treatment • with antimicrobials P=0.150 Cholangiographic within 1 week before No cases of C. difficile evidence of bile surgery, judged detected. leakage. ineligible by the Post-operative attending physician, Reoperations: NR complications: and non-consent to Length of stay: conditions in which the study. Intervention: 15.24±6.84 the admission days period after Control: 15.11±6.07 surgery exceeded days 22 das P=0.896 (mean±SD), Perioperative Mortality: None during the care: NR admission period in Other notes: either group None Adverse events: Follow-up: 30 No severe complications days after observed. surgery Funding Source Conflicts: Authors: None Institution: None Study: None Supplies: None Ali RCT To compare Number of patients: Intervention group: SSI Definitions: 2006 17 4, 5 the proportion N=200 n=100 All SSI Wound evaluation: (ES) of early Patient 1dose: 1 dose of 2g 1dose: 8/100 (8%) done using the postoperative Characteristics:·Age, ceftazidime Multi: 6/100 (6%) prescribed infection y: NR intravenously 30 proforma for © 2017 American Medical Association. All rights reserved. 173

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score cases in clean ·Gender: NR minutes before the Deep SSI postoperative orthopedic ·Obesity: NR initial operative incision Total: 4/200 (2%) fever developing surgery after a ·Comorbidities: NR and 2 placebo doses 1 dose: 1% or persisting single dose of Procedures: mix of after 12h each. Multi: 3%; 48hours after prophylactic clean orthopedic Timing of intervention: p=0.34 the surgery, antimicrobial fracture surgeries pre and postop. discharge from and multiple Setting: 1 public Duration of intervention: Superficial SSI the wound, and doses of hospital preop up to 24h postop. Total of 10 (5%) superficial overlying skin prophylactic Location: Pakistan Device/agent: SSIs and no difference:: inflammation. antimicrobial Dates: April 2004 – ceftazidime. 1dose: 7% Wound infection March 2005 Control group: n=100 Multi: 3%; was noted to be Inclusion Criteria: Any 3dose: 1 dose of 2g p=0.21 superficial or age and either ceftazidime deep. gender undergoing intravenously 30 Antimicrobial resistance: Other notes: None clean orthopedic minutes before the Staphylococcus aureus Follow-up: 28 surgery and initial operative incision was the commonest days available for and 2 doses after 12h organism isolated, Funding Source complete follow-up. each. followed by E. coli. Conflicts: Exclusion Criteria: Eight of the 14 SSIs Authors: NR Patients with any Standard preventive had a negative wound Institution: NR generalized measures: culture (7 superficial, 1 Study: NR debilitating disease, Weight adjusted dosing: in deep). No mention of Supplies: NR diabetes mellitus, patients under 12y, the resistance any infective focus in antimicrobial the body, poor prophylaxis dose quality of the skin at adjusted for weight. the incision site, allergy to cephalosporin, open fracture, revision surgery within last 6 weeks, use of antimicrobials within the last 7 days and duration of surgery >3h.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Mui RCT To investigate Number of patients: Intervention1 group: n= SSI: (follow up 30 days) Definitions: 2005 11 1, 6, 7, the infective N=269 92 Intravenous Wound infections Wound infection: (ES) 8, 9 complications Patient cefuroxime (1.5g) and Intervention1: 6/92 discharge of pus rate after open Characteristics: All metronidazole (500mg) (6.5%) that required appendectomy baseline were given at induction Odds Ratio (95% CI): surgical for non- characteristics were of general anesthesia. 1 drainage before perforated comparable Intervention2 group: n= Intervention2: 6/94 discharge appendicitis ·Age, y: mean (SD) 94 Intravenous (6.4%) Intra-abdominal (NPA)receivin Intervention1: 36.3 cefuroxime (1.5g) and Odds Ratio (95% CI): collection or g different (15.6) metronidazole (500mg) 1.01 (0.34-3.26) abscess: a fluid durations of Intervention2: 32.1 were given at induction Control: 3/83 (3.6%) collection prophylactic (13.2) of general anesthesia Odds Ratio (95% CI): diagnosed at antimicrobials Control: 35.1 (13.4) followed by two more 0.89 (0.46-7.79) ultrasound or cefuroxime P=0.12 doses of IV P I1&I2=0.97 computed and ·Gender: m/f antimicrobials. P I1orI2 & C= 0.5 tomography metronidazole Intervention1: 65/27 Timing of intervention: which required perioperative Intervention2: 66/28 Pre operatively All required local wound drainage regimens: Control: 54/29 Duration of intervention: exploration with daily C. difficile 1) single dose P=0.68 Single dose at induction dressing enterocolitis- preoperative, ·Obesity: NR of anesthesia vs. up to All infected wounds healed diagnosed by 2) 1 preop and ·Comorbidities: NR 5 days postoperatively by 30-days positive fecal 2 postop Procedures: for controls postoperative follow up. clostridium toxin (three-dose/1- Emergency open Device/agent: Intra-abdominal Perioperative day) and appendectomy Intravenous cefuroxime Infections/abscesses care: 3) preop and through right lower 1.5g, and No patients developed Discharge: when 5-days postop quadrant incision metronidazole 500mg. intra-abdominal fully mobilized, using muscle Monitoring intervention: collection or abscesses. could tolerate a splitting approach NR Other infections: NR normal oral diet and appendices Control group: n= 83 Topic-specific with evidence of were removed in the Intravenous cefuroxime outcomes: bowel activity standard fashion (1.5g) and The incidence of AMP- (normal bowel Indications: acute non- metronidazole (500mg) related complications sounds and perforated given at induction of was significantly higher passing flatus or appendicitis general anesthesia in the control group (5d) stool), apyrexial Setting: 1 university followed by a 5-day as compared with for 12h (<37oC hospital course of Intervention 1 (single tympanic), and Location: China antimicrobials. IV dose): had adequate Dates: July 1995 – Antimicrobials were OR, (95% CI) pain control on December 2000 administered until 1.05(1.001-1.1); oral analgesics. © 2017 American Medical Association. All rights reserved. 175

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Inclusion Criteria: patients could tolerate a P=0.048 Other notes: Study Patients aged 15-70 semi-solid or solid diet C. difficile enterocolitis is underpowered with the clinical when IV antimicrobials Intervention1 (single Patients were diagnosis of acute, were substituted by oral dose): 0/92 randomized after non-perforated formula: 250mg Odds Ratio (95% CI): open appendicitis cefuroxime 2x/day and 1 appendectomy undergoing 400mg metronidazole Intervention2 (3d): 1/94 determined NPA emergency open 3X/day (1.1%) Follow-up: After appendectomy Standard preventive Odds Ratio (95% CI): discharge all Exclusion Criteria: measures: 1.01 (0.99-1.03) patients were Patients who had a Closure: The peritoneum, Control (5d): 4/83 (4.8%) followed up at history of oblique muscles and Odds Ratio I1 vs. C 10 days preadmission the Scarpa’s fascia (95% CI): 1.05 (1.001- postoperatively antimicrobials, closed with 3/O 1.1) for wound diabetes mellitus, polyglycolic sutures and P I1&I2=1.0 assessment and steroid therapy, the skin was closed P I1 & C= 0.048 via stitches removal known drug allergy with interrupted vertical Fisher’s exact test and the second to the study mattress with 3/O All cases of C. diff follow up was antimicrobials, monofilament sutures in enterocolitis recovered conducted for ruptured appendicitis a standardized manner. uneventfully after 7d wound problems and appendicular Peritoneal lavage: none course of oral occurring at 30 mass or abscess Wound Lavage: none vancomycin days formation. Also, Local antimicrobials: Reoperations: postoperatively pregnant women none By definition (see next Funding Source and patients who column) all wound Conflicts: refused consent. infections (15/15) Authors: NR required surgical Institution: NR drainage Study: NR All infections were treated Supplies: NR by laying open the wound site, and packing with normal saline ribbon gauze twice per day to allow healing by secondary intention. All infected wounds were healed at 30d f/u Length of stay, d: mean © 2017 American Medical Association. All rights reserved. 176

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (SD) Intervention1: 4.3 (1.3) Intervention2: 4.6 (1.2) Control: 4.8 (2.3) P=0.13 Mortality: No perioperative mortality Adverse events: See topic specific events for AMP adverse events Chang RCT To investigate Number of patients: Intervention group: n=74 SSI: (follow up within 7 Definitions: 2005 41 (pilot whether a N=156 Intravenous push stat of days of discharge) Operative site (ES) study) short course Patient 2g cephalothin followed Operative Site Infection infection: 1, 2, 9, of Characteristics: No by a 1g injection every Intervention: 2/74 (2.7%) includes pelvic 10 antimicrobials differences in patient 6 hours. Gentamycin 1/2: Trocar site wound cellulitis, vaginal (<24 hours or operative began with an 80mg IV infection cuff abscess, between the characteristics drip followed by a 60- 1/2: 1 cuff abscess pelvic abscess, first and final between groups. 80mg injection every 8 Control: 3/82 (3.6%) and wound doses) is as ·Age, y: mean ±SD hours. The first dose 1/3: infection infection efficacious as Intervention: 41.1±5.8 was administered within 1/3: cellulitis (Sharpiro 1982) longer courses Control: 42.3±7.1 1 hour prior to the 1/3: trocar site wound Urinary tract (30-60 hours) ·Gender: 100% Female incision and continued infection during infection (UTI): in ·Obesity: NR for <24 hours hospitalization (instead diagnosed from laparoscopical ·Comorbidities: NR Timing of intervention: of within 7 days of patients’ ly assisted Pre and postoperatively discharge) symptoms and vaginal Procedures: Duration of intervention: P=0.735 signs and to hysterectomy Laparoscopically From 1 hour prior to whether there (LAVH). assisted vaginal incision to either <24 Other infections: Urinary was a positive hysterectomy hours or 30-60hours Tract Infection: urinalysis (LAVH) Device/agent: Intervention: 2 (2.7%) Perioperative Indications: Cephalothin 2g IV and 1/2: during care: NR Myoma uterus: 70 gentamycin 80mg IV hospitalization Other notes: Pilot Intervention: 37 Monitoring intervention: 1/2: w/in 7 days of study with low Adenomyosis: 53 NR discharge power to Intervention: 28 Control group: n=82 Control: 2 (2.4%) determine Cervical carcinoma in Intravenous push stat of 2/2: w/in 7 days of statistically situ: 17 2g cephalothin followed discharge significant Intervention:10 by a 1g every 6 hours. P=0.917 differences in Cervical carcinoma Ia1: Gentamycin began with the rate of © 2017 American Medical Association. All rights reserved. 177

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score 9 an 80mg IV drip Topic-specific operation site Intervention:3 followed by a 60-80mg outcomes: NA infection and UTI Other: 7 injection every 8 hours. Reoperations: NR between the 2 Setting: 1 medical The first dose was Length of stay, groups. To center injected within 1 hour d:mean±SD achieve power Location: Taiwan prior to the incision and Intervention: 4.3±1.1 of 0.80, 3,800- Dates: June 2001-July continued for 24 hours Control: 4.2±1.3 5,200 cases in 2002 P=0.89 both groups Inclusion Criteria: Standard preventive Mortality: NR would be Patients undergoing measures: Adverse events: NR necessary LAVH. Preop serum NR Follow-up: Within hemoglobin 7 days of level>9g/dL and discharge normal renal function collected from tests (serum patients’ charts BUN/Creatinine) Funding Source Exclusion Criteria: Conflicts: LAVH cases with Authors: None complications and Institution: None those patients who Study: None required therapeutic Supplies: None antimicrobials and other associated surgical procedures were excluded from the study Su RCT To compare Number of patients: Intervention group: n= SSI: (follow up 90 days) Definitions: 2005 13 1, 2 the efficacy of N=531 267 Serious infectious Infectious (ES) a single-dose Patient One dose of 1g cefazolin morbidity morbidity: versus a 1-day Characteristics: intravenously before Intervention: 1/267 If body temperature course of (N=548 before 17 surgery upon induction (0.37%) was greater than prophylactic patients excluded of anesthesia by the 1/1: Trocar wound 38.5oC, the antimicrobials due to loss to f/u) anesthesiologist within infection at postop day patient was for There were no 30 minutes before 27 from LAOC surgery assessed for postoperative differences between surgery. If the surgery Control: 1/264 (0.37%) signs and wound groups regarding duration was greater 1/1: vaginal cuff symptoms of infection general status than 4h, and additional infection with pelvic infection outcomes and ·Age, y: mean±SD dose of 1.g cefazolin abscess at postop day including one or cost- Intervention: administered 7 from LAVH surgery more of the © 2017 American Medical Association. All rights reserved. 178

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score effectiveness 45.77±9.74 intravenously. following: in gynecologic Control:45.18±9.31 Timing of intervention: Other infections: • An abdominal o operations. ·Gender: 100% Female Pre, intra and Fever (>38.5 C on two wound infection or 2 ·Obesity: BMI, kg/m , postoperatively occasions 4 or more trocar wound mean±SD Duration of intervention: hours apart excluding infection (including Intervention: Either preoperatively, or the night of surgery) wound discharge 23.21±1.13 Preoperatively through Intervention: 112 or abscess) Control:23.32±1.05 24 hours /267(41.9%) • Pelvic Abscess or ·Comorbidities: NR postoperatively. 67/112 had blood tubo-ovarian Wound classification: Device/agent: Cefazolin drawn for cultures but abscess Clean: LAOC 1g IV none had septicemia • Vaginal cuff Clean contaminated: Monitoring intervention: Control: 120/264 abscess TVH, TAH, LAVH NR (45.4%) • Postoperative Operative Control group: n= 264 74/112 had blood septicemia characteristics: One dose of 1g cefazolin drawn for cultures but Duration of surgery, intravenously before none had septicemia Perioperative min: surgery upon induction Topic-specific care: mean±SD of anesthesia by the outcomes: Anesthesia Intervention: anesthesiologist within Timing of AMP before Genera/spinal 98.14±35.54 30 minutes before incision, min: mean±SD Intervention Control: 98.87±35.48 surgery followed by Intervention: 21.07±9.96 n=273: 257/16 Procedures: Total another three doses of Control:22.70±13.22 Control vaginal 1g cefazolin every 6hr n=275:260/15 hysterectomy (TVH) after surgery X1 day. If Antimicrobial resistance: Total abdominal the surgery duration none reported. Other notes: NNIS hysterectomy (TAH) was greater than 4h, Intervention trocar wound SSI risk Laparoscopic-assisted and additional dose of culture: P. aeruginosa stratification. vaginal 1.g cefazolin was Control vaginal cuff Follow-up: hysterectomy administered cultures: E coli, B. During (LAVH) intravenously. fragilis hospitalization, Laparoscopic assisted Standard preventive Reoperations: abdominal and ovarian cystectomy measures: There were Intervention: Infection perineal exams (LAOC) no differences between required debridement of were performed LAOC/LAVH/TAH/TVH groups regarding trocar wound and daily by Intervention: preoperative drainage with pen-rose gynecological 36/190/27/20 examination and drain. Readmission stay staff to assess Control:34/195/25/21 preparation, skin was 8 days for infection. If Indications: NR disinfection, Control: Infection & signs/symptoms Setting: 1 hospital postoperative abscess required developed, © 2017 American Medical Association. All rights reserved. 179

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Location: Taiwan intravenous fluid drainage with pen-rose examiner Dates: June 1, 2001 – therapy (for 36h only), drain and readmission collected January 31, 2003 and indwelling urethral stay was 4 days. samples from Inclusion Criteria: catheterization (for 24h Length of stay, days, pelvic cavity and Women ≥18 years only). mean±SD wound site for old scheduled to Skin Prep: The surgical Intervention: 3.97±1.27 culture before undergo elective site was prepared by Control:4.02±1.51 initiating vaginal or abdominal swabbing with antimicrobial hysterectomy (total povidone-iodine or Mortality: NR therapy. vaginal alcohol—iodine for Adverse events: NR After discharge: 90 hysterectomy (TVH) about 5 min and days and total abdominal Hair removal-trimming/ postoperatively hysterectomy (TAH), shaving of the surgical at the first, laparoscopic- area according to the second and third assisted vaginal “standard practice” in months after hysterectomy or our hospital (did not surgery, vital ovarian cystectomy specify how many in signs, physical (LAVH or LAOC) for each). examination, nonmalignant and pelvic disease. sonography Exclusion Criteria: were performed Women who had when patient major surgery in the returned to the month before clinic for elective gynecologic evaluation. surgery, had known Funding Source or suspected Conflicts: hypersensitivity or Authors: None intolerance to Institution: None cephalosporin, or Study: None had any coexisting Supplies: None disease that would require antimicrobial therapy during the study. Also, patients who had taken antimicrobials the week before surgery

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Carroll RCT To clearly Number of patients: Intervention group: n= SSI: (follow up: Definitions: 2003 40 1, 4, 8, address the N=74 35 discharge or 7days Head and neck (ES) 9, 10 duration of Patient Short course (1 day): postop) wound and antimicrobial Characteristics: No 900mg Clindamycin Wound infection donor site prophylaxis statistically intravenously initiated Intervention: 4/35 (11%) evaluated for: (either 3 significant difference immediately Control: 4/39 (10%) Wound color doses [1 day] existed between preoperatively to total 3 P=0.99 1: normal or 15 doses [3 study groups or doses every 8 hours. 2: pink days]) in between patients Timing of intervention: Other infections: 3: red or swollen patients with with and without Pre and postoperatively Women were more likely Drainage head and neck complications (data Duration of intervention: than men to develop 1: none cancer listed below is for From preoperatively to Remote Infections 2: serious requiring free- entire population (N). 16-56 hours (specifically UTI) 25% 3: purulent flap ·Age, y: postoperatively. vs. 2%; P=0.004 Wound infection reconstruction mean±SD61.6±12.5 Device/agent: Other/ remote infections A wound was of cancer range 21-88 years Clindamycin (including UTI & considered defects. ·Gender (m/f): 46/28 Monitoring intervention: enterocolitis) infected when ·Obesity: NR NR Intervention: 4/35 (11%) the color ·Comorbidities: NR Control group: n= 39 Control: 4/39 (10%) became red or Previous radiotherapy: Long Course (3 days) P=0.99 the wound was 24/74 (32%) 900mg Clindamycin swollen. A pink Flap Type: intravenously initiated Topic-specific wound that Fibula/jejunum/radial preoperatively to total outcomes: developed forearm/rectus: 15 doses every 8 hours. purulent 9/19/31/15 C. difficile enterocolitis: drainage was Tumor site: Buccal/floor Standard preventive 1/74 (1%) they don’t also considered of measures: NR specify in which group infected. mouth/hypopharynx/ Reoperations: NR larynx/maxilla/ Length of stay: NR Perioperative oropharynx/roof of Mortality: care: NR mouth/ tongue: Intervention: 1/35 (3%) Other notes: 5/15/14/7/11/8/10/4 Control: 1/39 (3%) Accrual of Procedures: Surgical P=0.99 patients for the ablation of head and study was neck malignancies Adverse events: stopped when with immediate free- Pharyngocutaneous annual review of flap reconstruction Fistula the data including: radial Intervention: 3/35 (9%) disclosed that forearm, jejunum, Control: 3/39 (8%) differences © 2017 American Medical Association. All rights reserved. 181

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score rectus and fibula by P=0.99 between the descending order of Postoperative fistula was study groups frequency. more common in men were much lower Indications: (n) but P=0.08 than those Stage II/III/IV: 7/21/46 Flap Necrosis projected in (91% stage III or IV) Intervention: 0/35 initial sample Setting: 1 center Control: 1/39 (3%) size Location: USA P=0.99 determinations. Dates: January 1, Vascular Compromise of A difference of 1998- April 30, 2001 flap 1%, recalculated Inclusion Criteria: Intervention: 2/35 (6%) estimate of Patients scheduled Control: 1/39 (3%) sample size for 2 to undergo surgical P=0.99 sided ablation of head and significance level neck malignancies of 0,005 with with immediate free- 80% power flap reconstruction would require Exclusion Criteria: more than Patients undergoing 10,000 subjects secondary in each reconstruction and treatment arm. those whose tumor Follow-up: did not involve the Wounds were mucous membranes evaluated daily of the upper for 7 days aerodigestive tract postoperatively (or until discharge) by a blinded faculty head and neck surgeon. Funding Source Conflicts: Authors: None Institution: None Study: None Supplies: None

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Hall RCT To compare Number of patients: Intervention group: n= SSI: (follow up 42 days Definitions: 1998 38 1, 2, 6, the incidence N=302 153 postop) Wound infections: (ES) 7, 8, 9 of wound Patient Single Dose Overall rate of wound discharge of pus infection after Characteristics: 3g ticarcillin/ 0.1g morbidity: (wound + minor or a serous emergency Both groups were clavulanate by slow wound): 101/302 (34%) discharge that elective comparable with intravenous infusion contains vascular respect to putative (over 30 minutes) Wound infection: 43/302 pathogenic surgery risk factors for a immediately after the (14%) organisms following the wound infection at induction of anesthesia. Intervention: 28/153 Graft infection: an administration baseline and during Patients received an (18%) overt clinical event of the same the perioperative additional dose if the Control: 15/149 (10%) characterized by agent as period. surgery was prolonged P=0.041 the need for either short- ·Age, y: median (range) beyond 3 hours. Relative risk estimate aggressive term Intervention: 70 (64- Timing of intervention: (95%CI) interventions and prophylaxis or 75) Pre, intra and = 2.00 (-1.02-3.92) confirmed by a multiple Control: 69 (64-76) postoperatively Median time to microbiology. dose regimen. ·Gender: m/f Duration of intervention: presentation of wound Minor wound Intervention: 116/37 From immediately after infection: 13 days infections: Local Control: 103/46 the induction of (range: 2-43 days) abscess or ·Obesity, BMI, kg/m2, anesthesia to vs. five Minor wound infections: serous mean (range) days in controls. 58/302 (19%) discharge not Intervention: 25 (22- Device/agent: 3g Intervention: 35/153 meeting their 27) ticarcillin/ 0.1g (23%) established Control: 24 (22-27) clavulanate Control: 23/149 (15%) criteria for ·Comorbidities Monitoring intervention: Graft infection: 2/302 wound infection IDDM: NR (<1%) Intervention: 3/153 Control group: n= 149 Intervention: 1/153 Vascular surgery: (2%) Multiple Dose (<1%) All open arterial Control: 3/149 (2%) 3g ticarcillin/ 0.1g Control: 1/149 (<1%) procedures. NIDDM: clavulanate by slow Patients undergoing lower Shock: (Dellinger Intervention: 31/153 intravenous infusion limb surgery had 1985) (20%) (over 30 minutes) greatest risk of wound clinical signs of Control: 16/149 (11%) immediately after the infection (24/95 or 25%) reduced Current Smoker induction of anesthesia. Other infections: NR peripheral Intervention: 53/153 Patients received an Topic-specific perfusion plus (35%) additional dose if the outcomes: any two of the Control: 39/149 (26%) surgery was prolonged No major side effects following: Previous myocardial beyond 3 hours. After associated with the • Systolic blood infarction the initial dose, patients parenteral pressure (BP) <80 © 2017 American Medical Association. All rights reserved. 183

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 38/153 received 3g ticarcillin/ administration of AMP mm HG for 1 hour (25%) 0.1g clavulanate • Pulse rate Control: 37/149 (25%) intravenously at 6 Diarrhea with C. difficile >120bmp (sinus Previous stroke hourly intervals for a Intervention: 2/153 minute rhythmia) Intervention: 20/153 maximum total of 20 (1.3%) for more than 1 (13%) doses (i.e., until the Control: 1/149 (0.7%) hour Control: 16/149 (11%) lines are removed • Urine output less Previous ischemic but<5 days) Antimicrobial resistance: than 80ml for any attack Authors state that they 4 hour period Intervention: 15 Standard preventive did not detect any • Use of pressors (10%) measures: appreciable difference to maintain the Control: 9 (6%) Skin prep: preoperative in the resistance blood pressure for Previous cardiovascular chlorhexidine skin patterns of the isolates at least 1 hour. surgery wash. between groups Obesity: Body Intervention: 62/153 Wound closure & Drains: (statistical significance mass index (BMI) (41%) there was uniform not tested) Among weight/ the square Control: 65/149 (44%) wound closure and several isolates from 25 of the height. Comparable with drain tubes did not exit patients are the Insulin dependent regards to operation through wounds. following: diabetes mellitus type, duration, ABX irrigation: No local S. aureus (IDDM): an intraoperative shock, irrigation of tissues with Intervention: 5/15 (33%) episode of wound closure antibiotic solutions. Control: 4/10 (40%) ketoacidosis or technique, total Diarrhea: Patients with MRSA dependence on length of wounds postop diarrhea had Intervention: 1/5 SA (20%) insulin and duration of stools evaluated for or 1/15 isolates (7%) Non-Insulin drainage in days. enteropathogens. Control: 2/4 SA (50%) or dependent Intervention vs. Control 2/10 isolates (20%) diabetes mellitus Use of Cell saver: S epidermis (SE) (NIDDM): 47 (31%) vs. 51(34%) Intervention: 1/15 (7%) indicated by a Peri-op blood Control: 3/15 (20%) requirement for transfusion Resistance not reported oral hypoglycemic 32 (21%) vs. 40 (27%) for SE medication Number of wounds per Length of stay = patient: Reoperations: number of 1: 86 (56%) vs. 83 Intervention: 16 (10%) postoperative days (56%) 8/16 Amputation/ in hospital 2: 34 (22%) vs. 41 debridement of tissue Perioperative (28%) 5/16 Revision of graft care: 3: 31 (20%) vs. 22 2/16 Hemostasis Nosocomial © 2017 American Medical Association. All rights reserved. 184

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (15%) 0/16 CABG infections were 4: 2 (1%) vs. 3 (2%) 1/16 Intestinal managed in Procedures: Adhesions accordance with Emergency or Control: 17 (11%) the institutional Elective: 7/17 Amputation/ antimicrobial Abdominal aortic debridement of tissue guidelines. aneurysm: 86/ 302 3/17 Revision of graft Other notes: As (28.5%) 4/17 Hemostasis might be Groin-distal bypass: 2/17 CABG expected, the 73/302 (24.2%) 1/17 Intestinal patients tended Aorto-groin bypass: Adhesions to be elderly and 49/302 (16.2%) Length of stay: median debilitated. Carotid (range) More intervention endarterectomy: Intervention: 9/153 (6-13 patients were 37/302 (12.3%) Control: 9/149 (7-13%) smokers, Miscellaneous lower 86% of patients admitted NIDDM and had limb: 28/302 (9.3%) to ICU were discharged severe cardiac Groin procedures: w/in 48 hours. disease. 22/302 (7.3%) Mortality: Follow-up: 42 Other: 7/302 (2.3%) Intervention: 8/153 (5%) days after Indications: NR Control: 5/149 (3%) surgery Setting: 1 hospital No patient died as a result Funding Source Location: Australia of a wound or graft Conflicts: Dates: January 1993 – infection. Authors: NR October 1995 Adverse events: Institution: NR Inclusion Criteria: All Administration of Study: Industry adults undergoing antimicrobials Supplies: NR Vascular surgery (all Intervention: 37/153 open arterial (24%) procedures.) Control: 27/149 (18%) Exclusion Criteria: Requirement of wound Patients undergoing dressing endovascular Intervention: 23/153 procedures, (15%) administration of Control: 22/149 (15%) antimicrobial agents within 48 hours of surgery, a history of hypersensitivity to © 2017 American Medical Association. All rights reserved. 185

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score penicillin, and profound comorbidity. Kow RCT To evaluate Number of patients: Intervention group: SSI Definitions: 1995 22 1, 2, 6 the efficacy of N=1010 n=516 All procedures Wound infection: (ES) one dose of Patient 1dose CFX: n=252: 2g Total: 58/1010 (5.7%) the presence of antimicrobial Characteristics cefoxitin intravenously 1dose: 31/516 (6.0%) purulent vs. 3 doses There was an even on induction of 3dose: 27/494 (5.5%) discharge from covering the distribution of anesthesia P>0.19 the wound or a 24h patients for each 1dose CTX+M: n=264: 1g serous postoperative antimicrobial cefotaxime + 500mg 1dose CFX: 17/252 (6.7%) discharge with period using a regimen. metronidazole on 3dose CFX: 17/254 (6.7%) positive culture new Procedures: Elective induction of anesthesia of pathogenic antimicrobial and emergency Timing of intervention: 1dose CTX+M: 14/264 organisms. prophylaxis intra-abdominal pre and postop (5.3%) Perioperative consisting of surgeries. Duration of intervention: 3dose CTX+M: 10/240 care: NR cefotaxime Setting: 2 hospitals. preop and up to 12h (4.2%) Other notes: Study plus Location: Australia postop was not metronidazole Dates: September Device/agent: cefoxitin or sufficiently or cefoxitin 1989 - January 1992 cefotaxime plus powered for Inclusion Criteria: metronidazole Elective colorectal smaller sub Patients 16 years Control group: n= procedures analyses. and older, admitted 3dose CFX: n=254: 2g CTX+M: suggests no Follow-up: 28-41 to the two hospitals cefoxitin intravenously difference day follow-up. for all types of intra- on induction of Total: 12/138 (8.7%); Funding Source abdominal surgery anesthesia followed by 1dose: 5/71(7.0%) Conflicts: (elective and another 2g at 6 & 12h 7/67(10.4%); p =0.48 (28- Authors: NR emergency) postop 41 day follow up) Institution: NR Exclusion Criteria: if 3dose CTX+M: n=240: 1g Study: Industry there was a history cefotaxime + 500mg CFX: suggests no Supplies: NR of allergy to metronidazole on difference: cephalosporins, induction of anesthesia Total: 16/135 (11.9%); penicillin, or followed by 1g of 1dose: 8/65(12.3%) metronidazole, had cefotaxime at 6 & 12h 3dose: 8/70(11.4%); received postop. p=0.87 antimicrobials. Also Standard preventive if operative findings measures: Emergency colorectal indicated the need Skin prep: PI Solution procedures: for prolonged Plastic wound protectors: Total: 6/46 (13.0%); © 2017 American Medical Association. All rights reserved. 186

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score antimicrobials, or the not allowed. 1dose: 4/21 (19.0%) vs. need for delayed Bowel Prep: all patients 3dose: 2/25 (8.0%); primary wound undergoing elective p=0.28 closure were colorectal surgery were excluded. Also if a given mechanical (non- Appendectomy: patient died in the 14 antimicrobial) bowel Drug regimen 1: n=112: days after the prep of up to 3 L of a 1doseCFX: 4/54 (7.4%) operation with no colonic lavage solution 3dose CFX: 4/58 (6.9%) evidence of prior to operation. Drug regimen 2: n=117 infection, they were 1doseCTX+M: 2/63 excluded from the (3.2%) analysis. 3dose CTX+M: 0/54

Esophageal, gastric, and small bowel surgery Drug regimen 1: n=82: 1doseCFX: 1/42 (2.4%) 3dose CFX: 3/40 (7.5%) Drug regimen 2: n=81 1doseCTX+M: 1/41 (2.4%) 3dose CTX+M: 1/41 (2.4%)

Biliary Surgery: Drug regimen 1: n=158: 1doseCFX: 2/83 (2.4%) 3dose CFX: 2/75 (2.7%) Drug regimen 2: n=140 1doseCTX+M: 3/76 (3.9%) 3dose CTX+M: 0/64

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score McArdle RCT To compare Number of patients Intervention group: n=45 SSI Definitions: 1995 47 1, 7, 8 an oral N=87 Patients administered Total: 20/87 (23.0%) Wound sepsis: the (ES) ciprofloxacin/ Patient gentamicin 120mg and Single day: 13/45(28.9%) presence of pus parenteral Characteristics: the metronidazole 500mg 3day: 7/42(16.7%); either metronidazole groups were intravenously at p=0.18 discharging regimen with a comparable in in induction of anesthesia spontaneously parenteral terms of followed by gentamicin or requiring aminoglycosid characteristics. 80mg and drainage. e/metronidazol Procedures: colorectal metronidazole 500mg Major wound e combination surgery at 8h & 16h post-op sepsis: the commonly Setting: 1 university (3doses total) discharge of pus used for hospital Timing of intervention: with prophylaxis in Location: United pre and postop constitutional colorectal Kingdom Duration of intervention: disturbance surgery, and Dates: NR 1 shot or 3 days postop Minor wound the value of Inclusion Criteria: Device/agent: gentamicin infections: 1day versus 3 patients undergoing 120mg or 80mg and patients with days of colorectal surgery. metronidazole 500mg cellulitis and a antimicrobial Exclusion Criteria: NR Control group: n=42 positive wound cover. Patients administered culture. gentamicin 120mg and Perioperative metronidazole 500mg care: NR intravenously at Other notes: NR induction of anesthesia Follow-up: 4 followed by 80mg weeks post gentamicin and discharge metronidazole 500mg Funding Source 3times/ day for 3 days Conflicts: postop. Authors: NR Standard preventive Institution: NR measures: NR Study: Industry Supplies: NR

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Nooyen RCT To compare a Number of patients: Intervention group: SSI: (7 day follow up) Definitions: 1994 33 1, 2, 4, single dose of N=844 n=419 Overall (sternal + leg Wound infection: (ES) 7, 8 cefuroxime Patient After placement of a wounds): 54/844 diagnosed if all with their Characteristics: peripheral line in the (6.3%) Note: authors of the following currently Risk factors and operating room, report it as 5.3% using criteria were recommended patient patients received N=1016 even though met: 3-day course characteristics were 20mg/kg cefuroxime they excluded 172 • Redness of cefuroxime similar between intravenously at patient from all other • Purulent with regard to groups. induction of anesthesia. final analysis ( see discharge effectiveness ·Age range Timing of intervention: NOTE at bottom of • Positive culture in preventing Intervention: 34-86 Pre, intra and results) (if pathogenic postoperative Control: 33-86 postoperatively Sternal Site organisms were wound Age>70 years Duration of intervention: Total complications of isolated) infection. Intervention: 79/419 From induction of healing Infection of the (18.9%) anesthesia to 3 days Intervention: 58/419 sternum was Control: 86/425 postop (13.8%) differentiated into (20.2%) Device/agent: Cefuroxime Control: 56/425 (13.2%) superficial ·Gender: m/f Monitoring intervention: P=0.35 infection or Intervention: 329/90 NR Mediastinitis mediastinitis Control: 353/72 Control group: n=425 Intervention: 2/419 Mediastinitis: ·Obesity: NR After placement of a (0.5%) fever>38°C, chest ·Comorbidities peripheral line in the Control: 0/425 pain or sternal Diabetes Mellitus operating room, No cases of late onset instability and a Intervention: 34/419 patients received mediastinitis were purulent (8.1%) 20mg/kg cefuroxime reported after discharge discharge from Control: 41/425 intravenously at from hospital.(but they the mediastinal (9.6%) induction of anesthesia don’t indicate how long area from which COPD then continued postop) pathogenic Intervention: 14/419 cefuroxime three times Wound infection microorganisms (3.3%) a day intravenously for Intervention: 5/419 could be isolated. Control: 11/425 3 consecutive days. (1.2%) Respiratory Tract (2.6%) Control: 4/425 (0.9%) infection: If History of smoking Standard preventive Minor Complication patients were Intervention: 354/419 measures: Intervention: 51/419 febrile, Gram (84.5%) SA Decolonization: (12.2%) stain of sputum Control: 363/425 Starting two days prior Control: 52/425 (12.2%) demonstrated (82.4%) to surgery, all patients Donor site leg many Use of corticosteroids undergoing Intervention: n=377 polymorphonucl Intervention: 10/419 cardiopulmonary Control: n=389 ear leukocytes © 2017 American Medical Association. All rights reserved. 189

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (2.4%) surgery are treated Total complications of and a Control: 10/425 intra-nasally with a healing predominant (2.4%)Operative: cream consisting of Intervention: 118/377 organism, and Primary/ re-operation 0.1% chlorhexidine and (31.3%) the chest X-ray Intervention: 398/21 0.5% neomycin to Control: 130/389 showed a new Control: 398/27 eliminate possible (33.4%) pulmonary Emergency/ elective Staphylococcus aureus. P=0.41 infiltration Intervention: 411/8 Closure: All skin wounds Wound infection Urinary Tract Control: 407/18 were closed with intra- Intervention: 5/377 Infection (UTI): if (18 vs. 8, P<0.08) cutaneous re- (1.3%) the urine culture though the rate of absorbable sutures Control: 2/389 (0.5%) was positive infection was not Jugular Vein Catheter Minor complications (≥105 cfu/ml) in higher among Removal: catheter was Intervention: 95/377 the presence of emergency removed after 48 hours (25.2%) fever for which procedures. in all cases Control: 110/389 no other cause Donor vessels (28.3%) could be found. Leg veins only// Left Wound dehiscence Perioperative internal mammary Intervention: 18/377 care: artery +/- leg veins// (4.8%) Graft: The internal Both internal Control: 18/389 (4.6%) mammary artery mammary arteries Other infections: graft, when +/- leg veins UTI used, was Intervention: Intervention: 4/377 harvested on a 94//223//102 (1.0%) pedicle of soft Control: 118//212//95 Control: 1/389 (0.2%) tissue equal in Respiratory tract infection width to that of Procedures: Coronary Intervention: 5/377 both mammary Artery Bypass (1.3%) veins. Leg veins Grafting (CABG) Control: 3/389 (0.7%) were obtained Indications: NR by standard Setting: 1 hospital Topic-specific measures Location: The outcomes: NR Postoperative Netherlands. Reoperations: NR-See samples of Dates: October 1989 - NOTE below sputum and December 1990 Length of stay: NR urine and if Inclusion Criteria: All Mortality: none- See necessary patients undergoing NOTE below wound exudates coronary artery Adverse events: NR- see were collected bypass grafting NOTE below on first and © 2017 American Medical Association. All rights reserved. 190

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (CABG) including following days. elective and NOTE: Of 1016 patients Other notes: See emergency surgery, included in the study, results for primary and 172 were excluded reasons for reoperation. from final analysis for exclusion from Exclusion Criteria: the following reasons final analysis Exclusion from (in some more than one randomization: reason was present): Follow-up: On the Refusal of consent, Reason: Intervention seventh day administration of (n)/control (n) postop, the systemic Chest open>6h: 42/27 sternotomy and antimicrobial Repeat thoracotomy within donor site treatment within the 7 days: 22/30 wounds were previous 48 h, Intra-aortic balloon pump: examined for hypersensitivity to 8/6 healing, cefuroxime or the Artificial ventilation >24h: redness, presence of 7/10 discharge of prosthetic valves or Death within 7d (non- fluid without a vascular infectious): 1/8 ( all died signs of prosthesis. in OR or did not come infection, or off IABP) infection by a Additional antimicrobials: blinded 15/3 physician Other operative procedure: Funding Source 0/5 Conflicts: No wound inspection: 1/1 Authors: Industry They report that neither Institution: NR wound infection nor Study: Industry mediastinitis occurred Supplies: NR in any of these patients Bernard RCT To determine Number of patients: Intervention group: n= SSI: (follow up 8 days) Definitions: Deep 1994 36 1, 2, 3, whether a N=203 101 Total deep infections: Infections: (ES) 4, 5, 7, longer Patient 48 hour cefuroxime Intervention: 47/101 46% Wound 8, 9 antimicrobial Characteristics: All A 1.5g dose of cefuroxime Control: 66/102 (65%) infections + prophylaxis characteristics were was delivered P=0.005 Pneumonia + regimen for 48 balanced except intravenously at the Difference in infection severe hours after those with a P-value moment of induction of rates (19%±11%) bronchopneumo pulmonary below anesthesia. A second remained significant (p=- nia +empyema+ operation ·Age, y: mean (range) dose was .01) after adjusting for fistula) © 2017 American Medical Association. All rights reserved. 191

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score decreases the Intervention: 56 (19- systematically delivered multiple variables) Pneumonia: rate of deep 78) 2 hours later to obtain Wound infection defined on the infections in Control: 61 (17-81) high seric Intervention: 1/101 (1%) basis of the x- pleura, P=0.02 concentrations until the Control: 1/102 (1%) ray film with bronchi and ·Gender: m/f end of the procedure. P=0.9 specific parenchyma. Intervention: 91/10 1.5g cefuroxime was Empyema parenchymal Control: 85/17 given every 6 hours Intervention: 1/101 (1%) features ·Obesity: NR after the operation for Control: 6/102 (6%) associated with ·Comorbidities 48 hours. The first P=0.03 temperatures Tobacco packs/year: postoperative infusion Pneumonia between 37.5o – mean (range) was given exactly 6 Intervention: 17/101 38oC. Intervention: 33 (0- hours after the second (17%) X-ray appearance 120) infusion. Control: 31/102 (30%) Class 1: normal Control: 33 (0-120) Timing of intervention: P=0.01 Class 2: moderate Quit Smoking more Pre, intra and Severe infiltrate than 1 month postoperatively Bronchopneumonia Class 3: important Intervention: 18/101 Duration of intervention: Intervention: 25/101 infiltrate/atelecta (18%) From induction of (25%) sis Control: 15/102 (15%) anesthesia until 48 Control: 25/102 (25%) Severe P(not significant) hours after the second P=0.9 Bronchopneumo Alcohol: (L/day), mean dose during surgery Fever (>38oC) nia an (range) Device/agent: Cefuroxime Intervention: 5/101 (5%) association of Intervention: 0.4 (0-3) Monitoring intervention: Control: 10/102 (10%) purulent Control: 0.5 (0-5) NR P=0.09 expectorations Chronic bronchitis: Control group: n=102 and atelectasis Intervention: 30/101 Flash cefuroxime. Other infections: on the plain (29.7%) A 1.5g dose of cefuroxime Fistulas chest x-ray film Control: 36/102 was delivered Intervention: 2/101 (2%) associated with (35.3%) intravenously at the Control: 7/102 (7%) a temperature Diabetes moment of induction of P=0.045 higher than Intervention: 5/101 anesthesia. A second 38oC. (5.0%) dose was Topic-specific Empyemas and Control: 4/102 systematically delivered outcomes: septicemias: (3.92%) 2 hours later to obtain Antimicrobial resistance: when associated Cardiac insufficiency high seric Pathogens cultured with a Intervention: 5/101 concentrations until the from pleura, bronchi, temperature (5.0%) end of the procedure. A drains and blood were higher than Control: 6/102 (5.9%) placebo was similar in the two 38oC. As soon Previous administered every 6 groups. Did not specify as a septic © 2017 American Medical Association. All rights reserved. 192

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Chemotherapy hours after the antimicrobial condition, Intervention: 16/101 operation for 48 hours. resistance. bacteriologic (15.8%) Standard preventive Reoperations: NR samples were Control: 8/102 (7.8%) measures: Length of stay, days: obtained from P=0.07 Skin prep: local cutaneous mean±SD expectorations, Previous Radiotherapy disinfection with Intervention: 13±1 pleura, drains, Intervention: 5/101 povidone-iodine at 12 Control: 15±1.6 and blood. (5.0%) and 1 hour pre-op. Mortality: 4/203 (2%) Perioperative Control: 3/102 (2.9%) Analgesic: all patients Intervention: 3/101 (3%) care: Transfusion, units: were given the same Control: 1/102 (1%) Respiratory mean(range) analgesia: Morphinic 1/4: Pulmonary recovery: Intervention: 0.32(0-8) antalgic drugs were embolism aerosols were Control: 0.5 (0-12) infused intravenously 1/4: Cerebral given to each Procedures: every 4 hours. hemorrhage patient on a Lobectomy: 108/203 1/4: Mesenteric regular basis (53.2%) infarction and a respiratory Pneumonectomy: 1/4: Respiratory failure program of 71/203 (35.0%) with acute physiotherapy Wedge resection: bronchopneumonia followed. 23/203 (11.3%) Other notes: Indications: Adverse events: No side Statistical Lung cancer: 160/203 effects of the treatment α & β errors fixed at (78.8%) were noted. 5% level. Lung metastasis: Duration of chest Infection 17/203 (8.4%) drainage: estimated risk Benign tumor: 20/203 Intervention: 5.5±0.8 was 30% with (9.9%) days aim to reduce Chronic pulmonary Control: 5.7±1 days risk to 10% (20% emphysema with reduction). blebs: 6/203 (3.0%) Needed to Setting: 1 hospital include 200 Location: France patients (total or Dates: January 1, each arm?) 1991- June 30, 1992 Five patients Inclusion Criteria: All included in the patients undergoing analysis (2 thoracotomy with intervention, 5 lung resection for controls were lung cancer, lung not given full © 2017 American Medical Association. All rights reserved. 193

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score metastasis or treatment chronic pulmonary because of emphysema with missing blebs. prescriptions) Exclusion Criteria: Follow-up Temperature > 38oC, Abnormal purulent pulmonary expectoration, features on plain curative x-ray, antimicrobial therapy expectorations that had been and temperature stopped less than 8 were recorded days prior, infected daily from tumor, purulent postoperative pleurisy, lung day 3 up to 8 abscess, days) No bronchiectasis, specific about exploratory wound follow up. thoracotomy, Funding Source mediastinal tumor, Conflicts: chronic renal Authors: NR insufficiency, or β- Institution: NR lactamase allergy. Study: NR Supplies: NR

Karran RCT To investigate Number of patients: Intervention group: SSI Definitions: 1993 50 1, 7, 8 the use of the N=227 n=113 All SSI (some patients Surgical Infection: if (ES) antimicrobial Patient 2dose: patients received suffered more than 1 a purulent imipenem for Characteristics intravenously imipenem infection) discharge perioperative Patients were well 1g at induction of 2dose: 34/113 (30.1%) occurred from prophylaxis in matched for anesthesia with a single 4dose: 29/114 (25.4%); the wound, a elective demographic and further dose of positive colorectal surgical data imipenem 1g at 3h Intra-pelvic abscess: bacteriological surgery at collected. postop. 2dose: 2/113 (1.8%) culture was both single ·Age, y: NR Timing of intervention: 4dose: 2/114 (1.8%); obtained, or a dose and ·Gender: NR pre and postop deep abscess multiple dose ·Obesity: NR Duration of intervention: Intra-abdominal abscess developed at the regimens. ·Comorbidities: NR up to 16h postop 2dose: 2/113 (1.8%) site of operation. Procedures: elective Device/agent: imipenem 4dose: 1/114 (0.9%); © 2017 American Medical Association. All rights reserved. 194

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score colorectal Control group: n=114 p=0.56; Perioperative Setting: 1 University 4dose: patients received care: NR hospital imipenem 1g Peritonitis Other notes: None Location: UK intravenously at 2dose: 0/113 Follow-up: 6-8 Dates: NR induction of anesthesia 4dose: 1/114 (0.9%) weeks postop Inclusion Criteria: with further doses and Funding Source Patients over 18 of imipenem: 1g at 3h Abdominal wound: Conflicts: years of age postop and 500mg at 2dose: 23/113 (19.5%) Authors: NR undergoing elective 8h and 16h postop 4dose: 22/114 (19.3); Institution: NR colorectal surgery. p=0.84 Study: Industry Exclusion Criteria: Standard preventive Supplies: NR Pregnancy, known measures: skin prep: Perineal wound: allergy to any study use of antiseptic lavage 2dose: 7/113 (6.2%) drug, concomitant was left to the 4dose: 3/114 (2.6%); infection, serious discretion of the p=0.20 comorbidity or operating surgeon. Adverse events inflammatory bowel Adverse events possibly disease. Also, related to antimicrobial patients who had agent included 2 been treated with patients with phlebitis in antimicrobials in the the group receiving <24 preceding 72h or AMP and in the group who had received receiving longer AMP 2 steroids, cases of hypotension, 1 antineoplastic phlebitis, 1 erythema, agents or and 1 rash radiotherapy before surgery.

Mayer RCT To perform a Number of patients: Intervention group: n=37 SSI Definitions: NR 1993 27 1, 7 prospective n=66 1dose: 4g piperacillin and 1 abdominal wound Perioperative (ES) randomized Patient 800mg tinidazole infection was reported care: NR study Characteristics intravenously 30 min in each group Other notes: none comparing Groups were not before surgery 1dose: 1/37 (3.0%) Follow-up: 8 days single dose significantly different. Timing of intervention: 3dose: 1/29 (3.5%) postop antimicrobials ·Age, y: NR pre and postop Funding Source prophylaxis ·Gender: NR Duration of intervention: Conflicts: with multiple- ·Obesity: NR 1 dose or 3 does. (up to Length of stay: Authors: NR dose regimen ·Comorbidities: NR 16h postop) No differences: Institution: NR © 2017 American Medical Association. All rights reserved. 195

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score in patients Procedures: Radical Device/agent: piperacillin 1dose: 18 days (range 12- Study: NR undergoing surgery for a and tinidazole 23) Supplies: NR radical surgery gynecological Control group: n=29 3dose: 19 days (range, 12- for malignancy patients who received 23 days) gynecologic Setting: 1 university 4g piperacillin and 800 malignancy hospital mg tinidazole 30 min Location: Austria before surgery and at 8 Dates: June 1987 – & 16h postop. September 1988 Standard preventive Inclusion Criteria: measures: NR Patients undergoing radical surgery for a gynecological malignancy. Exclusion Criteria: Patients who had infections within the last two weeks, received antimicrobials or had a history of allergic reaction to either study antimicrobial. Also if radical surgery was not possible or indicated. Bates RCT To study a Number of patients: Intervention group: SSI Definitions: 1992 25 1, 2, 4, large number N=900 n=449 All procedures: Wound sepsis: (ES) 7, 8 of patients in Patient One dose of antimicrobials None: 48/449 Major minor or two hospitals Characteristics: given on induction of ≤24h: 49/451 late within the patients were anesthesia Perioperative same health matched between Timing of intervention: Colorectal Sub-Population: care: NR district to groups except for: Pre and post op (N=224) in at-risk Other notes: None determine if ·Age: age>80y Duration of intervention: abdominal surgery Follow-up: 1 there is a 1 dose: 57/446 1 pre op dose or 16h 1 dose: 23/113(20.4%) month significant (12.8%) postop. 3 doses: 17/111(15.3%) Funding Source difference 3 dose: 46/550 (8.4%) Device/agent: augmentin P>0.2 Conflicts: between ·Gender: NR (1:10 combination of Appendectomy Sub- Authors: NR © 2017 American Medical Association. All rights reserved. 196

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score single and ·Obesity: NR amoxicillin and Population: (n=247): Institution: NR multiple dose ·Comorbidities: NR clavulanic acid.) 1 dose: 11/114 (9.6%) Study: NR regimes of Indications: Control group: N = 551 3 dose: 21/133(15.8%) Supplies: Industry amoxicillin Inflamed appendix Three doses of p=0.16 250mg/ 1 dose: 71/114 (62%) antimicrobials with the clavulanic acid 3 dose: 101/133 first given on induction 125mg for (76%) of anesthesia and two prophylaxis in Dose violation additional injections at 8 at-risk 1 dose: 3/446 (0.7%) & 16h later. surgery. 3 dose: 13/550 (2.4%) Procedures: Standard preventive Appendectomies measures: NR and all open gastric, esophageal, colonic or biliary surgery. All patients coming to laparotomy for intestinal obstruction including that due to strangulated hernia were entered into the study as well as patients with intra- abdominal malignancy Setting: 2 General Hospitals Location: United Kingdom Dates: May 1986 – June 1988 Inclusion Criteria: All patients aged 16 or over admitted under 2 surgical firms at 2 adjacent district general hospitals for at-risk abdominal surgery with © 2017 American Medical Association. All rights reserved. 197

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score potential opening of a viscus. Exclusion Criteria: All patients known to be allergic to penicillin. If patients had received antimicrobials within the previous 48h or if the surgeon considered that preoperative antimicrobial administration were essential, they were also excluded. Also, declination of consent was excluded although all received prophylactic antimicrobials. Patients found to have purulent (fecal) peritonitis were withdrawn from the study Turano RCT To compare Number of patients: Intervention group: SSI Definitions: 1992 29 1 the efficacy N=608 n=385 All Surgeries Wound infection: (ES) and safety of Patient 1dose: 1g cefotaxime 1dose: 28/1802 (1.6%) discharge of two schedules Characteristics intravenously 30 min 3dose: 39/1765 (2.2%) serous or of prophylactic Recorded, not reported before incision and seropurulent cefotaxime in ·Age, y: NR might be repeated in 6h subpopulation of 608 material from the abdominal ·Gender: NR if the surgery lasted patients undergoing wound within 7 gynecologic ·Obesity: NR more than 3h. unspecified gynecologic days of and urologic ·Comorbidities: NR Timing of intervention: procedures, operation. surgery Procedures: pre and postop 1dose: 12/385 (3.1%) Perioperative care unspecified Duration of intervention: 3dose: 4/223 (1.8%) : NR gynecologic preop or p=0.53 Other notes: None © 2017 American Medical Association. All rights reserved. 198

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score procedures. Device/agent: cefotaxime Follow-up: Indications: NR Control group: n=223 minimum 7 day Setting: 226 Surgical 3dose: 1g cefotaxime follow-up (or units intravenously 30 min until discharge). Location: Italy before incision and 1.g Funding Source Dates: January 1, 1990 doses at 6 and 12h Conflicts: – June 30, 1991 postop. (3doses total). Authors: NR Inclusion Criteria: Institution: NR patients of any age Standard preventive Study: Industry undergoing measures: NR Supplies: NR gynecologic procedures (abdominal and vaginal hysterectomy and myomectomy.) Exclusion Criteria: known or suspected β-lactam sensitivity, treatment with any antimicrobial in the 7 days preceding surgery, requirement for combination antimicrobial treatment resulting from the nature of the patient’s condition or type of surgical procedures (e.g. immunosuppression or colorectal surgery) or terminal illness.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Wymenga RCT To establish Number of patients: Intervention group: SSI (13 months) Definitions: 1992 20 1, 2, 7, the efficacy of N=2651 n=1327 Confirmed joint (ES) 8 a single Patient 1dose: 1500mg 1dose: 11/1327 (0.83%) sepsis: a perioperative Characteristics cefuroxime given 3dose: 6/1324 (0.45%); positive antimicrobial The two trial arms were intravenously upon p=0.17; bacteriologic dose for well matched with induction of anesthesia RR: 1.83, 95%CI (0.68- culture at infection respect to the 30min before the 4.93). reoperation or a prophylaxis in general and operation draining sinus joint orthopedic Timing of intervention: Strong evidence of replacement diagnoses, risk pre and postop sepsis: four or with a factors and Duration of intervention: more possible randomized, medications. preop and up to 16h signs of controlled, ·Age, y: NR postop infection: multicenter ·Gender: NR Device/agent: cefuroxime Category I: in study. ·Obesity: NR Control group: n=1327 patients who ·Comorbidities: NR 3dose: 1500mg only showed two cefuroxime given or three possible Procedures: THA, TKA intravenously upon signs of sepsis; and hemiarthroplasty induction of anesthesia Category II: a procedures 30min before the definite Indications: NR operation then 750mg diagnosis could Setting: 27 hospitals given at 8 & 16h not be made; Location: The postop. Category III: Netherlands were not Dates: July 1, 1986 – Standard preventive suspected of July 1, 1988 measures: having joint Inclusion Criteria: AMP Skin prep: in 3 sepsis. Patients undergoing centers, the wound was Wound infection in total hip rinsed with a fluid postop period: replacement, containing an erythema more hemiarthroplasty of antimicrobial, whereas than 1cm from the hip or total knee 2 centers used PI to the incision. arthroplasty rinse the wound. Perioperative Exclusion Criteria: care: NR allergy to Other notes: Study cephalosporin, was sufficiently penicillin powered. anaphylaxis, the use Follow-up: 13 of antimicrobials less months © 2017 American Medical Association. All rights reserved. 200

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score than 48h before the Funding Source operation, use of Conflicts: perioperative Authors: NR antimicrobial Institution: NR administration other Study: Industry than cefuroxime, Supplies: Industry malignancy, former or current sepsis in the joint and the use of gentamicin- impregnated bone cement for prosthetic fixation. Aberg RCT To compare Number of patients: Intervention group: n= SSI: Definitions: 1991 26 1, 7, 8 the triple N=415 patients; 200 All Procedures: Deep surgical (ES) versus single 428 operations 1 dose of cefuroxime (with 1dose: 8/207 (3.9%) sepsis: dose of Patient the addition of 3dose:15/221 (6.8%) peritonitis, intra- cefuroxime Characteristics metronidazole for abdominal (with the Patients were well surgery of the jejunum, subanalysis of 48 elective abscess, or addition of matched between ileum, colon, and rectal surgery patients: septicemia. metronidazole groups. rectum-anus. 1dose: 2/19 (10.5%) Perioperative for the ·Age, y: NR Timing of intervention 3dose: 1/29 (3.4%); care: NR surgeries of ·Gender: NR Duration of intervention p=0.35 Other notes: None the jejunum, ·Obesity: NR Device/agent: cefuroxime Follow-up: within 1 ileum, colon ·Comorbidities: NR (with metronidazole for subanalysis gastric month and rectum- Procedures: rectal surgeries) procedures (n=64) Funding Source anus). laparotomy, Control group: n=215 including gastrectomy Conflicts: Concomitantly vagotomy, 3 doses of cefuroxime (n=8), gastric banding Authors: None to introduce a gastrectomy, gastric (with the addition of (n=35) and other gastric Institution: None system for banding, other metronidazole for (n=21) Study: None continuous gastric, surgery of the jejunum, deep surgical sepsis: Supplies: None surveillance of cholecystectomy, ileum, colon, and 1dose: 1/24 (4%) postoperative choledochal surgery, rectum-anus. 3dose: 4/40 (10%); wound pancreatectomy, Standard preventive p=0.41 infections. surgery of jejunum, measures: NR ileum, or colon, rectal anterior resection, rectal amputation. © 2017 American Medical Association. All rights reserved. 201

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Indications: NR Setting: 1 county hospital Location: Sweden Dates: February 1988 – May 1990 Inclusion Criteria: Consecutive patients 16 years or older scheduled for elective abdominal surgery during the study dates. Exclusion Criteria: due to unscheduled perioperative antimicrobial therapy Becker RCT To study in a Number of patients: Intervention group: n=18 SSI Definitions: 1991 43 1, 3, 4, prospective, n=40 After 12h postop, patients no wound or intra- Wound was (ES) 5, 6, 7, double-blind Patient received 1g cefoxitin abdominal infections in considered 8, 9 randomized, Characteristics: intravenously every 6h either group at 1yr uninfected if it fashion, the Patient for 5 days beginning 6h follow up: was healing efficacy of a characteristics were after fixed postop dose 5 day: 0/22 vs. without evidence short similar between Timing of intervention: 12h: 0/18 of erythema or perioperative groups except: postop Length of stay: discharge. course versus Entry into bowel Duration of intervention: No difference, days: Infected: if purulent an extended lumen: 5 days (mean±SD) drainage was postoperative 5day: 9/18 (50%) Device/agent: 1g cefoxitin 5 day: 8.7±0.4 present, course of 12h: 6/22 (27%) but intravenously. 12h: 8.4±0.2. regardless of intravenous major contamination Control group: n=22 culture results or antimicrobials was not statistically After 12h postop, patients if nonpu8rulent in patients significantly different. received placebo material undergoing ·Age, y: NR (dextrose in water) contained colectomy, ·Gender: NR intravenously every 6h pathogenic mucosal ·Obesity: NR for 5 days beginning 6h bacteria. protectomy ·Comorbidities: NR after fixed postop dose Deep infection – if and ileal Procedures: Standard preventive infection pouch-anal Colectomy, mucosal measures: extended below anastomosis. protectomy, and ileal 1) clear liquid diet for 4 fascia © 2017 American Medical Association. All rights reserved. 202

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score pouch-anal days before surgery; 2) Moderate – when anastomosis. mechanical bowel prep subcutaneous Indications: chronic consisting of 300ml of tissues were ulcerative colitis, oral magnesium citrate involved. familial polyposis, or and 2 tap water Possibly infected – Gardner’s syndrome enemas administered evidence of Setting: 1 university on preop day 2 and induration and hospital 300ml of oral inflammatory Location: USA magnesium citrate and changes of the Dates: NR (9months) tap water enemas until skin but without Inclusion Criteria: clear administered on purulent Patients with chronic preop day 1; 3) oral discharge ulcerative colitis, antimicrobial Perioperative familial polyposis or preparation consisting Care: NR Gardner’s syndrome of 1g neomycin and 1g Other notes: None who required erythromycin base by Follow-up: 8 colectomy and who mouth at 1:00pm, weeks post were candidates for 2:00pm,. And 11:00pm discharge when mucosal protectomy on preop day 1; 4) 2g loop ileostomy with ileal pouch-anal cefoxitin administered was closed. anastomosis. intravenously during a Patients were Exclusion Criteria: 20 min period then followed for Allergy to penicillin immediately before 12 months after or cephalosporin; surgery with additional closure. antimicrobial use 2g iv doses of cefoxitin Funding Source within 1 week before given at 6h and 12h Conflicts: operation, after the initial dose. Authors: NR mechanical bowel Also, rectum was irrigated Institution: NR obstruction or any with PI solution via Study: Industry other functional or transanal rectal Supplies: NR anatomic reason catheter. precluding mechanical bowel prep; or the presence of an existing ileostomy or colostomy.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Garotta RCT To evaluate Number of patients: Intervention group: SSI: Definitions : 1991 19 1, 2 the relative N=614 n=301 1dose: 2/301 (0.66%) Wound infection: (ES) effectiveness Patient 1dose: given 2g Multi: 3/313 (0.96%) purulent of two Characteristics: ceftizoxime exudation with cephalosporin both arms were intravenously 30 positive antimicrobials, homogeneous for minutes before the microbiologic ceftizoxime vs. several operation culture. cefuroxime, in characteristics such Timing of intervention: preventing the as patients’ age, pre and postop Perioperative development sex, length and type Duration of intervention: care: NR of of operation and preop and up to 12h Other notes: none complicating postop procedures. after operation Follow-up: 1 year infections in ·Age, y: NR Device/agent: ceftizoxime Funding Source patients ·Gender: NR Control group: n=313 Conflicts: submitted to ·Obesity: NR 2dose: given 2g Authors: Industry elective ·Comorbidities: NR ceftizoxime Institution: NR surgery in Procedures: Hip or intravenously 30 Study: NR orthopedic knee replacement or minutes before the Supplies: NR departments. fracture fixation operation and 12h Indications: NR postop. Setting: 30 hospitals Standard preventive Location: Italy measures: NR Dates: NR Inclusion Criteria: Patients >18 years, undergoing orthopedic surgeries such as hip or knee replacement and fractures fixed by foreign bodies. Exclusion Criteria: Evidence of acute infection; antimicrobial treatment within 48 hours prior to operation or use of local antimicrobials; © 2017 American Medical Association. All rights reserved. 204

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score and open fractures

Buckley RCT To determine Number of patients: Intervention1 group: n= SSI: (Follow up 6 weeks) Definitions: 1990 14 1, 3, 4, whether or not N=312 108 Wound infection Definite Wound (ES) 5 cefazolin Patient AMP Four doses: 2g Intervention1+2: 4/191 infection: if there decreased Characteristics: All Cefazolin administered (2.0%) was a purulent early groups similar in age intravenously when Control: 4/121 (3.7%) discharge, postoperative (P=0.75) and sex anesthesia was P=0.46 whether or not wound distribution (P=0.86) induced, then 1g When not combined organisms were infection rates, ·Age, y: mean±SD cefazolin every 6 hours Intervention1: 2/108 cultured. and whether (range) intravenously for three (1.6%) Possible wound single-dose Intervention1: doses making a total of Intervention2: 2/83 infection: cefazolin was 76.3±14.9 (18-100) four doses of cefazolin (2.4%) inflammation as effective as Intervention2: Intervention2 group: n= Control: 4/121 (3.7%) without multiple dose 77.1±12.1 (33-94) 83 All superficial except for 1 discharge and (4 doses) Control: 76.1±13.4 AMP single dose: 2g control group deep wounds that cefazolin in (29-96) Cefazolin administered infection in a 96-year- drained culture- preventing ·Gender m/f intravenously when old woman which was positive serous early Intervention1: 32/89 anesthesia was implicated in her death fluid. The patient postoperative Intervention2: 22/61 induced, then saline at 14 days postop. was followed up wound Control: 3/75 every 6 hours All other infected patients until the wound infections ·Obesity NR intravenously for three were discharged from healed or resulting from ·Comorbidities NR doses. the study after 6 weeks drained pus. hip surgery. Procedures: Timing of intervention: with healed wounds. Perioperative They also Prosthetic Hip: Pre, intra and Wound infection by care: NR compared Intervention1: 56/108 postoperatively Operation Type Other notes: Due single and 3 (51.9%) Duration of intervention: Prosthetic Hip: to low infection doses to no Intervention2: 32/83 From induction of Intervention1+2: 2/191 rates, groups AMP. (38.6%) anesthesia to 24 hours (1.0%) Intervention1 & Control: 33121 postop. Control: 2/121 (1.9%) Intervention2 (27.3%) Device/agent: Cefazolin Pins + Compression were combined Multiple Pins: (21 Total) Monitoring intervention: Screws to increase the Intervention1: 8/108 Blood cefazolin levels Intervention1+2: 2/191 power. (7.4%) were examined (1.0%) Statistics: Intervention2: 5/83 intraoperatively for the Control: 2/121 (1.9%) Sample size of 120 (6.0%) first 14 patients and P=0.72 per arm selected Control: 8121 (6.6%) found to be 10 times Average age of infected to detect Compression Screw: the minimal inhibitory patients: 84.2 years (8 difference in © 2017 American Medical Association. All rights reserved. 205

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (170 Total) concentration years older than non- infection rate of Intervention1: 57/108 Control group: n= 121 infected patients though 9% with (52.8%) No AMP: Saline not statistically probability of Intervention2: 46/83 administered significant (p=0.11) type a error of (55.4%) intravenously for four <0.10 and type β Control: 67/121 doses. Other infections: NR error of <0.20. (55.4%) Standard preventive Topic-specific Follow-up: Type of surgery was measures: NR outcomes: NR Complete follow- not evenly Non-standard preventive Antimicrobial resistance: up at 6 weeks distributed between measures All infections were S. post-op. groups: (P=0.05) but Surgery: Fractured hip aureus sensitive to Funding Source this variable did not was treated with either hip cephalothin. No gram Conflicts: turn out to be a pinning (with compression negatives were Authors: NR confounder screw or multiple pins) or a isolated. Institution: NR Drain Used (179 Total hip prosthesis implant. Reoperations: NR Study: NR Intervention1: 67/108 Drain: At surgeon’s Length of stay: NR, but Supplies: NR (62.0%) discretion, a drain was no patients’ length of Intervention2: 49/83 placed for subcutaneous stay was lengthened by (59.0%) tissue drainage. a drug-related Control: 63/121 complication (52.1%) Mortality: P=0.85, χ2= 5.95, df = Total: 15 deaths (4.8%) 2 Intervention1: 3/108 Indications: Fractured (2.8%) hip (interochanteric Intervention2: 4/83 or subcapital) (4.8%) Setting: 1 hospital Control: 8/121 (6.6%) Location: Canada Cause of all deaths was Dates: December 1, cardiopulmonary except 1985 – December1 , for the patient 1988 described above who Inclusion Criteria: All died of multi-organ adults with an system failure (the deep interochanteric or wound infection subcapital hip possibly contributed) fracture. All patients who died were Exclusion Criteria: in their ninth or tenth Cephalosporin decade of life. allergy, pathologic Adverse events: No © 2017 American Medical Association. All rights reserved. 206

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score fracture due to anaphylactic reactions, tumor, previous allergies or renal surgery on the toxicity related to fractured hip, cefazolin treatment with an administration. Also, no antimicrobial other cefazolin cross- than cefazolin, or a reactions with patients preoperative course who claimed a history in hospital longer of “penicillin rashes” than 7 days. Hall RCT To evaluate Number of patients: Intervention group: SSI Definitions: 1989 44 1, 2, 7, the efficacy of N=1027 n=519 patients given 1 • Total colorectal: Wound Infection: (ES) 8 moxalactam Patient 1g moxalactam Total: 22/245 (9.0%) purulent wound given as a Characteristics: NR intravenously at Single: 12/119(10.1%) discharge or a single dose or ·Age, y: NR induction of anesthesia 48h: 10/126(7.9%); serous wound as a 48-hour ·Gender: NR Timing of intervention: p=0.56 discharge with regimen for a ·Obesity: NR pre and post-operative • Elective colorectal culture of range of ·Comorbidities: NR Duration of intervention: procedures (n=207) pathogenic potentially Procedures: 1 dose or 48h postop. Single: 11/102(10.7%) organisms. contaminated Appendectomy, Device/agent: 1g 48h: 6/105(5.6%); Major wound abdominal cholecystectomy, moxalactam p=0.19 infection: if it operations. bile duct surgery, intravenously resulted in an elective colorectal, Control group: n=508 • Emergency Colorectal extension of the emergency patients who received (no bowel prep in hospital stay or colorectal, 1g of moxalactam emergency cases): required gastroduodenal, and intravenously at Single: 1/17(5.8%) dressings at small-bowel surgery. induction of anesthesia 48h: 4/21(20.0%); home for more Setting: 2 centers followed by 1g of p=0.26 than 7 days (both general moxalactam Minor wound hospitals) intravenously every 6h infection: if Location: Australia for a further 7 doses. neither of these Dates: NR Equaling a total of 8g in features Inclusion Criteria: 48h/ occurred. consecutive patients Standard preventive Peritoneal infection: >14 years of age measures: Patients if pus or who were were given 10mg of peritoneal fluid undergoing Vitamin K containing potentially intramuscularly prior to pathogenic contaminated operation due to reports organisms were © 2017 American Medical Association. All rights reserved. 207

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score abdominal surgery at of coagulopathy found at the one of 2 hospitals. associated with operations, if Exclusion Criteria: moxalactam. there was Postop antimicrobial Skin prep – Povidone spontaneous for residual infection; Iodine & no local discharge or antimicrobial antimicrobial or needle administration within antiseptic prep aspiration of pus 48h prior to Drain tubes – were from the operation; viscus not passed through a peritoneal cavity opened at operation; separate incision. or if there was a failure to give Bowel prep – all patients collection of pus informed consent received a two-day present at failure to give initial mechanical bowel prep autopsy. dose of moxalactam (no oral antimicrobials Other notes: Study history of were administered) was sufficiently cephalosporin powered to sensitivity or detect a penicillin difference in anaphylaxis; wound infection established renal or rates. liver failure; reaction Follow-up: 5th to initial dose of postoperative moxalactam. week. Ritter RCT To identify the Number of patients: Intervention group: n=98 SSI Definitions: NR 1989 21 1, 7, 8 relationship N=196 2dose: Two intraoperative In the second smaller Perioperative (ES) between the Patient doses of cefuroxime study (N=196), in care: NR duration of Characteristics (1500mg & 750mg) unilateral or bilateral Other notes: None prophylaxis Reported but not Timing of intervention: THA or TKA patients no Follow-up: and the significant intergroup intra and postop infections (including 12month follow incidence of differences. Duration of intervention: deep wound infections) up latent wound Procedures: primary intraop up to 24h were reported in either Funding Source infection- unilateral or bilateral postop group Conflicts: TKA or THA Device/agent: cefuroxime 2dose: 0/98 Authors: NR Indications: NR Control group: n=98 5dose: 0/98 Institution: NR Setting: 1 university 5dose: Two intraoperative Study: NR Hospital doses of cefuroxime Supplies: NR Location: USA (1500mg & 750mg) Dates: NR followed by 24h of Inclusion Criteria: postop cefuroxime © 2017 American Medical Association. All rights reserved. 208

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Patients undergoing (750mg every 8 hours) primary unilateral or bilateral THA or TKA Standard preventive Exclusion Criteria: NR measures: NR Moesgaa- RCT To investigate Number of patients: Intervention group: SSI Definitions: rd 1, 2, 7, the N=428 n=209 Total: 45/428 (11%); Wound infection: 1989 48 8 relationship Patient Short-term prophylaxis: 6hr: 22/209 (11%) presence of pus, (ES) between Characteristics: gentamicin 80mg iv + 2day: 23/219 (11%) either preoperative groups were well metronidazole 500mg iv p=0.99 discharging cell-mediated matched and equally at the start of the spontaneously immunity distributed. operation followed by Intra-abdominal abscess: or requiring (CMI) and ·Age, y: NR repetition of these Total: 14/428 (3%) drainage. postoperative ·Gender: NR doses 6 hours later. 6hr: 6/209 (3%) Intra-abdominal infection and ·Obesity: NR Timing of intervention: 2day: 8/219 (4%) abscess: verified whether ·Comorbidities: NR pre and postop p=0.65 by surgical patients with Procedures: elective Duration of intervention: drainage or impaired CMI colorectal surgery 6h or 2 days ultrasound would benefit Indications: NR Device/agent: gentamicin guided from Setting: 1 university 80mg iv + aspiration of prolonged hospital metronidazole 500mg iv pus. antimicrobial Location: Denmark Control group: n=219 Perioperative prophylaxis. Dates: 1982-1986 Long term prophylaxis: Care: NR Inclusion Criteria: all gentamicin 80mg iv + Other notes: none patients undergoing metronidazole 500mg iv Follow-up: 30 elective colorectal at the start of the days surgery. operation followed by Funding Source Exclusion Criteria: repetition of these Conflicts: Those admitted for doses every 8hours for Authors: NR rectal amputation, 2 days. Institution: NR known allergy to the Standard preventive Study: NR antimicrobials used, measures: Bowel prep Supplies: NR pregnancy, age<15 NR years, and any antimicrobial therapy 5 days prior to surgery.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Grundm- RCT To define Number of patients: Intervention group: n=25 SSI Definitions: NR ann 1 whether a N=154 Patients who received a SSI: Perioperative 1987 24 single Patient single dose of 1dose: 4/77 (5.2%) care: NR (ES) preoperative Characteristics: metronidazole and 3dose: 4/77 (5.2%) Other notes: None dose of While statistical mezlocillin (5g/0.5g) Follow-up: NR mezlocillin/ significance is not prior to the operation Intra-abdominal abscess Funding Source metronidazole indicated, the 1 dose Timing of intervention: 1dose: 2/77 (2.6%) Conflicts: is sufficient in group had a higher pre and postoperative. 2doses: 1/77 (1.3%); Authors: NR colon surgery percentage of high Duration of intervention: p=0.57 Institution: NR or whether risk patients up to 6h postop Study: NR under certain including patients Device/agent: Peritonitis Supplies: NR circumstances with age>58 years, metronidazole and 1dose: 2/77 (2.6%) (long operation time mezlocillin (5g/0.5g) 3doses: 2/77 (2.6%); operation >2.5h, Body Monitoring intervention: time, weight>69kg, pre, intra and postop. insufficient insufficient bowel Control group: n=28 bowel prep, lavage and blood Patients received 5g high blood transfusions. metronidazole/ 0.5g loss) a ·Age, y: NR mezlocillin prior to the multiple ·Gender: NR operation, a second administration ·Obesity: NR dose 90 minutes post- of ·Comorbidities: NR skin incision and 6 antimicrobials Procedures: elective hours after the second is more colorectal surgery dose. justified. Indications: NR Standard preventive Setting: 1 university measures: hospital Bowel Prep: Orthograde Location: Germany bowel prep with no Dates: NR antimicrobial Inclusion Criteria: ingredients. And no patients undergoing preop oral antimicrobial colon surgery. for the purpose of Exclusion Criteria: NR bowel prep.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Juul RCT To evaluate Number of patients: Intervention group: SSI Definitions : 1987 45 1, 2, 7, the N=294 Patients received 1.5g Deep wound infections: Deep wound (ES) 8 prophylactic Patient metronidazole and 3g Total: 17/294 (5.8%); infection: effect of a Characteristics: No ampicillin intravenously Single Dose: 9/149 (6%) accumulation of single dose significant at induction of Multiple: 8/145 (6%) pus either with versus differences between anesthesia spontaneous multiple doses groups. Timing of intervention: Intra-abdominal abscess: discharge or of systemic ·Age, y: NR Pre and postoperative Total: 3/294 (1.0%) requiring ampicillin and ·Gender: NR Duration of intervention: Single: 1/149 (1%) surgical metronidazole ·Obesity: NR 1 dose or 3 postop days Multiple 2/145 (1%) drainage. in elective ·Comorbidities: NR Device/agent: Wound dehiscence: colorectal Procedures: Elective metronidazole & Topic Specific subcutaneous surgery. colorectal surgery ampicillin outcomes: and fascial Indications: NR Control group: No difference in bacterial breakdown, but Setting: 1 university Patients received 1.5g isolates and no report without pus hospital metronidazole and 3g of antimicrobial accumulation. Location: Denmark ampicillin intravenously resistance Intra-Abdominal Dates: October 1983- at induction of Abscess- April 1986 anesthesia followed by intraperitoneal or Inclusion Criteria: Metronidazole 0.5g and pelvic collection Patients 18y or ampicillin 1g each 3 of pus with older, undergoing times during the second spontaneous elective colorectal and third postoperative discharge or surgery during the days. which required study dates. Standard preventive surgical Exclusion Criteria: measures : drainage. Patients receiving Bowel prep: bowel was antimicrobials in the emptied either Perioperative preoperative period conventionally or by care: NR or those with a whole gut irrigation. Other notes: None history of Follow-up : 30 hypersensitivity to days ampicillin or Funding Source metronidazole. Also, Conflicts: patients not Authors: NR receiving full does or Institution: NR the bowel note being Study: NR opened during Supplies: NR surgery. © 2017 American Medical Association. All rights reserved. 211

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Mendel RCT To assess the Number of patients: Intervention group: n=54 SSI Definitions: NR 1987 46 1 prophylactic N=100 Patients receiving a “single Perioperative (ES) value of a Patient shot” of 5g mezlocillin Total: 3/100 (3.0%); care: NR one-shot Characteristics: NR and 500mg Single dose: 2/54 (3.7%) Other notes: none regimen of ·Age, y: NR metronidazole 3day: 1/46 (2.1%); Follow-up: NR antimicrobials. ·Gender: NR Timing of intervention: p=0.66 Funding Source ·Obesity: NR pre and postop Conflicts: ·Comorbidities: NR Duration of intervention: Authors: NR 1dose or 3 days postop Institution: NR Procedures: elective Device/agent: Study: NR excision of colorectal mezlocillin5g and Supplies: NR carcinoma or metronidazole 500mg diverticulitis. Control group: n=46 Indications: NR patients receiving 9 Setting: 1 Hospital doses of 5g mezlocillin Location: Germany and 500mg Dates: NR metronidazole (a 3 day Inclusion Criteria: regimen) Patients requiring Standard preventive excision of colorectal measures: carcinoma or Bowel prep: all patients diverticulitis underwent standard Exclusion Criteria: preop bowel prep (from Patients with a 4 days preop!) colostomy or who had received other antimicrobials within 72h of operation. Gatell RCT To compare Number of patients: Intervention group: SSI Definitions: 1987 18 1, 3, 4, the use of five N=717 n=382 1dose: 20/382 (5.2%) Wound infection: (ES) 5, 7, 8, doses of Patient 1dose: 1 preoperative 5dose: 3/335 (0.9%) diagnosed when 10 cefamandole Characteristics: intravenous dose of p=0.004 the wound with a single Characteristics were cefamandole (2g) given drained pus preoperative similar between ½ hour before starting Hemiarthroplasties: spontaneously dose for groups. the operation. This was 1dose: 5/76 (6.5%) or was inflamed preventing ·Age, y: NR followed by 4 doses of 5dose: 0/74 (0%); to the point that wound ·Gender: NR placebo following the p=0.03 it had to be infection s ·Obesity: NR control drug schedule opened by the after so-called ·Comorbidities: NR Timing of intervention All other procedures surgeon and © 2017 American Medical Association. All rights reserved. 212

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score clean Duration of intervention combined: then drained orthopedic Procedures: Clean Device/agent: 1dose: 15/306 (5%) purulent operations in orthopedic cefamandole 5dose: 3/261(1%); material. A which there operations in which 5dose: patients receiving p=0.006. hematoma or was there was a metal a 2g cefamandole dose wound draining implantation of device implanted. intravenously 30 min Antimicrobial Resistance serous material a metal Indications: NR preop and 2g 31 organisms isolated was considered device. Setting: 1 university intravenously at 2h after from 23 wound to be infected hospital the start of surgery. This infections: 9 only when it Location: Spain was followed by 1 gram Staphylococcus aureus, cultured positive. Dates: NR intravenously or 4 S. epidermis and 4 E. Inclusion Criteria: All intramuscularly at 8, 14, & coli all sensitive to the Perioperative adults scheduled for 24 hours thereafter. AMP. In addition, 4 care: NR an orthopedic Control group: n=335 Pseudomonas Other notes: None surgical procedures Standard preventive aeruginosa, and 3 Follow-up: that required measures: Streptococcus faecalis Minimum insertion of a metal Skin prep: skin was all resistant to the AMP 12months device for fixation of shaved with disposable and 7 strains of other (range 12-24 bone. razor & cleaned with gram negative bacilli, 2 months) or if Exclusion Criteria: antiseptic soap just of them resistant to the patients had an total joint before entering OR. AMP. infection, until replacement, a Alcoholic PI was metal device known allergy to applied to the operative Mortality was removed. penicillin or site and allowed to There were 30 deaths Funding Source cephalosporins, and remain for 2min. (4%); 1 patient had an Conflicts: those who had Patients in both groups uncontrolled wound Authors: None immunosuppressive were hospitalized for infection but the cause Institution: None treatment, those who approximately 5 days of death was a stroke. Study: None had an open fracture before surgery. Supplies: None or a previous infection of the operative field, and those receiving any antimicrobials.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Oostvog- RCT To compare a Number of patients Intervention group: n=80 SSI Definitions: el 1, 2, 3, short term N=169 (1dose) Vascular surgery Wound infection: 16 1987 5, 6, 7 antimicrobial Patient Received 2 million U Single Dose: 3/80 (2.3%) presence of pus (ES) regimen (1 Characteristics: the benzylpenicillin i.v. + 3 Dose: 2/89 (3.8%) discharging preop & 2 two groups did not 120mg tobramycin i.m. p>0.5 spontaneously postop doses) differ significantly. 1hr preop or requiring with a single- ·Age, y: NR Timing of intervention: drainage dose regimen ·Gender: NR pre and postop Perioperative of intravenous ·Obesity: NR Duration of intervention: care: NR antimicrobials. ·Comorbidities: NR 1 dose or 12h postop. Other notes: None Procedures: vascular Device/agent: Follow-up: 1 surgery benzylpenicillin + month Indications: NR tobramycin Funding Source Setting: 1 general Control group: n=89 Conflicts: hospital (3dose) Authors: NR Location: the Received 2 million U Institution: NR Netherlands benzylpenicillin i.v. + Study: NR Dates: November 1983 120mg tobramycin i.m. Supplies: NR – January 1985 1hr preop plus 1million Inclusion Criteria: All U benzylpenicillin i.v. + patients admitted for 80mg tobramycin i.m. at emergency or 6h & 12h postop. elective surgery during the study Standard preventive dates if the operation measures: NR was classified as “clean- contaminated” or “contaminated” according to the NRC criteria; or when a vascular operation was planned (“Clean” operation) Exclusion Criteria: patients with multiple trauma or mechanical intestinal © 2017 American Medical Association. All rights reserved. 214

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score obstruction or who were already receiving antimicrobials for reasons other than prevention of wound infections, or who had severely impaired renal function or known hypersensitivity to one of the study antimicrobials. Also excluded were all patients found at operation to have bacterial peritonitis. Also perineal wounds. Wenzel RCT To investigate Number of patients: Intervention group: n=30 SSI Definitions: 1985 49 1, 2, 7, and compare N=60 1dose: 1 dose of 100mg Total SSI Wound infection: (ES) 8, 9 the extent of Patient ornidazole and 80mg 1dose: 6/30 (20%) edematous the reduction Characteristics gentamicin 48hDose: 10/30 (33.3%) and/or red in post- No significant administered p=0.25 wound with a operative differences in patient intravenously 45min Intra-abdominal abscess: purulent infection risk parameters. before operation with No difference: secretion. in patients ·Age, y: NR pre-medication. 1dose: 2/30 (7%) Perioperative undergoing ·Gender: NR Timing of intervention: 48hdose: 2/30 (7%); care: NR elective ·Obesity: NR pre and postop Other notes: colonic ·Comorbidities: NR Duration of intervention: Peritonitis :no difference: Complication surgery using Procedures: Surgery up to 48h postop 1dose: 1/30 (3%) rates were high two of the colon and Device/agent: ornidazole 48hdose: 3/30 (10%); for both groups. prophylaxis rectum and gentamicin p=0.32 Follow-up: NR regimens. 1) A Indications: NR Control group n=30 Funding Source “one shot” Setting: 1 hospital. 48h: 1 dose of 100mg Superficial SSI: Conflicts: method versus Location: Germany ornidazole and 80mg 1dose: 3/30 (10%) Authors: NR 2) pre-op Dates: NR gentamicin 48h Dose: 5/30 (16.7%) Institution: NR combined with Inclusion Criteria: administered Study: NR postop Patients who had to intravenously 45min Supplies: NR © 2017 American Medical Association. All rights reserved. 215

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score antimicrobial undergo abdominal before operation with infusions for surgery involving pre-medication. up to 48h. opening of the colon. Followed by 3 further Exclusion Criteria: doses of 500mg Patients who were to ornidazole at 12h have intervals and 3 doses of appendectomies, 80mg gentamicin at 8h those known intervals. hypersensitivity to Standard preventive ornidazole or measures: patients aminoglycosides, with non-stenosing those who received tumors were fed a full antimicrobial calorie diet and were treatment less than fed orally or enterally up 5d before the to the day preceding operation and those the operation. Patients with pre-operative with stenosing tumors fecal contamination. were given parenteral feeding additionally or exclusively. Bowel Prep: NR Carr RCT To establish Number of patients: Intervention group: n=22 SSI: Definitions: 1984 23 1, 3 whether N=90 Patients receiving only a all durations ≤24h Infected wound: (ES) additional Patient pre-operative bolus of combined suggest no one from which doses of Characteristics: the 500ml intravenous difference between there was a intravenous four groups of metronidazole. groups for purulent metronidazole patients were well Timing of intervention: Total Wounds discharge from for up to 24h matched. pre and postop 1 dose: 8/25 (32%) the main suture after elective ·Age, y: NR Duration of intervention: 2-4doses: 18/81 (22.2%) line even if colorectal ·Gender: NR up to 24h culture was surgery would ·Obesity: NR Device/agent: Abdominal wounds: negative. reduce the ·Comorbidities: NR metronidazole Total 18/90 (20%): Perioperative wound Procedures: Intestinal Control group: n=68 1dose: 7/22 (31%) care: NR infection rate anastomoses. Patients receiving 2-4doses: 11/68 (16%) Other notes: None further. Indications: NR postoperative p=0.12 Follow-up: 6 Setting: 1 teaching intravenous 500mg weeks post op. hospital injections of Perineal wounds: Funding Source Location: United metronidazole every 8h 1/3 (33.3%) vs. Conflicts: Kingdom up to 24h postop. 7/13 (53.8%); Authors: NR © 2017 American Medical Association. All rights reserved. 216

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Dates: April 1980 – Standard preventive p=0.53, at 6 week follow Institution: NR February 1982 measures: up. Study: NR Inclusion Criteria: Bowel prep consisted of Supplies: Industry Patients who magnesium sulphate 2g underwent elective TDS for 3 days before colorectal surgery the operation and a during the study standard mechanical dates. method of bowel prep Exclusion Criteria: containing no Patients who antimicrobials. received antimicrobials in the preceding 2 weeks and patients with inflammatory bowel disease who had abscesses, fistulas or toxic dilatation of the colon. Hasselg- RCT To evaluate Number of patients: Intervention group: SSI Definitions: ren 1, 3, 4, the effects of a N=121 1day: patients Wound infection: 1984 37 5, 6, 7, 1 day versus a Patient administered 3 doses of 1day: 2/52 (3.8%) accumulation of (ES) 8 3-day course Characteristics: cefuroxime 1.5g 3day: 3/69 (4.3%) pus that drained of cefuroxime relative distribution intravenously beginning p=0.89 spontaneously on infection of risk factors did not 1 hour before surgery or after rates in differ significantly and then every 8 hours debridement. peripheral between the study ( up to 16h postop) Graft infection: vascular groups. Timing of intervention: defined as any surgery. ·Age, y: NR pre and postop persistent ·Gender: NR Duration of intervention: wound infection ·Obesity: NR 1 or 3 days postop communicating ·Comorbidities: NR Device/agent: 1.5g with graft Procedures: vascular cefuroxime iv material. surgery Control group: Indications: NR 3day: patients Perioperative Setting: 1 university administered 9 doses of care: NR hospital cefuroxime 1.5g Other notes: NR Location: Sweden intravenously beginning Follow-up: 30 day Dates: January 1981 – 1 hour before surgery follow up © 2017 American Medical Association. All rights reserved. 217

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score June 1983 and then every 8 hours Funding Source Inclusion Criteria: ( up to 64h postop) Conflicts: Patients scheduled Standard preventive Authors: NR for vascular measures: Institution: NR reconstructive Skin prep: wash with Study: NR surgery of the lower chlorhexidine soap 3 Supplies: NR limbs and patients times on day prior to undergoing acute surgery. femoral Hair removal: shaving embolectomy or immediately prior to thrombectomy. surgery. Exclusion Criteria: Patients scheduled for an aortic bifurcation graft; patients having received antimicrobials within 1 week prior to surgery; patients with cellulitis or wet gangrene on lower extremities; and patients with a history or penicillin or cephalosporin allergy. Hemsell RCT To compare a Number of patients: Intervention group: n=58 SSI Definitions: 1984 28 1, 2, 4, preoperative N=112 1 dose: patients received 1 Minor postop (ES) 5, 6, 7, dose with Patient preoperative dose of 2g 1dose: 1/58 (1.7%) infection: cystitis 8 three Characteristics cefoxitin i.m. when 3dose: 2/54 (3.7%) – when a perioperative Clinical and surgical called into the operating woman had doses of variables were room. Cefoxitin was lower urinary cefoxitin given statistically similar diluted with 0.5% Length of stay: tract irritative to between groups. lidocaine without No difference, days: mean symptoms and premenopaus ·Age, y: NR epinephrine in the hip ±SD: 105 or more al women ·Gender: NR Timing of intervention: 1dose: 4.4±1.1 colonies of a scheduled for ·Obesity: NR preop or postop 3dose: 4.7±1.2 days single vaginal ·Comorbidities: NR Duration of intervention: uropathogen per © 2017 American Medical Association. All rights reserved. 218

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score hysterectomy. Procedures: vaginal up to 12h postop milliliter of urine. hysterectomy Device/agent: cefoxitin Major postop Indications: NR Control group: n=54 infection: pelvic Setting: 1 university 3dose: patients received 1 cellulitis – an hospital preoperative dose of 2g extra-peritoneal Location: USA cefoxitin i.m. when infection Dates: February – called into the operating involving December 1982 room. Cefoxitin was primarily the Inclusion Criteria: diluted with 0.5% parametrial premenopausal lidocaine without tissues. This women undergoing epinephrine in the hip; involved vaginal this was followed by complaints of hysterectomy intravenous infusion of increasing lower Exclusion Criteria: 2g cefoxitin dose at 6 & abdominal known allergy to 12h postop. and/or pelvic cephalosporins, pain, tenderness cephamycins, or Standard preventive to the gentle lidocaine; history of measures: deep palpation immediate Povidone-iodine douche of the hypersensitivity was taken the night inferolateral reaction to penicillin; before the surgery abdominal wall, history of and an elevated antimicrobial therapy temperature. within the 48h before Tenderness was surgery; temperature always of greater than or asymmetrical. equal to 38oC during Perioperative the 24h before care: NR surgery, concomitant Other notes: none infection or any other Follow-up: 3-6 condition that might weeks post- preclude accurate surgery. evaluation of Funding Source response to therapy. Conflicts: Authors: NR Institution: NR Study: Industry Supplies: NR

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Austin RCT To examine Number of patients: Intervention group: n=38 SSI Definitions: 1980 34 1 the effect the n=85 2dose: Patients who Superficial sternal SSI Infections: (ES) need for Patient received cephalothin 2g 2dose: 1/38 (2.6%) diagnosed chemoprophyl Characteristics intravenously 3days: 1/47 (2.1%) clinically and axis beyond Findings of the two immediately before f/u NR supported by the immediate groups were similar cardiac bypass was total and operative ·Age, y: NR begun and 2g at the Antimicrobial resistance: differential period in ·Gender: NR end of the operation. Both incisional SSIs were leukocyte Aortocoronary ·Obesity: NR Timing of intervention: Staphylococcus aureus counts, by local Bypass ·Comorbidities: NR pre and postop. cultures and by procedures. Procedures: Duration of intervention: Length of stay, days blood cultures aortocoronary either for the surgery or Significantly shorter length and bypass up to 3days postop. of stay with roentgenograms Indications: NR Device/agent: cephalothin postoperative AMP in where indicated. Setting: 1 university Control group: n=47 one small (N=85) RCT Duration of hospital 3days: Patients who with data collected 35 hospitalization: Location: Canada received cephalothin 2g years ago: defined as the Dates: Sept 1, 1977 – intravenously 2dose: 12.03±4.2 number of days June 30, 1978 immediately before 3day: 14.6±7.5 form operation Inclusion Criteria: All cardiac bypass was P<0.05 until discharge. patients who begun and 2g at the Perioperative underwent end of the operation. care: NR aortocoronary This was then followed Other notes: None bypass operation at by 1g cephalothin q6h Follow-up: NR the study hospital for 3 days. Funding Source during the study Conflicts: dates. Standard preventive Authors: NR Exclusion Criteria: IF measures: Institution: NR patients had a Skin prep: surgical field Study: NR history of an was sprayed with a Supplies: NR accelerated allergic combination of reaction to penicillin polymyxin and or allergy to bacitracin. cephalosporins, or if they refused to give consent.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Conte RCT To evaluate Number of patients: Intervention group: n=30 SSI Definitions: 1972 32 1, 3, 4, single-dose N=64 1dose 1g cephalothin Organ/Space Sternal SSI Major infection: a (ES) 5, 6, 7 versus Patient intravenously during 1dose: 1/30 (3.3%) wound infection multiple dose Characteristics surgery. 20dose: 1/34 (2.9%) with purulent regimens of The groups were Timing of intervention: drainage and cephalothin in randomly distributed pre, intra and postop Superficial Sternal SSI positive cultures patients and did not differ Duration of intervention: 1 dose: 2/30 (6.7%) with our without undergoing significantly. intraop or from the night 20 dose: 2/34 (5.9%) bacteremia that cardiac ·Age, y: NR before surgery until 4th required surgical surgery. ·Gender: NR day postop Antimicrobial resistance: drainage and ·Obesity: NR Device/agent: cephalothin Incisional SSI: The “no prolonged the ·Comorbidities: NR Control group: n=34 postoperative AMP postoperative Procedures: cardiac 20dose: received 1g group” course. surgery cephalothin before, 1dose: had 1 Minor infection was Indications: NR during and after surgery Staphylococcus aureus defined as Setting: 1 university at 6 hour intervals from and 1 Staphylococcus wound infection hospital 6pm the night before epidermis infection as with little or no Location: USA the surgery until noon compared to purulent Dates: 1969 – of the 4th postop day. 20dose: 1 Serratia drainage, a December 1970 Standard preventive marcescens and 1 positive culture, Inclusion Criteria: measures : NR Enterococcus infection minimal edge patients scheduled Organ/Space Sternal SSI: separation, and for cardiac surgery 1dose: The one case of a rapid response with endocarditis was a to local care. cardiopulmonary Staphylococcus Perioperative bypass. epidermis care: NR Exclusion Criteria: Other notes: None unwilling to Follow-up: participate, if there 6months - 2 was a language years barrier, or if there Funding Source was difficulty in Conflicts: comprehension to Authors: Industry prevent performed Institution: NR consent. If they were Study: Industry under 21 years of Supplies: Industry age, if the case was an emergency, if they had received © 2017 American Medical Association. All rights reserved. 221

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score penicillin in doses greater than 400,000 units/day or any other antimicrobials during the 2 weeks prior to surgery, or if they had a history of allergic reaction to the protocol drug. Also, death from a noninfectious cause within 24h after surgery, significant deviations from the protocol or apparent allergy to the protocol drug.

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2.1A3. RISK OF BIAS ASSESSMENTS: Q1 PARENTERAL AMP STUDIES eTABLE 29. Risk of Bias Assessments of Randomized Controlled Trials for Q1 Parenteral AMP Funding Randomiza- Outco- Attrition source(s) Describ- tion Describ- me smaller than Attrition disclosed and ed as appropriat- ed as asses- Study Investiga- Attrition 10-15% of appropriat- no obvious Overa- Author randomi- ely double- sor participa- tor describ- assigned ely conflict of ll Risk Year Q zed performed blind blinded nt blinded blinded ed patients analyzed interest of Bias Question 1: Parenteral Antimicrobial Prophylaxis (AMP) Aberg Mode- 26 1    1991 rate Akinyoola 1 1   High 2011 Ali 17 1   High 2006 Austin 34 1  High 1980 Bates Mode- 25 1      1992 rate Becker 43 1         Low 1991 Bernard 36 1         Low 1994 Buckley Mode- 14 1     1990 rate Carr 23 1   High 1984 Carroll Mode- 40 1      2003 rate Chang Mode- 41 1     2005 rate Conte 32 1       Low 1972 Cuthbertson Mode- 10 1     1991 rate Fujita 15 1       Low 2007 Garotta 19 1   High 1991 Gatell 18 1        Low 1987 Grundmann 24 1  High 1987 © 2017 American Medical Association. All rights reserved. 223

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Funding Randomiza- Outco- Attrition source(s) Describ- tion Describ- me smaller than Attrition disclosed and ed as appropriat- ed as asses- Study Investiga- Attrition 10-15% of appropriat- no obvious Overa- Author randomi- ely double- sor participa- tor describ- assigned ely conflict of ll Risk Year Q zed performed blind blinded nt blinded blinded ed patients analyzed interest of Bias Haga 52 1   High 2012 Hall 38 1       Low 1998 Hall Mode- 44 1     1989 rate Hasselgren 37 1        Low 1984 Hemsell 28 1        Low 1984 Hirokawa 54 1        Low 2013 Hussain Mode- 31 1      2012 rate Imamura Mode- 51 1     2012 rate Juul Mode- 45 1     1987 rate Karran Mode- 50 1    1993 rate Kow Mode- 22 1    1995 rate Lin 35 1  High 2011 Liu 39 1         Low 2008 Lyimo30 Mode- 1       2013 rate Macones 4 1        Low 2011 Mayer 27 1   High 1993 McArdle Mode- 47 1    1995 rate Mendel 46 1  High 1987 Moesgaard 1     Mode- © 2017 American Medical Association. All rights reserved. 224

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Funding Randomiza- Outco- Attrition source(s) Describ- tion Describ- me smaller than Attrition disclosed and ed as appropriat- ed as asses- Study Investiga- Attrition 10-15% of appropriat- no obvious Overa- Author randomi- ely double- sor participa- tor describ- assigned ely conflict of ll Risk Year Q zed performed blind blinded nt blinded blinded ed patients analyzed interest of Bias 1989 48 rate Mohri 53 1       Low 2007 Mui Mode- 11 1      2005 rate Nooyen Mode- 33 1      1994 rate Oostvogel 16 1       Low 1987 Osman Mode- 3 1      2013 rate Ritter Mode- 21 1    1989 rate Soriano Mode- 2 1      2008 rate Su 13 1   High 2005 Sullivan 8 1           Low 2011 Suzuki Mode- 42 1      2011 rate Tamayo 12 1       Low 2008 Thigpen 7 1          Low 2005 Togo 55 1        Low 2007 Turano 29 1  High 1992 Wax 9 1           Low 1997 Wenzel Mode- 49 1      1985 rate Witt 5 1          Low 2011 Wymenga Mode- 20 1     1992 rate © 2017 American Medical Association. All rights reserved. 225

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2.1B. Q2 NON-PARENTERAL AMP 2.1B1. GRADE TABLE Q2: NON-PARENTERAL AMP eTABLE 30. GRADE Table for Q2 Non-Parenteral AMP Increase Decrease GRADE

GRADE GRADE

Overall

Quantity Starti- of GRADE and Type ng Eviden- Comparison Outcome Findings of of GRAD- ce for Eviden- Evidence E response Outco- Large ce Base

Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Q2. What are the most effective strategies for administering non-parenteral AMP at the surgical incision to reduce the risk of SSI? Q2A. How safe and effective is antimicrobial irrigation? Colorectal Surgeries • In one small RCT (N=103), in elective colorectal cancer surgeries, use of clindamycin-gentamicin was associated with a reduction in SSI: 4% vs. 14%; 56 p<0.01. OR: 4.94 (1.27-19.19) SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate • Antimicrobial solution was allowed to rest in the abdominal cavity for 3 minutes. Clindamycin- • Both groups received preoperative AMP Gentamicin with an intraoperative bolus after 4 hours, Solution vs. with no mechanical bowel prep normal saline • Post- irrigation samples were taken only in the intervention group (post antimicrobial Antimicrob- irrigation). These cultures were positive in ial 1 RCT 56 2 patients (4%). Detected microorganisms High 0 0 0 -2 0 0 0 0 Low Low resistance were Klebsiella spp and Streptococcus salivarius. Both of these organisms were resistant to clindamycin and gentamicin. © 2017 American Medical Association. All rights reserved. 226

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Increase Decrease GRADE

GRADE GRADE

Overall

Quantity Starti- of GRADE and Type ng Eviden- Comparison Outcome Findings of of GRAD- ce for Eviden- Evidence E response Outco- Large ce Base

Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Acute Appendectomies • In one RCT (N=246), in acute appendectomies, irrigation with ampicillin solution was associated with an overall 57 reduction in SSI: 1/117 (0.9%) vs. 7/132 SSI* 1 RCT High 0 0 0 -2 0 0 0 0 Low (5.3%); p<0.05 • A reduction was specifically seen in SSI for acute appendicitis cases: 0/88 vs. 6/102 (5.9%); P<0.05 Ampicillin Product Solution vs. Low Related 57 • One patient in each group noted some Normal saline 1 RCT High 0 0 0 -2 0 0 0 0 Low Adverse redness in the wound Events • Almost all Streptococci and Enterococci were sensitive to Ampicillin and 30% of E. Antimicrob- 57 coli isolates were sensitive to ampicillin in ial 1 RCT High 0 0 0 -2 0 0 0 0 Low samples cultured from intraoperative resistance peritoneal and wound swabs. E. coli results were not reported by group. Q2B. How safe and effective are topical antimicrobial agents applied to the surgical incision? Topical Ampicillin - Solution Colorectal Surgeries • In 1 RCT (N=203) in elective colorectal surgeries, use of topical ampicillin was associated with no difference in SSI: 5/105 (4.8%) vs. 5/98 (5.1%), (95%CI: - Ampicillin 5.6-6.2), p=NS solution vs. 58 Low SSI* 1 RCT • Both groups received preoperative AMP High 0 0 0 -2 0 0 0 0 Low no topical of ampicillin and metronidazole which was antimicrobial continued 3 times daily for 3 days postoperatively, and standard or whole- gut bowel prep • These surgeries included some patients © 2017 American Medical Association. All rights reserved. 227

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication with known infections including one with Fournier’s Gangrene (not indicated which group) Product Related 58 • No product related hypersensitivity or any 1 RCT High 0 0 0 -2 0 0 0 0 Low Adverse other adverse events were observed Events Acute Appendectomies • In 1 RCT (N=246) of emergency acute appendectomies, cleaning the subcutaneous tissues with ampicillin solution soaked gauze reduced surgical Ampicillin site infections: 5/126 (4%) vs. 15/120 solution vs. (13%); p<0.02. No topical SSI* 1 RCT 59 • Differences were not significant in the High 0 0 0 -1 0 0 0 0 Moderate Moderate antimicrobial simple appendicitis cases, but were agent significant in the gangrenous and perforated cases (advanced) 5/58 (9%) vs. 14/52 (27%); p<0.02 • Both groups received intramuscular antimicrobial prophylaxis. Topical Ampicillin - Powder • In 1 RCT (N=170) in elective colorectal surgeries, ampicillin powder applied to the subfascial and subcutaneous layers of the Ampicillin wound before closure was not associated powder vs. 60 with a reduction in SSI: 5/81 (6.2%) vs. No topical SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate 6/89 (6.7%); p>0.05 antimicrobial • Both groups received parenteral agent antimicrobial prophylaxis preoperatively and 2 additional doses up to 12h postop. • Follow up was not reported Topical Chloramphenicol

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication • In a study of 92 hip fracture repairs, no difference between groups: 12 (13.0%), Chloramphenic- 4/47 (8.5%) vs. 8/45 (17.8%); p=0.20. ol vs. 61 • Both groups received parenteral No topical SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate antimicrobial prophylaxis antimicrobial • agent Chloramphenicol ointment was applied to the surgical site at the end of the procedure and on postoperative day 3 Topical Rifampin • In a small (N=48), lower-quality study of patients after video laparoscopic cholecystectomy, use of rifampin associated with reduced risk of umbilical port site infection (defined as purulent wound leakage: (p<0.005) and fewer local signs of inflammation (p<0.001) • According to results reported in a histogram, at 12 hours postoperatively, purulent wound leakage was present 62 among 34/48 (70.8%) of the study Rifampin vs. SSI* 1 RCT High -1 0 0 -1 0 0 0 0 Low population: 10/24 (41.7%) vs. 24/24 No topical (100%). At 24 hours: 0/24 vs. 24/24 and Low antimicrobial by postoperative day seven: 0/24 vs. 2/24 agent of the normal saline group. Unclear if any of these were truly infections. • Both groups received parenteral AMP • Sterile rifampin (250mg) applied to the umbilicus (formulation not specified) preoperatively, intraoperatively, and postoperatively (every 12 hours for 72 hours) Wound 62 • Rifampin associated with reduced risk for Dehiscen- 1 RCT High 0 0 0 -1 0 0 0 0 Moderate dehiscence (p<0.01) ce © 2017 American Medical Association. All rights reserved. 229

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Vancomycin Paste • In one RCT at high risk of bias, in 416 heart operations performed via median Vancomycin sternotomy there was a reduction in powder mixed SSI* sternal / mediastinal SSI with vancomycin with hemostatic 63 Mediastinal 1 RCT powder mixed with a hemostatic paste High -1 0 0 -1 0 0 0 0 Low Low paste vs. /sternal made from absorbable gelatin and topical Hemostatic thrombin and applied to the cut sternal paste edges vs. hemostatic paste alone: 1/223 (0.45%) vs. 7/193 (3.6%); p=0.02 Autologous Platelet Rich Plasma • In a meta-analysis (N=452) of 4 small RCTs in cardiac surgery and total knee arthroplasty, use of autologous platelet 4 RCT 64- rich plasma was not associated with a Autologous SSI* 67 High 0 0 0 -1 0 0 0 0 Moderate difference in SSI OR: 1.14 (0.56-2.31); Platelet rich 2 p=0.72; I =0 plasma-APRP Moderate • Each individual study did not find a (gel or spray) vs. difference No APRP • At two weeks after surgery, use of a spray Total 65 was associated with decreased likelihood wound 1 RCT High 0 0 0 -1 0 0 0 0 Moderate of total wound closure: 11% vs. 35%; closure p=0.02 Q2C. How safe and effective are antimicrobial-coated sutures; when and how should they be used? Antimicrobial- • In a meta-analysis (N=5388) of 14 RCTs coated suture that included heterogeneous surgeries (absorbable) vs. and patients, sutures, closure levels, and Non- 14 RCT closure types in both intervention and 68-81 Moderate antimicrobial- SSI* comparator arms across studies, there High 0 0 0 0 0 0 0 0 High

coated suture was a reduction in SSI: OR: 0.69 (0.55 – (absorbable and 0.86); p<0.01; I2=28%. All studies used non-absorbable) triclosan-coated suture as the antimicrobial-coated suture.

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication • In a meta-analysis (N=1081) of 4 RCTs that included heterogeneous surgeries and patients, no difference in organ/space SSI rates was observed: OR: 0.49 (0.07 – 3.43); p=0.47; I2=71%. All studies used triclosan-coated suture as the antimicrobial-coated suture. • 1 RCT74 abdominal wound was closed with interrupted sutures using either triclosan coated vs. uncoated 910 braided polyglactin. Skin was closed with staples Organ/ 4 RCT 78 74,78-80 • 1 RCT abdominal sheath was closed High 0 -1 0 -1 0 0 0 0 Low Space SSI using either triclosan coated vs. uncoated 910 braided polyglactin. Skin closure was not reported • 1 RCT79 wound was closed using either triclosan coated vs. uncoated 910 braided polyglactin. Skin closure was not reported • 1 RCT80 galea and fascia were closed with using either triclosan coated vs. uncoated 910 braided polyglactin. Skin closure was with absorbable monofilament sutures • In a meta-analysis (N=1285) of 2 RCTs that included colorectal and abdominal surgeries, no difference in deep SSI rates was observed: OR: 0.86 (0.49 – 1.54); p=0.62; I2=0. 2 RCT • 1 RCT 77 fascia closure occurred via Deep SSI* 77,78 High 0 0 0 -1 0 0 0 0 Moderate continuous mass closure using triclosan coated or uncoated polydioxanone sutures. Skin was closed using staples • 1 RCT78 abdominal sheath was closed using either triclosan coated vs. uncoated 910 braided polyglactin. Skin closure was © 2017 American Medical Association. All rights reserved. 231

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication not reported.

• In a meta-analysis (N=1922) of 4 RCTs that included heterogeneous surgeries, no difference in superficial SSI rates was observed: OR: 1.06 (0.76 – 1.48); p=0.72; I2=0. • 1 RCT 77 fascia closure occurred via continuous mass closure using triclosan coated or uncoated polydioxanone sutures. Skin was closed using staples • 1 RCT78 abdominal sheath was closed using either triclosan coated vs. uncoated 910 braided polyglactin. Skin closure was not reported Superficial 4 RCT 79 72,77-79 • High 0 0 0 0 0 0 0 0 High SSI 1 RCT wound was closed using either triclosan coated vs. uncoated 910 braided polyglactin. Skin closure was not reported • 1 RCT72 the subcutaneous and subcuticular layers were closed with triclosan coated or uncoated braided 910 polyglactin or with triclosan coated or uncoated poliglecaprone 25 at the surgeon’s discretion. Wounds were dressed with butterfly stitches, sterile adhesive dressing and either transparent adhesive wound covering or non- transparent adhesive wound covering or wound covering alone • In 1 RCT73 mean ASEPSIS score was lower in the triclosan coated suture group ASEPSIS 2 RCT 72,73 at all times measured (day 4, 30, 60) but High 0 0 0 -1 0 0 0 0 Moderate score never reached statistical significance at all specified endpoints © 2017 American Medical Association. All rights reserved. 232

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication • In 1 RCT72 mean ASEPSIS score was lower in the triclosan-coated suture group at two weeks postop but this did not reach statistical significance. There was no difference at 6 weeks postop. • No studies reported specific testing for triclosan resistance. • In 3 RCT68,69,71 wounds were cultured and no antibiotic resistant strains were reported at 30 days follow up. • In 1 RCT78 wounds were cultured and no antibiotic resistant strains were found at 1 year follow up. • In 1 RCT79 wounds were cultured and no MRSA was recovered from wounds in either group at 30 days follow up. • In 1 RCT75 preoperatively screened Antimicrob- 8 RCT patients at risk for MRSA or with previous 68,69,71,74, ial MRSA incidence and decontamination High 0 0 0 -2 0 0 0 0 Low 75,78-80 resistance had wounds cultured 2 weeks post op with no resistant bacteria reported. • In 1 RCT80 in pediatric cerebrospinal fluid shunt implants and revisions, wounds were cultured: MRSA: 1/2 (50%) vs. 1/8 (12.5%) for antimicrobial suture vs. standard, both in revision surgeries at up to 6 months follow up. • In 1 RCT74 in elective colorectal surgeries, wounds were cultured and suggested no difference in the incidence of MRSA: 0/9 vs. 1/19 (5.3%); missing data: 2/9 (22.2%) vs. 6/19 (31.6%) at 30 days follow up. Wound 3 RCT • Meta-analysis of 3 RCTs (N=1582): OR: Dehiscen- 70,73,77 2 High 0 -1 0 -1 0 0 0 0 Low 0.89 (0.31 – 2.58); p=0.83; I =76% ce © 2017 American Medical Association. All rights reserved. 233

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication • 1 RCT73 of 374 CABG leg harvesting sites suggested no difference in non-infectious leg wound dehiscence within 60 days: 11/161 (6.8%) vs. 13/152 (8.5%); p=NS • 1 RCT77 (N=1185) in mixed open abdominal surgeries suggested no difference in non-infectious wound dehiscence: 66/587 (13.4%) vs. 81/598 (16.3%), OR: 0.80 (0.56-1.14); p=0.21; however the study suggested a decrease in reoperation for burst abdomen with triclosan-coated sutures as compared to controls: 9/587 (1.9%) vs. 22/598 (4.5%); OR: 0.80 (0.18-0.88); p=0.02. • 1 RCT70 suggested a reduction in dehiscence with triclosan coated sutures: 1/91 (1.1%) vs. 7/93 (7.7%); p=0.03. Adverse events- 4 RCT • 4 RCT77,78,80,81 no serious adverse events 77,78,80,81 High 0 0 0 -2 0 0 0 0 Low product reported for either suture type. related Colorectal Surgery • In a meta-analysis (N=1912) of 5 RCTs in colorectal surgery, no difference in SSI: OR: 0.71; (0.47 – 1.08); p=0.11; I2=48%. Antimicrobial- • 2 RCTs suggested a reduction in SSI: 1 coated suture large RCT74 (N=410) at 30 day follow up (absorbable) vs. 5 RCT where abdominal wounds were closed Non- 70,71,74,75, SSI* with interrupted sutures using either High 0 0 0 -1 0 0 0 0 Moderate Moderate antimicrobial- 77,82 triclosan coated vs. uncoated 910 braided coated suture polyglactin and skin was closed with (absorbable and staples. 1 small RCT 70 (N=182), with non-absorbable) follow up not reported, the abdominal wall was closed with single-layer mass technique (peritoneum, muscle & fascia) © 2017 American Medical Association. All rights reserved. 234

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication using triclosan coated or uncoated braided size 0 polyglactin 910. Skin was closed with non-absorbable monofilament polyamide. Both suggested a reduction in SSI 9/206 (4.3%) vs. 19/204 (9.3%); p=0.05; and 4/91 (4.3%) vs. 12/91 (13/2%); p=0.04 respectively. Preoperative AMP was followed by an intraoperative bolus delivered at 3h and antibiotics were continued for 48h postop in the larger study. AMP was delivered at induction of anesthesia in the smaller study and wound infection was not defined. • 1 subanalysis75 of 243 colorectal surgeries in a study of abdominal surgeries where abdominal fascia was closed with coated or uncoated 2-0 monofilament polydioxanone loop; no subcutaneous sutures were used; skin was closed with staples; suggested a reduction in SSI though not significant: 17/143 (12%) vs. 19/100 (19%). This study was conducted as a part of a clinical care pathway. • 1 subanalysis of a large, multicenter RCT77,82 (N=690) and 1 RCT71 (N=385) suggested no difference in SSI at 30 days.1 Subanalysis77,82 of 690 colorectal surgeries suggested no difference: 62/344 (18.0%) vs. 60/346 (17.3%); p=0.81. Continuous mass closure with triclosan- coated or uncoated polydioxanone sutures were used for the fascia, skin closure was achieved with staples and antimicrobial prophylaxis was given prior © 2017 American Medical Association. All rights reserved. 235

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication to skin incision, 1 RCT 71 (N=385) suggested no difference: 23/188 (12.2%) vs. 24/197 (12.2%); Preoperative AMP was delivered 30 minutes before incision. Triclosan coated sutures were used in skin closure for both intervention and control groups. Abdominal Surgeries, Laparotomies & Appendectomies (excluding colorectal) • In a meta-analysis (N=1208) of 3 RCTs, antimicrobial sutures reduced SSI: OR: 0.63; 95% CI: 0.42 – 0.95; p=0.03; I2=0. • 1 subanalysis75 of 612 abdominal surgeries suggested a reduction in SSI: 14/341 (4.1%) vs. 23/271 (8.5%). This study was conducted as a part of a clinical care pathway where abdominal fascia was closed with coated or uncoated 2-0 monofilament polydioxanone loop; no Antimicrobial- subcutaneous sutures were used; and coated suture skin was closed with staples. (absorbable) vs. • 77 Non- 3 RCT 1 subanalysis of 495 mixed abdominal SSI* 75,77,78 surgeries where fascia closure occurred High 0 0 0 0 0 0 0 0 High High antimicrobial- via continuous mass closure using coated suture triclosan coated or uncoated (absorbable and polydioxanone sutures and skin was non-absorbable) closed using staples at 30 day follow up: no difference in SSI: 25/243 (10.3%) vs. 36/252 (14.3%); Preop AMP was administered 30-60 minute before incision in both studies. • 1 small (N=100) RCT78 in appendectomies, where the abdominal sheath was closed using either triclosan coated vs. uncoated 910 braided polyglactin and skin closure was not © 2017 American Medical Association. All rights reserved. 236

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication reported, suggested no difference at 1 year follow up: 5/50 (10%) vs. 4/50(8%); p=0.73; all were superficial SSIs except for 1 deep SSI in the control group All Surgeries except Colorectal and Abdominal Surgeries, Laparotomies & Appendectomies Antimicrobial- coated suture • In a meta-analysis (N=2183) of 8 RCTs in (absorbable) vs. 8 RCT heterogeneous surgeries and patient Non- 68,69,72,73, SSI* populations, antimicrobial sutures reduced High 0 0 0 0 0 0 0 0 High High antimicrobial- 76,79-81 SSI OR: 0.68 (0.49 – 0.95); p=0.02; coated suture 2 I =24%. (absorbable and non-absorbable) Cardiac Surgery • One RCT 79 (N=510) suggested no difference in sternal infections at 30 day follow up: 4/170 (2.4%) vs. 12/340 (3.5%); Sternal 79 OR: 0.66 (0.21-2.07); p=0.48. Triclosan 1 RCT High 0 0 0 -1 0 0 0 0 Moderate SSI* coated or uncoated polyglactin 910 sutures were used, but the level of closure was not specified, AMP and skin prep Antimicrobial- were not reported. coated suture • In a meta-analysis (N=1099) of 3 RCTs in (absorbable) cardiac surgeries, there was a suggestion versus non- that antimicrobial sutures reduced SSI Moderate antimicrobial- (OR: 0.72 (0.48 – 1.09); p=0.12; I2=0. coated suture • 79 69 (absorbable and 2 RCT (N=510 and N=328 ) suggested Donor Site no difference in donor site SSI at 1 month non-absorbable) 3 RCT Superficial 69,73, 79 follow up: 5/142 (3.5%) vs. 10/260 (3.8%); High 0 0 0 0 -1 0 0 0 Moderate

SSI* p=1.00; and 16/160 (10%) vs. 17/163 (10.4%) respectively. The larger of the two did not report AMP or standard preventive measures and wounds were closed with either triclosan coated or uncoated polyglactin 910 (level of closure not © 2017 American Medical Association. All rights reserved. 237

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication specified). The smaller RCT utilized triclosan coated or uncoated polyglactin 910 (level of closure was not specified), alcohol CHG skin prep and preoperative AMP, an intraoperative bolus at 3h with antibiotics administered up to 24h postop. • 1 RCT 73 (N=374) suggested a decrease in donor site SSI at 60 days follow up: 23/184 (12.5%) vs. 38/190 (20.0%); p=0.05. Patients were administered AMP 30 minutes prior to incision, an intraoperative bolus at 2h and were given 2 additional antibiotic doses up to 24h postop. Normothermia was maintained. This study utilized antimicrobial sutures in both the subcutaneous and cutaneous layers in the intervention arm. Breast Cancer Surgery • 1 RCT 72 in mixed breast cancer surgeries Antimicrobial- (N=146) suggested no difference at 6 coated suture weeks follow up: 10/66 (15.2%) vs. 14/61 (absorbable) vs. (22.9%); p=NS. Triclosan coated sutures Non- 72 were used in both subcutaneous and SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate antimicrobial- subcuticular closure in the intervention coated suture arm. 8/146 patients were administered (absorbable and preoperative AMP and 0/8 developed SSI. non-absorbable) Not reported which group these 8 belonged. Mixed Surgeries Antimicrobial- • A meta-analysis (N=597) of 2 RCTs of coated suture mixed surgical populations, suggested no (absorbable) vs. 2 RCT difference SSI OR: 0.76 (0.13-4.46); SSI* 76,81 2 High 0 0 0 -1 0 0 0 0 Moderate Moderate Non- p=0.76; I =45%. antimicrobial- • 1 RCT 76 in mixed surgeries (N=450) coated suture suggested a decrease in SSI at 60 days © 2017 American Medical Association. All rights reserved. 238

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication (absorbable and follow up: 17/230 (7%) vs. 33/220 (15%); non-absorbable) p=0.01. • Triclosan coated or uncoated polyglactin 910 sutures were used in all surgical steps, except in some cases polypropylene sutures were used for laparotomy closure and vascular sutures. Poliglecaprone 25 was used for skin closure for the entire uncoated suture group. In the triclosan coated suture group, skin closure was not uniform across surgical specialties. Standard of care was not uniform and not in line with current standards in some instances. It is not reported which group these patients belonged to. • 1 RCT 81 (N=147) in mixed pediatric general surgery patients used coated or uncoated polyglactin 910 for unspecified levels of closure and suggested an increase in SSI with triclosan coated sutures 80 days follow up, however this difference was not significant: 3/98 (3.1%) vs. 0/49; p=0.22. AMP was not reported Lower Limb Revascularization • 1 RCT in lower limb revascularization Antimicrobial- surgeries (N=276) where triclosan coated coated suture or uncoated polyglactin was used for (absorbable) vs. subcutaneous closure, and triclosan Non- 68 coated or uncoated poliglecaprone SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate antimicrobial- sutures were used for intracutaneous coated suture closure; suggested no difference in SSI at (absorbable and 30 days follow up: 31/139 (22.3%) vs. non-absorbable) 30/137 (21.9%); OR: 1.02 (0.58-1.81); p=0.94. Although AMP was not © 2017 American Medical Association. All rights reserved. 239

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication standardized across hospitals, differences were evenly distributed across groups. Triclosan coated sutures were used in both subcutaneous and intracutaneous closure in the intervention arm. Pediatric Cerebrospinal Fluid Shunt Surgeries • 1 RCT in pediatric cerebrospinal shunt fluid surgeries (N=61) where galea and fascia were closed with triclosan coated Antimicrobial- or uncoated polyglactin 910 and skin was coated suture closed with absorbable poliglecaprone 25 (absorbable) vs. sutures, suggested a reduction in SSI at Non- 80 6 month follow up: 2/46 (4.3%) vs. 8/38 SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate antimicrobial- (21%); OR: 0.17 (0.03-0.86); p=0.03. coated suture Skin prep with CHG & PI; Pre-op AMP; (absorbable and iodine-impregnated adhesive drapes; non-absorbable) antibiotic wound irrigation prior to closure. Silicone shunt components were soaked in antibiotic solution before implantation Q2D. How safe and effective are antimicrobial dressings applied to surgical incisions following primary closure in the operating room? • One small RCT 83 (N=112) in elective colorectal cancer surgeries suggested no difference in SSI rates when comparing a moisture retentive dressing containing Silver 1.2% ionic silver with standard dressing: impregnated 9/58 (15.5%) vs. 11/54 (20.4%); p=0.62 dressing vs. 2 RCT 84 SSI* 83,84 • One small RCT (N=109) in elective High 0 -1 0 0 0 0 0 0 Moderate Moderate standard colorectal surgeries suggested a reduction dressing or in SSI using silver nylon dressing vs. gauze standard gauze and tape: 7/ 55 (13%) vs. 18/54 (33%); p=0.01. Any questionable SSI treated with antibiotics was included in SSI definition

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication • One small RCT 83 (N=112) in elective colorectal cancer surgeries suggested no Organ/ 83 difference in organ/space SSI rates when 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Space SSI* comparing a moisture retentive dressing containing 1.2% ionic silver with standard dressing: 1/58 (1.7%) vs. 1/54 (1.9%) • One small RCT 83 (N=112) in elective colorectal cancer surgeries suggested no difference in deep SSI rates when comparing a moisture retentive dressing containing 1.2% ionic silver with standard dressing: 3/58 (5.2%) vs. 2/54 (3.7%). 2 RCT 84 Deep SSI* 83,84 • One small RCT (N=109) in elective High 0 0 0 -1 0 0 0 0 Moderate

colorectal surgeries suggested no difference in deep SSI using silver nylon dressing vs. standard gauze and tape: 2/ 55 (4%) vs. 4/54 (7%); p=0.4. Any questionable SSI treated with antibiotics was included in SSI definition. • One small RCT 83 (N=112) in elective colorectal cancer surgeries suggested no difference in superficial SSI rates when comparing a moisture retentive dressing containing 1.2% ionic silver with standard dressing: 5/58 (8.6%) vs. 8/54 (14.8%); Superficial 2 RCT p=0.80 83,84 High 0 0 0 -1 0 0 0 0 Moderate SSI* • One small RCT84 (N=109) in elective colorectal surgeries suggested a reduction in superficial SSI using silver nylon dressing vs. standard gauze and tape: 5/ 55 (9%) vs. 14/54 (26%); p=0.02. Any questionable SSI treated with antibiotics was included in SSI definition.

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Precision me Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication • No difference in median length of stay Length of 83 1 RCT between groups: 6 (3-21) vs. 6.5 (2-17) High 0 0 0 -1 0 0 0 0 Moderate Stay days

Adverse 83 • No adverse events were noted relating to 1 RCT High 0 0 0 -1 0 0 0 0 Moderate events the study intervention *Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

2.1B2. EVIDENCE TABLES: Q2 NON-PARENTERAL AMP Q2. What are the most effective strategies for administering non-parenteral antimicrobial prophylaxis at the surgical incision to reduce the risk of SSI? eTABLE 31. Evidence Table for Q2A. How safe and effective is antimicrobial irrigation? Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Ruiz- RCT To evaluate Number of patients: Intervention group: n= SSI: (30 days) Definitions: Tovar 1, 2, 4, the effects of N= 108 52 Wound infection: Wound infection: 2012 56 5, 7, 8, peritoneal Patient Irrigation of the entire Intervention:4% (2/54) presence of a (ES) 9, 10 lavage with Characteristics: ·Age, abdominal cavity was Control:14% (7/51) purulent normal saline y: (mean±SD) performed with 500mL P=0.009 discharge from or an antibiotic Intervention: normal saline followed OR: 4.94 (1.27-19.19) the surgical solution 69.9±11.5 by a second lavage with wound and (clindamycin- Control: 68.5±10.2 a 500mL gentamicin- Intraabdominal abscess: confirmed with gentamicin) on ·Gender: female/male clindamycin solution Intervention: 0/54 microbiologic intra- Intervention: 60/40 (gentamicin 240mg – Control: 6% (3/51) culture. abdominal Control: 62/38 Clindamycin 600mg) P=0.014 Intra-abdominal abscesses ·Obesity: NR During this lavage; the OR: 2.14 (1.13-3.57) abscess: the and wound ·Comorbidities: solution was allowed to All abscesses were presence of fluid infection, and Diabetes Mellitus sit in the abdominal smaller than 4cm and collection at CT to determine Intervention: 32% cavity for 3 minutes. were managed without scan in a the Control: 29% Timing of intervention: requiring percutaneous symptomatic microbiologic Procedures: Intraoperatively drainage. patient, impact of both Sigmoidectomy, right Duration of intervention: Other infections: NR presenting with irrigations on colectomy, upper Intraoperatively Topic-specific fever, abdominal © 2017 American Medical Association. All rights reserved. 242

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score peritoneal anterior resection of Device/agent: 500mL outcomes: NR pain, prolonged contamination. rectum, Hartmann gentamicin-clindamycin Reoperations: NR postoperative procedure, Miles solution (gentamicin Length of stay: NR ileus, or septic procedure, Lower 240mg – Clindamycin Mortality: NR status. anterior resection of 600mg) Adverse events: NR Anastomotic leak: rectum, left Monitoring intervention: evidence of colectomy, total NA Antimicrobial rectal contrast colectomy, palliative Control group: n=51 Resistance: extravasation at colostomy, palliative Irrigation of the entire Post- irrigation samples CT scan. ileostomy. No abdominal cavity was were taken only in the Perioperative significant difference performed with 500mL intervention group (post care: NR between groups in normal saline followed antimicrobial irrigation). Other notes: NR surgery distribution. by aspiration of the Cultures were positive in 2 Follow-up: 30 Indications: Tumor liquid and abdominal patients (4%) Detected days post stage wall closure. microorganisms were discharge I Standard preventive Klebsiella spp and Funding Source Intervention: 26% measures: Streptococcus salivarius. Conflicts: Control: 22% Antimicrobial Prophylaxis: Both of these organisms Authors: None II ciproflaxin 400mg and were resistant to Institution: None Intervention: 50% metronidazole 1,500 gentamicin and Study: None Control: 54% mg. Single dose clindamycin. Supplies: None III preoperatively, within Intervention: 20% 30 minutes of incision Control: 24% and redosed after 4 Setting: 1 hospital hours when surgery is Location: Spain prolonged. Dates: January 2010 – Mechanical bowel prep: December 2010 none. Inclusion Criteria: Surgical Approach: open Diagnosis of Bowel clamping: colorectal performed by all neoplasms and surgeons elective colorectal Closure: abdominal wall surgery. was closed using Exclusion Criteria: continuous sutures of Preoperative absorbable diagnosis of chronic monofilament renal failure (due to polydioxanone (size no risk of nephrotoxicity 2). Skin was closed with © 2017 American Medical Association. All rights reserved. 243

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score associated with staples. intraperitoneal gentamicin absorption) or anastomotic leak in the postoperative course which would represent a bias in the diagnosis of intra-abdominal infection. Al-Shehri RCT To investigate Number of patients: Intervention group: SSI: (1 month) Definitions: 1994 57 1, 6, 7, the efficacy of N= 249 n=117 Total Wound infection: (ES) 8, the addition of Patient Wounds were irrigated Intervention: 1/117 purulent topical Characteristics: with 1g ampicillin in 100 (0.9%) discharge in the ampicillin to groups were ml sterile normal saline Control: 7/132 (5.3%) wound systemic comparable by at closure P<0.05 regardless of the antimicrobials characteristics listed Timing of intervention: Acute appendicitis: culture results or in reducing below intraoperatively Intervention: 0/88 occurrence of post ·Age, y: mean (range) Duration of intervention: Control: 6/102 (5.9%) serous appendectomy Intervention: 24 (4-66) NA P<0.05 discharge with a wound Control: 21 (5-80) Device/agent: 1 g positive growth infection rate ·Gender: male ampicillin on 100ml Other infections: NR on culture. in a properly Intervention: 77/117 sterile normal saline Perioperative controlled (65.8%) Monitoring intervention: Topic-specific care: NR randomized Control: 90/132 NA outcomes: Other notes: prospective (68.2%) Control group: n=132 Intraabdominal pelvic Follow-up: one trial ·Obesity: NR Wounds were irrigated abscesses: none in month ·Comorbidities: NR with 100 ml sterile either group Funding Source Procedures: normal saline at Postoperative ileus Conflicts: appendectomy closure. Intervention: 1/117 Authors: NR through gridiron Standard preventive (0.9%) Institution: NR incision measures: Control: 2/132 (1.5%) Study: NR Indications: Mechanical bowel prep: Fever (attributed to Supplies: NR Normal Appendix: AMP: intravenous atelectasis and treated Intervention: 26/117 metronidazole (500mg with chest physiotherapy (22.2%) for adults and and early ambulation) Control: 27/132 15mg/kg/body weight Intervention: 3/117 (20.5%) for children) and (2.6%) © 2017 American Medical Association. All rights reserved. 244

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Acute Appendix: gentamicin (75mg for Control: 2/132 (1.5%) Intervention: 88/117 adults and (75.2%) 1.5mg/kg/body weight Length of stay: Control: 102/132 for children) one hour Intervention: 77/117 (77.3%) before surgery. If (65.8%) Advanced appendicitis appendix was found to Control: 90/132 (68.2%) (histologically proven be gangrenous or gangrenous or perforated antibiotics Mortality: perforated appendix) were continued for 5 Adverse events: Intervention: 3/117 days postoperatively. Redness in wound (2.6%) Intervention: 1/117 Control: 3/132 (2.3%) (0.9%) Setting: 1 University Control: 1/132 (0.8%) Hospital Antimicrobial Location: Saudi Arabia Resistance: Dates: Almost all streptococci and Inclusion Criteria: enterococci were patients undergoing sensitive to ampicillin appendectomy besides 30% of the E. through gridiron coli isolates. (overall incision for clinically numbers not reported) suspected acute appendicitis Exclusion Criteria: Allergy to ampicillin and other systemic diseases requiring systemic antibiotic administration

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eTABLE 32. Evidence Table for Q2B. How safe and effective are antimicrobial agents applied to the surgical incision? Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Dorge RCT To investigate Number of patients: Intervention group: n= SSI: (at 30 days) Definitions: 2013 67 1 whether the N=196 97 Deep sternal wound Deep sternal (ES) topical Patient PRP and thrombin were infection: wound infection application of Characteristics: injected simultaneously Intervention: 6/97 (6.2%) requiring autologous There were no between the sternal Control: 3/99 (3.0%) revision surgery: PRP (platelet differences with edges after the sternal P=0.293 CDC definition rich plasma) respect to age, sex, wires had been placed Other infections: NR and clinical reduces the type of operation, and to the presternal Topic-specific evidence of incidence of and operative data tissue using the outcomes: NR mediastinitis deep sternal between groups. recommended dual Reoperations: all DSWI seen at revision wound Risk factors were spray applicator required reoperation. surgery. infections in distributed equally immediately prior to Length of stay: NR Perioperative patients at between groups sternal closure. Mortality: NR care: high risk ·Age, y: mean±SD Timing of intervention: Adverse events: NR Other notes: undergoing Intervention: 68 (±8.6) intraoperative Follow-up: 30 cardiac Control: 67 (±9.5) Duration of intervention: days surgery with ·Gender male intraoperative Funding Source full Intervention: 76/97 Device/agent: blood was Conflicts: sternotomy. (78.4%) drawn just prior to Authors: NR Control: 66/99 surgery and mixed with Institution: NR (66.6%) 6 and 1.2mL Study: Industry ·Obesity: BMI >30 anticoagulant calcium Supplies: NR kg/m2 citrate 5.5% Intervention: 29/97 respectively. The (29.9%) anticoagulated blood Control: 37/99 was then processed (37.4%) using a platelet ·Comorbidities separation system to Diabetes mellitus yield 12mL autologous Intervention: 43/97 PRP and 8mL thrombin. (44.3%) Monitoring intervention: Control: 32/99 NA (32.3%) Control group: n=99 Renal failure: Thrombin injected only Intervention: 0/97 during closure. Control: 3/99 (3.0%) Standard preventive Procedures: elective measures: cardiac surgery with Preop Skin prep: shower © 2017 American Medical Association. All rights reserved. 246

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score full sternotomy on morning prior to surgery cardiopulmonary Hair Removal: patients bypass and were shaved the cardioplegic cardiac morning prior to the arrest. operation. Indications: NR AMP: intravenous Setting: 1 university antibiotic prophylaxis hospital with 3 x 2g cefazolin. Location: Germany Skin prep: operative field Dates: 9 months NR was wiped with when. povidone-iodine Inclusion Criteria: at alcohol. least one risk factor Drapes: patients were for deep sternal draped in standard wound infection fashion & operative field (DSWI)including was covered in an diabetes mellitus adhesive transparent (oral anti-diabetic drape. medication or insulin dependent), chronic obstructive lung disease (inhalative steroids), renal insufficiency (chronic dialysis), obesity (BMI>30kg/m2), reduced left ventricular function (*ejection fraction <35), old age (>80 years) use of double IMA, and chronic use of systemic corticosteroids. Exclusion Criteria: emergency operation (operation within 24 hours of admission) and © 2017 American Medical Association. All rights reserved. 247

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score acute infection. Patients were excluded postoperatively if the thorax had to be left open with a secondary closure, or if they had to undergo rethoracotomy of any cause except DSWI. Almdahl RCT To explore the Number of patients: Intervention group: n= SSI: (Day 3 and 6 w Definitions: 2011 64 1, 2, 7, potential of N=139 69 postop) SSI: ASEPSIS (ES) 8, 9 Platelet-rich Patient PRP was sprayed on the Harvest Site Infection (6 Score (day 3); plasma (PRP) Characteristics: wound immediately weeks): CDC definitions spray Relevant baseline before closure. Platelet Overall: 17/139 (12%) (6w postop). treatment to variables were well pure plasma (PPP) was Intervention: 9/69 (13%) Perioperative prevent leg matched between applied after wound Control: 8/70 (11%) care: Same wound groups except the closure. P=0.80 (95%CI: -13% to between groups. infections from lesser preoperative Timing of intervention: 9%) Other notes: The open use of statins in the Intraoperatively There was no correlation confounding saphenous control group (see Duration of intervention: between early (day 3) effect of statins vein below) Intraoperatively secretion and is explained to harvesting for ·Age, y: mean±SD Device/agent: Platelet- development of wound have minor Coronary Intervention: 64.8±8.6 rich plasma spray infection (p=0.64) importance and Artery Bypass Control: 66.0±8.8 (made using autologous Positive cultures it doesn’t affect Graft (CABG) ·Gender, male: thrombin). A measure Intervention: 6 the conclusions. Intervention: 84.1% of 55cc whole blood Control: 4 They had expected Control: 84.3% was collected giving All contained S. aureus an SSI rate of ·Obesity: BMI kg/m2 about 7ccof PRP and except in one with B. 20% with goal of mean±SD about 30cc of platelet fragilis and one 15% reduction to Intervention: 27.2±3.9 pure plasma (PPP). betahemolytic 5% with PRP Control: 27.7±3.8 Monitoring intervention: Streptococcus treatment (not ·Comorbidities NR Other infections: NR achieved). Current smoker Control group: n= 70 Topic-specific Follow-up: Intervention: 21.7% Standard surgical outcomes: Wounds were Control: 14.3% technique with no Cosmetics (Self scored: 1- inspected at day Previous smoker additional wound 10) 3 (ASEPSIS © 2017 American Medical Association. All rights reserved. 248

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 31.9% spraying or Intervention: mean 8.7 Score). 6 weeks Control: 47.1% applications. (range 2-10, median 9) postoperatively, Diabetes Standard preventive Control: mean 8.6 (range the patients Intervention: 23.2% measures: 5-10, median 9) were called and Control: 18.6% Vein harvesting: P=0.34 assessment of Statin undertaken by the full Top Score (10) wound infection Intervention: 94.2% open technique. Intervention: 29 (42.0%) occurrence was Control: 78.6% Closure: harvest wound Control: 18 (25.7%) made according P=0.01 was closed with P=0.50 to a specific form Procedures: CABG- intracutaneous ASEPIS Score (Day 3) (CDC criteria). related open poliglecaprone Intervention: 13 patients Follow-up was saphenectomy according to local & total scores 33 100%. Indications: NR routine. Control: 14 patients and Funding Source Setting: I hospital Antimicrobial prophylaxis: total scores 34 Conflicts: Location: Norway 2g intravenous P=0.51 Authors: NR Dates: January – cephalothin 5 times Reoperations: NR Institution: NR October 2008 until the first Length of stay: NR Study: NR Inclusion Criteria: postoperative day. Mortality: All patients Supplies: Industry Patients undergoing survived first-time CABG Adverse events: No using treatment related cardiopulmonary adverse events were bypass and cold observed. crystalloid Note: 3 intervention and 4 cardioplegic arrest control patients who Exclusion Criteria: fulfilled SSI criteria Patients with received antimicrobial bleeding disorders treatment without prior and those on microbiological immunosuppressive specimen. medication (including cyclooxygenase (COX)-II inhibitors). Litmathe RCT To answer Number of patients: Intervention group: n= SSI: (follow up 40 days) Definitions: NR 2009 66 1, 3, 4, whether the N=44 22 No statistically significant Perioperative (ES) 5 application of Patient Autologous platelet gel differences in healing care: autologous Characteristics: (APG) was applied to between groups. Surgical platelet gel ·Age, y:mean±SD the surgical wounds. Major sternal bone and techniques: © 2017 American Medical Association. All rights reserved. 249

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (APG) will Intervention: 65.8±8.1 This included the soft tissue complication CABG was lead to a Control: 66±9.1 sternal bone, the leading to surgical performed using reduction in ·Gender: m:f presternal soft tissue, revision (with the standard sternal wound Intervention:14:8 and the vein-harvesting satisfactory results after approach of a and vessel Control: 17:5 site. secondary surgery): median harvest site ·Obesity, BMI; kg/m2, Timing of intervention: Total: 4/44 (9%) sternotomy infections and mean±SD Intraoperatively Intervention: 1/22 (4.5%) using the a reduction in Intervention: 32.4±4.3 Duration of intervention: Control: 3/22 (13.6%) extracorporeal postoperative Control:34.2±12.3 Application time circulation (ECC) blood loss in ·Comorbidities Device/agent: Autologous Major healing and warm blood high-risk Diabetes Mellitus: platelet gel (APG) complications at vein cardioplegia patients 44/44 patients prepared using a max harvest site according to undergoing IDDM: 10/22 (45.5%) in of 16ml whole blood (successfully treated Calafiore. cardiac each group collected through an with vacuum assisted Combined surgery. existing line and closure therapy) procedures were Procedures: Elective anticoagulated with Total: 4/44 (9%) carried out using Coronary artery citrate dextrose Intervention: 2/22 (9%) cold crystalloid bypass grafting solution. Per patient a Control: 2/22 (9%) cardioplegic (CABG) or combined maximum of 9-30ml of solution coronary surgery platelet-rich plasma Other infections: NR Other notes: and valve was produced. Topic-specific Wound healing replacement without Monitoring intervention: outcomes: The need of data was redo. NR transfusion was lower in presented in bar Indications: NR Control group: n= 22 the intervention group graphs. Setting: 1 hospital The sternal wound and but not statistically Follow-up: at 4, 15 Location: Germany vein harvesting site significant. and 40 days. Dates: NR received conventional Cumulative ventilation time Funding Source Inclusion Criteria: All treatment only Intervention: 11.7±8.4h Conflicts: patients at risk for Control: 14±12.2h Authors: NR the development of Standard preventive P=0.5 Institution: NR surgical wound measures: Drainage blood loss at 6, Study: NR infections who Anti-platelet drug 12h and before removal Supplies: NR required cardiac medication: (at least of chest tube was surgery including aspirin) 7 days prior to slightly higher for those with diabetes surgery. intervention group but mellitus, obesity not statistically (BMI>25kg/m2, significant active smoker, Total ~1000ml vs. 800ml; peripheral vascular P=0.14 © 2017 American Medical Association. All rights reserved. 250

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score disease and heart Reoperations: failure according to Surgical revision: NYHA III-IV. Intervention: 1/22 (4.5%) Exclusion Criteria: Control: 3/22 (13.6%) Emergency Calculated and operations, active microbiologically endocarditis, lung specific antimicrobial infections or drug therapy was pneumonia, i.v. drug applied in all 4 cases. abuse, HIV or Vacuum assisted closure thrombopenia. therapy was utilized to heal vein harvesting site was used in 2 patients in each group (9.1%) Length of stay: ICU stay slightly shorter in intervention group: 48.6±44.4 h vs. 51.3 ±53.3h; p=0.67 Mortality: NR Adverse events: One patient in each group (4.5%) underwent re- intubation due to cardiopulmonary failure. NOTE: Lowest rectal temperature showed hypothermia in both groups but they do not specify when this was recorded or if it was corrected 34.2○C±1.4 vs. 34.4○C±1.4; p=0.5

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Peerbo- RCT To investigate Number of patients: Intervention group: n=32 SSI: (follow up 3 Definitions: oms 1, 3, 4, whether the N=102 but complete The wound was dried and months) SSI: a wound score 2009 65 5, 6, 7, application of data were recorded subcutaneous tissues Superficial wound infection form was used for (ES) 8, 9 a platelet for 73 patients. were sprayed with at 2 weeks scoring wound concentrate Denominators in approximately 6mL of Intervention: 1/32 healing: where 0 = (in spray form) results vary. Platelet-Rich Plasma (2.8%) dry wound with no might improve Patient (PRP) at a distance of Control: 1/41 (2.2%) signs of infection the repair of Characteristics: 10-15 cm with the knee Both were successfully and 100=wound wounds after Baseline patient flexed at 90 degrees treated with antibiotics. leakage with signs primary characteristics were which exposes the knee of infection. Wound unilateral total similar between cavity. After closure of Total wound closure scoring was knee groups. the joint capsule, with Third day postop conducted by a arthroplasty Both groups had the platelet poor plasma Intervention: 7/32 blinded trained (TKA) with a normal wound (PPP) fraction (approx. (21.8%) orthopedics primary focus healing. Missing 10mL) and the skin was Control: 6/41 (14.6%) resident on wound data was analyzed closed with staples. 95% CI: 7% (-11% to Wound Closure: healing and a to compare per Timing of intervention: 25%) P=0.5 wound score 0: secondary protocol and ITT Intraoperatively Fourth day postop no leakage or focus on knee populations and no Duration of intervention: Intervention: 7/32 signs of infection function, use differences were Intraoperatively (21.8%) Wound leakage: of analgesics, found (duration of spray time). Control: 13/41 (31.7%) scores>0 and ·Age, y: mean(SD) Device/agent: Autologous 95% CI: -9% (-30% to WOMAC Score hemoglobin Intervention: 77 (4.4) platelet gel (APG) 10%) P=0.4 utilized to values. Control: 78 (5.1) prepared using a max Two weeks postop determine pain, ·Gender: male of 16ml whole blood Intervention: 4/36 stiffness and Intervention: 13 collected through an (11.1%) physical function (26%) existing line and anti- Control: 16/46 (34.9%) Perioperative Control: 11 (21%) coagulated with citrate 95% CI: -24% (-41% to care: ·Obesity (exclusion dextrose solution. Per 17%) P=0.02 Knee incision was criteria) patient a maximum of dressed Height, cm: mean(SD) 9-30ml of platelet-rich Other infections: NR postoperatively Intervention: 168 (9.1) plasma was produced. Topic-specific wit compression Control: 168 (8.1) outcomes: Using bandages and Weight, kg: mean(SD) Monitoring intervention: N=102, Drop in rehabilitation Intervention: 83 (16) NR hemoglobin, pain at was started on Control: 79 (12) Control group: n-41 rest, pain during the day after ·Comorbidities: NR Received no spraying with walking, use of pain surgery using (exclusion criteria) PRP or PPP medication, WOMAC crutches Procedures: Primary Standard preventive score, and Range of according to the © 2017 American Medical Association. All rights reserved. 252

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score unilateral total knee measures: motion were not Joint Care arthroplasty. (TKA) Surgical procedure: all statistically significantly Program Indications: procedures took place different between (created by the Osteoarthritis of the in a training hospital control and intervention. medical knee. using the same surgical Reoperations: NR instrumentation Setting: 1 training procedure performed by Length of stay: NR company who hospital an orthopedic Mortality: NR sponsored this Location: The consultant or a Adverse events: NR study). Netherlands supervised senior Other notes: Due Dates: June 2005 – orthopedic resident. to a partial March 2007 Surgical Approach: The reorganization of Inclusion Criteria: No medial parapatellar the ward, no or age limit for inclusion approach was used, partial but the criteria for averting the patella measurements participation laterally. were recorded included pain and Tourniquet: was used and for a number of radiographic knee after implantation, the the study osteoarthritis. tourniquet was deflated patients. Missing Exclusion Criteria: and primary hemostasis data were Platelet count was achieved. attributed to the ≤150x109/L, Prosthesis: A cemented “last known hemoglobin level posterior cruciate result carried ≤6.5mmol/L, retaining prosthesis forward” BMI>33kg/m2, and was used in all cases. principle. This systemic disorders Irrigation: before closure of resulted in a loss such as diabetes, the wound layers, the of power for the rheumatoid arthritis, soft tissues and knee study. and hepatitis. joint were rinsed with Follow-up: Wound saline solution to and function remove all debris scores were Drains: Deep or measured at subcutaneous drains days 3-5, and at were not used. regular control Analgesic: paracetamol every 2 weeks. (3g daily) and Functional diclofenac (50mg 3 scores were also times daily) with measured at 6 pantaprazol (40mg and 12 weeks daily) for protection postoperatively. © 2017 American Medical Association. All rights reserved. 253

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score against ulcers. Funding Source Anticoagulant: Conflicts: subcutaneous injection Authors: NR of 0.3mL low-molecular- Institution: NR weight-heparin daily Study: Industry before the operation Supplies: NR and continued until a sufficient effect of oral anticoagulants (acenocoumarol) was achieved. Non-standard preventive measures: Anticoagulant: oral anticoagulants were used up to 12 weeks postoperatively. Neri RCT To evaluate Number of patients: Intervention group: n=24 All data presented in bar Definitions: NR 2008 62 1, 7, 8, the use of N=48 12 hr. Preop: graph rather than Parameters (ES) 9 topical Patient • Disinfection of the numerical form. evaluated: prophylactic Characteristics: umbilical and SSI: (follow up 60 days) • Umbilical region antimicrobial ·Age, y: mean (range): periumbilical skin with Topical administration of pain (pain scale 0- (i.e., rifamycin) 38 (21-64) iodopovidone rifamycin reduced the 5) for prevention ·Gender m:f: 418:30 • Application of a sterile incidence of omphalitis • Analgesic drug of post- video ·Obesity: NR medication with 3ml of (statistically significant) administration for laparoscopic ·Comorbidities: NR rifamycin (250mg) on the Mean values of local signs localized umbilical cholecystecto Procedures: Video- umbilicus of inflammation was region pain my (VLC) at laparoscopic Intraop: statistically significantly • Signs of the umbilical cholecystectomy • Suture of the umbilical higher in the control inflammation port-site. (VLC) access: muscular fascia versus the intervention (rubor, calor, Indications: and of the skin wound group (P<0.001) tumor) of the uncomplicated with polyglycolic sutures Occurrence of umbilical umbilical wound cholelithiasis • Disinfection of the wound leakage was (on a scale of 1-5) Setting: 1 university umbilical wound and peri- statistically significantly including wound hospital. umbilical skin with lower at 12, 24, 36, and warmness, Location: USA iodopovidone first then 48, and day 3, 4, 5, 6 hyperemia, Dates: September with 0.9% saline solution. and 7 in the intervention umbilical wound 2006 – April 2007 • Application of a sterile versus control group swelling and Inclusion Criteria: medication with 3mL of (p<0.005) redness © 2017 American Medical Association. All rights reserved. 254

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Patients with rifamycin (250mg) on the Dehiscence of umbilical • Purulent leakage uncomplicated umbilical wound. wound sutures occurred through the cholelithiasis Postoperative. in fewer patients in the umbilical wound. undergoing • At 12, 24, 36, 48 & 72 h intervention versus • Dehiscence of the uncomplicated post-VLC, rifamycin was control groups at 12, umbilical skin video-laparoscopic applied in a sterile fashion 24, 36, and 48, and day sutures. cholecystectomy to the umbilical wound of 3, 4, 5, 6 and 7 • Incisional hernia (VLC) all the patients. (p<0.001) in umbilical region Exclusion Criteria: at postoperative Acute cholecystitis Timing of intervention: Other infections: NR day #60 with localized Pre, intra and Topic-specific peritonitis; umbilical postoperative outcomes: Perioperative hernia; Duration of intervention: Pain- postoperative care: NR immunodepressed from 12hours prior to observation of pain Other notes: none patients; VLC to 72 hours localized in umbilical Follow-up: Clinical uncompensated postoperatively. region in patients in data were diabetes; perforation Device/agent: Topical both groups statistically registered at 12, of the gallbladder in rifamycin less in intervention 24, 36 and 48h the peritoneal cavity Monitoring intervention: group (P<0.001) after VLC and during VLC; and NR on the 3rd, 4th, perforation of the Control group: n=24 Number of patients 6th, and 7th post- gallbladder during 12 hr. Preop: requiring additional VLC day. For removal through the • Disinfection of the analgesics (yes/no) patients umbilicus with bile umbilical and presented in bar graph dismissed before leakage. periumbilical skin with form but shows fewer 3rd postoperative iodopovidone patients in intervention day, there was Intraop: than control requiring an ambulatory • Suture of the umbilical additional analgesics at outpatient access: muscular fascia hour 12, 24, 36, and 48, control on the and of the skin wound and day 3, 4, 5,and 6 60th day post- with polyglycolic sutures P<0.005 VLC, the • Disinfection of the Reoperations: NR possible umbilical wound and peri- Length of stay: Mean presence of umbilical skin with (range) incisional hernia iodopovidone first then Intervention: 3 (1-8) days in the umbilical with 0.9% saline solution. Control: 4 (3-8) days. region was Mortality: NR registered. Standard preventive Adverse events: Funding Source measures: Conflicts: © 2017 American Medical Association. All rights reserved. 255

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Laparoscopic technique: Authors: NR Hasson open technique Institution: NR AMP: IV administration of Study: NR 2g ceftriaxone, followed Supplies: NR by a second intraoperative dose and a final dose after 24 hours.

Kamath RCT To study the Number of patients: Intervention group: n= SSI: (follow up 30 days) Definitions: 2005 61 1, 4, 6, role of the N=92 47 Superficial Infection: Surgical site (ES) 7, 8, 9 topical Patient Topical chloramphenicol Intervention: 4/47 (8.5%) surveillance was antimicrobial Characteristics: ointment was applied to Control: 8/45 (17.8%) based on the chloramphenic ·Age, y: mean 78.6 (44- the surgical site at the Positive wound swabs in 5 guidelines ol in reducing 101) end of procedure and of 8 in control group: 1 issued by the the incidence ·Gender: m:f = 28:72 3rd day postoperatively Pseudomonas, 2 Scottish Centre of superficial ·Obesity NR and wound dressed MRSA, and 2 MSSA. for Infection and surgical site ·Comorbidities: with low adherence None in the intervention Environmental infection Rheumatoid arthritis:4 dressing (rayon group had positive Health (SCIEH) following Diabetes: 9 absorbent pad with wound swabs. Superficial SSI surgery for hip Cardiac, respiratory, adhesive border) 1. infection occurs fractures. renal or other Timing of intervention: Univariate estimated w/in 30 days systemic pathology: Intra and relative risk (95% CI) of after operation 91 postoperatively infection 2. and involves only Smoking history Duration of intervention: Smoking (no infected (%)) skin and (current or past): intra and Current: 8/31 (25.8%) subcutaneous 100% postoperatively Former/never: 4/61 tissue of incision Preop hospitalization: Device/agent: (6.6%) 3. Patient has at average 1.7 days (1- Chloramphenicol RR: 4.957 (1.359-18.084) least one of the 8) Monitoring intervention: Gender (no infected (%)) following Procedures: NR Male: 5/25 (20%) ·purulent discharge Hemiarthroplasty Control group: n=45 Female: 7/67 (10.4%) form the (uncemented No antimicrobial ointment RR: 2.143 (0.611-7.512) superficial prosthesis) 54/92 administered. Wound Age (no infected (%)) incision (58.7%) dressed with low >71 years: 10/70 ·organisms isolated Internal fixation of the adherence dressing (14.3%) form an fracture with (rayon absorbent pad >70 years: 2/22 (9.1%) aseptically dynamic hip screw: with adhesive border) RR: 1.667(0.335-8.259) obtained culture © 2017 American Medical Association. All rights reserved. 256

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score 46/92 (23.9%) Standard preventive Treatment (no infected of fluid or tissue Indications: fracture of measures: (%)) form the the neck of femur AMP: intravenous Intervention: 4/47 (8.5%) superficial Intracapsular fracture: cefuroxime Control: 8/45 (17.8%) incision 54/92 (58.7%) Anticoagulant: RR: 0.430 (0.120-1.544) ·at least one of the Extra capsular fracture: postoperative following signs 46/92 (23.9%) subcutaneous injection Multivariate estimated or symptoms of Setting: 1 hospital of enoxaparin for DVT relative risk (95% CI) of infection: pain or Location: Scotland prophylaxis infection tenderness, Dates: April 2002 – Non-standard preventive Current Smoker: localized March 2003 measures: ARR: 7.29 (1.62-32.67); swelling, Inclusion Criteria: Closure: P=0.009 redness or heat Patients who could Clips: 97/100 (97%) Male Gender and superficial give informed (removed 12 days ARR: 0.92 (0.19-4.31); incision, is consent and who postop) P=0.912 deliberately were admitted with Subcuticular stitches: Age<70 years opened by fracture neck of 2/100 (2%) ARR: 0.30 (0.05-1.96) surgeon unless femur. Interrupted nylon: 1/100 P=0.209 incision is Exclusion Criteria: (1%) IC Fracture: culture negative. Pathological Grade of surgeon: ARR: 0. 52 (0.06-1.13); ·Diagnosis of SSI fractures and Middle grades: 82/100 P=0.072 by physician. undisplaced (82%) Treatment: Intervention: The following are intracapsular neck of Senior house officers ARR: 0.36 (0.08-1.56); NOT SSI femur fractures under senior P=0.172 1. Stitch abscess needing internal supervision: 10/100 (minimal fixation. (10%) Other infections: inflammation and Consultant: 8/100 (8%) Chest infections: 7/92 discharge (7.6%) confined to the 1/7: intervention and points of suture also had wound penetration) infection 2. Infected burn 1/7: control and also wound had wound infection 3. incisional SSI UTI: 5/92 (5.4%) that extends into 1/5: control and also had the fascial and wound infection muscle layers Topic-specific (Deep incisional outcomes: SSI) 9 patients in the study had Perioperative © 2017 American Medical Association. All rights reserved. 257

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score no associated illness care: and none of these had Mobilization: wound infections. according to Reoperations: NR standard Length of stay: average protocol. inpatient stay: 18.5 (10- Other notes: None 90) days either in an Follow-up: The orthopedic ward or wound was rehabilitation ward checked on the following which patients 3rd, 6th, 12th and were either sent back to 30th day postop their own home or care Funding Source home as appropriate. Conflicts: Mortality: 7 patients died Authors: NR because of unrelated Institution: NR causes during follow Study: NR up. Supplies: NR 1/7 hemiarthroplasty had malignancy confirmed on histology & excluded. Adverse events: 1 Intervention and 2 control patients’ wounds continued to discharge through sinuses for up to 3 months but all eventually settled down with oral antimicrobials and dressings. Seco RCT To compare Number of patients: Intervention group: SSI: (4-6 weeks by mail) Definitions: 1990 59 1, 2, 5, the results of N= 246 n=126 Total: Wound infection: (ES) 6, 7, 8, systematic Patient Patients were treated with Intervention: 5/126 (4%) patients in whom 9 clindamycin , Characteristics: the 1g Ampicillin in 20ml Control: 15/120 (13%) pus appeared or with our median age and sex Saline as topical P<0.02 if there was without topical ratio were similar solution. Gauze was (only one infection serious ampicillin to between groups impregnated with occurred post- discharge and a determine if ·Age y: median (range) ampicillin solution. The discharge) positive culture © 2017 American Medical Association. All rights reserved. 258

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score the Intervention: 29 (12- subcutaneous tissues Simple: Perioperative combination of 93) were cleaned with this Intervention: 0/68 care: the antibiotics Control: 29 (12-79) gauze and the Control: 1/68 (1%) Approach: 96% is more ·Gender: male remaining solution was P=NS through a grid- effective than Intervention: 83/126 allowed to rest in the Advanced: iron incision the (66%) wound. Intervention: 5/58 (9%) Other notes: clindamycin Control: 82/120 (68%) Timing of intervention: Control: 14/52 (27%) Follow-up: 7-10 alone is ·Obesity: NR intraoperatively P<0.02 days postop in sufficient ·Comorbidities: NR Duration of intervention: Appendicitis with person. 4-6 NA Peritonitis with or weeks via mail. Procedures: Device/agent: 1g abscess (only Funding Source emergency ampicillin in 20mL percentages given. Conflicts: appendectomy for saline Numerator and Authors: NR acute appendicitis Monitoring intervention: denominator not Institution: NR Indications: acute NA reported) Study: NR appendicitis: Control group: n=120 Intervention: 13% Supplies: NR Simple: Patients did not receive Control: 35% Intervention: 68/126 topical ampicillin Other infections: NR (54%) Standard preventive Topic-specific Control: 68/120 (57%) measures: outcomes: Gangrenous: AMP: 600mg clindamycin Intervention: 83/126 Intervention: 32/126 intramuscularly. (66%) (25%) Skin prep: with povidone- Control: 82/120 (68%) Control: 29/120 (24%) iodine. Reoperations: Perforated: Retroperitoneal abscess Intervention: 26/126 as cause (E. coli was (21%) isolated) Control: 23/120 (19%) Intervention: 0/126 Control: 1/120 (1%) Setting: 1 Tertiary Length of stay: Median hospital (range), days Location: Spain Intervention: 7 (3-18) Dates: 1 year, when Control: 7 (3-40) NR. Mortality: NR Inclusion Criteria: Adverse events: Patients undergoing Fever emergency Intervention: 3/126 (1%) appendectomies for Control: 1/120 (1%) acute appendicitis. Wound hematoma © 2017 American Medical Association. All rights reserved. 259

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Exclusion Criteria: Intervention: 1/126 (1%) Patients <12 years Control: 1/120 (1%) old, those who Postoperative ileus underwent elective Intervention: 0/126 surgeries, and those Control: 2/120 (1%) who had previously Pulmonary embolism: been treated with Intervention: 0/126 antibiotics Control: 1/120 (1%) Acute respiratory insufficient Intervention: 1/126 (1%) Control: 0/120 Unspecific diarrhea Intervention: 1/126 (1%) Control: 0/120 Raahave RCT To conduct a Number of patients: Intervention group: n= SSI: (follow up NR) Definitions: 1989 60 1, 5, 7, randomized N= 170 81 Intervention: 5/81 (6.2%) Wound infection: a (ES) 8 controlled trial Patient Patients had 2g ampicillin Control: 6/89 (6.7%) collection of pus, to investigate Characteristics: powder applied in the P>0.05 draining either the effect of ·Age, y: median (range) wound subfacially and Other infections: NR spontaneously ampicillin Intervention: 72 (32- subcutaneously during or at the site of applied locally 90) closure. Topic-specific incision. in combination Control: 69 (28-90) Timing of intervention: outcomes: Wound rupture – with a 12 hour ·Gender: male intraoperatively Wound dehiscence: recorded parenteral Intervention: 39/81 Duration of intervention: Intervention: 2/81 (2.5%) separately antibiotic (48.1%) NA Control: 1/89 (1.1%) Evidence of regimen with Control: 46/89 Device/agent: Monitoring P>0.05 anastomotic cefotaxime. (51.7%) intervention: NA Intra-abdominal abscess leakage: air or ·Obesity: NR Control group: n= 89 Intervention: 3/81 (3.7%) feces or both ·Comorbidities: NR Not described Control: 2/89 (2.2%) delivered by the Standard preventive P>0.05 drains. Procedures: Elective measures: Patients with anastomoses Perioperative colorectal surgeries: Mechanical bowel prep: Intervention: 66 care: NR Right transverse three day liquid diet Control: 71 Other notes: None colonic resection: plus 250ml of a Anastomotic leakage Follow-up: NR Intervention: 22/81 complete nutrient Intervention: 3/66 (4.5%) Funding Source (27.8%) powder in 500ml of Control: 6/71 (8.5%) Conflicts: Control: 22/89 water twice per day; P>0.05 Authors: NR (24.7%) 30ml of 50% Reoperations: NR Institution: NR © 2017 American Medical Association. All rights reserved. 260

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Left colonic & sigmoid magnesium sulfate Length of stay: NR Study: NR resection: twice/ day Mortality: NR Supplies: NR Intervention: 21/81 Anastomoses: done in two Adverse events: Patients (25.9%) layers through and showed no allergic Control: 23/89 through polyglycolic reactions to or other (25.8%) acid and seroserous side effects from the Low anterior resection: silk sutures. antibiotics used. Intervention: 20/81 Low anterior resections: (24.7%) stapling instrument was Control: 21/89 often used instead of (23.6%) sutures and an Abdominoperineal extraperitoneal drain excision: was inserted. Intervention: 6/81 Closure: all abdominal (7.4%) wounds were closed Control: 12/89 with PGA sutures in the (13.5%) peritoneum, fascia and Laparotomy with subcutis; nylon sutures colostomy: were used in the skin Intervention: 4/81 AMP: 2g cefotaxime (4.9%) intravenously at Control: 5/89 (5.6%) induction of anesthesia. Other: Dose was repeated at Intervention: 4/81 6h and 12h postop. (4.9%) Control: 2/89 (2.2%) Indications: Adenocarcinoma: Intervention: 70/81 (86.4%) Control: 72/89 (80.9%) Benign neoplasms: Intervention: 4/81 (4.9%) Control: 2/89 (2.2%) Diverticulitis: Intervention: 4/81 (4.9%) © 2017 American Medical Association. All rights reserved. 261

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Control: 8/89 (9.0%) Other: Intervention: 3/81 (3.7%) Control: 7/89 (7.9%) Setting: 1 University Hospital Location: Denmark Dates: NR Inclusion Criteria: Consecutive patients scheduled for elective colorectal surgery. Exclusion Criteria: Patients who were allergic to the antibiotics used patients under antibiotic treatment during the last three preoperative days, patients who did not adhere to the planned antibiotic regimen and patients whose colon was not opened. Vander RCT To test the Number of patients: Intervention group: n= SSI: (at 1 month) Definitions: Salm 1 hypothesis N=417 223 Sternal/ mediastinal SSI not defined: 1989 63 that topical Patient Hemostatic paste mixed infection Sternal & (ES) vancomycin Characteristics: with 250g powdered Intervention: 1/223 mediastinal (to which S. Characteristics of vancomycin was (0.45%) necessitated a non-aureus is patients were applied to sternum: At Control: 7/193 (3.6%) major almost always indistinguishable end of operation before P=0.02 reoperation and sensitive) between groups sternum closure, a both were applied to the except for repeat hemostatic paste Other infections: NR counted as cut sternal operations containing 1gm Topic-specific sternal edges will ·Age, y: mean powdered absorbable outcomes: NR infections. © 2017 American Medical Association. All rights reserved. 262

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score reduce the Intervention: 62.5 gelatin, and topical Superficial incidence of Control: 62.0 thrombin was applied to S. aureus infections infections were these ·Gender, male the cut edges of the Intervention: 1/223 counted as “no infections. Intervention: 154/223 sternum. (0.4%) sternal (69%) Timing of intervention: Control: 2/193 (1.0%) infections” Control: 129/193 intraoperative Perioperative (67%) Duration of intervention: S. non-aureus infections care: NR ·Obesity: NR intraoperative Intervention: 0/223 Other notes: NR ·Comorbidities Device/agent: hemostatic Control: 5/193 (2.6%) Follow-up: 1 Diabetes mellitus paste containing month Intervention: 47/223 vancomycin powder Reoperations: Funding Source (21%) Monitoring intervention: Length of stay: NR Conflicts: Control: 37/193 (19%) NA Mortality: Authors: NR Repeat operations Control group: n=193 Intervention: 15/223 Institution: NR Intervention: 29/223 Hemostatic paste alone (6.7%) Study: NR (13%) was applied to sternum: Control: 9/193 (4.6%) Supplies: NR Control: 11/193 At end of operation P=NS (5.7%) before sternum closure, P=0.008 a hemostatic paste Adverse events: Procedures: heart containing 1gm No complication resulted operations powdered absorbable from the topical performed via gelatin, and topical vancomycin median sternotomy. thrombin was applied to Indications: NR the cut edges of the Setting: 1 university sternum. medical center Standard preventive Location: USA measures: Dates: May 1986 – July Hair removal: with an 1986 electric razor the day Inclusion Criteria: all before the operation for patients of 3 scheduled operations surgeons who had AMP: cefazolin or heart operations vancomycin in case of performed via a penicillin allergy. median sternotomy Preoperatively and for during the study 36h postop. dates (including emergency operations) © 2017 American Medical Association. All rights reserved. 263

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Exclusion Criteria: NR

Juul RCT To evaluate Number of patients: Intervention group: SSI: (days) Definitions: 1985 58 1, 2, 3, the role of N= 203 n=105 Deep wound infection Deep Wound (ES) 4, 5, 7, topical Patient Received subcutaneous Intervention: 5/105 infection: 8 ampicillin Characteristics: the and subfascial (4.8%) accumulation of when systemic two groups were application of 1g of Control: 5/98 (5.1%) pus requiring perioperative considered similar ampicillin in 10ml of P=NS surgical antibiotic according to gender saline in each of the Other infections: NR drainage. prophylaxis age, efficiency of surgical wounds. Topic-specific Wound dehiscence: with ampicillin preoperative bowel Timing of intervention: outcomes: included and prep, and type of intraoperatively Dehiscence subcutaneous metronidazole surgery. Duration of intervention: Intervention: 7/105 as well as fascial is used. ·Age, y: mean (range) NA (6.7%) breakdown but Intervention: 69 (21- Device/agent: 1g Control: 4/98 (4.1%) not pus 96) ampicillin in 10ml saline P=NS accumulation. Control: 69 (26-91) Monitoring intervention: Hernia Perioperative ·Gender: male NA Intervention: 10/105 care: Intervention: 56/105 Control group: n=98 (10.8%) Other notes: (53.3%) Received no further Control: 3/98 (3.3%) Follow-up: Control: 61/98 (62.2%) prophylactic antibiotic P=NS observed daily ·Obesity: NR treatment. Unclear if until the ·Comorbidities: NR wounds were irrigated Reoperations: cutaneous Procedures: with saline. - 7 patients with sutures were Abdominoperineal Standard preventive dehiscence were re- removed. resection measures: operated upon because Funding Source Intervention: 11/105 Mechanical bowel prep: of rupture of the fascia. Conflicts: (10.5%) Either conventional or Not reported which Authors: NR Control: 12/98 (12.3%) whole-gut irrigation group. Institution: NR Low anterior resection Blind evaluation of - 6 patients had temporary Study: NR Intervention: 21/105 bowel prep efficiency transverse colostomies Supplies: NR © 2017 American Medical Association. All rights reserved. 264

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (20%) was conducted during because of anastomotic Control: 19/98 (19.4%) surgery breakdown after low Colonic resection AMP: all received anterior resection. Not Intervention: 44/105 ampicillin 1g 3x/day and reported which group. (41.9%) metronidazole 0.5g Length of stay: Control: 47/98 (48.0%) 3x/day intravenously Mortality: Colostomy n1 from induction of 2 patients died from Intervention: 15/105 anesthesia to 3 days cardiopulmonary (14.3%) postoperatively. complications in the first Control: 7/98 (7.1%) Closure: abdominal and postoperative week. Closure of colostomy perineal wounds were Not reported which n1 closed primarily with group. Intervention: 11/105 absorbable sutures in Adverse events: (10.5%) peritoneum and fascia, No hypersensitivity Control: 7/98 (7.1%) Drains: retroperitoneal reactions or other side Other drainage was used after effects were Intervention: 3/105 low anterior resection encountered from (2.9%) and abdominoperineal treatment with Control: 6/98 (6.1%) excision of the rectum. antibiotics. Indications: Colorectal cancer Intervention: 80/105 (76.2%) Control: 89/98 (90.8%) Diverticulitis Intervention: 11/105 (10.5%) Control: 8/98 (8.2%) Inflammatory bowel disease Intervention: 7/105 (6.7%) Control: 2/98 (2.0%) Other Intervention: 7/105 (6.7%) Control: 3/98 (3.1%) **NOTE – other includes previously © 2017 American Medical Association. All rights reserved. 265

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score known infections including one case of Fournier’s gangrene which resulted in a deep wound infection. Setting: 1 University Hospital Location: Denmark Dates: April 1982 – September 1983 Inclusion Criteria: Patients undergoing elective colonic and rectal surgery. Exclusion Criteria: Patients receiving antibiotics in the preoperative period or those with a history of hypersensitivity to ampicillin or metronidazole

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eTABLE 33. Evidence Table for Q2C. How safe and effective are antimicrobial-coated sutures; when and how should they be used? Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Diener RCT To yield Number of patients: Intervention group: SSI: Definitions: 2014 77,82 1, 2, 4, reliable data N=1185 n=587 Composite SSI within 30 Superficial & deep (ES) 5, 6, 7, for the Patient Closure of the abdominal days SSI: CDC: 8, 9 effectiveness Characteristics: the fascia after midline Intervention: 87/587 Superficial SSI: of triclosan study was balanced laparotomy with (14.8%) within 30 days coated in terms of patient triclosan-coated Control: 96/598 (16.1%) postop and polydioxanone and operation polydioxanone sutures. OR: 0.91 (0.66-1.25) involved only sutures for characteristics Timing of intervention: P=0.64 skin or abdominal ·Age, y: mean (SD) intraoperative Multiple imputations of the subcutaneous fascia closure Intervention: 64.7 Duration of intervention: missing data yielded in tissue around in the (11.8) closure until absorption a similar result (p=0.62) the incision plus prevention of Control: 65.0 (12.1) Device/agent: triclosan- Superficial at least one of surgical site ·Gender: female, coated or uncoated Intervention: 53/587 the following: infections, Intervention: 226/587 polydioxanone sutures. (9.2%) purulent compared with (38.5%) Monitoring intervention: Control: 56/598 (9.4%) drainage from non-coated Control: 230/598 assessed in person and Deep the incision site; polydioxanone (38.5%) validated via Intervention: 22/587 organisms sutures. The ·Obesity, BMI (mg/kg2): assessment of (3.7%) isolated by null mean (SD) photographs of Control: 25/598 (4.2%) culture from the hypothesis to Intervention: 26.1 (4.3) abdominal wound by an Missing incision; pain or be tested Control: 26.1 (4.6) independent primary Intervention: 12/587 tenderness, states that the ·Comorbidities: outcome validation (2.0%) localized rate of Diabetes mellitus: committee consisting of Control: 15/598 (2.5%) swelling, superficial and Intervention: 81/587 3 board-certified redness, or heat deep (13.8%) surgeons who reviewed SSI By Surgery and the incision incisional Control: 96/598 all photographs blinded Colorectal: N=690 is opened surgical site (16.1%) to group. Intervention: 62/344 deliberately by a infections COPD Control group: n=598 (18.0%) surgeon unless within 30 days Intervention: 38/587 Closure of the abdominal Control: 60/346 (17.3%) the culture is after midline (6.5%) fascia after midline P=0.81 negative; or incision is Control: 51/598 (8.5%) laparotomy with Hepatiopancreato-biliary: diagnosis of equal in both Malignant disease uncoated N=74 superficial treatment Intervention: 407/587 polydioxanone sutures. Intervention: 4/34 surgical site groups. (69.3%) (11.8%) infection by a Control: 442/598 Standard preventive Control: 3/40 (7.5%) surgeon or (73.9%) measures: P=0.53 attending Anemia Closure: achieved by Upper-gastrointestinal physician. © 2017 American Medical Association. All rights reserved. 267

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 167/587 continuous mass tract: N=140 Deep SSI: occurred (28.4%) closure with use of two Intervention: 5/67 (7.5%) within 30 days Control: 166/598 loops – one from the Control: 15/73 (20.5%) postop, were (27.8%) cranial and the caudal P=0.03 related to the Chronic Renal end of the incision in a procedure, and insufficiency continuous suture involved deep Intervention: 23/587 technique Factors associated with soft tissues, (3.9%) Skin closure – staples. SSI within 30 days OR such as the Control: 20/598 (3.3%) Drains – no drains (95%CI); p fascia, and allowed. BMI: 1.09 (1.05-1.14); muscles, plus at Surgeon Experience: Antibiotic prophylaxis – P<0.0001 least one of the No certificate patients had to receive following: Intervention: 58/587 antibiotic prophylaxis Chronic renal insufficiency: purulent (9.9%) before the incision. 2.96 (13.6-6.46); p=0.0064 drainage form Control: 75/598 the incision but (12.5%) Anemia: 1.73 (1.16-2.59); not from the p=0.0071 organ or space Wound Status of the surgical Clean No Antibiotic prophylaxis site; dehiscence Intervention: 144/587 5.19 (1.56-17.1); 0.0074 of a deep (24.5%) incision or a Control: 138/598 Malignant disease: deep incision is (23.1%) 0.060 (0.38-0.93); 0.0236 opened by a Clean-contaminated surgeon Intervention: 430/587 Combination of target because of pain, (73.3%) organ (vs. other) – fever or Control: 450/598 colon, rectum, liver, tenderness; (75.3%) pancreas, & stomach. abscess or other Contaminated 6.37 (2.71-14.98), 0.0193 evidence of Intervention: 11/587 infection at the (1.9%) Surgeon’s expertise incision site or Control: 9/598 (1.5%) 1.73 (1.02-2.93); p=0.0405 diagnosis of Dirty deep surgical Intervention: 2/587 Other infections: NR site infection by (0.3%) Topic-specific a surgeon or Control: 1/598 (0.2%) outcomes: attending Wound dehiscence physician. Duration of surgery, Intervention: 66 (13.4%) min (SD) Control: 81 (16.3%) Perioperative © 2017 American Medical Association. All rights reserved. 268

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 179.3 OR: 0.80 (0.56-1.14) care: NR (87.1) P=0.21 Other notes: Control: 185 (90.9) Missing Wounds were Intervention: 96 (13.4%) inspected at Blood loss ml, Control: 81 (16.3%) postop days 10 mean(SD) & 30 Intervention: 478.9 Burst abdomen Follow-up: (639.6) Intervention: 9/587 30 days postop Control: 503.0 (666.7) (1.9%) Funding Source Control: 22/598 (4.5%) Conflicts: Antibiotic Prophylaxis OR: 0.40 (0.18-0.88) Authors: NR Intervention: 578/587 P=0.0194 Institution: NR (98.5%) Missing Study: Industry Control: 586/598 Intervention: 104/587 Supplies: NR (98.0%) (17.6%) Antibiotic Therapy Control: 109/598 Intervention: 126/587 (18.2%) (21.5%) Control: 112/598 Reoperations: NR (18.7%) Length of stay: Postop hospital stay, days, Procedures: mean (SD) Abdominal midline Intervention: 13.0 (7.4) laparotomy. Control: 12.5 (6.3) Resection & MD: 0.47 (-0.32-1.25) anastomosis P=0.99 Intervention: 422/587 (71.9%) ICU Stay, days, mean Control: 442/598 (SD) (73.9%) Intervention: 2.3 (3.8) Resection & resection + Control: 2.3 (3.6) exploration MD: 0.01 (-0.41 – 0.43) Intervention: 72/587 P=0.54 (12.3%) Control: 63/598 Mortality: (10.5%) Intervention: 9/587 Exploration (1.5%) Intervention: 12/587 Control: 20/598 (3.3%) (2.0%) OR: 0.46 (0.21-1.01) © 2017 American Medical Association. All rights reserved. 269

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Control: 14/598 (2.3%) P=0.48 Resection or All deaths classified as anastomosis & other unrelated to Intervention: 5/587 intervention and most (0.9%) were due to septic Control: 3/598 (0.5%) shock, multiple organ Resection & other failure or cardiac and Intervention: 0/587 pulmonary Control: 3/598 (0.5%) decompensation. Exploration & other Adverse events: Intervention: 2/587 Wound dehiscence (0.3%) Intervention: 66/587 Control: 2/598 (0.3%) (13.4%) Resection & resection Control: 81/598 (16.3%) or anastomosis OR: 0.80 (0.56-1.14) Intervention: 0/587 P=0.21 Control: 1/598 (0.2%) Missing Intervention: 96/587 Indications: (13.4%) Target Organ for Control: 81/598 (16.3%) surgery Colon Burst abdomen Intervention: 189/587 Intervention: 9/587 (32.2%) (1.9%) Control: 214/598 Control: 22/598 (4.5%) (35.8%) OR: 0.40 (0.18-0.88) Rectum P=0.0194 Intervention: 145/587 Missing (24.7%) Intervention: 104/587 Control: 117/598 (17.6%) (19.6%) Control: 109/598 Stomach (18.2%) Intervention: 67/587 Serious Adverse Events (11.4%) Unrelated to intervention: Control: 73/598 130/146 (86.1%) vs. (12.2%) 137/138 (87.3%) Pancreas Possibly related to Intervention: 32/587 intervention: (5.5%) 21/146 (13/9%) vs. 17/138 © 2017 American Medical Association. All rights reserved. 270

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Control: 37/598 (6.2%) (87.3%) Liver Probably related to Intervention: 2/587 intervention: (0.3%) 0/146 vs. 2/138 (1.3%) Control: 3/598 (0.5%) Not Assessable: Combination of the 0/146 vs. 1/138 (0.6%) above Missing: 0/146 vs. 1/138 Intervention: 33/587 (0.6%) (5.6%) Surgical site infection: 7 Control: 37/598 (6.2%) (4·6%) vs. 10 (6·3%) Other Burst abdomen 8 (5·3%) Intervention: 119/587 vs. 10 (6·3%) (20.3%) Anastomotic insufficiency: Control: 117/598 39 (25·8%) vs. 34 (19.6%) (21·5%) Intra-abdominal fluid Setting: Multi-center collection or abscess: (24 secondary and 14 (9·3%) vs. 7 (4·4%) tertiary care centers) Bleeding: 12 (7·9%) vs. 14 Location: Germany (8·9%) Dates: April 7, 2010 (as Cardiovascular: 9 (6·0%) single center trial) vs. 14 (8·9%) and Jan 24, 2011 as Pulmonary: 15 (9·9%) vs. multicenter trial. 13 (8·2%) Both ended October Renal 7 (4·6%) vs. 8 19, 2012 (5·1%) Inclusion Criteria: Other gastrointestinal Adults (≥18 years) problems: 21 (13·9%) who underwent vs. 24 (15·2%) midline abdominal Other: 15 (9·9%) vs. 21 laparotomy for any (13·3%) reason. Not assessable: 4 (2·6%) Exclusion Criteria: vs. 3 (1·9%) Impaired mental state or language problems or if they were participating in another intervention trial that interfered © 2017 American Medical Association. All rights reserved. 271

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score with the intervention or outcome of this trial.

Thimour- RCT To test the Number of patients: Intervention group: n= SSI: Definitions: Bergstr- 1, 2, 3, hypothesis N=374 184 CDC Criteria SSI: CDC – om 4, 5, 6, that wound Patient Wound closed Intervention: 23/184 Superficial SSI 2013 73 7, 8 closure with Characteristics: subcutaneously with (12.5%) must have at (ES) sutures coated baseline patient triclosan coated Control: 38/190 (20.0%) least one of the with triclosan characteristics not monofilament P=0.0516 (by Fisher’s following would reduce significantly different polyglactin suture and exact test) features: (i) SSI after open between groups intracutaneously with a P=0.497 (by χ2 test) purulent vein ·Age, y: mean ±SD 4.0 triclosan coated RR: 0.63 (0.39-1.00) drainage; (ii) harvesting. Intervention: 67.6±8.3 monofilament Culture Proven positive culture, Control: 66.9±8.1 polyglecaprone suture. Intervention: 14/184 (iii) pain, P=0.45 Timing of intervention: (7.6%) tenderness, ·Gender: Female intraoperative Control: 23/190 (12.1%) swelling, Intervention: 39/184 Duration of intervention: P=0.15 redness and (21.1%) closure until absorption Antibiotic Treated deliberately Control: 31/190 Device/agent: triclosan Intervention: 20/184 opened incision (16.3%) coated or conventional (10.9%) by surgeon and P=0.23 monofilament Control: 35/190 (18.4%) culture proven or ·Obesity: BMI, kg/m2: polyglactin suture and P=0.039 (by χ2 test) not cultured, and Mean±SD 4.0 triclosan coated or P=0.042 (by Fisher’s (iv) infection Intervention: 27.6±4.1 conventional exact test) diagnosis by Control: 27.6±4.1 monofilament physician. P=0.67 polyglecaprone suture. Leg SSI and Deep SSI: had to ·Comorbidities: Monitoring intervention: Demographics involve fascia or Diabetes: trained nurse BMI muscle layers Insulin treatment: Control group: n=190 SSI: 28.3±4.3 Secondary Intervention: 22/184 Wound closed No SSI: 27.4±3.8 endpoints: (11.9%) subcutaneously with P=0.081 (i) purulent Control: 21/190 conventional Diabetes – Insulin drainage; © 2017 American Medical Association. All rights reserved. 272

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (11.1%) monofilament treatment (ii) antibiotic-treated P=0.78 polyglactin suture and Intervention: 12/61 SSI according to Oral Treatment: intracutaneously with a (19.7%) CDC’s definition Intervention: 20/184 4.0 conventional Control: 31/313 (9.9%) within 60 days (10.8%) monofilament P=0.029 postop. Control: 22/190 polyglecaprone suture. (iii) ASEPSIS score (11.6%) Operative Characteristics at Days 30 & 60 P=0.83 Standard preventive and Infections postop Dietary Treatment measures: Number of bypasses (iv) non-infectious Intervention: 4/184 Surgical technique: all SSI: 3.4±1.0 leg-wound (2.2%) patients were No SSI: 3.1±1.0 dehiscence Control: 7/190 (3.7%) performed P=0.014 within 60 days P=0.38 Cardiopulmonary postop Smoking bypass Other infections: NR Perioperative On-going Normothermia: was Topic-specific care: NR o Intervention: 29/184 maintained (35-36 C) outcomes: Other notes: (15.8%) Transfusion: cold Noninfectious dehiscence Study power: Control: 31/190 intermittent blood Intervention: 11/161 Based on a 20% (16.3%) cardioplegia. (6.8%) infection rate P=0.88 Antibiotic prophylaxis: all Control: 13/152 (8.5%) found by a pilot Number of bypasses patients received 4 P=0.57 study, an 80% Intervention: 3.0±0.9 parenteral doses of ASEPSIS score, day 4 power and a p- Control: 3.2±1.0 cloxacillin 2g. First Mean and SD value of 0.05 P=0.008 administered 20min Intervention: 0.4±1.2 showed 180 prior to skin incision, Control: 0.3±0.8 patients were Procedures: second 2h after first P=0.44 needed in each CABG does and following Median and range group to show a Intervention: 164/184 doses 6h & 24h later. Intervention: 0 (0-12) 50% reduction in (89.1%) Patients with allergy to Control: 0 (0-5) SSI Control: 167/190 cloxacillin received P=0.78 Wounds inspected (87.9%) clindamycin. ASEPSIS score, day 30 at postop days 4 P=0.71 Closure: leg incision Mean and SD & 30 by trained CABG+ AVR closed with one Intervention: 3.0±7.6 research nurse Intervention: 17/184 subcutaneous Control: 4.7±9.4 and at 60 days (9.2%) continuous suture and P=0.070 postop, patients Control: 22/190 one continuous Median and range interviewed by (11.6%) intracutaneous suture. Intervention: 0 (0-45) telephone. P=0.46 Covered with drape, Control: 0 (0-43) Follow-up: CABG+mitral repair compresses and elastic P=0.20 60 days postop © 2017 American Medical Association. All rights reserved. 273

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 3/184 bandages. Drape ASEPSIS score, day 60 Funding Source (1.6%) removed on Postop Mean and SD Conflicts: Control: 1/190 (0.5%) Day 4. Intervention: 3.7±8.7 Authors: None P=0.30 Control: 5.4±10.0 Institution: NR Indications: NR P=0.097 Study: Industry Setting: 1 university Median and range Supplies: NR hospital Intervention: 0 (0-45) Location: Sweden Control: 0 (0-43) Dates: March 2009 – P=0.46 February 2012 Inclusion Criteria: Operation Time, min: Leg Patients planned for vein harvesting Coronary Artery Intervention: 61±32 Bypass Graft, Control: 48±19 CABG+Aortic Valve P<0.001 (This replacement (AVR) significance remained or CABG+mitral after adjusting for valve repair or operating surgeon level replacement of experience Exclusion Criteria: Cultures taken: No ongoing sepsis or resistant bacteria septicemia, ongoing reported Staphyloccous bacterial infections aureus: or antibiotic Intervention: 7/23 (44) treatment, Control: 15/38 (52) participation in other p=0.61 clinical studies, or Reoperations: NR other severe disease Length of stay: NR that might influence Mortality: considered lost wound healing, to follow up emergency surgery Intervention: 1/184 (0.5%) or known allergy to Control: 1/190 (0.5%) triclosan. Adverse events: Postoperative bleeding (ml/12h) Intervention: 470 (95- 1950) Control: 482 (110-4550) P=0.94 © 2017 American Medical Association. All rights reserved. 274

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Postoperative Bleeding SSI: 430 (95-1485) No SSI: : 500 (140-4550) P=0.050 Justinger RCT To investigate Number of patients: Intervention group: SSI Definitions: 2013 75 1, 3, 4, the effect of N=856 n=485 Total: SSI- CDC NHSN (ES) 5, 6, 7, impregnating, Patient Abdominal fascia closed Intervention: 31/485 definitions used: 8 with triclosan, Characteristics with triclosan-impregnated (6.4%) Wound infection polydioxanone ·Age, y: mean±SD, polydioxanone loop. Control: 42/371 (11.3%) was identified by sutures used Intervention: 63±13 OR: 0.501 (0.3-0.9) the presence of for abdominal Control: 63±13 Timing of intervention: P<0.05 erythema, wall closure P=0.923 intraoperative induration, pain on the rate of ·Gender: M:F Duration of intervention: SSI by Wound and discharge of SSI Intervention:301:184 closure until absorption Classification: P<0.05 serous or Control: 224:147 Device/agent: Clean: contaminated ·Obesity: BMI>30 polydioxanone sutures Intervention: 14/286 fluid. Intervention: 76/485 either conventional or (4.8%) Perioperative (16.4%) triclosan coated. Control: 22/245 (8.9%) care: A Control: 54/371 Monitoring intervention: Clean-Contaminated: standardized (15.8%) postop wounds were Intervention: 14/162 clinical pathway P=0.713 assessed daily by 2 (8.6%) was used ·Comorbidities blinded observers. Control: 16/97 (16.5%) Other notes: Diabetes mellitus Control group: n=371 Contaminated: Sample size: An Intervention: 49/485 Abdominal fascia closed Intervention: 3/37 (8.1%) assumed SSI (10.1%) with conventional Control: 4/25 (16%) reduction from Control: 35/371 (9.4%) polydioxanone loop. Septic 12% to 6% P=0.4.19 Standard preventive Intervention: 0/0 resulted in a measures: Control: 0/4 calculated Procedures: MRSA- patients with sample size of Wound classification: previous methicillin- 350 patients for p<.05 resistant SSI by Surgery each arm to Clean: Staphylococcus aureus Upper GI Tract achieve a power Intervention: 286/485 contamination of Intervention: 3/59 (5%) of 1-b=0.08 for (59%) patients at risk for Control: 2/41 (5%) the one-sided χ2 Control: 245/371 MRSA contamination Hepatopancreatobiliary test at a level (66%) were screened Intervention: 9/201 (4%) a=0.025 and a Clean contaminated preoperatively and Control: 14/173 (8%) low dropout rate Intervention: 162/485 decontaminated, if Small Intestine of 5% (33.4%) elective Intervention: 1/19 (5%) Study used groups © 2017 American Medical Association. All rights reserved. 275

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Control: 97/371 Bowel Prep- all patients Control: 3/14 (21%) of 50 – 100 (26.1%) undergoing colorectal Vascular Surgery consecutive Contaminated resections had preop Intervention: 0/26 patients either to Intervention: 37/485 bowel prep with 3L of Control: 0/24 control or the (7.6%) prepacol Other triclosan Control: 25/371 (6.7%) Preop shower – all Intervention: 1/27 (4%) treatment group Septic patients had a regular Control: 4/19 (21%) Follow-up: within 2 Intervention: 0/485 shower without iodine Colorectal weeks post- Control: 4/371 (1.1%) within 24h preop Intervention: 17/143 discharge Indications: NR Hair removal: abdominal (12%) Funding Source Setting: One University wall hair removed but Control: 19/100 (19%) Conflicts: Hospital when and how was not Total SSI Colorectal Authors: NR Location: Switzerland described. Procedures: Institution: NR Dates: September Antibiotic prophylaxis: all SSI/Colo Procedures = Study: Industry 2009 - September patients received 36/243 (14.8%) Supplies: NR 2011 metronidazole and OR: 3.3 (1.9-5.7) Inclusion Criteria: all ceftriaxone; P<0.05 patients scheduled metronidazole and to undergo open clindamycin in case of BMI >30 and SSI abdominal allergy) within 60 14/130 (10.8%) exploration and minutes prior to OR: 1.68 (*0.8-3.2) surgery and closure incision. Additional P=0.12 of the incision in a doses were standard fashion administered in Other infections: NR (laparotomy) who surgeries >4h Topic-specific gave consent. Skin prep: Alcohol-based outcomes: Exclusion Criteria: povidone-iodine Wound culture results Refusal of surgery, Drape: skin drape used (reported in %) minimally invasive and wound edges were Staphylococci procedures or protected with surgical Intervention: 23.1% nonsurgical swaps. Swabs were Control: 23.1% therapies, burst soaked in povidone Enterococci abdomen, planned iodine solution for Intervention: 23.1% revision within 30 patients with a Control: 30.1% days, or an on- contaminated Streptococci demand re- abdominal cavity. Intervention: 5.1% laparotomy for Normothermia: Control: 5.1% organ/space temperature was kept Pseudomonas spp. infections. Mortality >35oC in patients with a Intervention: 0 © 2017 American Medical Association. All rights reserved. 276

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score in the follow up warming device. Control: 2.5% period and abdomen Found organ/space Enterobacteriacae not closed during the infection: patients with Intervention: 15.4% initial procedure. an organ/space Control: 23.1% infection upon Others laparotomy underwent Intervention: 15.4% an abdominal lavage Control: 23.1% with Ringer’s lactate MDRO not reported solution of at least 5L Closure: abdominal wall Reoperations: NR closed with continuous suture & peritoneum Length of stay: was not closed In hospital stay: mean±SD separately. Skin closed (range), days with staples. Intervention: 15±13 (2- Wound rinsing: post- 134) closure, wound rinsed Control: 11±18 (2-209) with Ringer’s solution. P=0.300 Oxygenation: in patients with a history of Mortality: Exclusionary Cardiovascular disease, 10 patients died. Cause of oxygen was supplied death an d study arm via nasal tube to not reported maintain oxygen Adverse events: NR saturation of >95% postop. Glycemic control: patients requiring intensive care treatment had a tight postoperative glucose control and correction of hyperglycemic states by continuous or intermittent insulin administration.

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Nakamur- RCT To evaluate Number of patients: Intervention group: SSI: Definitions: a 1, 4, 5, whether the N=410 n=206 Total: 28/410 (6.8%) Wound infection: 2013 74 7, 8, 9 incidence of Patient Wounds closed with Wound Infection CDC 1999 (ES) wound Characteristics: no triclosan-coated Intervention: 9/206 Guideline. infections can significant difference polyglactin 910 (4.3%) Perioperative care be reduced existed between antimicrobial sutures Control: 19/204 (9.3%) Other notes: The when groups Timing of intervention: P=0.047 assumed triclosan- ·Age, y: mean±SD intraoperative expected wound coated sutures Intervention: Duration of intervention: Organ/space infection rates of are used for 69.4±11.3 closure until absorption Intervention: 5/206 4% to 5% for the abdominal Control: 70.2±11.1 Device/agent: polyglactin (4.3%) study group and wound P=0.44 910 sutures either Control: 4/204 (9.3%) 10% to 11% for closures and ·Gender M:F conventional or P=0.74 the control to evaluate the Intervention: 130:76 triclosan coated group. With a 2- impact on Control: 112:92 Monitoring intervention: Wound infection by sided costs P=0.09 daily checks until surgery type alpha=0.05, the associated ·Obesity: discharge followed by Laparoscopic: 12/227 study was with wound BMI, kg/m2: mean±SD 30 day postop checkup (5.3%) expected to infections after Intervention: 23.2±3.6 Control group: n=204 Open: 16/183 (8.7%) have 80% power colorectal Control: 23.4±3.8 Wounds closed with P=0.16 to detect a surgery. P=0.61 conventional polyglactin Laparoscopic surgery: relative risk ·Comorbidities: 910 antimicrobial Intervention: 5/119 reduction of 5%; Diabetes mellitus: sutures (4.2%) a total of 400 Intervention: 41/206 Standard preventive Control: 7/108 (6.5%) patients were (19.9%) measures: P=0.43 estimated to be Control: 31/204 Antibiotic prophylaxis: Open Surgery needed. (15.2%) intravenous Intervention: 4/87 (4.6%) Follow-up: 30 P=0.21 cephalosporin 30 min Control: 12/96 (12.3%) days post Procedures: colorectal prior to incision; every P=0.061 discharge. surgeries including 3h of operative time; Funding Source right, left, and and for 48h postop in Other infections: NR Conflicts: transverse both groups. Topic-specific Authors: NR colectomy; Wound protectors: used outcomes: Institution: NR sigmoidectomy; low during open surgery, Cultured organism (note Study: NR anterior and and lap protectors used some infections had Supplies: NR abdominoperineal during delivery of were multi-organism) resection; total specimens during Enterococcus colectomy; and laparoscopic surgery. Intervention: 5/9 simple colostomy Closure technique: Control: 6/19 © 2017 American Medical Association. All rights reserved. 278

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Laparoscopic Surgery interrupted sutures and Enterobacter Intervention: 119/206 surgical staples for skin Intervention: 0/9 (57.8%) by 7 surgeons. Control: 3/19 Control: 108/204 Bacteroides (52.9%) Intervention: 3/9 P=0.33 Control: 5/19 Open Surgery MRSA: 0/9 vs. 1/19 (5.3%) Intervention: 87/206 Missing data: 2/9 (22.2%) (42.2%) vs. 6/19 (31.6%) Control: 96/204 Reoperation: NR (47.1%) Length of stay: (patients P=0.33 with infected wounds Indications were discharged and Setting: 1 hospital wounds were managed Location: Japan from outpatient clinic) Dates: April 2009 – Postop Hospital Stay, March 2011 days: median (SD), Inclusion Criteria: Intervention: 11 (6-79) Patients undergoing Control: 11.5 (6-93) elective colorectal P=0.08 surgery during the Postop Hospital Stay, study dates. days: mean ±SD Exclusion Criteria: NR Intervention: 15.2±11.6 Control: 15.6±10.4 P=0.71 Mortality: NR Adverse events: NR Turtiain- RCT To determine Number of patients: Intervention group: SSI Definitions: en 1, 2, 3, whether the N=276 n=139 Overall: 22% Surgical wound 2012 68 5, 6, 7, use of Patient Arterial exposure and vein Intervention: 31/139 infection: any (ES) 8, 9 triclosan- Characteristics harvest incisions closed (22.3%) complication of coated sutures No significant with triclosan-coated Control: 30/137 (21.9%) surgery was for wound differences seen polyglactin 910 and designated an closure would between groups. poliglecaprone 25 Superficial: infection if reduce the risk ·Age, y: mean (SD) sutures. Intervention: 24/139 bacteria were of surgical Intervention: 72 (11) Timing of intervention: (17.3%) isolated from the wound Control: 72 (11) intraoperative Control: 22/137 (16.2%) wound or if infection after ·Gender: m/f Duration of intervention: Deep localized peripheral Intervention: 87/25 closure until absorption Intervention: 5/139 redness, © 2017 American Medical Association. All rights reserved. 279

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score vascular (63%/37%) Device/agent: Triclosan- (3.6%) warmth, surgery. Control: 86/51 coated or standard Control: 5/137 (3.7%) swelling, and (63%/37%) polyglactin 910 and Graft Infection pain around the ·Obesity: BMI (kg/m2) poliglecaprone 25 Intervention: 2/139 wound appeared mean (SD) sutures. (1.5%) within 30 days Intervention: 26 (5) Monitoring intervention Control: 3/137 (2.2%) after the Control: 26 (4) Control group: n=137 operation (CDC ·Comorbidities Arterial exposure and vein Other infections: NR definition) Diabetes harvest incisions closed Topic-specific Superficial: if only Intervention: 43/139 with standard outcomes: skin and (31%) polyglactin 910 and Graft Thrombosis: subcutaneous Control: 44/137 (32%) poliglecaprone 25 Intervention: 7/139 tissue are COPD sutures. (5.0%) involved Intervention: 16/139 Control: 6/137 (4.4%) Deep: if wound (12%) Standard preventive P=0.80 infection Control: 23/137 (1%) measures: Stroke involves both Concurrent use of Antibiotic prophylaxis: Intervention: 4/139 fascia and corticosteroids: At 3 hospitals: 3g (2.9%) muscle layers Intervention: 19/139 cefuroxime Control: 1/137 (0.7%) Graft/O/S: if an (14%) administered P=0.18 artery or a graft Control: 15/137 (11%) intravenously within 1h Cultures taken: no (vein or prior to incision. resistant bacteria prosthesis) Procedures: lower limb At 2 hospitals: 1.5g reported. becomes arterial cefuroxime Reoperations: NR infected. reconstruction administered Length of stay: days (SD) Indications: intravenously 1h prior to Intervention: 5.5 (6.5) Perioperative Claudication incision and then every Control: 5.2 (4.3) care: NR Intervention: 44/139 8h for the first 24h after P=0.68 Other notes: (32%) operations. Sample size: for Control: 27/137 (31%) At 1 hospital: if a Mortality: 10 patients died the study to Rest pain prosthetic graft was within 30 days of provide an 80% Intervention: 48/139 used, patients also surgery. (9 had no SSI) power for (35%) received intravenous 30 day mortality detecting a 50% Control: 42/137 (31%) vancomycin. Intervention: 6/139 reduction in Ischemic ulcer (4.3%) infection rate at Intervention: 34/139 Control: 4/137 (2.9%) α=0.05, there (25%) P=0.55 should be at Control: 39/137 (29%) Adverse events: least 137 Other Major amputation patients in both © 2017 American Medical Association. All rights reserved. 280

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 13/139 Intervention: 4/139 groups. (9%) (2.9%) Follow-up: At least Control: 29/137 (21%) Control: 5/137 (3.6%) 1 month postop Setting: 3 tertiary or until the referral hospitals and wound healed two secondary Funding Source referral hospitals. Conflicts: Location: Finland Authors: NR Dates: July 2010 – Institution: NR January 2011 Study: NR Inclusion Criteria: Supplies: NR adult patients who underwent nonemergency lower limb arterial surgery. Exclusion Criteria: Aortoiliac procedures and the patient’s refusal to participate. Seim RCT To evaluate Number of patients: Intervention group: SSI Definitions: 2012 69 1, 5, 6, the effects of N-=323 n=163 Overall infection rate: SSI – positive (ES) 7, 8 Triclosan Patient Let wound closure with 33/323 (10.2%) bacterial culture coated Characteristics: triclosan-coated Intervention: 16/160 and clinical polyglactin demographic and polyglactin 910 suture (10%) judgment 910 suture on perioperative Timing of intervention: Control: 17/163 (10.4%) Perioperative standard characteristics Intraoperative care: NR polyglactin between groups are Duration of intervention: BMI and infection (kg/m2) Other notes: 910 suture comparable at Intra and postoperative mean±SD: Study power: a- with regard to baseline except for Device/agent: Standard Infection (n=33): priori, in order to surgical leg blood glucose (see or triclosan-coated 29.5±0.8 detect an wound below). polyglactin 910 sutures No-infection (m=290): estimated 50% infections ·Age, y mean±SD Monitoring intervention: 27.5±0.2 reduction in following Intervention: 63.5±0.7 by hospital staff in p=0.02 infection rate in saphenous Control: 63.1±0.8 hospital, by patient IDDM the triclosan- vein ·Gender: female postdischarge. coated suture harvesting in a Intervention: 17/160 Control group: General Perioperative group and a prospective (10.6%) Leg wound closure with Data statistical power randomized Control: 19/163 conventional polyglactin There were no significant level of 0.8, this © 2017 American Medical Association. All rights reserved. 281

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score study. (11.7%) 910 suture differences except: study required a Secondly, to ·Obesity: BMI (kg/m2), Standard preventive Cardiopulmonary bypass minimum sample examine mean±SD measures: time (min) size of 302 patient- and Intervention: 27.7±0.3 Hair removal: with electric Infection (n=33): patients operative Control: 27.5±0.3 razor on the afternoon 86.4±5.5 Follow-up: 4 characteristics ·Comorbidities of the day before Control/intervention weeks post , which are Diabetes mellitus, surgery. (n=17/n=16): discharge (a assumed to Intervention: 31/160 Pre-Op bathing: in the 81.3±9.1/92.2.9±6.0 registration form predict leg (19.4%) evening before the No-infection (m=290): was returned at wound Control: 40/163 operation, all patients 77.2±1.2 4 weeks postop) infections. (24.5%) took a shower including Control/intervention Funding Source IDDM washing with soap and (n=146/n=144): Conflicts: Intervention: 9/160 chlorhexidine gluconate 75.7±1.7/79.2±1.9 Authors: None (5.6%) 40mg/ml. This shower p=0.03 Institution: None Control: 17/163 repeated on the day of Study: None (10.4%) surgery. Aortic cross clamping time Supplies: None Blood Glucose Standard CABG (min) (mmol/l), mean±SD technique: using CPB, Infection (n=33): Intervention: 6.6±0.3 moderate hypothermia 48.3±4.1 Control: 8.5±0.8 (32oC), cold crystalloid Control/intervention P=0.05 or cold blood (n=17/n=16): cardioplegia and aortic 44.4±5.8/53.7.9±5.8 Procedures: Coronary cross clamping. No-infection (m=290): Artery Bypass Graft Skin disinfection: with 41.4±1.1 (CABG) chlorhexidine solution, Control/intervention Indications: NR 5 mg/ml with 70% (n=146/n=144): Setting: 1 university ethanol. 40.1±1.1/43.5±3.5 hospital Saphenous vein p=0.05 Location: Switzerland harvesting: from the Dates: September medial malleolus by a Other infections: NR 2009 - September continuous skin Topic-specific 2011 incision, ending either outcomes: Inclusion Criteria: below or over the knee. Bacterial cultures taken for patients undergoing Side branches were confirmation results not CABG at the study ligated or clipped. For reported center practical reasons, the Reoperations: NR Exclusion Criteria: left leg was Length of stay: NR Patients with leg predominantly Mortality: NR wounds, bilateral preferred. Adverse events: NR © 2017 American Medical Association. All rights reserved. 282

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score vein harvesting, Antibiotic prophylaxis: harvesting of the cefalotine as a single short saphenous dose of 2g vein, varicose veins intravenously before and those skin incision and undergoing continued with 3-h emergency CABG intervals to a total of 8g in both groups. Drape: wound covered with drape, compresses and elastic bandages. First day postop, the compresses and elastic bandages were removed and third postop day the drape removed. Isik RCT To evaluate Number of patients: Intervention group: SSI Definitions: 2012 79 1, 3, 4, whether the N=510 n=170 Superficial Sternum SSI SSI – CDC (ES) 5, 10 incidence of Patient Wound closure with Total: 16/510 (3.1%) definitions. sternal and leg Characteristics: triclosan-coated Intervention: 4/170 Perioperative wound patients were similar polyglactin 910 suture (2.4%) care: NR infections is in demographic and Timing of intervention: Control: 12/340 (3.5%) Other notes: reduced when lab characteristics. intraoperative P=0.596 Study power was coated sutures ·Age >65 y: Duration of intervention: Mediastinitis: 0 cases calculated on are used for Intervention: 70 closure until absorption Leg Site SSI the assumption wound (41.2%) Device/agent: Polyglactin Total: 17/402 (3.7%) that SSI would closure, Control: 138 (40.6%) 910 suture either Intervention: 5/142 be reduced from compared with ·Gender: Male coated or uncoated (3.5%) 6% to 1%, the non-coated Intervention: 111 Monitoring intervention: Control: 10/260 (3.8%) study group was sutures (64.7%) Patients inspected daily P=1.000 to be ½ the size Control: 228 (67.1%) by nurse in hospital. of the control ·Obesity: BMI>30kg/m2 Post discharge, patients Gender and SSI group with a Intervention: 41 were seen every 10 Male total of 510 (24.1%) days in the cardiac No SSI 324/338 (95.9%) patients. Which Control: 84 (24.7%) rehabilitation center for SSI 14/338 (4.1%) was performed ·Comorbidities: 30 days. Female with a risk Diabetes mellitus Control group: n=340 No SSI 158/172 (91.9%) coefficient (α) of Intervention: 57 Standard polyglactin 910 SSI 14/172 (8.1%) 0.05, a © 2017 American Medical Association. All rights reserved. 283

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score (33.5%) suture P=0.067 confidence Control: 120 (35.3%) Standard preventive interval (1-α) of EuroSCORE Risk measures: NR Both sternal and leg 0.95, a risk Score <5 infections developed in coefficient (β) of Intervention: 119 3 patients (not stated 0.20 and a (70.0%) which group they power (1-β) of Control: 210 (61.8%) belong to) 0.80 EuroSCORE Risk Follow-up: 30 Score >5 SSI in patient with days postop Intervention: 51 diabetes Funding Source (30.0%) OR 3.23 (1.45-7.23), Conflicts: Control: 130 (38.2%) p=0.04 Authors: None P=0.077 Institution: None Procedures: SSI in patients with Study: None Emergency: EuroSCORE > 5 Supplies: None Intervention: 2 (1.2%) OR 0.98 (0.91-1.05); Control: 14 (4.1%) P=0.164 P=0.104 Procedures: p=0.78 Other infections: NR CABG Topic-specific Intervention: 147 outcomes: (86.5%) Wound Culture Results Control: 263(77.4%) S. aureus Valve repair Intervention Sternum: 0 Intervention: 17 Intervention Leg: 0 (10.0%) Control Sternum: 4 Control: 50 (14.7%) Control Leg: 1 CABG and valve repair S. epidermis Intervention: 6 (3.5%) Intervention Sternum: 1 Control: 25 (7.4%) Intervention Leg: 0 Other operations Control Sternum: 1 Intervention: 0 Control Leg: 1 Control: 2 (0.6%) Corynebacterium spp. Indications: NR Intervention Sternum: 0 Setting: Single private Intervention Leg: 0 hospital Control Sternum: 1 Location: Turkey Control Leg: 0 Dates: April 2008 – Pseudomonas aeruginosa September 2009 Intervention Sternum: 1 © 2017 American Medical Association. All rights reserved. 284

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Inclusion Criteria: Intervention Leg: 0 Patients undergoing Control Sternum: 0 cardiac surgery Control Leg: 0 during the study Klebsiella pneumonaie period Intervention Sternum: 1 Exclusion Criteria: NR Intervention Leg: 2 Control Sternum: 0 Control Leg: 0 Swabs taken for suspected wounds. MRSA was not recovered from any wounds in study Reoperations: NR Length of stay: NR Mortality: NR Adverse events: NR Williams RCT To assess the Number of patients: Intervention group: n=75 SSI Definitions: 2011 72 1, 2, 4, effect of N=150 Wounds closed with Overall rate SSI – all (ES) 5, 6, 7 triclosan Patient triclosan-coated 2 weeks Postop: 13.7% investigators coating of Characteristics: subcutaneous (20/146) were conversant polyglactin ·Age: media, years polyglactin and Intervention: 9/73 with the CDC and (Range) triclosan-coated (12.3%) definition of SSI poliglecaprone Intervention: 61 (32- subcuticular Control: 11/73 (15.1%) and the sutures for 87) poliglecaprone. P=NS ASEPSIS and skin closure Control: 59 (30-80) Timing of intervention: 6 weeks postop: 18.9% Southampton after elective ·Gender: all female intraoperative (24/127) wound scores. breast cancer ·Obesity: NR Duration of intervention: Intervention: 10/66 Perioperative surgery. ·Comorbidities: NR closure to absorption (15.2%) care: Procedures: Breast Device/agent: triclosan- Control: 14/61 (22.9%) Anesthesia: cancer surgery: coated subcutaneous P=NS general Wide lump excision, polyglactin and Other infections: NR anesthesia sentinel node triclosan-coated Topic-specific Other notes: biopsy, Axillary node subcuticular outcomes: patients given clearance, poliglecaprone or Patients lost to follow up diaries to record mastectomy and standard polyglactin Two weeks (n=4) events occurring localized wire and poliglecaprone Patient request within the 6 excision or some Monitoring intervention: Intervention: 1 weeks postop. combination of the patients reviewed Control: 1 Significant © 2017 American Medical Association. All rights reserved. 285

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score above regularly by nurses and Lost to follow up events were Indications: NR at two and six weeks Intervention: 0 corroborated by Setting: Single center postop as outpatients or Control: 1 an attending Location: United at a home visit. Need for further surgery physician. Kingdom Control group: n=75 Intervention: 0 Power: estimated Dates: November 2008 Wounds closed with Control: 1 sample size of – February 2011 subcutaneous Six weeks (n=19) 150 patients (75 Inclusion Criteria: polyglactin and Patient request in each group) Women >18 years subcuticular Intervention: 1 was considered undergoing primary poliglecaprone. Control: 0 to have 80% elective breast Lost to follow up power to show a surgery under the Standard preventive Intervention: 1 statistically care of two breast measures: Control: 2 significant surgeons at the Antibiotic prophylaxis: 8 Need for further surgery difference of study center patients considered Intervention: 5 p<0.05 Exclusion Criteria: high risk received a Control: 10 Follow-up: 6 Inflammatory breast single intravenous dose weeks postop. cancer or skin of 1g of amoxicillin Reoperations: Funding Source ulceration; neo- clavulanate. (high BMI, exclusionary criteria Conflicts: adjuvant mastectomy or axillary 6/24 SSI needed an Authors: Industry chemotherapy or clearance_ none of intervention to Institution: NR radiotherapy; these developed SSI) open/pack or aspirate Study: Industry surgery for benign or Closure: wounds closed axillary collections. Supplies: NR reconstructive after surgery using 3/6 required reasons; known subcutaneous readmission immune deficiency polyglactin and 1/24 had a delay in or allergy to subcuticular starting adjuvant triclosan; and poliglecaprone at the chemotherapy. inability to give discretion of the Need for further surgery: consent or suspicion operating consultant Intervention: 5/9 (55.6%) that the patient was surgeon. Control: 10/14 (71.4%) unlikely to comply Wound dressing: butterfly Length of stay: NR with the follow-up. stitches and waterproof, Mortality: NR transparent dressing or Adverse events: NR one of two types of adhesive wound dressing. OR an adhesive wound dressing alone. © 2017 American Medical Association. All rights reserved. 286

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score All other interventions such as pre-medication, anesthesia, and phlebothrombosis prophylaxis were standard for both groups.

Baracs RCT To compare Number of patients: Intervention group: SSI Definitions: 2011 71 1, 2, 5, polydioxanone N=385 n=188 Intervention: 23/188 SSI – SSI (ES) 7, 10 suture with Patient Triclosan-coated running (12.2%) described as and without Characteristics: looped polydioxanone Control: 24/197 (12.2%) divided into triclosan in groups showed used to close the P=NS superficial seven high- homogeneity in abdominal fascia. incisional, deep volume demographic Timing of intervention: Late infection (post incisional, Hungarian features intraoperative discharge) abdominal surgical ·Age, y: mean Duration of intervention: Intervention: 4/188 dehiscence but institutions Intervention: 62.6 closure and up to 30 (2.1%) these were not over a one- Control: 63.5 days until absorption Control: 9/197 (4.6%) defined. year period ·Gender: m:f Device/agent: Running P=0.41 Perioperative Intervention: 110:78 looped polydioxanone care: Adjuvant Control: 111:86 sutures either triclosan- SSI By Operations therapy was not ·Obesity: mean BMI of coated or standard Right-sided colon allowed to be patients with SSI Monitoring intervention: resection started within the Intervention: 23.14 examination of incision Intervention: 11/46 30-day follow-up Control: 27.97 site during hospital stay (24%) period ·Comorbidities: and telephone call Control: 5/44 (11%) Other notes: Pilot Type II Diabetes follow up at 30 days P=0.006 study of 50 mellitus post discharge Rectal resection patients showed Intervention: 27/188 Control group: n=197 Intervention: 6/89 (7%) a 5% SSI rate in (14.4%) Standard running looped Control: 14/95 (15%) the Triclosan Control: 26/197 polydioxanone used to P=0.033 coated (13.4%) close the abdominal Left sided colon and polyglactin 910 Neoadjuvant therapy: fascia. sigmoid resection suture and a Intervention: 47/188 Intervention: 4/40 (10%) 20% SSI rate in (25%) Standard preventive Control: 3/45 (7%) the standard 910 Control: 40/197 measures P=NS suture. This (20.3%) Closure: separate Segmental resection and study showed © 2017 American Medical Association. All rights reserved. 287

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score peritoneal closure and colectomy SSI was about Procedures: subcutaneous sutures Intervention: 2/10 (20%) 10% in each hemicolectomies, were optional Control: 1/8 (13%) group. transversectomies, depending on surgeon’s P=NS Polyglactin is cecal resection, preference. If Total and subtotal braided and colostomies, A-P employed, 2-0 suture colectomy polydioxanone is resections of the utilized. Interrupted 2-0 Intervention: 0/3 monofilament. rectum, sigmoid poliglecaprone 25 used Control: 1/5 (20%) Follow-up: 30 resections, for the skin closure. days post abdominal Antibiotic Prophylaxis: a BMI and SSI discharge via resections of the second-generation BMI<20kg/m2 telephone call. rectum, subtotal cephalosporin and Intervention: 3/7 (42.8%) Funding Source colectomies, total metronidazole 30 Control: 3/11 (27.3%) Conflicts: colectomy and minutes before incision) Normal BMI (20-30 kg/m2): Authors: None abdominal resection Drapes – disposable Intervention: 16/147 Institution: None of the rectum. drapes used. (10.9%) Study: None Indications: Benign or Incision locations: not Control: 16/139 (11.5%) Supplies: None malignant colon or standardized in either Obese (BMI >30kg/m2): rectal disease rectal or hemicolectomy Intervention: 3/34 Setting: 7 hospitals (3 surgeries) (11.8%) university, 4 high- Control: 5/47 (10.6%) volume hospitals) Location: Hungary Normal BMI (20-30 Dates: December 2009 kg/m2): 11.2% (32/286) – November 2010 BMI<20kg/m2: 33.3% Inclusion Criteria: (6/18) Patients between the P<0.05 ages of 18-80 years Other infections: NR old with benign or Topic-specific malignant colon or outcomes: rectal disease Cultured Organisms undergoing and Gram Positive: elective open Pseudomonas surgical procedure aeruginosa, involving an Enterococcus faecium, enterotomy E. coli, Enterococcus Exclusion Criteria: spp. – cultured from Patients with both groups, numbers systemic disease not reported. © 2017 American Medical Association. All rights reserved. 288

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score influencing local Gram Negative: S. surgical site healing epidermis: (e.g. type I diabetes Intervention: 0 mellitus, Child-Pugh Control: 2 class B-C liver cirrhosis, and Reoperations: NR chronic kidney Length of stay: NR disease Mortality: NR necessitating Adverse events: NR dialysis) or those having immunosuppressive treatment or inflammatory bowel disease. Also, acute operations with unprepared bowel (9 cases) & patients who refused consent. Some patients with intraoperative findings such as locally incurable tumor or sepsis (abscess, necrotic tumor), or with postoperative findings such as further surgical intervention through the site and patients who withdrew the consent later. Undesirable complications such as sterile surgical site dehiscence and suture breakage © 2017 American Medical Association. All rights reserved. 289

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score during the postoperative period also led to exclusion from the trial.

Galal RCT To assess the Number of patients: Intervention group: SSI: Definitions: CDC 2011 76 1, 2, 3, incidence of N=450 n=230 Total SSI: 50/450 (11%) definitions: an (ES) 4, 5, 6 surgical site Patient Surgeries where Intervention: 17/230 (7%) infection within infection using Characteristics: absorbable, braided Control: 33/220 (15%) 30 days of triclosan- there were no polyglactin 910 triclosan P=0.011 surgery (or coated significant coated suture used in (please note that the within a year in polyglactin differences between all steps except in some numbers for clean, case of 910 groups regarding cases polypropylene clean contaminated and prosthetic antimicrobial age was used for contaminated surgery surgery): (1) ·Age: laparotomy closure and do not add up to the “n” diagnosis 21-30 y vascular suture. for the intervention & consists of Intervention: 42/230 Poliglecaprone 25 used control group) infection of an (18.3%) in skin closure. Other infections: NR anatomic plane Control: 40/220 Timing of intervention: by one of the (18.2%) intraoperative Topic-specific following 31-40 y Duration of intervention: outcomes: NR manifestations: Intervention: 75/230 suturing to absorption collection; (32.6%) Device/agent: Reoperations: NR inflammatory Control: 85/220 absorbable, braided Length of stay: mean±SD signs (pain, (38.6%) polyglactin 910 suture (range) days tenderness, 41-50 y coated with triclosan. SSI 7.10±3.92 (3-16) edema, Intervention: 90/230 Or polyglactin 910 No SSI 3.39±1.48 (1-13) redness); (39.1%) suture. P<0.001 dehiscence; or Control: 75/220 Monitoring intervention: positive culture; (34.1%) NR Mortality: NR (2) classification 51-60 y Control group: n=230 Adverse events: NR according to Intervention: 23/230 Surgeries where anatomic plane (10.0%) conventional as follows: Control: 20/220 (9.1%) absorbable, braided superficial © 2017 American Medical Association. All rights reserved. 290

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score P=0.567 polyglactin 910 suture incisional ·Gender male was used in all surgical surgical site Intervention: 148/230 steps except in some infection: (64.3%) cases, polypropylene infection of skin Control: 127/220 was used for and (57.7%) laparotomy closure and subcutaneous P=0.1499 vascular suture, and tissue; deep ·Obesity: NR Poliglecaprone 25 was incisional ·Comorbidities: used in skin closure. surgical site Diabetes: infection: Intervention: 32/230 Standard preventive infection of deep (13.9%) measures: soft tissue Control: 42/220 Closure: in both groups, (fascia and (19.1%) monofilament sutures muscles); or P=0.1386 were the only kind of organ/space Procedures: suture material used for surgical site Vascular surgery: n=86 the following infection: Intervention: 50/230 applications: infection of (21.7%) polyglecaprone used for organ/space. Control: 36/220 skin closure in plastic Perioperative care (16.4%) surgery, hernia, Other notes: Plastic Surgery: n=82 thyroidectomy, Patients were Intervention: 40/230 mastectomy, lipoma assessed daily (17.4%) and hand surgery; in the hospital. Control: 50/220 polypropylene used for Post discharge (19.1%) vascular, fascial patients were Gastrointestinal closure, and skin in requested to surgery: n=65 surgeries other than return to the Intervention: 38/230 aforementioned outpatient clinic (16.5%) surgeries. weekly for 30 Control: 27/220 In this study, they days (then (12.3%) followed the local monthly until the Biopsy: n=64 protocol of the end of the first Intervention: 32/230 infection control unit year in the case (13.9%) at their institute. This of prosthetic Control: 3/220 (14.5%) may deviate from surgery) Hernia: n=63 current modern This was a Intervention: 30/230 practices. This multicenter (13.0%) protocol used for both study, however, © 2017 American Medical Association. All rights reserved. 291

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Control: 33/220 (15%) groups. (Modern results were only Thyroidectomy: n=30 protocol is considered reported for 1 Intervention: 9/230 by this study to be: center (3.9%) clippers rather than Follow-up: 30 Control: 21/220 (9.5%) razors for hair removal; days or 1 year in Mastectomy: n=15 local skin warming; the case of Intervention: 10/230 antibiotic prophylaxis orthopedic (4.3%) given before clean surgery. Control: 5/220 (2.3%) surgery involving the Funding Source Lipoma: n=13 placement of a Conflicts: Intervention: 7/230 prosthesis or implant, Authors: NR (3.0%) clean contaminated Institution: NR Control: 6/220 (2.7%) surgery, and Study: NR General surgical contaminated surgery. Supplies: NR procedures: n=11 This antibiotic Intervention: 4/230 prophylaxis is not (1.7%) routinely used for clean Control: 7/220 (3.2%) non-prosthetic Exploration: n=9 uncomplicated Intervention: 3/230 surgeries and it should (1.3%) be timely and Control: 6 /220 (2.7%) appropriate for the Amputation: n=5 organisms expected.) Intervention: 3/230 (1.3%) Control: 2/220 (0.9%) Also, the following surgeries had no SSI: Hand surgery: n=4 Shoulder Tumor: n=1 Knee tumor: n=1 Orchiectomy: n=1 Indications Setting: 1 university hospital Location: Egypt Dates: NR Inclusion Criteria: All © 2017 American Medical Association. All rights reserved. 292

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score patients of different age, sex, and risk factors who were candidates for surgical intervention during the study period Exclusion Criteria: Patients with an established preoperative infection at the surgical site Rasic RCT The aim of this Number of patients: Intervention group: n=93 SSI Definitions: wound 2011 70 1, 2, 4, study was to N=184 Abdominal wall was closed Presence of wound infection not (ES) 5, 6 compare the Patient with a continuous infection: defined. effect of Characteristics: single-layer mass Intervention: 4/91 Postoperative data: triclosan there was no technique (peritoneum, (4.3%) was collected coated statistical difference muscle, & fascia) with Control: 12/91 (13.2%) from operation polyglactin in demographic or triclosan coated P=0.035 reports, nurses 910 or preoperative data polyglactin 910 sutures Other infections: NR wound reports, polyglactin between groups. Timing of intervention: chart review and 910 on ·Age, years, mean±SD intraoperative Topic-specific microbiology abdominal Intervention: 58±14.5 Duration of intervention: outcomes: reports. wall healing in Control: 57±14.7 closure Postop inflammatory Perioperative patients ·Gender: male, Device/agent: triclosan reactions to skin care: NR undergoing Intervention: 49/91 coated or standard sutures: Other notes: None elective (54%) polyglactin 910 sutures Intervention: 7/91 Follow-up: NR surgery for Control: 50/91 (54%) Monitoring intervention: (7.5%) Funding Source colorectal ·Obesity: BMI>25 biochemical markers of Control: 16/91 (17.5%) Conflicts: carcinoma kg/m3, inflammation were P=0.039 Authors: NR Intervention: 7/91 monitored: white blood Dehiscence Institution: NR (8%) cell count (WBC); Intervention: 1/91 Study: NR Control: 9/91 (9%) postoperative (1.1%) Supplies: NR ·Comorbidities: NR procalicitonin –PCT; Control: 7/91 (7.7%) Duration of surgery and C-reactive protein – P=0.027 Intervention: CRP) 95.5±17.3 Control group: n=91 Incisional hernia Control: 91.3±18.6 Abdominal wall was closed Intervention: 2/91 © 2017 American Medical Association. All rights reserved. 293

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score P=0.8933 with a continuous (2.2%) single-layer mass Control: 5/91 (5.5%) Procedures: surgery technique (peritoneum, P=0.235 for removal of muscle, & fascia) with colorectal carcinoma polyglactin 910 Reoperations: Indications: Colorectal Intervention: 1/91 cancer Standard preventive (1.1%) Setting: 1 university measures: Control: 8/91 (8.8%) hospital Antibiotic prophylaxis: P=0.015 Location: Croatia Gentamycin 160mg and Intervention Reoperations: Dates: September metronidazole 500mg, 1/1 = Dehiscence 2008 - September given intravenously Control Reoperations 2009 during induction of 7/8 = dehiscence Inclusion Criteria: anesthesia. 1/8 = peritonitis patients diagnosed Operative technique: all Length of stay: with colorectal operations performed Mean hospitalization cancer scheduled for through a midline period elective surgery. incision. Skin was Intervention: 1.2±1.3 Exclusion Criteria: NR incised (15-18cm days length) with a scalpel; Control: 21.4±2.8 days all other layers P<0.05 transected with Mortality: no deaths in diathermy. either group Closure: running sutures Adverse events: were 1cm apart and Inflammatory reactions to 1.5cm from the wound skin sutures: edge. Skin closed with Intervention: 7/91 a polyamide. (7.5%) Control: 16/91 (17.5%) P=0.039

Mingma- RCT To evaluate Number of patients: Intervention group: n=50 SSI: (follow up 12 Definitions: NR lairak 1, 2, 3, the efficacy of N=100 Antibacterial-coated months) Perioperative 2009 78 4, 5, 6, triclosan Patient absorbable suture SSI (total) care: NR (ES) 7, 8, 9, coated Characteristics: No (triclosan) used to close Overall rate: 9/100 9% Other notes: All 10 absorbable statistically the abdominal sheath. Intervention: 5/50 (10%) patients suture in significant Timing of intervention: Control: 4/50 (8%) completed the reducing the differences in Intraoperatively P=0.727 study surgical site demographic Duration of intervention: Superficial Authors set the © 2017 American Medical Association. All rights reserved. 294

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score infection rate characteristics, Intraoperatively Intervention: 5/50 (10%) discontinuation associated preoperative Device/agent: Control: 3/50 (6%) criteria infection with information and Antibacterial Deep rate >10% in the appendectomy operative information absorbable suture Intervention: 0/50 intervention compared with between groups. (triclosan coated) Control: 1/50 (2%) group or >2 traditional, ·Age, y: mean Monitoring intervention: Organ/Space times in the non-coated Intervention: 29.1 NR Intervention: 0/50 control group braided Control: 29.8 Control group: n=50 Control: 0/50 compared with absorbable ·Gender: m:f Traditional braided the intervention. suture. Intervention: 26:24 absorbable suture used Infections were more Or mechanical Control: 35:15 to close the abdominal common in cases of problems in the ·Obesity sheath. ruptured appendicitis intervention Height: cm ,mean Standard preventive (Infected 5/9 vs. Non- group such as Intervention: 161.5 measures: infected 11/91 strength, knot Control: 164.0 AMP: Gentamicin 240mg P=0.007) tight and P=0.039 and metronidazole The rate of SSI was higher anaphylactic Weight, kg, mean 500mg given in men than in women. allergy. Intervention: 59.73 intravenously 30-60 (3:2) Follow-up: At day Control: 59.53 minutes before the 1, 3, 7, 14, and ·Comorbidities: NR operation. Risk factors associated 30, and at 6 and White Blood Cell count, Surgery: appendectomy with infection 12 months cell/mm3, mean: done with standard Infected patients tended to Funding Source Intervention: 16,564 technique, mainly by a be older, with slightly Conflicts: Control: 15,062 second year physician. higher temperature, higher Authors: None P=0.036 white blood cell counts, Institution: None Operative: and slightly longer Study: None Preop time, operative operative times, but these Supplies: None time, type of differences were not appendicitis and degree statistically significantly of contamination not different. statistically significant Type of appendicitis: Appendicitis case type Intervention/control Suppurative: Acute: 24/24 Non- infected: 50/91 Suppurative: 56/48 (54.9%) Gangrene: 6/10 Infected: 2/9 (22.2%) Ruptured: 14/18 P=0.050 Degree of Ruptured: contamination: Non-infected: 11/91 © 2017 American Medical Association. All rights reserved. 295

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention/Control (12.1%) Mild: 86/80 Infected: 5/9 (55.6%) Moderate: 8/12 P=0.007 Severe: 6/8 Procedures: Other infections: NR Appendectomy Topic-specific Via grid-iron incision: outcomes: 86% Cultures: No Resistance Indications: Acute and reported ruptured Intervention: 1 S. aureus appendicitis. Control: 1 (deep) P. Uncomplicated: 76% aeruginosa Acute Reoperations: NR Intervention: 24% Length of stay: days Control: 24% (mean) Suppurative Intervention: 3.7 Intervention: 56% Control: 3.7 Control: 48% P=0.500 Gangrene Infected vs. uninfected. Intervention: 6% Uninfected: 3.6 days Control: 10% Infected: 7.4 days Ruptured P=0.006 Intervention:14% Control: 18% Mortality: NR (all Setting: 1 university available for follow-up) hospital Adverse events: No Location: Thailand medical complications Dates: August 2006 – during the present March 2007 study and no Inclusion Criteria: complications related to Patients aged 15-60 suture identified after 1 years, both sexes, year of follow-up. appendicitis diagnosed intraoperatively through a right lower quadrant incision and included both acute and ruptured © 2017 American Medical Association. All rights reserved. 296

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score appendix. Exclusion Criteria: Patients with diabetes, immunocompromise d host, HIV, on immunosuppressive drug, malignancy, missed diagnosis intraoperative, history of allergy to the substance, or pregnancy Rozzelle RCT To determine Number of patients: N Intervention group: n=46 SSI: (follow up 6 Definitions: 2008 80 1, 2, 3, whether = 61 patients with Antimicrobial (triclosan) months) Shunt infection: (ES) 4, 5, 6, wound closure 84 shunt coated absorbable SSI at 2nd interim period diagnosis 7, 8, 9, with triclosan- procedures sutures were utilized to Overall: 10/84 (11.9%) obtained by 10 coated Patient close the subcutaneous Intervention: 2/46 (4.3%) positive culture absorbable Characteristics: layer around the CSF Control: 8/38 (21%) from CSF sutures after Groups differed shunt P= 0.038 sampled through cerebrospinal slightly but no Timing of intervention: There was no statistically the shunt or from fluid (CSF) significant difference Intraoperatively significant difference explanted shunt shunt surgery was found in patient Duration of intervention: between historical rate components. would reduce characteristics, Intraoperatively and either the Perioperative the incidence shunt type, Device/agent: intervention or control care: NR of early shunt indication, or which Antimicrobial (triclosan) group rates. Other notes: infection (<6 surgeon between coated sutures Intervention was No patients were months groups. Monitoring intervention: associated with lost to follow up. postoperativel ·Age median (range): CSF cultures. Absolute risk reduction Patients requiring a y) 6.3 y (1 day – 48 y) Control group: n= 38 0.167 (95% CI 0.027- new shunt within ·Gender: male no (%) Standard (uncoated) 0.235) the 6-month Intervention: 30/46 absorbable sutures Relative risk reduction surveillance (65%) were utilized to close 3.84 (95% CI 0.257 – window were Control: 18/38 (47%) the subcutaneous layer 18.78) reenrolled in the P=0.154 around the CSF shunt Predict intervention suture program using (Distribution unequal (not the same kind of wound closure would the same suture between groups with material as the prevent 1 shunt infection assignment as a weak statistical intervention) for every 6.0 procedures in before. Patients trend towards the which it is used: receiving new © 2017 American Medical Association. All rights reserved. 297

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention group Standard preventive Number to treat=6.0; shunts following for males.) measures: 95%CI 4.2-36.5) successful ·Obesity: NA Surgeon Grade: all shunt 8/10 diagnosed w/in 6 treatment of a weight <4kg procedures performed weeks shunt infection Intervention: 7/46 by one of two attending 2/10 diagnosed at 12 and and patients (15%) pediatric 14 weeks postop. undergoing Control: 6/38 (16%) neurosurgeons. revision >6 ·Comorbidities AMP: all participants 8/10 (+) CSF cultures months after Recent CSF infection received preoperative 1/10 blood and distal randomization Intervention: 6/46 intravenous catheter cultures grew were re- (13%) antimicrobials same organism (VA randomized. Control: 3/38 (8%) (cefazolin, or Shunt) Enrollment ceased Mean shunt procedure vancomycin if allergic to 1/10 (-) CSF culture, (+) at the second time was slightly cephalosporins) wound purulence over interim analysis longer in intervention Skin Prep: all patients distal tubing due to a marked group but not received preoperative Other infections: NR difference in statistically chlorhexidine skin Topic-specific infection rates significant. cleansing, povidone- outcomes: between groups. Procedures: iodine skin prep. 60 shunts (71.4%) No additional shunt Implantation or Drapes: all surgeries remained functional and infections revision of utilized iodine- apparently infection free at diagnosed after implantation for impregnated adhesive 6 months. enrollment cerebrospinal fluid drapes Pathogenic isolates n=10 ceased (CSF) shunting Wound irrigation: all SSIs: Follow-up: 6 devices. patients received Intervention: months Implants: 40 (47.6%) antibiotic wound 1 MRSA Funding Source Revisions: 44 (53.4%) irrigation prior to 1 coagulase negative Conflicts: VP Shunt type: 68 closures. (coag neg) Authors: Industry operations (81%) Shunt cleaning: Silicone Staphylococcus Institution: None VPI Shunt type: 9 shunt components were Control: Study: None operations (10.7%) soaked in bacitracin 1 MRSA Supplies: None Subdural-peritoneal solution before 3 MSSA shunt: 6 operations implantation. No 3 coag neg Staph spp. (7.1%) antibiotic-impregnated 1 P. aeruginosa VA shunts: 1 operation shunt components used Reoperations: (1.2%) in this study. 10/84 (11.9%) shunts were Indications: Closure: skin closures for removed due to hydrocephalus. all procedures infection prior to 6 Setting: 1 hospital performed with month follow up. © 2017 American Medical Association. All rights reserved. 298

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Location: USA poliglecaprone 25 14/ 84 (16.7%) Revision Dates: April 2005 - sutures. procedures w/in 6 mo December 2006. where infection was not Inclusion Criteria: suspected. (Shunt tap Patients of all ages CSF cultures remained requiring CSF shunt negative) implantation or 2/84 (2.4%) revision revision surgery. procedures >6mo Exclusion Criteria: postop. Patients receiving Reasons for revisions NR ventricular access 7/61 (11.5%) patients devices or receiving new shunts ventriculosubgaleal were re-randomized shunts, patients with after removal of an active shunt infected shunt that had infections, and been placed during the immunocompromise study and appropriate d patients. antimicrobial therapy Wounds cultured, MRSA: 1/2 (50%) vs. 1/8 (12.5%) both in revision surgeries MSSA: 0/2 vs. 3/8 (37.5%) all in primary implant surgeries

Length of stay: NR Mortality: 2 patients with shunt infections died (3.3%). Both were infants with severe congenital anomalies whose parents ultimately decided to withdraw care. Adverse events: All shunt infections treated with complete shunt removal, external © 2017 American Medical Association. All rights reserved. 299

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score ventricular drainage, and appropriate intravenous antimicrobial therapy until daily CSF cultures remained negative for ≥5 days, followed by the replacement of a new shunt. Ford RCT To Number of patients: Intervention group: n= SSI: (follow up 80 days) Definitions: 2005 81 1, 4, 5, characterize N=147 98 Infection Day 1-2 Infection: observed (ES) 7, 8, 9 further the Patient Antimicrobial (triclosan) Intervention: 0% redness >3-5 clinical Characteristics: no coated absorbable Control: 0% mm from the performance differences in suture was used as Infection Day 14 wound margins, of baseline suture of various sizes Intervention: 2% edema antimicrobial characteristics dependent on surgery Control: 0% (characterized (triclosan) between groups. Timing of intervention: Infection Day 80 by increased coated ·Age, y: mean (range): Intraoperatively Intervention: 1% tissue firmness), absorbable 9.8 y (1-18) Duration of intervention: Control: 0% purulent suture and ·Gender: 52% male Intraoperatively Edema, any day 1 discharge, pain, traditional ·Obesity: NR Device/agent: Triclosan- Intervention: 10% and increased non- Mean Height: 137.2 cm coated absorbable Control: 18% skin antimicrobial (range 67-191 cm) suture. Edema, any Day 14 temperature. coated Mean Weight: 41.3 kg Monitoring intervention: Intervention: 3% Confirmatory absorbable (range 8-130 kg) NR Control: 2% culture was not suture in ·Comorbidities Control group: n=49 Edema, any Day 14 required. pediatric “Risk factors that could Non-antimicrobial coated Intervention: 0% FLACC behavior patients affect wound healing absorbable suture was Control: 3% pain assessment undergoing were present in used as suture of Erythema Day 1 scale was used various similar proportion”: various sizes Intervention: 9% in non-verbal general individual results by dependent on surgery Control: 7% patients (infants) surgical risk factor not Erythema Day 14 unable to procedures. reported Standard preventive Intervention: 9% provide reports Intervention 29% measures: NR Control: 2% of pain. (face, Control: 33% Non-Standard Preventive Erythema Day 80 legs, activity, “The most common Measures: Intervention: 1% cry, risk factors were Perioperative antimicrobial Control: 3% consolability) obesity and administration: Other infections: 3 Intraoperative chemotherapy” Intervention: 24% infections developed handling: © 2017 American Medical Association. All rights reserved. 300

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Actual numbers not Control: 31% and judged not to be overall, ease of reported related to the suture. passage, first Received IV 1/3: Day 14 a 13 year old throw, tie-down, antimicrobials (they male undergoing security, hand, do not specify if pilonidal cystectomy memory, and AMP or AMP and developed a new sinus non-fraying. treatment) tract that was related to Perioperative Intervention: 65% the location of the cyst care: NR Control: 82% 1/3: on day 14, a 14-year Other notes: Taking other old female who had Patient population medications undergone laparoscopic at each wound Intervention: 5% cholecystectomy evaluation: Control: 10% developed a superficial 1-2 days: Procedures: NR fungal rash around the Intervention: 88 (variable) umbilicus that was Control:45 Indications: NR believed to be due to 14 days: (variable) body habitus. Intervention: 91 Setting: 1 center 1/3: day 80, a 14 year old Control:44 Location: USA female patient who 80 days Dates: NR underwent a pilonidal Intervention: 76 Inclusion Criteria: cystectomy developed Control:38 Pediatric patients a new sinus tract distal aged 1-18 years to the original site of Follow-up: Wound undergoing clean or excision that was filled healing clean-contaminated with hair (most likely evaluated at general surgical represented a new follow-up visits procedures. lesion) at 1-2 days, 14 Exclusion Criteria: Topic-specific (±2) days and 80 Contaminated outcomes: (±5) days post- wound sites; use of Intraoperative handling: implantation. retention sutures; Overall: Funding Source inappropriate age; Intervention mean 71% Conflicts: evidence of Control mean 59% Authors: Industry malnutrition or Both sutures>94% “very Institution: NR debilitation; good” or “excellent” Study: Industry coexisting conditions Not statistically significant Supplies: NR that may impair Specific: wound healing Excellent including acquired Intervention mean 75% © 2017 American Medical Association. All rights reserved. 301

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score immunodeficiency Control mean 62% syndrome (AIDS); Both sutures>94% “very incision sites prone good” or “excellent” to expand, stretch, Not statistically significant distend, or require Pain Day 1 support; ophthalmic, Intervention: 68% cardiovascular, or Control: 89% neurologic surgical P=0.01 sites; a need for Pain Day 14 more than one Intervention: 12% surgical procedures; Control: 9% prior participation in Pain Day 80 this study; or allergy Intervention: 3% to triclosan. Control: 0% Reoperations: Adverse events requiring surgery Intervention: 17/98 (17%) Control: 10/49 (20%) Length of stay: NR Mortality: NR Adverse events: The most common events consisted of admissions for chemotherapy. Any Adverse Events: Intervention: 17/98 (17%) Control: 10/49 (20%) Severe Adverse Events: Intervention: 1/98 (1%) Control: 1/49 (2%) Serious Adverse Events: Intervention: 13/98 (13%) Control: 8/49 (16%) Requiring Surgery: 17/98 (17%) vs. 10/49 (20%) Device Related: 0/98 vs. © 2017 American Medical Association. All rights reserved. 302

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score 0/49

Day 1 Antimicrobials received: Intervention: 24% Control: 31% Day 14 Antimicrobials received: Intervention: 13% Control: 23% Day 80 Antimicrobials received: Intervention: 22% Control: 29%

Received other medications that could impede wound healing: Day 1 Intervention: 10% Control: 13% (not significant) Day 14 Intervention: 14% Control: 14% Day 80 Intervention: 12% Control: 21% Suture sinus: none

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eTABLE 34. Evidence Table for Q2D. How safe and effective are antimicrobial dressings applied to surgical incisions following primary closure in the operating room? Author Study Year Design Study Population and (Data Intervention Results Comments Quality Objective Setting Extrac- Score tor) Biffi RCT To compare the Number of patients: Intervention group: n=58 SSI (30 days) Definitions: 2012 83 1, 2, 3, efficacy of a N=112 Surgical incision was Overall: 20/112 (17.9%) SSI: CDC (ES) 4, 5, 6 sterile moisture Patient dressed with a sterile Intervention: 9/58 Definitions 7, 8, 9 retentive Characteristics: moisture retentive (15.5%) Perioperative dressing with patients were similar dressing with 1.2% Control: 11/54 (20.4%) care: NR 1.2% iconic with regards to their iconic silver covered by P=0.623 Other notes: NR silver with that demographic a self-adherent Superficial SSI Follow-up: 30 of a common characteristics breathable dressing. Overall: 13/112 (11.6%) days postoperative between groups. Timing of intervention: Intervention: 5/58 (8.6%) Funding Source dressing for ·Age, y: mean ±SD postoperative Control: 8/54 (14.8%) Conflicts: preventing Intervention: 63.6±9.2 Duration of intervention: P=0.802 Authors: None SSIs in elective Control: 62.9±9.0 removed 7th Deep SSI Institution: NR colorectal ·Gender: female postoperative day Overall: 5/112 (4.5%) Study: Industry cancer surgery. Intervention: 22 Device/agent: sterile Intervention: 3/58 (5.2%) Supplies: NR (37.9%) moisture retentive Control: 2/54 (3.7%) Control: 25 (46.3%) dressing with 1.2% ·Obesity: BMI iconic silver Organ/space SSI Mean±SD Monitoring intervention: Overall: 2/112 (1.8%) Intervention: 25.7±4.3 NR Intervention: 1/58 (1.7%) Control: 25.4±4.4 Control group: n=54 Control: 1/54 (1.9%) ·Comorbidities Surgical incision was Procedures: colorectal dressed with a self- Other infections: cancer surgery adherent breathable Infection within 30 days rectal: dressing which was Overall: 14/112 (12.5%) Intervention: 17/58 then covered by Intervention: 6/58 (29.3%) another self-adherent (10.3%) Control: 18/54 breathable dressing to Control: 8/54 (14.8%) (33.3%) maintain blinding P=0.802 P=0.687 Standard preventive measures: Topic-specific Indications: colorectal AMP: 30 minutes before outcomes: NA cancer initial incision. Reoperations: NR Setting: Two Skin prep; preoperative Length of stay: NR university-affiliated scrub and paint with Mortality: NR hospitals 10% povidone-iodine; Adverse events: None Location: Italy Mechanical bowel prep: all related to this study Dates: June 2008 - patients received it © 2017 American Medical Association. All rights reserved. 304

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Author Study Year Design Study Population and (Data Intervention Results Comments Quality Objective Setting Extrac- Score tor) September 2010 Inclusion Criteria: Patients aged 18-75 years old undergoing elective colorectal cancer surgery by laparotomic approach. Exclusion Criteria: History of allergy to dressing components, evidence of active infection at or adjacent to the operative site, coagulopathy (defined as platelet count less than 50,000 cells/ µL or a prothrombin time >18 seconds), intestinal obstruction, active bowel bleeding, life expectancy less than 6 months, inability to give written informed consent or a program of minimally invasive surgery (laparoscopy or robot-assisted) Krieger RCT To conduct a Number of patients: Intervention group: n=55 SSI Definitions: 2011 84 1, 2, 7, prospective, N=109 Silver nylon dressing, Total SSI: CDC (ES) 8, 9 randomized, Patient hydrated in sterile water Intervention: 7/55 (13%) Definitions. controlled trial Characteristics before application. Control: 18/54 (33%) Superficial incision directly ·Age, y: median Instructions were to P=0.011 definition was comparing Intervention: 62 rehydrate the dressing Superficial modified to © 2017 American Medical Association. All rights reserved. 305

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Author Study Year Design Study Population and (Data Intervention Results Comments Quality Objective Setting Extrac- Score tor) silver nylon Control: 58 daily and then replace Intervention: 5/55 (9%) include all with standard P=0.49 with a new dressing Control: 14/54 (26%) patients who gauze ·Gender: female: after 7 days. On P=0.021 were placed on dressings in Intervention: 27/55 discharge patients had Deep antibiotics patients (49%) a new dressing applied Intervention: 2/55 (4%) specifically for undergoing Control: 28/54 (52%) that remained for an Control: 4/54 (7%) these signs or elective ·Obesity: NR additional 7 days. P=0.438 symptoms. colorectal ·Comorbidities Timing of intervention: Perioperative operations. Diabetes mellitus: postoperative Other infections: NR care: NR Intervention: 5/55 Duration of intervention: Topic-specific Other notes: NR (9%) Device/agent: silver nylon outcomes: NR Follow-up: 30 Control: 4/54 (7%) wound dressing Reoperations days P=1.00 Monitoring intervention Debridement Funding Source Transfusion: Control group: n=54 Intervention: 0/55 Conflicts: Intervention: 7/55 Incisions were dressed Control: 2/54 (4%) Authors: None (13%) only with sterile gauze P=0.234 Institution: Control: 0 /54 and paper tape. On Industry P=0.013 discharge, patients Length of stay: median Study: Industry instructed to replace (range) Supplies: NR Procedures: elective their dressings as Intervention: 6 (3-21) colorectal surgery. needed. days Indications: Standard preventive Control: 6.5 (2-17) days Neoplastic, IBD, measures: P=0.210 Other Food restriction: clear Mortality: NR Setting: One liquid diet 24 hours Adverse events: NR university-based before surgery. hospital Mechanical Bowel Prep Location: USA not used with the Dates: July 2009 – exception of patients April 2010 undergoing left colon or Inclusion Criteria: rectal surgery, who Patients undergoing were given an enema elective colorectal the morning of their surgery with operation. anticipated Antimicrobial prophylaxis: abdominal incision of 30-60 minutes prior to at least 3cm. surgery. Standard Exclusion Criteria: coverage is ertapenem. Incision <3cm, Patient with penicillin © 2017 American Medical Association. All rights reserved. 306

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Author Study Year Design Study Population and (Data Intervention Results Comments Quality Objective Setting Extrac- Score tor) known allergy to allergies given silver, signs of alternative prophylaxis abdominal wall with ciprofloxacin and infection, conditions flagyl or gentamicin and that would prevent clindamycin. All full closure of the perioperative antibiotics skin at the primary discontinued within 24 operation, or prior hours. abdominal mesh that was not planned to be fully removed at the time of operation. Pregnant or lactating women and patients who had received antibiotics within 1 week of surgery also excluded.

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2.1B3. RISK OF BIAS ASSESSMENTS OF STUDIES: Q2 NON-PARENTERAL AMP eTABLE 35. Risk of Bias Assessments of Randomized Controlled Trials for Q2 Non-Parenteral AMP Funding Randomiza- Outco- Attrition source(s) Describ- tion Describ- me smaller than Attrition disclosed and ed as appropriat- ed as asses- Study Investiga- Attrition 10-15% of appropria- no obvious Overa- Author randomiz ely double- sor participa- tor describ- assigned tely conflict of ll Risk Year Q ed performed blind blinded nt blinded blinded ed patients analyzed interest of Bias Question 2: Non-Parenteral Antimicrobial Prophylaxis Almdahl Mode- 64 2      2011 rate Al-Sheri Mode- 57 2     1994 rate Baracs Mode- 71 2      2011 rate Biffi 83 2          Low 2012 Diener 77 2         Low 2014 Dorge 67 2  High 2013 Ford 81 2       Low 2005 Galal 76 2       Low 2011 Isik Mode- 79 2      2012 rate Justinger 75 2        Low 2013 Juul Mode- 58 2        1985 rate Kamath 61 2       Low 2005 Krieger Mode- 84 2      2011 rate Litmathe Mode- 66 2     2009 rate Mingmalai- rak 2           Low 2009 78 Nakamura 74 2       Low 2013 Neri 2     Mode- © 2017 American Medical Association. All rights reserved. 308

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Funding Randomiza- Outco- Attrition source(s) Describ- tion Describ- me smaller than Attrition disclosed and ed as appropriat- ed as asses- Study Investiga- Attrition 10-15% of appropria- no obvious Overa- Author randomiz ely double- sor participa- tor describ- assigned tely conflict of ll Risk Year Q ed performed blind blinded nt blinded blinded ed patients analyzed interest of Bias 2008 62 rate Peerboo- ms 2         Low 2009 65 Raahave Mode- 60 2     1989 rate Rasic Mode- 70 2      2011 rate Rozzelle 80 2           Low 2008 Ruiz- Tovar 2         Low 2012 56 Seco Mode- 59 2        1990 rate Seim Mode- 69 2      2012 rate Thimour- Bergstrom 2         Low 2013 73 Turtiainen 68 2         Low 2012 Vander Salm 2  High 1989 63 Williams 72 2       Low 2011

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2.1C. Q3 GLYCEMIC CONTROL 2.1C1. GRADE TABLE: Q3 GLYCEMIC CONTROL eTABLE 36. GRADE Table for Q3 Glycemic Control Increase Decrease GRADE GRADE

Quantity GRADE of Overall and Type Starting Evidence GRADE of Comparison Outcome Findings of GRA-DE for Evidence

Evidence response Outcome Base Precision Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Large Magnitude Large Q3. How do perioperative blood glucose and hemoglobin A1C levels impact the risk of SSI and what are their optimal perioperative target levels in diabetic and non-diabetic patients? • Two RCTs in 480 cardiac surgery predominantly non-diabetic (70%-80%) populations. Glycemic control protocol instituted intraoperative and postoperatively in the SICU for 24-36 hours. Both RCTs report a primary composite outcome variable that includes SSI (underpowered to detect differences in individual outcomes). • 1 large 85 (N=371) and one small 86 (N=109) RCT, comparing strict (80-100mg/dL) to standard (<200mg/dL) glycemic control found Strict no difference in either the composite outcome glycemic variable which included SSI: RR 1.0 (0.8-1.2); 2 RCT Moderat control vs. 85,86 p=0.71 (adjusted OR: 0.09 (0.6-1.4); p=0.68; Moderate SSI* High 0 0 -1 0 0 0 0 0 e standard or in deep sternal SSIs: RR 0.9 (95%CI, 0.3-

glycemic 2.5); p=0.79. In subanalyses of separate control diabetic (n=73) and non-diabetic (n=298) populations, no difference was noted between groups for either the composite (p=0.40) or deep sternal SSI (p=0.61) variables. The study could not examine whether outcomes differed by diabetes status. • 1 small RCT 86 (N=109), comparing strict (80- 130mg/dL) to standard (160-200mg/dL) glycemic control found no difference in either the composite infection outcome variable: 19.2% vs. 35.3%; p=0.12.and no difference in SSIs: 11.1% vs. 16.7%; p=0.09.

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Increase Decrease GRADE GRADE

Quantity GRADE of Overall and Type Starting Evidence GRADE of Comparison Outcome Findings of GRA-DE for Evidence

Evidence response Outcome Base Precision Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Large Magnitude Large • 1 large RCT 85 defined hypoglycemia as <60mg/dL, reported it as number of episodes in each treatment group. While the study found no difference between groups for hypoglycemic episodes in the SICU, it did find that for both groups a higher proportion of the episodes occurred in the SICU: 8 (4%) vs. 14 (8%); p=1.00, RR 1.01 (0.06-15.95) as Hypo- 2 RCT compared to intraoperatively: 1 (1%) vs. 1 High 85,86 High 0 0 0 0 0 0 0 0 glycemia* (1%); p=0.19, RR 1.76 (0.76-4.09). • 1 small RCT 86 defined hypoglycemia as <50mg/dL and reported it as the ratio of hypoglycemic episodes per number of glucose measurements. It also noted no difference between groups for hypoglycemic episodes: 2.9% vs. 2.1%, (0.84-1.43); p=0.67. • Neither study reported clinical complications resulting from hypoglycemia. • Mortality was rare, reported only in the strict 85 glycemic control group, and not associated Mortality 1 RCT High 0 0 0 -1 0 0 0 0 Moderate with blood glucose target levels: 4/185 vs. 0/186.

• Length of hospital stay (p=0.66) and length of Length 85 1 RCT SICU stay (p=0.37) were not associated with High 0 0 0 -1 0 0 0 0 Moderate of stay blood glucose targets.

*Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

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2.1C2. EVIDENCE TABLE: Q3 GLYCEMIC CONTROL eTABLE 37. Evidence Table for Q3. How do perioperative blood glucose and hemoglobin A1C levels impact the risk of SSI and what are their optimal perioperative target levels in diabetic and non-diabetic patients? Study Author Design Year Study Population and Setting Risk of Intervention Results Comments (Data Objective (N) Bias Extractor) Score Chan RCT To Number of patients: Intervention group SSI Definitions: 86 2009 1, 5, 7, 10 investigate N=109 (intensive) n=54 Intervention: 11.1% Hypoglycemia: Defined as (ES) whether Patient Characteristics: Intervention: 80 -130mg/dL Control: 16.7% <50mg/dL different the groups were glucose P=0.09 targets of comparable with Timing of intervention: Perioperative care: intraoperativ respect to age, gender perioperative Other infections: NR parenteral care was not e and and height. Duration of intervention: Topic-specific outcomes: prescribed for any patients postoperativ ·Age: NR from arrival in OR until36h Hypoglycemia in the study. e glucose ·Gender: NR postop Reported as: hypoglycemic Other notes: authors (80-130 ·Obesity: BMI Device/agent: Glucose episodes per number of indicate that 11 patients mg/dl, 4.4- Intervention: 24 (±3.4) Monitoring intervention: glucose measurements were lost to follow up and 7.2 mEq/l or Control: 26 (±4.9) Measurements of whole 2.9% vs. 2.1% P=0.67 (0.84- “may have biased the 160-200 ·Comorbidities: blood glucose in undiluted 1.43) results” AND “this pilot mg/dl, 8.8- ASA status P4: arterial blood every 1-4h study sample size was not 11.1 mEq/l) Intervention: 70.2% using a glucose analyzer. Reoperations: NR large enough to allow for could affect Control: 86.3% Glucose dose was adjusted Length of stay: (days) any definite conclusions or postoperativ Length of CBP (min) by ICU nurses according to Intervention: 12 (±7) recommendations on the e clinical Intervention: 97.9 a titration algorithm (Leuven Control: 17 (±16) effect of strict glucose outcomes (±45.3) modified). algorithm given P= 0.060 (0.24-1.01) control vs. less intensive after cardiac Control: 116.3 (±54) as guidance rather than control” surgery with P=0.060 exact targets Mortality: (%) Follow-up: 30 days cardiopulmo Procedures: Open-heart Control group: (less Intervention: 6.4% Funding Source Conflicts: nary bypass. surgery requiring intensive) n=55 Control: 5.9% Authors: None cardiopulmonary Control: 160-200mg/dL Institution: None bypass (CBP). glucose Adverse events: Study: None Indications: NR No clinical complications Supplies: None Setting: 1 university Standard preventive reported resulting from hospital measures: hypoglycemia at follow up (30 Location: Brazil AMP: 2nd generation days). Dates: NR (over a period cephalosporin of 12 months) Transfusion threshold: Inclusion Criteria: adults hematocrit<30% from both genders who were older than 21 years of age and who

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Study Author Design Year Study Population and Setting Risk of Intervention Results Comments (Data Objective (N) Bias Extractor) Score were undergoing open- heart cardiac surgery requiring CBP. Exclusion Criteria: (1) renal failure (creatinine>1.5g/dl), (2) neurological dysfunction (diagnosis from medical records), (3) chronic pulmonary obstructive disease (COPD), (4) current use of any type of antimicrobial, (5) current use of inotropic support, (6) emergency and urgent surgeries, and (7) reoperations. Ghandi RCT To Number of patients Intervention group: n=185 Definitions: 85 2007 1, 4, 5, 7, determine N=371 Intraoperative glycemic OR: 0.9, 95%CI (0.3-2.5) Primary outcome = (ES) 8 whether Patient Characteristics: control of 80mg/dL – P=0.79 composite of death, sternal maintenance Baseline characteristics 100mg/dL (4.4mmol/L – 5.6 Other infections: NR wound infections, of near did not differ statistically mmol/L) Topic-specific outcomes: prolonged pulmonary normoglyce significantly between Hypoglycemia ventilation, cardiac mia during groups. Timing of intervention: Intraoperative (1 patient in each arrhythmias, stroke, and cardiac ·Age: NR intraoperative group) acute renal failure within surgery by ·Gender: NR Duration of intervention: RR 1.01 (95%CI 0.06-15.95) 30 days postop. using ·Obesity: NR intraoperative only Postoperative (ICU): Hypoglycemia: glucose intraoperativ ·Comorbidities: Device/agent: Glucose Intervention: 14 (8%) <60mg/dL; e 20% had known diabetes Monitoring intervention: Control: 8(4%) Perioperative care : NR intravenous Arterial blood glucose levels RR 1.76 (95% CI 0.76-4.09) Other notes: this single insulin Procedures: were measured with a All mild without adverse center study used a infusion Cardiopulmonary glucometer. consequences composite end point and reduced bypass surgery Control group: n=186 could not examine whether perioperative Indications: NR Intraoperative glycemic Reoperations: NR outcomes differed by death and Setting: 1 tertiary care control target of <200mg/dL Length of stay: diabetes status. morbidity teaching hospital (11.1mmol/L) if glucose median and mean LOS in Primary outcome variable when added Location: USA level reached >250mg/dL hospital and ICU P=-.66 and was a composite variable to rigorous Dates July 2004 – April (13.9mmol/L), then p=0.37 because “not feasible to postoperativ 2005 intraoperative bolus was Mortality: power study to detect © 2017 American Medical Association. All rights reserved. 313

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Study Author Design Year Study Population and Setting Risk of Intervention Results Comments (Data Objective (N) Bias Extractor) Score e glycemic Inclusion Criteria: Adults given until level was less Overall& In hospital differences in individual control. undergoing elective than 150mg/dL (8.3mmol/L) 4/185 (2%) vs. 0% components such as cardiac surgery during Post discharge (up to 30d death, because the rare study dates Standard preventive postop) occurrences would Exclusion Criteria: measures: 0% vs. 0%; P=0.061 mandate a very large Patients who had off- Both groups had strict NOTE: POST DISCHARGE F/U sample size.” pump cardiopulmonary postoperative glycemic in only 4% vs. 5% of patients Follow-up: 30 days bypass procedures. control of 80mg/dL – Funding Source Conflicts: 100mg/dL) Adverse events: None reported Authors: Industry Institution: NR Study: NR Supplies: NR

2.1C3. RISK OF BIAS ASSESSMENTS: Q3 GLYCEMIC CONTROL eTABLE 38. Risk of Bias Assessments of Randomized Controlled Trials for Q3 Glycemic Control Funding Attrition source(s) Described Randomizati- smaller than disclosed and as on Described Outcome Study 10-15% of Attrition no obvious Overall Author randomize- appropriately as double-assessor participant InvestigatoAttrition assigned appropriate- conflict of Risk of Year Q ed performed blind blinded blinded blinded described patients ly analyzed interest Bias Question 3: Glycemic Control Chan 86 3     High 2009 Gandhi 85 3      High 2007

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2.1D. Q4-5 NORMOTHERMIA 2.1D1. GRADE TABLE: Q4-5 NORMOTHERMIA eTABLE 39. GRADE Table for Q4-5 Normothermia Increase Decrease GRADE

GRADE

Quantity GRADE of Overall and Type Starti-ng Evidence GRADE of Comparison Outcome Findings Of GRA-DE for Evidence

Evidence response Outcome Base Large Precision Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Q4. How safe and effective is the maintenance of perioperative normothermia in reducing the risk of SSI? • Meta-analysis of 2 RCT (N=616) found that maintenance of normothermia associated with reduced risk for SSI (OR: 0.29; 95% CI: 0.16 – 0.53; p<0.0001; I2=0) • Mixed surgical populations, multiple warming techniques • Maintenance of perioperative normothermia with warming techniques associated with reduced risk of surgical 2 RCT SSI* 87,88 site infection High 0 0 0 0 0 0 0 0 High

• 1 RCT 87 in 416 patients undergoing elective hernia repair, varicose vein and breast surgery, preoperative systemic warming only : 13/277 (5%) vs. 19/139 Warming vs. (14%); p<0.01 at 2-6 week follow up High no warming • 1 RCT 88 in 200 elective colorectal surgery patients using intraoperatively only warming: 6/104 (6%) vs. 18/96 (19%); p<0.01 at 2 week follow up. • ASEPSIS wound scores were higher in control groups (p<0.01 87 88) • In a meta-analysis of the two studies, ASEPSIS 2 RCT 87, 88 warmed patients were less likely to have High 0 0 0 0 0 0 0 0 High score ASEPSIS wound scores >20 (Relative Risk: 0.19; (95% CI, 0.09 – 0.39); p<0.01; I2=26% • Mortality within 30 days was rare (4 Mortality, 88 1 RCT deaths in 200 patients), with no difference High 0 0 0 -1 0 0 0 0 Moderate 30 days observed between groups © 2017 American Medical Association. All rights reserved. 315

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Increase Decrease GRADE

GRADE

Quantity GRADE of Overall and Type Starti-ng Evidence GRADE of Comparison Outcome Findings Of GRA-DE for Evidence

Evidence response Outcome Base Large Precision Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication • Normothermia associated with lower mean units of blood transfused per Blood Loss 1 RCT 88 patient: 0.4±1.0 vs. 0.8±1.2; p=0.01 and High 0 0 0 -1 0 0 0 0 Moderate fewer patients transfused: 23/104 (22%) vs. 34/96 (35%) • 1 RCT 87 found that core temperature was increased by either local or systemic warming techniques, delivered preoperatively for 30 minutes. The impact of systemic warming (mean increase: 0.35 C; p<0.01) was greater than local Core 2 RCT warming (mean increase: 0.13 C; ⁰ Temperatu- 87,88 High 0 0 0 0 0 0 0 0 High p=0.03). The mean core temperature after re surgery was within normal limits.⁰ • 1 RCT88 found that core temperature at end of surgery was increased with intraoperative systemic warming (p<0.01), and remained higher for more than 5 hours following surgery • Normothermia associated with reduced Length of 88 length of stay (net reduction: 2.6 days; Hospital 1 RCT High 0 0 0 -1 0 0 0 0 Moderate p<0.01); difference remained when Stay analysis was limited to uninfected patients Duration of 2 RCT • Normothermia not associated with 87,88 High 0 0 0 0 0 0 0 0 High Surgery increased duration of surgery • Warming: Perioperative warming associated with perioperative decreased incidence of SSI (12.8% vs. SSI* 1 RCT 89 High 0 0 0 -1 0 0 0 0 Moderate (carbon polymer 26.8%), but this finding was not significant mattress [2hours OR 0.4 (0.14-1.13); p=0.08; sample size Moderate preop, intraop, based on all complications and 2 hours 89 • 3 deaths in 103 patients, with no postop], forced Mortality 1 RCT High 0 0 0 -1 0 0 0 0 Moderate air warming and difference observed between groups

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Increase Decrease GRADE

GRADE

Quantity GRADE of Overall and Type Starti-ng Evidence GRADE of Comparison Outcome Findings Of GRA-DE for Evidence

Evidence response Outcome Base Large Precision Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication fluid warmer 89 • Perioperative warming associated with Blood Loss 1 RCT High 0 0 0 -1 0 0 0 0 Moderate intraop) lower blood loss (p<0.01) vs. intraoperative • Perioperative systemic warming group, only (carbon higher core temperature achieved polymer immediately after 2 hours of preoperative mattress, forced Core warming (p<0.01) 89 air warming and Temperatu- 1 RCT • Perioperative systemic warming group High 0 0 0 -1 0 0 0 0 Moderate fluid warmer) re maintained higher core temperature during the first 90 minutes of surgery (median 36.2 vs. 36.1) but not at 2 hours postoperatively (p=0.47) Length of 89 • Perioperative warming not associated with Hospital 1 RCT High 0 0 0 -1 0 0 0 0 Moderate reduced length of hospital stay (p=0.22) Stay

• Perioperative systemic warming was not Duration of 89 1 RCT associated with increased duration of High 0 0 0 -1 0 0 0 0 Moderate Surgery surgery (p=0.15) Q5. What are the most effective strategies for achieving and maintaining perioperative normothermia? Our search did not identify RCTs or SRs that evaluated the most effective strategies for achieving and maintaining perioperative normothermia and their impact on the risk of SSI. *Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

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2.1D2. EVIDENCE TABLE: Q4-5 NORMOTHERMIA eTABLE 40. Evidence Table for Q4. How safe and effective is the maintenance of perioperative normothermia in reducing the risk of SSI? Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting (N) Extractor) Bias Score Wong RCT To examine No. patients: N=103 Intervention: n=47 SSI Definitions: 2007 89 1, 2, 4, 6, the effects of Patient Mattress warmed to Intervention: 6/47(12.8%) SSI- CDC: (1) when pus could (SIBT) 7, 8, 9 extending Characteristics: 40°C 2 hours before Control: 15/56 (26.8%) be expressed from the surgical systemic (age, sex, ASA surgery, during surgery, Other Infections incision or aspirated from a warming score, MBI, and for 2 hours after Chest infection loculated mass inside the duration to POSSUM scores, surgery in addition to Intervention: 2/47 (4.3%) wound (2) if the pus culture was include pre- baseline standard practice of Control: 6/56 (10.7%) positive for pathogenic bacteria and temperature, pulse systemic warming with Urinary tract infection: (3) if there was localized postoperative rate and mean forced air warming Intervention: 3/47 (6.4%) tenderness, localized swelling, periods and arterial pressure device set at 40°C and Control: 2/56 (3.6%) redness or temperature at the the potential were similar in both with a fluid warmer Topic specific outcomes surgical site, or (4) if the benefits in groups/not Timing of Intervention: median (range) ; P value treating medical practitioners reducing statistically pre, intra and post Core Temperature had diagnosed them as infected postoperative significant except for operatively. Immediately after preoperative and treated them with complications core temperature Duration of systemic warming: antimicrobials. in patients before start of intervention : 2h Intervention 36.4 (35.1-37.4) Hypothermia: <36°C undergoing surgery (see results) preoperatively, Control: 36.0 (35.1-36.9) Normothermia: ≥36°C elective major Age: ≥ 18years of intraoperatively and 2 P <0.001 Perioperative care: abdominal age hours post operatively Intraoperative: 90 minutes Anesthesia: Fentanyl and surgery.. Median (range) Device: conductive Interventions group vecoronium bromide. Isoflurane Intervention:62.0 carbon polymer mattress “maintained a significantly (in 60% nitrous oxide) titrated to (24-88) can provide sustained higher temperature during the maintain MAP within 20% of Control: 60.5 (20-84) heat up to 40°C. first 90 minutes of surgery” pre-induction values. Additional Gender: m/f Monitoring: (median 36.2) vs. controls fentanyl at end to improve Intervention: 24/23 Pre and postoperatively: (36.1). analgesia. Control: 29/27 before and immediately Core Temperature Postop Other notes: NR BMI: median (range) after surgery tympanic (2hours): Follow up: every day during Intervention: thermometer Intervention: 36.3 (34.3-38.1) hospitalization and at 6-8 23.0(15.5-39.2) Intraoperative: Control: 36.2 (34.3-37.9) weeks postoperatively (usually Control: nasopharyngeal P=0.471 in the home) 25.0 (16.5-36.3) temperature probe Blood loss (ml): Mean (range) Funding Source Conflicts: ASA score (every 30 minutes) Intervention: 200 (5-1000) Authors: NR ASA1:29/103 Control: n=56 Control: 400 (50-2300) Institution: NR (28.2%) Mattress warmed to P=0.011 Study: NR ASA2: 50/103 40°C only during surgery All other outcome variables (IV Supplies: NR (38.5%) in addition to standard fluids, urine output, blood © 2017 American Medical Association. All rights reserved. 318

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting (N) Extractor) Bias Score ASA3:24/103 practice of systemic transfusion units (none), (23.3%) warming with forced air duration of antimicrobials, More than 75% of warming device set at flatus passed, bowels opened, procedures 40°C and with a fluid diet tolerated, duration of performed by warmer hospital stay and follow up) consultant (senior) Standard Preventive showed no statistically surgeon Measures significant difference Procedure: Elective AMP- not described Reoperations: NR major abdominal AMP duration: mean Length of Stay: mean surgery (range) (range); P value Right Intervention:1 (0-28) Intervention: 11.0 (5-119) hemicolectomy Control: 2(0-12) Control: 9.0 (5-40) n=31 P=0.200 P value 0.217 Anterior resection Bowel Prep-not Mortality- 1 (surgical n=24 described emphysema from intubation Indications: complication) vs. 2 (renal & Colorectal cancer respiratory failure) (P=0.566) n=71 Inflammatory Adverse events: bowel disease n=15 Total Number of Adverse Diverticular disease events: n=7 Gastric Intervention: 15/47 (32%) carcinoma n=3 Control: 30/56 (54%) Benign colonic P=0.027 tumor n=2 Others Ileus 7/103 (14.9%) n=5 Pelvic collection 3/103 (2.9%) Setting: 1 university Cardiac complications 2/47 hospital (4.3%) Location: United Renal Failure 2/47(4.3%) Kingdom Anesthetic complications Dates: October 1/47(2.1%) 2002 to December Clostridium difficile diarrhea 2003 1/47(2.1%) Inclusion criteria: Pressure ulcer 1/47(2.1%) major open For SSI, chest infection and abdominal surgery urinary tract infection see requiring bowel “Other Infections” above resection, with or without anastomosis . Exclusion criteria: © 2017 American Medical Association. All rights reserved. 319

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting (N) Extractor) Bias Score laparoscopic procedures, use of corticosteroids or other immunosuppressive drugs (including cancer chemotherapy_ during the 4 weeks before surgery, recent history of fever, infection or both, serious malnutrition (serum albumin <3.3g.dl, a white cell count <2500 cells per ml or the loss of more than 20% of body weight within 3 months of surgery) and bowel obstruction. Melling RCT To assess the No. patients: N= Intervention1-Systemic SSI (2-6 weeks) Definitions: 2001 87 1, 2, 4, 6, use of a local 416 n=139 group-standard Overall rate of infection 32/416 SSI- purulent discharge or a (SIBT) 7, 8, 9 warming Patient preoperative care plus (8%) painful erythema that lasted 5 device and a characteristics: minimum 30 minutes SSI: days and was treated with warm air similar in all groups. preoperative warming to Interventions1&2 13/277 (5%) antimicrobials within 6 weeks of blanket for the Including age, BMI, the whole body using Control: 19/139(14%) surgery. Wounds swabbed for reduction of gender, fasting>8h, forced-air, warming P=0.001 culture if purulent discharge infection after hair removal blanket. ASEPSIS wound scores present at time of review. clean wound (shaving) >6 h, type Intervention 2- Local significantly higher in control Note: only 14 wound swabs surgery. of surgery, surgery n=138 standard group vs. combined were obtained because in last 3 months, preoperative care plus interventions (p=0.007) Postoperative antimicrobials- cancer diagnosis, minimum 30 minutes ASEPSIS >20 “Patients seen at 2 and 6 initial core preoperative warming to Interventions 1&2 10/277 (4%) weeks had often been temperature, AMP, just the planned wound Control: 17/138 (12%) prescribed antimicrobial length of surgery, area using a non- treatment by their general seniority of surgeon. contact, radiant heat Other wound complications practitioner without having © 2017 American Medical Association. All rights reserved. 320

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting (N) Extractor) Bias Score Age, years: ≥18 dressing. including hematoma, seroma, wound swabbed” years Mean (SD) Timing of intervention: and wound aspiration no Normothermia: NR Intervention preoperative statistically significant Hypothermia: NR 1:49.7(13.7) Duration of difference between groups. Perioperative care: Intervention 2: 50 Intervention: for a SSI : Intervention 2 -local vs. Anesthesia- not described (14.1) minimum of 30 minutes Intervention 1-systemic Follow up: 2-6 weeks Control: 50.4 (15.3) until just before surgery warming postoperatively in outpatient Gender m/f: 174/242 Device: No differences in outcomes clinic or home. Direct Obesity: Systemic-Forced-air between two warming observation, patient diary, if not BMI (mg/kg2): warming blanket methods. available for examination then Intervention Local- non-contact, Individually both local telephone assessment patient 1:25.7(4.3) radiant heat dressing. (p=0.003) and systemic questionnaire (6/10 Intervention Monitoring (p=0.026) warming had a questionnaires returned) 2:25.8(4.1) intervention: tympanic significant effect on rate of Funding Source Conflicts: Control:25.6(4.1) thermometers before SSI. Authors: NR Procedure: Elective any treatment, after any Effect of warming Institution: NR hernia repair n=155 warming and after interventions compared with Study: Industry varicose vein surgery control: Supplies: Industry surgery n=86 breast Control: - (n=139) Absolute risk reduction (95% surgery n=175 standard preoperative CI): Indications: NR care plus no warming Intervention 1 systemic Setting: 1 district Standard Preventive 10.1% (3.6-16.6) general hospital Measures: Intervention 2 Local Location: United Antimicrobial 7.9% (1.0-14.8) Kingdom prophylaxis- AMP: Relative risk reduction: Dates: April 1999 to 119/416 (29%) Intervention 1 systemic 73.7% May 2000 Hair Removal- Shaving Intervention 2 local 57.7% Inclusion criteria: No shaving Numbers needed to treat: Elective hernia 110/416(26.4%) Intervention 1 systemic 15 repair, varicose vein Shaving <7h preop: patients. surgery, or breast 116/416 (27.9%) Intervention 2 local 10 surgery that would Shaving>7h preop: SSI vs. No SSI result in a scar 183/416 (20%) Mean (SD) longer than 3 cm in Info missing n = 9 Stepwise logistic regression length. yielded only body mass index Exclusion criteria: as significant variable at the Pregnant, taking 5% level OR 1.12 (95% CI long-term oral 1.02-1.21) steroids, had BMI

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting (N) Extractor) Bias Score received SSI: 28.04 (4.44) radiotherapy ( to the No SSI 25.31(3.98) incision site) or Breast surgery had higher SSI chemotherapy in the rate than hernia repair and last 4 weeks, or had varicose veins an infection at the Hair Removal: time of surgery No shaving: SSI 9/32 (28%)

No SSI 101/384 (27%) Shaving within 7h of surgery SSI 6/32 (19%) No SSI 110/384 (30%) Shaving >7hrs before surgery SSI 17/32 (53%) No SSI 166/384 (44%) SSI and AMP: Had AMP SSI: 6/32 (19%) No SSI 115/384 (30%) Topic-specific outcomes mean (SD); P value Initial core temperatures were significantly increased by intervention 1 and 2 vs. control Intervention 1Systemic 0.35°C(0.58) P=0.001 Intervention 2 Local: 0.13°C( 0.57) P=0.028 Control initial core temp: 36.5 (0.55)

Postoperative core temperatures were within normal limits: 36.41 (0.59) Intervention 2-Local received longer period of warming (min) as compared to Intervention 1- systemic (44.94 vs. 38.73,

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting (N) Extractor) Bias Score p=0.005) Length of stay: NR Mortality: NR Adverse events: Prescribed postop antimicrobials: Intervention1&2: 18/277(7%) Control: 22/139 (16%) P=0.002 Kurz RCT To test No. patients: Intervention: n=104 SSI: 2 weeks Definitions 88 1996 1, 2, 4, 5, hypothesis N=200 Fluid warmer on. Overall: 24/200 (12%) Wound Infection (Suspected): If (SIBT) 6, 7, 8, 9 that Patient Forced-air cover 40°C Intervention: 6/104 (6%) pus could be expressed from hypothermia Characteristics: Patient target core Control: 18/96 (19%) the surgical incision or both characteristics, temp maintain near P=0.009 aspirated from a loculated mass increases diagnoses, types of 36.5°C SSI in smokers(n=62) vs. non- inside the wound susceptibility surgical procedure, Timing of Intervention: smokers (n=138) Wound Infection (Confirmed) - if to surgical duration of surgery, intra-operative Smokers: 14/62 (23%) pus culture was positive for wound hemodynamic Duration of Non-smokers10/138 (7%) pathogenic bacteria. infection and values, and types of intervention: P=0.004 ASPESIS score >20 lengthens anesthesia were intraoperative ( from SENIC score (1/2/3) Hypothermia 34.5°C hospitalization similar in both induction of anesthesia Intervention:3/95/6 Normothermia 36.5°C groups -no to end of surgery) Control:3/88/5 Perioperative care: statistically Device: NNISS scores (0/1/2) Anesthesia standardized: significant difference Fluid warmer and Intervention:32/49/23 thiopental sodium, fentanyl, Age: 18 to 80 years forced-air cover Control:31/39/26 vecuronium bromide, mean±SD Monitoring: P=0.6 isoflurane, and fentanyl at Age: Temperature: tympanic ASEPSIS scores: completion for analgesia. Gender: m/f 108/92 thermometer Intervention: 7±10 Follow up: 2 weeks: daily in Height ,cm: Preop- recorded Control: 13±16 hospital and at 2 weeks postop. Intervention:170±9 Intraop- 10 min intervals P=0.002 94% returned for 2 week visit, Control: 169±9 Postop-20 min intervals ASEPSIS scores>20: those who did not were evenly P=0.43 for 6h Intervention: 6% of patients distributed between the study Weight, kg Thermal comfort-visual Control: 32% of patients groups and most returned to Intervention:73±14 analog scale (VAS) P<0.001 visit private offices of attending Control: 71±14 Pain- VAS ASEPSIS Score in surgeons. Wound status P=0.31 Shivering-scale all smokers(n=62) vs. non- determined by calling physician. Procedure: Elective evaluated at 20min smokers (n=138) No previously unidentified SSIs colorectal resection intervals for 6 hours Smokers:15±18 detected in clinic for the first Indication: postop. Non-smokers: 8±10 time © 2017 American Medical Association. All rights reserved. 323

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting (N) Extractor) Bias Score Cancer 182/200 Control: n=96 P<0.001 Funding Source Conflicts: (91%) Inflammatory Fluid warmer off. SSI Risk Factors, multivariate Authors: None bowel disease Forced-air cover analysis Institution: NR 18/200 (9%) ambient temperature OR (95%CI) Study: Industry Setting: 3 hospitals Patient target core Tobacco use (Y/N): 10.5 (3.2- Supplies: NR 1 University n=155 temp: allowed to 34.1) 1 University n=30 decrease to ~34.5°C. Group assignment 1 other hospital Standard preventive (Intervention vs. Control) n=15 measures: 4.9 (1.7-14.5) Location: Austria Bowel Prep- standard Surgical site (rectum vs. colon) Dates: July 1993 mechanical bowel prep 2.7 (0.9-7.6) through March 1995 with an electrolyte NNISS score (per unit Inclusion criteria: solution. increase) Abdominal AMP-standardized- IV 2.5 (1.2-5.3) intraperitoneal pull- cefamandole and Age (per decade) 1.6 (1.0-2.4) through procedures metronidazole at Other infections: Exclusion criteria: induction of anesthesia Topic-specific outcomes: minor colon surgery and maintained for 4 mean ± SD; P value: (e.g., polypectomy days postoperatively Intraoperative or colostomy Fluids: “hydrated Transfusions (allogeneic performed as the aggressively during and blood) only procedure), use after surgery” – see Intervention: 0.4±1.0 of corticosteroids or details Control 0.8 ± 1.2 other Transfusion: Leukocyte P=0.01 immunosuppressive depleted blood at Vasoconstriction drugs (including surgeon’s discretion Intervention: 6% of patients cancer O2- supplemental, nasal Control: 74% of patients chemotherapy) prongs at 6L/min first P<0.001 during the 4 weeks 3hours postop, gradually Core Temperature at end of prior to surgery, a eliminated to maintainO2 surgery recent history of sat >95% Intervention:36.6±0.5°C fever, infection or Pain- opioids postop Control: 34.7±0.6°C both, serious (patient controlled) P=<0.001 and remained malnutrition (serum significantly different for >5 albumin <3.3g/dL, hours postoperatively white blood cell Postoperative count <2500 Vasoconstriction cells/mL, or the loss Intervention: 22% (short-lived) of more than 20% of Control: 78% (continued

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting (N) Extractor) Bias Score body weight), or throughout 6h recovery) bowel obstruction. P<0.001 Shivering: Intervention: “a few” Control: 59% of patients Thermal comfort score- VAS 1h postop: Intervention: 73±14mm Control: 35±17mm Remained statistically significant for 3h Other: Pain score and amount of opioid administered “virtually identical” in the two groups at every postop measurement; hemodynamic values also similar. Collagen deposition µg/cm Intervention: 328±135 Control: 254±114 P=0.04 Days to first solid food: Intervention: 5.6±2.5 Control: 6.5±2.0 P=0.006 Remained statistically significant even when analysis was limited to uninfected patients: Intervention: 5.2±1.6 Control: 6.1±1.6 P<0.001 Days to suture removal Intervention: 9.8±2.9 Control: 10.9±1.9 P=0.002 Remained statistically significant even when analysis

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting (N) Extractor) Bias Score was limited to uninfected patients: Intervention: 9.6±2.6 Control: 10.6±1.6 P=0.003 Days to suture removal in smokers (n=62) vs. nonsmokers (n=138) Smoker: 10.9±3.5 Non-smoker10.1±2.0 P=0.04 Length of stay, days: Intervention:12.1±4.4 Control: 14.7±6.5 P=0.001 Remained statistically significant even when analysis was limited to uninfected patients: Intervention: 11.8±4.1 Control:13.5±4.5 P=0.01 Analysis: smokers(n=62) vs. nonsmokers (n=138) Smokers: 14.9±6.7 days Non-smokers: 12.9±5.0 P=0.02 Mortality:30 days Intervention: 2/104(1.9%) Control: 2/96 (2.1%) Adverse events: ICU Admission- (wound dehiscence, colon perforation, peritonitis) Intervention: 4/104 (3.9%) Control: 7/96(7.3%) P=0.47

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Q5. What are the most effective strategies for achieving and maintaining perioperative normothermia? Our search did not identify RCTs or SRs that evaluated the most effective strategies for achieving and maintaining perioperative normothermia and their impact on the risk of SSI.

2.1D3. RISK OF BIAS ASSESSMENTS OF STUDIES: Q4-5 NORMOTHERMIA eTABLE 41. Risk of Bias Assessments of Randomized Controlled Trials for Q4-5 Normothermia Funding Attrition source(s) Described Randomizati- smaller than 10- disclosed and as on Described Outcome Study 15% of Attrition no obvious Overall Author randomize- appropriately as double-assessor participant Investigat- Attrition assigned appropriatelyconflict of Risk of Year Q ed performed blind blinded blinded or blinded described patients analyzed interest Bias Question 4: Normothermia Kurz 88 4         Low 1996 Melling 87 4        Low 2001 Wong 89 4        Low 2007

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2.1E. Q6-7 OXYGENATION 2.1E1. GRADE TABLE: Q6-7 OXYGENATION eTABLE 42. GRADE Table for Q6-7 Oxygenation Increase Decrease GRADE GRADE

Overall

Q6. In patients with normal pulmonary function, how safe and effective is the perioperative use of increased fraction of inspired oxygen (FiO2) in reducing the risk of SSI? General Anesthesia Intraoperative only (mechanical ventilation) • In one RCT of 434 routine gynecological and abdominal surgeries, analysis suggested no difference between groups: 15/226 (6.6%) vs. 15/208 (7.2%); RR: 0.92 (0.46 – 1.84); p= 0.81. However, this study did not describe maintenance of SSI, All* 1 RCT 90 normothermia or adequate volume High 0 0 0 -1 0 0 0 0 Moderate replacement. There were significant differences in deviation from protocol between study groups: 3/226 (1.3%) vs. 13/208 (6.3%), p<0.01, with reasons for 80% oxygen deviation in the control group including vs. 30% desaturation and bradycardia. oxygen (Both Moderate Organ/ 90 • No difference between groups: 4/226 (1.8%) groups without 1 RCT High 0 0 0 -1 0 0 0 0 Moderate nitrous oxide) Space vs. 5/208 (2.4%)

Deep 90 • No difference between groups: 5/226 (2.2) 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Infection vs. 4/208 (1.9)

Superficial 90 • No difference between groups: 6/226 (2.7%) 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Infection vs. 6/208 (2.9%) • No difference between groups in sternal pain, 5/226 (2.2%) vs. 6/208 (2.9%), p=0.66 Adverse 90 1 RCT • No significant difference between groups in High 0 0 0 -1 0 0 0 0 Moderate Events nausea and vomiting (17/226 (7.5%) vs. 11/208 (5.3%), p=0.34 or hypotension 3/226 © 2017 American Medical Association. All rights reserved. 328

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Intraoperative mechanical ventilation and postoperative non-rebreathing facemask or nasal cannula for 2-6 hours All Surgeries • A meta-analysis (N=2622) of 6 RCTs that included heterogeneous surgeries and patients, and differences in optimization of normothermia and adequate tissue perfusion suggested 80% oxygen was associated with reduction in SSI: OR: 0.63 (0.43 – 0.92); p=0.02; I2=52% • 3 high quality RCT91-93 totaling 1001 colorectal (n=791) and open appendectomy (n=210) patients, each reported a 40% reduction in SSI with 80% oxygen. Each study optimized perioperative tissue oxygen 80% oxygen delivery by standardizing patient core vs. 30% 91- temperature regulation strategies targeted 6 RCT oxygen (Both SSI, All* 96 at maintenance of normothermia and fluid High 0 -1 0 0 0 0 0 0 Moderate Moderate

groups without replacement to avoid hypo or hypervolemia nitrous oxide) • 1 high quality RCT of 21796 patients undergoing open reduction and internal fixation of 235 high-energy tibial plateau (n=78), tibial pilon (n=86) and calcaneus (n=61) fractures reported a 40% reduction in SSI with 80% oxygen though this difference was not significant with a multivariate adjusted OR: 0.54 (0.22-1.29); p=0.17. Normothermia and adequate fluid replacement were not described. • 1 high quality RCT94 in 1386 patients undergoing a variety of general and gynecologic surgical procedures found no © 2017 American Medical Association. All rights reserved. 329

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Quantity GRADE of GRADE and Type Starting Evidence Comparison Outcome Findings of of GRADE for Evidence Evidence response Outcome Base Precision Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Large Magnitude Large difference between groups. However, this study did not optimize tissue oxygen delivery as it failed to maintain perioperative normothermia and instituted aggressive perioperative fluid restriction. • Organ/space infections reported in 5% of Organ/ 2 RCT 1386 patients, and comprised 28% of all SSI Space 94,95 High 0 0 0 -1 0 0 0 0 Moderate • No difference between groups: 36/685 (5%) Infection vs. 39/701 (6%) • Deep infections reported in 3% of 1386 Deep 2 RCT patients, and comprised 15% - 18% of all 94,95, High 0 0 0 -1 0 0 0 0 Moderate Infection SSI; no difference between groups OR: 0.80 (0.42 – 1.51); p=0.52 • Superficial infections reported in 11% of Superficial 2 RCT 1386 patients, and comprised 54% - 57% of 94,95 High 0 0 0 -1 0 0 0 0 Moderate Infection all SSI; no difference between groups OR: 1.15 (0.71 – 1.85); p=0.63 • 2 RCTs 92,93 found that 80% oxygen was associated with lower ASEPSIS scores 91- ASEPSIS 4 RCT • 2 RCTs 91,94 suggested that 80% oxygen 94 High 0 0 0 0 0 0 0 0 High Scores was associated with fewer patients scoring >20 on ASEPSIS scale, but this finding was not significant • 1% mortality reported in elective colorectal surgery patients at 14days91,93 • 5% mortality reported in mixed emergency Mortality, 4 RCT and elective laparotomy patients at 30 14-30 91,93-95 94 High 0 0 0 0 0 0 0 0 High days Days • No difference between groups • Mortality unrelated to use of increased fraction of inspired oxygen

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(14 Days) oxygen was reported in 5% of patients • No difference between groups • Atelectasis diagnosis based on a Atelectas- radiologist’s evaluation and description on 2 RCT is (14 94,95 chest radiograph or computed tomography High 0 0 0 -1 0 0 0 0 Moderate

Days) • Reported in 8% of patients • No difference between groups • Subcutaneous tissue oxygen tension was higher in patients receiving 80% oxygen. Tissue 93 This was noted both intraoperatively (109 Oxygen 1 RCT High 0 0 0 -1 0 0 0 0 Moderate mmHg vs. 59mmHg; p<0.01) and Tension postoperatively (73 mm Hg vs. 54 mm Hg; p=0.02) • 3 RCTs91-93 found no statistical difference between groups • The 2 colorectal surgery studies91,93 suggested that 80% oxygen was associated with one day longer duration of hospital stay but the findings were not significant: 12 vs.11 days; P=0.26 93 and p=0.09 91 respectively Length of 5 RCT 91- • Only the 1 open appendectomy RCT92 94,96 High 0 -1 0 0 0 0 0 0 Moderate Stay reported a significantly longer hospital stay in the 30% oxygen group (p=0.01). • One RCT96 (N=235 fractures in 217 patients) in fracture fixation surgeries reported a longer length of hospital stay for the 80% oxygen group, but this difference was not significant: 3.5 days (SD 4.1 days) vs. 2.8 days (SD 2.6 days), p=0.11. • The 1 large, mixed surgical population © 2017 American Medical Association. All rights reserved. 331

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bowel prep, and adequate tissue perfusion suggested no maintenance of benefit to 80% oxygen OR: 0.64 (0.40 – tissue perfusion 1.04); p= 0.07; I2=59% and normothermia) Intraoperative mechanical ventilation and postoperative 30 minutes with nitrous oxide • One interim analysis 1 RCT (n=160) reported 29 (18%) SSIs 97 SSI, All* 1 RCT • 80% oxygen was associated with an High 0 0 0 -1 0 0 0 0 Moderate increased risk of SSI: OR: 2.63; (1.1 – 6.2); 80% oxygen p=0.02; RR: 2.22 (1.1-4.6) vs. 35% • Deep structures infection reported in 4/160 oxygen (both Deep (3%) of patients an no difference between groups with Structures 1 RCT 97 group: 3/80 (4%) vs. 1/80 (1%); OR 3.08 High 0 0 0 -1 0 0 0 0 Moderate Moderate nitrous oxide Infection (0.31-30.24); p=0.62 30 minutes • Comprised 11% - 15% of all SSI after incision) • Wound infection reported in 18/160 (11%) patients, comprising 56% - 65% of all SSI Wound 97 1 RCT • High 0 0 0 -1 0 0 0 0 Moderate Infection No difference between groups: 13/80 (16.25%) vs. 5/80 (6.25%): OR 2.91 (0.99 - 8.59); p=0.08

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Mortality 1 RCT 97 • 1 death reported, in the control group High 0 0 0 -1 0 0 0 0 Moderate

• This study suggested that 80% oxygen was Length of 97 associated with a longer mean length of 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Stay stay (8.3 days vs. 6.4 days), but the finding was not significant (p=0.07) NEURAXIAL ANESTHESIA (Intraoperative and postoperative non-rebreathing facemask) • A meta-analysis (N=1559) of 3 RCTs in heterogeneous patients undergoing cesarean section surgeries with Neuraxial anesthesia, and differences in optimization of normothermia and adequate tissue perfusion suggested no benefit to 80% oxygen: OR: 1.31 (0.90 – 1.90); p=0.16; I2=17% • 1 large RCT99 (n=831) in cesarean section 98- patients found no difference in SSI 3 RCT SSI, All* 100 incidence between groups: 8.2% (34/416) High 0 -1 0 0 0 0 0 0 Moderate Moderate

vs. 8.2% (34/415), p=0.89. This study ensured adequate tissue perfusion, fluid replacement and normothermia. Antimicrobial prophylaxis was administered post cord-clamp • 1 large RCT100 (n=585) and 1 small interim analysis98 (n=143) in cesarean section patients suggested 80% oxygen delivered through a non-rebreathing facemask was associated with non-significant increase in © 2017 American Medical Association. All rights reserved. 333

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itis significant in either study 7/288 (2.4%) vs.

2/297 (0.7%), p=0.08, and 9/69 (13%) vs.

5/74 (7%), p=0.26 respectively. Neither study was adequately powered to detect a statistical difference in this outcome. • 1 large RCT99 (n=831) suggested no difference in the incidence of endometritis with 80% oxygenation (2.4% vs. 2.7%, p=0.66). This study ensured adequate volume replacement and normothermia.

Length of 98 • No difference between groups: median days 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Stay (range): 3 (2-5) vs. 3 (2-6); p=0.92 POSTOPERATIVE ONLY (Facemask and/or nasal cannula) 28-30 % • In1 RCT102 of 274 lower limb vascular 2 RCT oxygen vs. SSI, All* 101,102 surgeries, multivariate analysis suggested High -1 0 0 0 0 0 0 0 Moderate Moderate

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Organ/ 102 • No infections in the intervention group vs. 2 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Space infections (3%) in the control group

Deep 102 1 RCT • No difference : 5.1% in each group High 0 0 0 -1 0 0 0 0 Moderate Infection

Superficial 102 • No difference: 18/137 (13%) vs. 29/137 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Infection (21%); OR 0.56; (0.30-1.07); p=0.11.

ASEPSIS 101 • All within satisfactory healing (Score 0-10) 1 RCT High -1 0 0 -1 0 0 0 0 Low Scores • No difference observed between groups • Mortality was rare (4 deaths among 274 Mortality, 102 patients) and did not differ by group: 3/137 1 RCT High 0 0 0 -1 0 0 0 0 Moderate 30 Days (2.2%) vs. 1/137 (0.7%); OR 3.0 (0.31- 28.99); p=0.62. • Adverse events were rare and did not differ between groups Adverse 2 RCT • Reported adverse events include: wound 101,102 High -1 0 0 -1 0 0 0 0 Low Events complications, graft thrombosis, cardiac complications, pneumonia, stroke, renal insufficiency, major amputation Tissue • Subcutaneous tissue oxygen tension was Oxygen 1 RCT 101 higher in patients receiving supplemental High -1 0 0 -1 0 0 0 0 Low Tension oxygen (63 mm Hg vs. 48 mm Hg; p<0.01)

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Length of 102 • No difference observed between groups: 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Stay 6.5d vs. 5.4d; p-=0.13. Q7. What is the optimal target FIO2 to reduce the risk of SSI; how and when should it be administered? Our search did not identify RCTs or SRs that both evaluated the optimal fraction of inspired oxygen, how and when it should be administered, and included SSI as an outcome. All studies evaluating the use of supplemental increased oxygenation both intraoperative and postoperatively used 80% FiO2 as the target level. \ *Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

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2.1E2. EVIDENCE TABLE: Q6-7 OXYGENATION eTABLE 43. Evidence Table for Q6. In patients with normal pulmonary function, how safe and effective is the perioperative use of increased fraction of inspired oxygen (FiO2) in reducing the risk of SSI? Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Duggal RCT To evaluate Number of patients N=831 Intervention group n=416 SSI Definitions: 2013 99 1, 2, 3, whether Patient Characteristics: the 80% oxygen – an aerosol face Composite infection (ITT) (SSI Surgical site infection – CDC (ES) 4, 5, 7, supplemental two groups were well mask delivered oxygen at 80% + Endometritis) % (n Definition: at least 1 of the 9, perioperative matched for age, race, concentration during surgery calculated by extractor) following criteria was oxygen could parity, BMI number of and for 1h postop. Flow rate Intervention: 8.2% (34/416) required: 1) purulent reduce the previous cesarean 10L/min. Control: 8.2% (34/415) discharge from incision site; occurrence of deliveries, elective Timing of intervention: intra- P=0..89 2) organisms isolated from an surgical site cesarean deliveries, and post-operatively SSI at discharge (usually PO aseptically obtained culture or infection or history of diabetes, Duration of intervention: day 3) tissue from the superficial endometritis in cardiac or pulmonary intraoperative and for 1h Intervention: 2.4% (10/416) incision; 3) at least one of the women disease, anemia, postoperative Control: 2.9% (10/415) following signs or symptoms: undergoing smoking, or chronic Device/agent: Aerosol face mask P=0.70 pain or tenderness, localized cesarean steroid use. was used for both intervention SSI assessed by 6wk swelling, redness or heat, deliver ·Age: mean ±SD, y and control Intervention: 3.1% (13/416) and the superficial incision Intervention: 29.2±5.6 Monitoring intervention Control: 2.9% (12/415) was opened by the surgeon Control: 29.5±5.8 Control group n=415 P=0.72 unless the incision culture ·Gender: all female 30% oxygen – an aerosol face Total SSI was negative; and 4) ·Obesity: (kg/m2) mask delivered oxygen at 30% Intervention: 5.5% (23/416) diagnosis of superficial Total ≥30 concentration during surgery Control: 5.8% (24/415) incisional surgical site Intervention: 331/416 and for 1h postop. Flow rate P=0.98 infection by the surgeon. (79.6) 10L/min. Total Endometritis Endometritis: diagnosed by the Control: 306/415 (73.7) Standard preventive measures: Intervention: 2.7% (11/416) clinical finding of a temp of BMI 30-34.9 AMP: usually cefazolin (2g) Control: 2.4% (10/415) more than 38oC associated Intervention: 142/416 intravenously after cord P=0.66 with uterine tenderness (34.1) clamping. If allergic to without any other source of Control: 127/415 (30.6) penicillin, patient received Diabetes Subanalysis fever identified. BMI 35-39.9 clindamycin (900mg). Composite (SSI + Perioperative care: NR Intervention: 100/416 Closure: if subcutaneous tissue Endometritis) Other notes: Study was (24.0) was >4cm thick, it was closed % (n/N) powered to demonstrate a Control: 97/415 (23.4) with 2-0 plain catgut. Method Intervention: 14.4% (13/90) 50% difference in infection BMI 40 or greater of skin closure was determined Control: 6.9% (6/87) rate with a two-sided α of Intervention: 89/416 (21.4) in operating room. P=0.11 0.05 and a power of 80%. Control: 82/415 (19.8) Fluid Replacement: care was SSI at discharge, % (n/N) The sample size estimation of ·Comorbidities taken to ensure the patients Intervention: 6.7% (6/90) 778 patients was determined Diabetes received adequate fluid Control: 2.3% (2/87) for the composite outcome of

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Intervention: 91/416 (21.9) resuscitation to ensure P=0.17 SSI and Endometritis Control: 87/415 (20.9) adequate tissue perfusion. SSI at 6week postop (baseline rate 12%) Normothermia: optimal room Intervention: 3.3% (3/90) Follow-up: 6 weeks Procedures: Cesarean temperature was maintained to Control: 1.1% (1/87) (postpartum visit) delivery ensure normothermia. A P=0.34 135 (16.5%) lost to follow up. Indications: NR warming blanket was used at Total SSI Intervention: 70/416 (16.8%) Setting: 1 tertiary medical the discretion of the Intervention: 10% (9/90) Control: 65/415 (15.7%) center anesthesiologist. Control: 3.4% (3/87) P=NS Location: USA Normoglycemia: a finger-stick P=0.09 Funding Source Conflicts: Dates: August 2006 – blood glucose test was done Total endometritis Authors: NR August 2010 on day of surgery to ensure Intervention: 4.4% (4/90) Institution: NR Inclusion Criteria: Women normoglycemia during surgery Control: 3.4% (3/87) Study: NR undergoing elective or P=0.75 Supplies: NR emergency cesarean delivery. Other infections: NR Exclusion Criteria: Fever Topic-specific outcomes: (temp ≥38oC), NR chorioamnionitis (temp of Diabetic patients were 38oC or higher with fetal analyzed separately or maternal tachycardia), Reoperations: NR patients who were group Length of stay: NR B Streptococci-positive Mortality: NR and had been started on Adverse events: NR antibiotics, immunocompromised or HIV-positive patients, planned general anesthesia, age <18 years, and incarcerated patients. Stall RCT To assess the Number of patients: N=222 Intervention group: n=119 SSI: Definitions: 96 2013 1, 2, 3, benefits of patients with N=235 After intubation, FiO2 was Overall – 33/222 (13%) High Energy Fracture: one (ES) 4, 5, 6, supplemental fractures adjusted to 80%. After Deep – 27/33 (82%) requiring delayed (>5 days 7, 8, 9, perioperative Patient Characteristics: extubation patients were Superficial – 6/33 (18%) after injury) definitive fixation 10 oxygen in an demographics and placed on high-flow because of soft tissue orthopedic perioperative risk factors nonrebreather masks at 15L Overall intervention: 14/119 concerns patient were similar in the two per minute for 2 hours postop. (12%) Surgical Site infection: based on population groups overall. Although Timing of intervention: Intra- Overall control: 19/116 (16%) CDC definitions. undergoing no statistically significant and postop P = 0.31 (40% decrease in Deep infections: involve © 2017 American Medical Association. All rights reserved. 338

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score open differences were Duration of intervention: infection rate in the debridement reduction and observed in the intraoperative and 2 h postop. treatment group) Superficial infections: treated internal distribution, some Device/agent: Nonrebreather Multivariate OR of all injuries with antibiotics alone. fixation of imbalances were shown. mask for intervention group, = 0.54 (95%CI: 0.22-1.29), Treatment-Related high-energy ·Age: mean (SD) y nasal cannula for control p=0.17 Complications: unexpected tibial plateau, Intervention: 42.3 (12.1) group. No statistically significant pulmonary complication, tibial pilon and Control: 42.5 (12.2) Monitoring intervention: pulse difference was seen prolonged intubation, and any calcaneus ·Gender: female oximetry between groups in other adverse outcome fractures. Intervention: 24/119 Adherence to protocol was subanalyses of the three thought to be related to (20.2%) verified by postanesthesia care types of surgeries oxygen treatment by the Control: 35/116 (30.2%) unit records. anesthesiologist or primary ·Obesity: BMI mean (SD) Control group n= 116 Deep - 27/222 (12.2%) team. 3 kg/m After intubation, FiO2 was Superficial – 6/222 (2.7%) Fractures: classified according Intervention: 28.4 (6.4) adjusted to 30%. After to AO classifications as Control: 28 (5.9) extubation patients were Other infections: NR determined by one ·Comorbidities: placed on nasal cannulae at 4L Topic-specific outcomes: fellowship-trained orthopedic Diabetes per minute to maintain oxygen NR traumatologist blinded to Intervention: 7/119 (5.9%) saturation of at least 92% as Reoperations: NR treatment and outcome. Control: 9/116 (7.8%) determined by pulse oximetry Length of stay:, mean (SD) d Perioperative care: NR for 2 hours postop Intervention: 3.5 (4.1) Other notes: Study is Procedures: open reduction Standard preventive measures: Control: 2.8 (2.6) underpowered to detect a and internal fixation of Multiple operations: P=0.11 statistically significant high-energy tibial plateau, - Patients with tibial plateau difference in composite SSI. tibial pilon and calcaneus and tibial pilon fractures were Mortality: NR Trial stopped because funding fractures. first managed with surgery to Adverse events: NR ran out. Indications: high tibial place a temporary external Prespecified criteria for early plateau, tibial pilon or fixator. These patients were termination of the trial were calcaneus fractures not yet enrolled in the study any adverse event directly Setting: University Hospital so the oxygenation for the attributable to the treatment Location: USA initial surgery was standard (hyperoxygenation) and a Dates: April 2007 – practice. A small group of reduction in surgical site November 2010 patients in the tibial pilon infections of greater than Inclusion Criteria: all adult group underwent two 50% in the treatment group at patients (≥18 years) who definitive operations, typically annual review. sustained high-energy one approach from the Follow-up: median follow up tibial plateau, tibial pilon, posterior ankle and another =344 days (range 84-1771 or calcaneus fractures anterior approach separated days; IQR 153-573 days) undergoing open by a number of days. In Wound monitoring: per routine reduction and internal these cases, the patients clinical practice, that is, on a © 2017 American Medical Association. All rights reserved. 339

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score fixation, received the same treatment daily basis until discharge Exclusion Criteria: The for both operations. There and at the 2, 6, and 12 week above surgeries except were also a small number of outpatient follow-up visits. All those requiring flap patients with more than one wound assessments were coverage (Gustilo and eligible study fracture, and blinded Anderson grade IIIB open each fracture was Funding Source Conflicts: fracture) and those with randomized individually Authors: None open fractures requiring AMP – Standardized for both Institution: None vascular repair for limb groups. Unless Study: None salvage (Grade IIIC open contraindicated, patients Supplies: None fractures). Also, evidence typically received 1 or 2 g of infection at the fracture of cefazolin administered site before definitive intravenously fixation. During the 1st preoperatively and every year of the trial, patients 8 hours for a total of 3 were excluded for any doses, per standard care diagnosis of infection of the institution. For requiring antibiotics, even open fractures, surgeons if it was distant to the site were allowed to continue of surgical incision. That antibiotics for up to 48h criterion was removed postop according to their because it became clinical practice. apparent that many of the Normothermia: NR patients received orally Adequate volume replacement:: administered antibiotics at NR rehabilitation centers before their definitive surgery for diagnosis of pin tract infections or other infections unrelated to the study fracture. Excluding them was detrimental to study design because patients who had recent infection might have been at increased risk of surgical site infection and therefore benefitted most. © 2017 American Medical Association. All rights reserved. 340

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Also, preoperative arterial hemoglobin saturation <90% without supplemental oxygen and a history of preexisting pulmonary disease that can be worsened by high- dose oxygen such as COPD and bleomycin toxicity. Also patients who were unable to provide informed consent and those who were unable to speak English or Spanish. Thibon RCT To evaluate Number of patients: N=434 Intervention group: n=226 SSI : Definitions: 2012 90 1, 2, 4, the effects of Patient Characteristics: Pre-oxygenation, induction, Total: 30/434 (6.9%) SSI: CDC definitions were used. (ES) 5, 6, 7, hyper- The two groups displayed emergence and extubation: Intervention: 15/226 (6.6) An investigator blinded to the 8, 9 oxygenation to no significant differences FIO2 100% Control: 15/208 (7.2) randomization conducted a 80% FiO2 in in baseline After pre-oxygenation, patients P=0.84 systematic review of the routine characteristics. were ventilated with an RR- 0.92 (95%CI [0.46- patient’s medical records abdominal and ·Age: y, mean (SD) anesthesia respirator. 1.84]) including the documentation gynecologic Intervention: 52.1 (13.7) Following induction of provided by physicians and surgery on the Control: 518 (13.3) anesthesia and tracheal Superficial nurses and lab reports. frequency of ·Gender: female intubation, patients received Intervention: 6/226 (2.7) Perioperative care: NR SSI occurring Intervention: 208/226 80% FiO2 Control: 6/208 (2.9) Other notes: Due to intention to during the 30 (92.0) Timing of intervention: treat analysis, patients days following Control: 184/208 (88.5) Intraoperative (postoperative at Deep remained in their group even surgery, and ·Obesity: BMI>30 physician’s discretion) not Intervention: 5/226 (2.2) if the oxygen concentration to compare Intervention: 29/226 (12.8) intended for postop. Control: 4/208 (1.9) was increased during the the Control: 27/208 (13.0) Duration of intervention: intervention to maintain frequencies of ·Comorbidities: intraoperative Organ/Space saturation peri- and Diabetes: Device/agent: facemask for both Intervention: 5/226 (2.2%) Follow-up: 30 days (if patients immediate Intervention: 7/226 (3.1) intervention and control Control: 5/208 (2.4%) did not attend their 30 day postoperative Control: 12/208 (5.8) Monitoring intervention: NR follow-up visit, their infection adverse Current Smoker: Protocol not maintained for the Other infections: NR status was assessed by effects Intervention: 39/226 (17.3) entire duration of the Topic-specific outcomes: calling the patient or their between a Control: 42/208 (20.2) operation: Oxygen saturation on pulse physician) group of Procedures: Intervention: 3/226 (1.3) oximetry at closure Loss to follow up: 4 patients hyper- Gastric/hernia: Control: 13/208 (6.3) (mmHg) mean (SD) were lost to follow up (2 in © 2017 American Medical Association. All rights reserved. 341

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score oxygenated Intervention: 13/226 (5.8) P=0.007 Intervention: 98.9 (1.1) each group). They were patients and a Control:16/208 (7.7) Reasons for deviation - Control: 98.6 (1.3) uninfected when they left the group of Hepatobiliary Intervention = intraoperative P=0.01 hospital and were considered patients Intervention: 7/226 (3.1) complications including one Reoperations: NR uninfected in the final receiving 30% Control: 11/208 (5.3) case of septic shock Length of stay: NR analysis. oxygen. Colon/Rectum: Control = desaturation and/or Time until diagnosis of SSI Funding Source Conflicts: Intervention: 19/226 (8.4) bradycardia Overall: 15.4 days±8.2 Authors: NR Control: 11/208 (5.3) Control group n= 208 Intervention: 16.9 days±8.0 Institution: NR Small Bowel Pre-oxygenation, induction, Control: 13.9 days±8.4 Study: Industry Intervention: 4/226 (1.8) emergence and extubation: Mortality: NR Supplies: NR Control: 5/208 (12.4) FIO2 100% Adverse events: Gynecologic After pre-oxygenation, patients Nausea and vomiting, Intervention: 73/226 (32.3) were ventilated with an Intervention: 17/226 (7.5%) Control: 66/208 (31.8) anesthesia respirator. Control: 11/208 (5.3)% Breast Following induction of P=0.34 Intervention: 110/226 anesthesia and tracheal Sternal pain, (48.7) intubation, patients received Intervention: 5/226 (2.2) Control: 99/208 (47.6) 30% FiO2 Control: 6/208 (2.9) Indications: NR Standard preventive measures: P=0.66 Setting: Multi-center (1 Pre-Oxygenation: before the Cough: cancer institute, 1 induction of anesthesia, each Intervention: 1/226 (0.4) university hospital& 2 patient was pre-oxygenated Control: 0/208 (0) private hospitals) (100% FiO2) via facemasks for Hypotension: Location: France at least 3 minutes until the tele- Intervention: 3/226 (1.3) Dates: June 1, 2003-June expiratory fraction of oxygen Control: 0/208 (0) 30, 2007 was at least 90%. P=0.10 Inclusion Criteria: Patients Normothermia: NR No auditory or visual disorder >18 years old, and Adequate volume replacement: was noted scheduled to undergo NR elective abdominal, gynecologic, and breast surgery provided that anesthesia was provided Exclusion Criteria: Recent history of fever and/or infection, chronic respiratory failure (oxygen PaO2 below 60 mmHg, 8.9kPa at rest), and © 2017 American Medical Association. All rights reserved. 342

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score bleomycin treatment (which may induce sensitivity to oxygen toxicity). Scifres RCT To assess the Number of patients: N=585 Intervention group: n=288 SSI: Definitions: 2011 100 1, 6, 7, effect of a high Patient Characteristics: Women received oxygen at a flow Endometritis: Endometritis: oral temp of >38oC (ES) 8, 9, 10 perioperative patient and operative rate of 10 L/min Intervention: 7/288 (2.4%) after the first 24h following oxygen characteristics were not (corresponding to approx. 80% Control: 2/297 (0.6%) procedure and either (1) concentration statistically significantly FiO2) by nonrebreather mask RR: 3.6; 95%CI, 0.8-17.2 fundal or lower abdominal on different unless listed both during surgery and for 2 P=0.08 tenderness greater than postcesarean below hours after cesarean delivery. Wound infection: expected or (2) foul-smelling delivery ·Maternal Age Timing of intervention: Intra and Intervention: 33/288 (11.5%) purulent lochia. Patients were infectious Intervention: 27.5±6.4y postoperatively Control: 26/297 (8.8%) diagnosed with endometritis morbidity in Control: 27.8±5.9y Duration of intervention: during RR: 1.3; 95%CI, 0.8-2.1 only if other causes for signs women ·Gender: all female and for 2 hours after cesarean P=0.28 and symptoms were not undergoing ·Obesity –BMI at delivery delivery. Composite (wound infection identified. Patients also had cesarean >30kg/m2 Device/agent: intervention group +endometritis) to be treated with IV delivery. Intervention: 208/288 used a nonrebreather mask Intervention: 35/288 (12.2%) antibiotics to be diagnosed (72.22%) and control group used a nasal Control: 26/297 (8.8%) with endometritis. Control: 230/297 (77.44%) cannula RR: 1.4; 95%CI, 0.9-2.3 Wound infection: only if wound ·Comorbidities: Monitoring intervention: P=0.18 opening >1cm or other Preterm Delivery <32wks: Compliance with the surgical intervention (such as Intervention: 20/288 (6.9%) supplemental oxygen by face Other infections: laparotomy or debridement of Control: 9/297 (3.3%) mask (intervention group) was Wound hematoma or seroma: tissue) plus at least 1 of the P=0.03 assessed by anesthesiologist Intervention: 16/288 (5.4%) following: (1) purulent Chronic hypertension: intraoperatively and by the Control: 17/297 (5.9%) drainage from the wound, (2) Intervention: 34/288 postpartum nurse at 30, 60, 90 RR: 1.1; 95%CI, 0.6-2.1 erythema or induration of the (11.8%) and 120 minutes postop. P=0.79 surrounding tissues, (3) Control: 21/297 (7.1%) Oxygen saturation was maternal oral temperature P=0.05 assessed both intraoperatively Topic-specific outcomes >38oC, or (4) radiographic Previous abdominal surgery and postoperatively for both Intravenous antibiotics >24h evidence of infection. including C-section, groups after delivery laparoscopy, laparotomy, Compliance with intervention Intervention: 38/288 (13.2%) Perioperative care: NR Intervention: 181/288 postop: Control: 35/297 (11.8%) Other notes: (62.9%) Intervention at 30min: 214/288 RR: 1.1; 95%CI, 0.7-1.7 Study utilized infectious Control: 210/297 (70.7%) (74.3%) P=0.61 morbidity composite P=0.04 Intervention at 60min: 189/288 Hospital readmission measure. (A combination of Rupture of membranes (65.6%) Intervention: 15/288 (5.2%) endometritis and wound before cesarean delivery. Intervention at 90min: 172/288 Control: 10/297 (3.4%) infection). Especially for © 2017 American Medical Association. All rights reserved. 343

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Intervention: 84/288 (59.7%) RR: 1.5; 95%CI, 0.7-3.4 subgroup analysis to (29.2%) Intervention at 120min: 97/288 P=0.27 determine effect of Control: 59/297 (19.9%) (33.7%) Neonatal outcomes differences between P<0.01 Control group: n=297 Umbilical artery pO2 (mmHg) populations for causes such Procedures: Cesarean Women received oxygen at a flow Intervention: 19.4±9.6 as rupture of membranes, section rate of 2 L/min (corresponding Control: 17.1±6.8 labor before cesarean, etc. Indications: scheduled or to approx. 25-30% FiO2) via P<0.01 intrapartum cesarean nasal cannula during cesarean Umbilical artery CO2 (mmHg) Most non-compliance was delivery. delivery only. Intervention: 57.0±11.4 related to discomfort Setting: One University Standard preventive measures: Control: 58.9±11.0 associated with wearing the Hospital Additional supplemental oxygen: P=0.05 non-rebreather mask. Location: USA with oxygen saturation <95% Antibiotics after birth Particularly in the period of Dates: February 2008 – were supplied supplemental Intervention: 75/288 (26.0%) 60-120min post-op. March 2010 oxygen as needed to maintain Control: 55/297 (18.5%) Follow-up: 2-4 weeks postop Inclusion Criteria: Patients appropriate oxygenation P=0.03 during the postop visit. who underwent scheduled Intervention: 0/288 Anyone who did not return for or intrapartum cesarean Control: 18/297 (5.9%) Reoperations: NR postop visit within 4 weeks or delivery with regional Length of stay: NR who had planned follow up anesthesia Skin Prep: Both groups received Mortality: visit at an outside clinic were Exclusion Criteria: standard preoperative skin Neonatal mortality contacted by the research Emergency surgery in prep. Intervention: 8/288 (2.7%) nurse by telephone with the which participant was AMP: both groups received Control: 1/297 (0.34%) data collection form used as unable to provide standard AMP (cefazolin was P=0.06 a prompt. informed consent, human primary antibiotic; clindamycin All deaths were analyzed and Funding Source Conflicts: immunodeficiency virus was used in the case of none were attributable to Authors: NR infection, chronic penicillin allergy. supplemental oxygen Institution: NR corticosteroid therapy or Closure: Subcutaneous sutures Adverse events: NR Study: NR other immunosuppressive were left to the decision of the Supplies: NR therapy, general surgical team anesthesia, and a Adequate fluid replacement: NR diagnosis of extra-uterine Normothermia: NR infection (i.e., pyelonephritis or pneumonia) before cesarean delivery. Acute chorioamnionitis was not an exclusion criterion.

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Staehr RCT To evaluate Number of patients: N: 213 Intervention: n=102 SSI (Follow up 14 days Definitions: 95 2011 1, 2, 3, the effect of a Patient Characteristics: Intraop: Patients were pre- postop) SSI: CDC definitions (Within 14 (ES) 4, 5, 6, high All demographic and oxygenated with 100% FiO2 Overall: 29% days) 7, 8, 9, inspiratory perioperative until tracheal intubation. Intervention: 32/102 = 31% Pneumonia: CDC (Within 14 10 oxygen characteristics were Patients were given 80% FIO2 Control: 29/111= 26% days) fraction (80%) similar between groups. from intubation until the end of Univariate OR: Adverse Event: ND on SSI and Population Characteristics surgery when 100% FIO2 was 1.29 (95% CI, 0.71-2.34) Serious adverse event: Serious pulmonary Age: ≥18 years given immediately before P= 0.40 if fatal, life threatening, complications Gender: m/f: 86/127 extubation. FIO2 was increased Adjusted OR: caused permanent disability, in obese Morbidly Obese: 73/213 to ensure arterial oxygen 1.22 (95%CI, 0.63-2.39) or required prolonged patients (32%) above 94%. P=0.57 hospitalization undergoing All characteristics below Postop: The first 2h after surgery Superficial infection Obese: BMI 30-34.9kg/m2 2 laparotomy. are given are for the patients received 80% FIO2 Intervention: 16/32 (50%) Morbidly Obese: BMI ≥ 35kg/m intervention group N=102: from the Nonrebreathing Control: 21/29 (73%) Overweight: BMI= 25.0- Median [5-95% range] or facemask and an oxygen flow Deep Infection 29.9kg/m2 Age: 63y [37-81] of 14 l/min and an air flow of 2 Intervention: 8/32 (25%) Normal Weight: BMI= 18.5- Gender: m/f:43/59 l/min. 2 hrs. after surgery, Control: 5/29 (29%) 24.9kg/m2 2 Obesity: supplemental O2 was Organ/Space Infection Underweight: BMI<18.5 kg/m Median BMI: 34 kg/m2 [30- administrated according to Intervention: 8/32 (25%) Perioperative Care: 44] clinical practice Control: 3/29 (10%) Anesthesia-standardized, non- BMI≥35kg/m2:39 (38%) Timing of Intervention: Intra and Incidence of SSI nitrous oxide Comorbidity: Postoperatively Obese Patients = 27% Other notes: Current smoker: 31 (30%) Duration of Treatment: Morbidly Obese Patients This was a planned subgroup Diabetes mellitus: 16 Intubation to 2 hours after n=73(32%) analysis of the PROXI trial; (16%) surgery. Sub-analysis of SSI Meyhoff 2009 Pulmonary Disease: 16 Device: Nonrebreathing between Intervention Adjusted OR adjusted for study (16%) facemask with a reservoir groups distributed by center, diabetes mellitus, Hypertension: 48 (47%) weight class. (interpreted acute surgery, COPD, current Other cardiovascular Control: n=111 from graph (%SSI [upper smoker, upper abdominal disease: 15 (15%) Intraop: Patients were pre- 95% CI]) incision, duration of surgery, 2 Duration of surgery: 145 [45- oxygenated with 100% FiO2 Underweight (BMI<18.5kg/m ) and age (≥40 years or <40 309] min until tracheal intubation. Intervention: 10% [25%] years) where possible Epidural analgesia: Patients were given 30% FIO2 Control:19% [37%] Preoperative SSI Risk thoracic/lumbar/none: from intubation until the end of Normal Weight (BMI 18.5- Stratification: 2 66/4/32 surgery when 100% FIO2 was 24.9 kg/m ) SENIC 1/2/3/4 Type of anesthesia: given immediately before Intervention: 17% [20%] Intervention: 24/32/42/4 Volatile: 25 (25%) extubation. FIO2 was increased Control:18% [21%] Control: 25/35/47/4 Total IV: 77(75%) to ensure arterial oxygen Over Weight (BMI 25.0- NNIS, 0/1/2/3 Procedure: Laparotomy above 94%. 29.9kg/m2) Intervention: 20/50/26/6 © 2017 American Medical Association. All rights reserved. 345

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Colorectal: Postop: The first 2h after surgery Intervention: 19% [24%] Control:28/47/29/7 Intervention: 40/102 (39%) patients received a mixture of Control:22% [28%] 2 Control: 49/111 (44%) O2 (2 l/min) and air (14 l/min) Obese (BMI 30.0-34.9 kg/m ) Pulmonary complications Primary Anastomic: through above face mask. 2 Intervention: 30% [42%] monitored by clinical exam Intervention: 31/102 (30%) hrs. after surgery, Control:26% [36%] (attending physician), Control: 41/111 (37%) supplemental O2 was Morbidly Obese (BMI ≥35.0 including chest radiographs Other surgeries: administrated according to kg/m2) or computed tomography Intervention: 62/102 (61%) clinical practice Intervention: 33% [49%] evaluated by radiologist Control: 41/111 (56%) Control:30% [48%] blinded to allocation Acute procedures: Monitoring Intervention: Pulse Follow-Up: visit conducted Intervention: 19/102 (19%) oximetry Per-protocol analysis (N= between postoperative day Control: 20/111 (18%) Standard Preventative 167) of primary and 13 and 30. Most outcomes Operation Classification Measures: secondary outcomes measured at 14 days post op Clean: 36 (35%) Analgesia: epidural showed results similar to except for mortality at Clean Contaminated: 21 Normothermia: ensured adequate those in the ITT analysis 30days. (21%) temperature (N=213): Funding Source Conflicts: Contaminated: 43 (42%) Glycemic: ensured adequate SSI-per protocol analysis Authors: None Dirty-infected 2 (2%) glucose control Intervention: 31/91 (34%) Institution: None AMP: appropriate and timely Control: 24/76 (32%) Study: None Indications: prophylactic antimicrobials P=0.73. Supplies: None Cancer Diagnosis Received Adequate AMP Intervention: 56/102 (57%) Intervention n=90(88%) Other infections: Control: 57/111 (51%) Control n=91 (82%) Pneumonia (Follow up 14 Other: days) Intervention: 46/102 (45%) Received Timely AMP Intervention:5.9% Control: 54/111 (49%) Intervention n=64 (63% ) Control: 4.5% Control n=75 (71%) Obese:6% Setting: Multi-Center Bowel Prep: absence of Morbidly obese: (3%) Location: Denmark preoperative oral bowel prep Dates of Study: October 8, Fluids: Given only once to replace Reoperation: n=43(20%); 2006 - October 6, 2008 measured or calculated deficits Intervention: 22/102 (22%) Inclusion Criteria: 18 years aiming at body weight increase Control: 21/111 (19%) or older, BMI≥ 30kg/m2, of less than 1kg. Blood loss Reoperation for SSI n=24 scheduled for acute or was replaced 1:1 with colloids (11%) elective laparotomy and blood transfusion was Debridement n=5 (2%) Exclusion Criteria: Inability initiated if blood loss exceeded Length of stay: to give informed consent, 20ml/kg Intervention: 6 (1-35) days chemotherapy for Control: 5 (2-45) days malignancy within 3 30 Day Mortality: Total: 2% © 2017 American Medical Association. All rights reserved. 346

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score months, surgery Intervention: 1/102 (1%) performed under general Control: 3/111 (2.7%) anesthesia within 30 Adverse Events: days, preoperative arterial Any adverse event oxygen saturation less Intervention: 52/102 (51%) than 90% w/o Control: 58/111 (52%) supplemental oxygen Wound related: assessed by pulse Intervention: 18/102 oximetry. (18%) Control: 20/111 (18%) Any serious event: Intervention: 22/102 (22%) Control: 22/111 (20%) Sepsis Intervention: 4/102 (3.9%) Control: 3/111 (2.7%) Pulmonary Complications: Not significantly different Atelectasis (Follow up 14 days postop) Intervention: 9/102(8.8%) Control: 7/111 (6.3%) Obese:9% Morbidly Obese:5% Respiratory Failure(Follow up 14 days postop) Intervention: 8/102 (7.8%) Control: 5/111 (4.5%) Obese: 6% Morbidly obese:5% Anastomotic leak Intervention: 2/31 (6%) Control: 2/41 (5%) Rupture of abdominal fascia 15/213 (7%) of patients had ruptured abdominal fascia compared with 9/658 (1%) of normal weight patients in © 2017 American Medical Association. All rights reserved. 347

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score PROXY trial Intervention: 9/102 (9%) Control: 6/111 (5%) Admission to ICU (within 14 days if not part of normal routine care) Intervention: 11/102 (10%) Control: 9/111 (8%) Turtiain- RCT To test the Number of patients: N=274 Intervention: n=137 SSI Definitions: en 1, 2, 4, hypothesis Patient Characteristics: Postop: 30% FIO2 was delivered Total SSI: 63/ 274 (23%) SSI – CDC definition 2011 102 6, 7, that Characteristics were via face mask in the recovery Superficial: 47/63 (74%) Surgical wound infection (SWI) (ES) 8, 9 supplemental analyzed and not found to room and on the 1st Deep: 14/63 (22%) was considered infection if postoperative be statistically different postoperative day. On the 2nd Organ/Space: 2/63 (3%) there were bacteria isolated oxygen between groups. postoperative day from the wound or if there decreases the Characteristics reported supplemental oxygen was Intervention vs. Control SSI: were areas of localized incidence of below are for the delivered via nasal cannula at Intervention: 25/137 patients redness, heat, swelling and Surgical intervention a constant flow rate of 5l/min. (18.2%) pain around the wound Wound Age: ≥ 18 (Mean: 73.5 [SD Timing of Intervention: Control: 38/137 patients appearing w/in 30 days after Infection 11]) Postoperatively (27.7%) operative procedure. (SWI) after Gender (m/f): 78/59 Duration of Treatment: P=0.06 Surgical wounds evaluated by lower limb Obesity: From the end of surgery until Multivariate vascular surgeon blinded to revascularizati BMI, mean: 26 kg/m2 (SD 4) 10PM on 2nd postoperative day OR 0.56 (95% CI, 0.30-1.04; study arm. on Co-Morbidities: (at least 48hrs)Device: P=0.07) Pneumonia: clinical diagnosis Coronary artery disease: A face mask for the 1st day to Superficial SSI: and correlative changes in 65 (47%) deliver 30% O2. Intervention: 18/137 (13%) chest x-ray film Diabetes: 50 (36%) On 2nd postop day, FIO2 delivered Control: 29/137 (21%) Hypertension: 89 (65%) via nasal cannula. Deep SSI: Perioperative Care: Rheumatoid arthritis: 7 Monitoring Intervention: Intervention: 7/137 (5.1%) Shaving around intended (5%) Oxygen level of a toe on operated Control: 7/137 (5.1%) surgical wound site done in COPD: 13 (9%) limb measured w/ pulse Organ/Space SSI (vascular operating room just before Asthma: 11 (8%) oximeter every 4 hours for 1st 2 graft) surgery. Dialysis: 5 (4%) days. Intervention:0/137 (0% Other notes: Current smoking: 37 (27%) Control: 2/137 (3%) Primary study design was to Blood loss (ml [SD]): 341 Control: n=137 deliver supplemental oxygen (337) Postop: Breathed room air Factors associated w/ SSI via face mask for the first two (multivariate analysis) postoperative days but Procedure: N=274 Standard Preventative Prosthetic material use patients found the face Non-emergency, lower limb Measures: 0.02 (95%CI 0.08-0.50) masks to be uncomfortable arterial surgery AMP: Antimicrobial prophylaxis p=0.001 so the initial plan was © 2017 American Medical Association. All rights reserved. 348

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score (revascularization) was standardized to 3g Asthma changed 2 weeks after data - 173 bypass procedures cefuroxime via IV w/in 1h 4.83 (95%CI 1.72-13.53) collection had started. 44/173 (25%) prosthetic before incision. If operation > p=0.003 grafts 4h or blood loss>1,500ml then Infrainguinal incision Whether patient received AMP Femoral endarterectomy another 1.5g Cefuroxime was 2.24 (95%CI 1.07-4.67) per protocol or not, did not n=84 administered. p=0.03 affect incidence of SWI. Femoral bypass n=12 AMP per protocol: n=244 (89%) Coronary Artery Disease Femoropopliteal bypass No AMP n=4 1.94 (95%CI 1.04-3.62) Follow-Up: For 30 days or until n=92 Received 1.5g cefuroxime n=10 p=0.04 the SWI healed Crural bypass n=46 Treated for infected ulcer n=11 Supplemental oxygen Funding Source Conflicts: Pedal bypass n=19 Treated for UTI n=3 0.56 (95%CI 0.30-1.04) Authors: NR Embolectomy n=3 Treated for sepsis n=2 p=0.07 Institution: NR Other n=18 Sub-group analysis Study: NR Operative area 103 patients w/ inguinal Supplies: NR Inguinal:n-105 (isolated groin) incision Infrainguinal: n=169 only Indications: SSI Claudication: 94/ 274 Total SSI 15/103 (15%) (34%) Intervention: 3/52 (6%) Rest pain: 68/ 274 (24.8%) Control: 12/51 (24%) Ischemic ulcer: 100/274 P=0.01 (36.5%) No differences in secondary Other: 7//274 (4.4%) outcomes between groups in the sub-group analysis Setting: 5 Secondary BMI>25kg/m2 was referral hospitals & 1 independent risk factor for tertiary referral hospital SWI Location: Finland OR 1.22, 95%CI 1.03- Dates of Study: May 2009- 1.45;P=0.02 February 2010 Supplemental oxygen was (Varied between 3 and 6 associated with reduced months between 6 risk hospitals.) OR, 0.20, 95%CI, 0.04- Inclusion Criteria: 0.95;P=0.04 Adult patients who Other infections: underwent non-emergency Pneumonia: p=0.18 lower limb arterial surgery Intervention: 1/137 (0.7%) Exclusion Criteria Control: 4/137 (2.9%) Refusal to participate, © 2017 American Medical Association. All rights reserved. 349

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score hypercapnic chronic Topic-specific outcomes: obstructive pulmonary Mean toe tip oxygen disease (COPD), or oxygen saturation after surgery. saturation less than 90% Was not significantly measured by a finger pulse different between 2 groups oximeter when breathing except at: room air. 24hrs after surgery Intervention: 94.4% Control: 91.9% P=0.034 28hrs after surgery Intervention: 95.0% Control: 92.4% P=0.025 Reoperation: 58/63 (92%) SSI patients were cured with treatment2/63 (3%) SSI patients required limb amputation due to SSI (one study one control group) Length of Stay: Postoperative stay Intervention: 6.5d (SD9.4) Control: 5.4d (SD4.3) P=0.13 Mortality: at 30 days Intervention: 3/137 (2.2%) Control: 1/137 (0.7%) Cause of death: 1 aspiration pneumonia 3 myocardial infarction (MI) including one intervention patient died from an MI on POD#30 and SWI had not yet healed, 3 had no SWI at the time of death

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Of note: 1 control group patient died of renal failure on POD#64 and had a SWI not cured at the time of death Adverse Events Graft Thrombosis: p=0.39 Intervention: 5/137 (3.6%) Control: 8/137 (5.8%) Cardiac complication: p=0.81 Intervention: 6/137 (4.4%) Control: 5/137 (3.6%) Stroke: p=0.08 Intervention: 3/137 (2.2%) Control: 0/137 (0%) Renal insufficiency: p=0.31 Intervention: 3/137 (2.2%) Control: 1/137 (0.7%) Bickel RCT To assess the Number of patients : Intervention: n= 107 SSI Definitions: 92 2011 1, 2, 3, influence of N=210 Intraop: FIO2 80% combined with Total SSIs: 20/210 (9.5%) SSI: Evaluated clinically (ES) 4, 5, 6, hyper- Patient Characteristics: No 20% air. Intervention: 6/107 (5.6%) according to obvious signs 7, 8 10 oxygenation statistically significant Postop: In recovery room, flow Control: 14/103 (13.6%) and symptoms such as local on surgical difference in rate was 10L/min (high-flow) P=0.04 induration & erythema, site infection characteristics between for 2 hours via non-rebreathing purulent discharge & need to by using the the 2 groups. (Including mask. SSI by patient subgroup explore the wound. most smoking history, obesity, Timing of Intervention: Normal appendix (n=9) Supportive results included homogeneous shaving, and timing of Intra- & post-operatively Intervention: 0/4 increased white blood cell study antimicrobial Duration of Treatment: Control: 0/4 count, fever, and radiological population: administration). All From Induction of anesthesia to 2 P >.99 evidence of infectious single patients categorized as hours post-operatively collections, positive culture diagnosis having ASA score of 1 or Device: Nasal cannula for control Acute appendicitis (n= 35) findings and resolution of (acute 2. and nonrebreathing mask with Intervention: 2/18 (11%) mild infectious findings appendicitis) Age, years: 28.0 (SD 11.5; a reservoir for the intervention Control: 0/17 following antimicrobial using 1 range 15-71) Monitoring Intervention: P=0.20 treatment. standard Gender (m/f): 152/57 Pulse oximetry during anesthesia ASEPSIS score taken surgical Obesity: NR & recovery period. Arterial Phlegmonous appendicitis approach Co-morbidities (out of blood obtained after (n=123) Perioperative Care: (open n=210) anesthesia induction & during Intervention: 1/63 Anesthesia introduced with appendectomy Ischemic heart disease: surgery and 2 hours after Control: 6/60 fentanyl citrate, propfol, or through a 3.1% recovery from anesthesia. P=0.049 thiopental sodium, and © 2017 American Medical Association. All rights reserved. 351

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score McBurney Hypertension: 7.4% Surgical wounds evaluated daily. rocuronium bromide or incision in the Diabetes: 0.6% After discharge, evaluation Gangrenous appendicitis atracurium besylate following right lower Pulmonary disease: 1.3% was done at surgical outpatient (n=43) pre-oxygenation via mask. quadrant of Procedure: Open clinic by senior surgeon w/in 2 Intervention: 3/22 (13.6%) It was maintained with nitrous the abdomen). appendectomy through a weeks of surgery Control: 8/21 (38.1%) oxide and oxygen, McBurney incision in the P=0.06 isofluorane, 1% rocronium right lower quadrant of the Control: n=103 bromide, or atracurium abdomen Intraop: FIO2 30% O2 combined ASEPSIS Score besylate, and fentanyl citrate. Indications: acute with 70%N. Satisfactory Healing Other Notes: appendicitis diagnosed by Postop: In recovery room, flow Intervention: 101 (94.4%) Preoperative SSI Risk clinical criteria (right lower rate was 4L/min for 2 hours. Control: 89 (86.4%) Stratification: quadrant pain, local Standard Preventative Disturbance of healing SENIC & NNIS tenderness, etc.), blood Measures: Intervention: 2 (1.8%) test results & results of Antimicrobial prophylaxis-: Control: 5 (4.9%) They note that while the rate of imaging modalities Preoperative antimicrobials: Minor wound infection: SSI reached statistical (ultrasonography or aminoglycosides (gentamicin Intervention: 2 (1.8%) significance (P=0.04), using abdominal computed sulfate) and metronidazole. Control: 3 (2.9%) the 2-tailed Fisher exact test tomography) suggestive When intraoperative findings Moderate wound infection: will lead to a P=0.06 of acute appendicitis indicated gangrenous or Intervention: 2 (1.8%) Follow up: 14 days for SSI, Setting: Department of perforated appendicitis, Control 5 (4.9%) then length of hospital stay surgery in a Government antimicrobial treatment lasted Severe wound infection: Funding Source Conflicts: Hospital 5 days. Intervention: 0 (0%) Authors: None Location: Israel Fluids: Adequate hydration was Control 1 (1.0%) Institution: None Dates of Study: November strictly maintained during the ASEPSIS Score: “A significant Study: None 1, 2006 – May 31, 2009 operation and convalescence difference was recorded Supplies: None Inclusion Criteria: Ventilation: mechanically between the two study Adults (>15 years) with controlled at a frequency and populations” (P=0.03)” acute appendicitis having tidal volume to maintain Wound problems open appendectomies normocapnea. Intervention: 6/ 107 (5.6%) Exclusion Criteria Normothermia: Core temperature Control: 14/ 103 (13.6%) Chronic obstructive was strictly maintained during Other infections: NR pulmonary disease, severe the operation and Topic-Specific outcomes: malnutrition (serum albumin convalescence Partial pressure of oxygen conc. <3g/dL) or Wound closure: Following (PO2) in arterial blood: mean immunodeficiency disease resection of inflamed appendix, (SD);P-value the surgical wound in the lower Before starting surgery: right quadrant of the abdomen Intervention: 263.30 (87) was meticulously irrigated and Control: 179.95(78) sutured with absorbable P=0.001 © 2017 American Medical Association. All rights reserved. 352

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score sutures. Skin was closed with During surgery before wound metal clips (including cases of closure gangrenous appendicitis). Intervention: 275.47 (95) Control: 149.37 (48) P=0.001 In recovery room Intervention 188.6 (73) Control 142.3 (65) P=-0.02

Reoperation: Wound exploration 12/20 SSIs Intervention: 4/6 (66.7%) Control: 8/14 (57.1%) P>0.99 Length of stay: mean (SD) Total: 2.71 days (1.25) Intervention: 2.51 days (0.88) Control: 2.92 days (1.05) P=0.1 Mortality: NR Adverse Effects: NR Meyhoff RCT To assess Number of patients: N = Intervention: n=690 in per SSI: Follow up 14 days Definitions: 2009 94 1, 2, 3, whether use of 1395 in per protocol protocol analysis. 685 in Intervention: 131/685 (19.1%) SSI: CDC definitions (ES) 4, 5, 6, 80% oxygen analysis. 1386 in intention intention to treat analysis Control: 141/701 (20.1%) Pneumonia- CDC Criteria 7, 8, 9, reduces the to treat analysis Intraop: 100% FIO2 at induction of Univariate OR (NNIS) 10 frequency of Patient characteristics: anesthesia until intubation. 0.94 (95%CI 0.72-1.22) Respiratory failure - the need for surgical site Pre-operative and Then 80% FIO2 from intubation p=0.64 controlled ventilation or infection perioperative until the end of surgery. Adjusted OR arterial oxygen saturation without characteristics compared Postop: The first two hours 0.91 (95%CI 0.69-1.2) p=0.51 below 90% despite increasing the and no statistically following intubation patients supplemental oxygen frequency of significant difference received 80% FIO2 via a Infection Location: BMI: <30 or ≥30 calculated as pulmonary found between groups. nonrebreathing mask with a Superficial: weight in kg divided by height 2 complications (data below listed for reservoir w/ a flow of 14L O2 & Intervention: 75/131 (57.3%) in m in patients intervention) 2L air per minute Control: 76/141 (53.9%) Risk of SSI assessed with NNIS undergoing Age: (median(5-95%)) : 64y Timing of Intervention: Deep and SENIC. abdominal (27-85) Intra & Postoperatively Intervention: 20/131 (15.3%) surgery Gender: Duration of Treatment: From Control: 26/141 (18.4%) Perioperative Care: © 2017 American Medical Association. All rights reserved. 353

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score (laparotomy). Men (no (%)): 228/690 induction of anesthetic to 2hrs Organ/ Space (Intra- Standardized inhalational or (41.7%) postop abdominal) intravenous anesthesia Obesity: Device: High concentration Intervention: 36/131 (27.5%) without nitrous oxide BMI, median (5-95%): oxygen mask Control: 39/141 (27.7%) depending on attending 25kg/m2 (18-35) Monitoring Intervention: Pulse anesthetist. BMI≥30, no (%): 102/690 Oximetry ASEPSIS Score>20: Other notes: (14.8%) Intervention: 32(4.7) Adjusted OR adjusted for study Comorbidity: Control: n=705 in per protocol Control: 36 (5.1) center, BMI (<30 or ≥30), Current smoker: 207/690 analysis. 701 in intention to Per protocol analysis diabetes mellitus, acute or (30.0%) treat analysis (N=1081) elective surgery, COPD, Alcohol consumption Intraop: 100% FIO2 at induction of SSI current smoker, incision >48g/d: 29/690 (4.2%) anesthesia until intubation. Intervention: 122/555 (22.0%) extending above umbilicus, Previous abdominal Then 30%FIO2 from intubation Control: 116/526 (22.1%) duration of surgery, and age surgery: 298/690 (43.2%) until end of surgery. P=0.98 (≥40 years or <40 years) Diabetes mellitus 51/690 Postop: During the first two hours Follow-Up: SSI monitoring for (7.4%) after surgery, patient received Other infections: 14 days, Then postop day COPD: 35/690 (5.1%) O2 via Nonrebreathing mask w/ Pneumonia: (14 days) 13-30 via telephone if Other pulmonary disease: a flow of 14L air & 2L O2 per Intervention: 41/685 (6.0%) necessary 45/690 (6.5%) minute. Control: 44/701 (6.3%) Funding Source Conflicts: Hypertension: 209 (30.3%) Univariate OR Authors: None Other cardiovascular In both groups FIO2 was 0.95 (95%CI 0.61-1.48) Institution: None disease: 125/690 (18.1%) increased if hypoxia was p=0.82 Study: None Current signs of infection: detected or suspected to Adjusted OR Supplies: None 76/690 (11.0%) ensure arterial oxygen 0.95 (95%CI 0.60-1.49) Immune deficiency: 27/690 saturation >94% and arterial p=0.81 (3.9%) oxygen tension >9kPa. Other disease209/690 Topic Specific outcomes: (30.3%) Standard Preventative NR Procedure: (N=1386) Measures: Reoperations: For all Colorectal: 633/1386 Analgesia - Epidural reasons- does not specify (45.7%) Normothermia: control of how many for SSI Gynecological: 268/1386 temperature Intervention: 104/685 (15.2%) (19.3%) Glycemic: Control of glucose level Control: 104/701 (14.8%) Small Bowel surgery: Bowel Prep: absence of pre- Length of stay: 158/1386 (11.4%) operative bowel preparation. Postoperative Appendectomy: 124/1386 AMP: first and second hospitalization (Mean? (8.9%) antimicrobial administered w/in (range)) Other: 203/1386 (14.6%) 60 minutes of skin incision. Intervention: 6d (1-34) Operation Classification: Cefuroxime & metronidazole Control: 7d (2-36) © 2017 American Medical Association. All rights reserved. 354

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Clean: 318/1386 (22.9%) given intravenously was OR -0.69 (-2.3-0.93) P=0.09 Clean-contaminated: standard choice, but ampicillin Mortality: at 30 days 796/1386 (57.4%) or benzylpenicillin in Intervention: 30/685 (4.4%) Contaminated: 235/1386 combination with gentamicin Control: 20/701 (2.9%) (17.0%) and metronidazole were also Univariate OR Dirty-Infected: 37/1386 allowed. 1.56 (95%CI 0.88-2.77) (2.7%) 1305/1386 (94%) received p=0.13 AMP. Adjusted OR Indications: (# of Of those that received AMP: 1.55 (95%CI 0.86-2.85) patients/1386) 1169/1305 (90%) p=0.15 Cancer: 714 (51.5%) Appropriate AMP Adverse Effects: Wound- Benign neoplasm: 108 880/1305 (67%) Timely related, UTI, Postoperative (7.8%) AMP nausea or vomiting, Appendicitis: 121 (8.7%) respiratory, circulatory, Intestinal obstruction due to Fluids: given only to replace gastrointestinal tract, benign disease: 124 measured or calculated deficits sepsis, or other recorded (8.9%) aiming at a post-op weight and not statistically Inflammatory bowel disease: increase of less than 1kg different between groups. 79 (5.7%) Transfusion: blood replaced 1:1 Diverticulitis: 57 (4.1%) with colloids & transfusion Topic specific outcomes Other: 183 (13.2%) initiated if blood loss exceeded Hypoxia: NR Setting:14 Hospitals 20 mL/kg. Atelectasis: (14 days) Location: Denmark Intervention: 54/685 (7.9%) Dates of Study: Oct 2006- Control: 50/701 (7.1%) Oct 2008 Univariate OR 1.11 (95%CI Inclusion Criteria: Patients 0.75-1.66) p=0.60 ≥18yrs who underwent Adjusted OR acute or elective 1.13 (95%CI 0.75-1.72) laparotomy. (When p=0.56 laparotomy was indicated for gynecological disease, Respiratory Failure (14 days) only patients with Intervention: 38/685 (5.5%) suspected malignancy Control: 31/701 (4.4%) [risk of ovarian OR 1.27 (95% CI, 0.78-2.07) malignancy index>200 or P=0.34 a specimen showing Adjusted OR 1.22 (95% atypical or neoplastic CI,0.74-2.03) cells] were included.) P=0.44 Exclusion Criteria: © 2017 American Medical Association. All rights reserved. 355

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Operations performed Admission to ICU (other than under general anesthesia normal postop-not w/in 30 days, statistically significant chemotherapy for malignancy w/in 3 months, inability to provide informed consent, and preoperative arterial hemoglobin oxygen saturation below 90% without supplemental oxygen assessed by pulse oximetry Gardella RCT To test the Number of patients: Intervention: n=69 SSI: Follow up 14 days Definitions: 98 2008 1, 2, 3, hypothesis N=143 80% Oxygen at 15L/min Intervention: 17/69 (25%, 15- SSI: Administration of (ES) 4, 5, 6, that high- Patient characteristics: Timing of Intervention: 35%) intravenous antimicrobials for 7, 8, 9, concentration, The study groups were Intra and post-operatively Control: 10/74 (14%, 6-22%) postpartum endometritis or 10 inspired similar for a large number Duration of Treatment: Relative risk of outcome oral and intravenous oxygen of clinical variables, From anesthesia induction to 2hrs associated with High O2 antimicrobial for wound delivered including body mass post-operatively. 1.8 (95%CI, 0.9-3.8)P=.12 infection during the initial during index, maternal diabetes, Device: Covered oxygen blender Cellulitis: hospital stay or within 14 cesarean group B streptococcus was set to predetermined Intervention: 10/69 (14%) days of surgery. Included delivery and colonization, gestational mixture of O2 & air to an adult Control: 7/74 (9%) cellulitis as well as deeper for 2 hours age at delivery, and nonrebreathing mask RR (95%CI): 1.5 (0.6-3.8) incisional infections that postoperativel duration of surgery, Monitoring Intervention: p=.44 required wound to be y decreases surgical blood loss & Venous Blood Gas collection from Postpartum endometritis: opened. the incidence prophylactic usage of the dorsum of the foot in a Intervention: 9/69 (13%) of surgical site antimicrobials. subset of the high-oxygen Control: 5/74 (7%) Endometritis: Fever ≥38.5oC infection Though not statistically group RR (95%CI): 1.9 (0.67-5.5) within the first 24 hours significant, more patients p=.26 postpartum or>38.0oC for at with diabetes mellitus were Control: n=74 Wound separation: least 4 hours after the first 24 randomized to the 30% oxygen at 15L/min Intervention: 5/69 (7%) post-partum associated with intervention group. Control: 2/74 (3%) uterine tenderness greater Hypertensive disorders Standard Preventative RR (95%CI): 2.7 (0.5-13.4) than expected without other were more prevalent in Measures: p=.26 identified fever sources the control group. Skin Prep: Routine surgical (Ernest 2000) Age: 16-47 y preparation with betadyne Subanalysis of SSI risk Relative Risk Adjustment- Gender: 100% female scrub. factors: adjusted for gestational or Obesity: AMP: All but one received Surgical blood loss chronic hypertension © 2017 American Medical Association. All rights reserved. 356

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score BMI median (range): 32 prophylactic antimicrobials. 97 Intervention: 900cc (range, Perioperative Care: kg/m2 (22-51) received it at cord clamp; 45 600-1250) Regional not general anesthetic Comorbidities: NR received it at case start. Control: 800cc (range, 300- (standard for cesarean Procedure: Cesarean 1500) section delivery) section P=0.04 Other notes: The P-value Indications: Not Recorded All other factors not exceeded the P-value for Setting:1 University Hospital statistically significant, futility suggesting these Location: USA including Intraoperative differences were unlikely to Dates of Study: October partial pressure of venous reach statistical significance 2001 – April 2007 oxygen mean and range with continued recruitment. Inclusion Criteria: Women (P=0.91) and intraoperative The study was ended early who underwent a clinically partial pressure of venous Eight documented protocol indicated caesarian oxygen >200mmHg or deviations occurred in each delivery after the onset of ≤200mmHg (P=0.76) group, most due to labor or rupture of Other infections: NR intermittent mask use due to membranes Topic Specific outcomes: nausea/vomiting during Exclusion Criteria: Venous Oxygen saturation, surgery or patient request Cesarean delivery before median % (range) post-partum to facilitate infant the onset of labor or Intervention: 99 (23-99) bonding. rupture of membranes, Control: 99 (57-99) Follow-Up: 14 days- All emergent cesarean P=0.006 participants followed delivery, general Partial pressure of venous throughout hospitalization; of endotracheal anesthesia oxygen, median mm Hg those without SSI during (those who started with (range) initial hospitalization, 7 regional anesthetic and Intervention: 177 (20-449) controls and 2 interventions converted to general were Control: 122 (20-449) were lost to 2 week not excluded), clinical P=0.001 postpartum follow up (they chorioamnionitis, & HIV Surgical Estimated Blood were kept in analysis and infection Loss: median (range) considered to not have an Intervention: 900cc (600- SSI) 1,250) Control: 800cc (300-1,500) Funding Source Conflicts: p=.04 Authors: None Reoperation: NR Institution: None Length of stay: days median Study: None (range) Supplies: None Intervention: 3 (2-5) Control: 3 (2-6) p=.92 © 2017 American Medical Association. All rights reserved. 357

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Mortality: NR Adverse Events: Readmission: Intervention: 3/69 (5%) Control: 2/74 (4%) RR (95%CI): 1.4 (0.2-8.4) p=.99 Intravenous antimicrobial treatment: Intervention: 10/69 (14%) Control: 5/74 (7%) RR (95%CI): 2.1 (0.8-6.0) p=.17 Belda RCT To test the Number of patients: N= Intervention: n=148 SSI (Follow up 14 days) Definitions: 2005 91 1, 2, 3, hypothesis 291 Intraop: At intubation-Oxygen/ air Total: 57/ 291 (39.3%) SSI (ES) 4, 5, 6, that Patient Characteristics: mixture with an FIO2 of 80%. Positive cultures for CDC definitions 7, 8, 10 supplemental Morphometric, demographic, Intraop: At extubation increased pathogenic bacteria: 50/57 Surgical wounds assessed daily oxygen & other preoperative to 100% at extubation. Intervention: 22/ 148 (14.9%) by blinded surgeon. Purulent reduces characteristics were Postop: First 6hrs non- Control: 35/ 143 (24.4%) exudates were cultured & infection risk similar in the 2 treatment rebreathing facemask with Analysis for increased risk of when positive for pathogenic in patients groups. reservoir with oxygen SSI bacteria, appropriate following Except that intervention was administered at the randomly 80% FIO2 Unadjusted antimicrobial given. elective shorter in height & had designated concentration univariate Wound Healing colorectal more women. (80%) at a total flow of 16L/min RR, 0.61; 95%CI 0.38-0.98; Evaluated using ASEPSIS score surgery Age: Specifics NR = 18-80 Postop after 6 hours-ambient air P=0.04 (>20 =infection) years with supplemental oxygen 80%FiO2: Adjusted Respiratory Disease- - history of Gender: m/f provided as necessary to multivariate COPD, asthma requiring routine Intervention: 71/77 maintain pulse oximetry of at RR 0.46; CI 95%, 0.22-0.95; medication or other clinically Control: 91/52 least 92% P=0.04 important respiratory Obesity: Timing of Intervention: Intra and (Risk of SSI reduced 54%) impairment. BMI: mean (SD): postoperatively Coexisting Respiratory Perioperative Care: Intervention: 27.1 (4.5) Duration of Treatment: disease: Anesthesia induction & Control: 26.5 (3.8) From anesthesia induction until 6 Unadjusted univariate treatment were standardized BMI> 30: hours postoperatively. RR 2.15 (95% CI, 1.03-4.48) across all patients. Intervention: 26/148 Device: Intraop- intubated; Post- Adjusted multivariate Blinded attending surgeon (17.5%) op= non-rebreathing face RR 3.23 (95% CI, 1.18-8.86) administered analgesic Control: 21/143 (14.9%) masks w/ a reservoir. P=0.04 agents, determined initiation Other than percentage of Monitoring Intervention: ASEPSIS Score >20 on any of feeding, ambulation & the inspired FIO2 and FIO2, pulse oximetry were postoperative day: duration of hospitalization. © 2017 American Medical Association. All rights reserved. 358

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score resulting PaO2 there were continuously monitored during Intervention: 25 (16.9%) Other notes: no significant differences the surgery and in the recovery Control: 37 (25.9%) Preoperative SSI Risk between the groups for room. P = 0.06 Stratification: >30 other potential intra Arterial blood sample obtained 1h Other infections: NR SENIC 1/2/3: (%) or postoperative after anesthesia induction to Topic specific outcomes: Intervention: 19.4/64.2/16.2 confounding factors. evaluate PaO2; another was Partial (arterial) pressure of Control: 15.4/74.1/10.5 Comorbidities: again 2 hours after intubation. oxygen: 1h postinduction in NNIS 0/1/2: (%) Respiratory disease: Control: n= 143 mm Hg: Intervention: 16.9/58.1/25.0 Intervention: 25/148 Intraop: At intubation Oxygen/ air Intervention: 285.9 (96.6%) Control: 12.6/68.5/18.9 (17.1%) mixture with an FIO2 of 30% Control: 117.5 (40.6%) Control: 16/143 (11.2%) Intraop: At extubation increased P<0.05 True ITT analysis was not PaO2 mmHg 1h post- to 100%. Partial (arterial) pressure of possible cause of incomplete induction Postop: First 6hrs non- oxygen: 2h postinduction: follow up date so they Intervention: 285.9 (96.6%) rebreathing facemask with Intervention: 233.7 (89.7%) conducted a sensitivity Control: 117.5(40.6%) reservoir with oxygen Control: 125.4 (49.0%) analysis based on treatment P<0.05 administered at the randomly P<0.05 group assignment that PaO2 mmHg 2h post- designated concentration included all patients except 4 induction (30%) at a total flow of 16L/min Reoperations: NR who should have been Intervention: 233.7 (89.7%) Postop after 6 hours-ambient air Length of stay: excluded because 2 had Control: 125.4 (49.0%) with supplemental oxygen Intervention: 11.7 days (7.0) laparoscopic surgery and 2 P<0.05 provided as necessary to (SD??) had low preop albumin Excepting post-op maintain pulse oximetry of at Control: 10.5 days (4.4) Follow-Up: 14 days after hemoglobin, all other least 92% P=0.09 surgery physiological variables, Mortality: Funding Source Conflicts: lab test results dada, Standard Preventative Control: 2 died of multi-organ Authors: None ASEPSIS index & Measures: failure of septic origin Institution: None extrinsic infection risk Mechanical Bowel Prep: using an Adverse Events Study: Industry factors were similar electrolyte solution w/ no ICU Admission (not planned): Supplies: Industry between groups. antimicrobials or antiseptics Intervention: 4/148 (2.7%) Postop hemoglobin: mean AMP: w/ metronidazole plus Control: 5/143 (3.5%) (SD) g/L cefoxitin or a 3rd generation P=0.74 Intervention: 11.0 (1.2) cephalosporin was Control: 11.5 (2.5) administered 60-90 minutes P< 0.05 before the surgical incision & continued postoperatively for Procedure: Colorectal up to 48 hours. surgery Aminoglycosides used as an Total or subtotal alternative to β-lactam colectomy: 11/291 (3.8%) antimicrobials in patients who © 2017 American Medical Association. All rights reserved. 359

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Hemicolectomy: 89/291 reported cephalosporin allergy (30.6%) history. Rectum resection with Type and duration of AMP in first abdominal-perineal repair: 48hrs similar in the two groups. 29/291 (10.0%) Normothermia: Maintained w/ Sigmoid anterior resection: circulating-water mattresses & 87/291 (29.9%) forced-air heaters. Rectal anterior resection: Fluids: administered 53/291 18.2%) intraoperatively at 15mL/kg per Other: 22/291 (7.6%) hour; blood loss restored with crystalloids or colloids &, when Indications: necessary, w/ leukocyte- Cancer filtered allogeneic red blood Intervention: 126/148 cell concentrate. Fluid (85.8%) administered at 3mL/kg per Control: 124/143 (86.7%) hour during first 6 Inflammatory bowel disease postoperative hours then Intervention: 14/148 (9.4%) reduced to 2mL/kg per hour Control: 10/143 (7%) after transferred to ward. Other Wound Closure: They were Intervention: 7/148 (4.7%) covered with conventional Control: 9/143 (6.3%) gauze bandages. An antiseptic Setting: 14 hospitals solution was applied to the Location: Spain surface of the wound but Dates of Study: March 1, neither intraperitoneal 2003 –October 31, 2004 antimicrobials nor antiseptics Inclusion Criteria: Patients were used. undergoing elective Analgesic: Patients who reported colorectal resection post-op pain score of more (abdominal-peritoneal than 3cm on a 10-cm visual reconstructions) analog scale (0=no pain, 10= Exclusion Criteria: Minor worst pain imaginable), patient colon surgery, was administered an (polypectomy, isolated intramuscular or IV morphine & colostomy), laparoscopic non-steroidal anti-inflammatory surgery, surgery less than drug. 1 hour, fever, existing signs of infection, diabetes mellitus type 1 or © 2017 American Medical Association. All rights reserved. 360

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score 2, HIV, weight-loss >20% in the previous 3mos, serum albumin conc. < 30g/L & a leukocyte count < 2500 cells/mL Pryor RCT To determine Number of patients: Intervention: n=80 SSI (Follow up 14 days) No Definitions: 97 2004 1, 2, 3, whether the N=160 Intraop: (%) SSI: SSI was assessed by (ES) 4, 5, 6, routine use of Patient Characteristics: Pre-oxygenation, induction, Overall: 29/160 (18.1%) investigator blinded to 7, 8, 9, high FIO2 Preoperative patient emergence and extubation: Intervention: 20/80 (25%) randomization via a 10 during the characteristics such as FIO2 100% Control: 9/80 (11.3%) retrospective chart review perioperative sex, age, etc. were Intraop: 80% Oxygen (FIO2 of P = 0.02 looking for SSI criteria being period alters recorded and not found to 0.80) OR 2.63 (95%CI, 1.1-6.2) met at one of two phases: (1) the incidence be statistically significant FIO2 could be increased as RR 2.22(95%CI, 1.1-4.6) during hospitalization and (2) of SSI in a except for BMI, Obesity & required to maintain arterial Multivariate analysis : FIO2 for those discharged in <14 heterogeneou Pulse though they were oxygen saturation >94%. (P=0.03) and staying days without evidence of SSI, s general not found to be indicators Postop Transport from OR: 80% intubated at the end of then at first postop visit with surgical of SSI in multivariate Oxygen 10 L/min via closed surgery remained surgeon, any emergency population in analysis. reservoir bag-mask predictive of infection department visits, telephone an academic Age: >18y In recovery extubated: 80% calls or other contacts within setting. Gender: NR Oxygen via a high-flow non- Superficial (Wound only) first 14 days postop. BMI mean (SD) rebreathing, humidified, Intervention: 13/20 (65%) Intervention: 27.1 (6.7) aerosol delivery system for 2 Control: 5/9 (56%) SSI Criteria prospectively Control: 25.1 (5.0) hours P = 0.84 defined: P=0.04 In recovery intubated: 80% Deep structures 1.surgical team clearly Obesity: BMI>30, No (%) Oxygen through ventilator for 2 Intervention: 3/20 (15%) documented clinical Intervention: 19/80 (23.8%) h, then recovery/ICU team Control: 1/9 (11%) assessment of SSI Control: 9/80 (11.3%) determined therapy P = 0.84 2.SSI precipitated management P=0.04 Timing of Intervention: Intra and Wound and Deep structures action (changing Fifteen obese patients had postoperatively Intervention: 4/20 (20%) antimicrobials, opening BMI<35. No significant Duration of Treatment: During Control: 3/9 (33%) wound, aspiration, drain difference between surgery and for the first 2 P = 0.84 placement , further surgery groups if BMI defined as hours postoperatively Time to first detection of 3.clinical assessment supported >32 or >35 Device: infection by at least 3 of the following Pulse, beats/min (SD) During Transport: Mean (SD) 5.6(2.4) days objective criteria Intervention: 83 (14) Intervention: Closed reservoir Other infections: NR prospectively assigned by the Control: 79 (14) bag-mask system Topic specific outcomes: study: P=0.04 Control: Nasal cannula Arterial Oxygen Saturation • WBC Count>11000μL Comorbidities: In recovery: high-flow (recovery) • Temperature>38.5oC COPD nonrebreathing, humidified, Intervention vs. control • Radiological Evidence © 2017 American Medical Association. All rights reserved. 361

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Intervention: 0/80 (0) aerosol delivery system with p=0.005 (rank sum of infection Control: 5/80 (6.3%) selector to provide stable FIO2 analysis) but values for • Extrusion of pus from P=0.06 to the facemask. both groups well within site Minimum temp ,mean (SD) Monitoring Intervention: Pulse acceptable range (99% • Positive culture from site °C oximetry [1%] vs. 98% [2%]) • New erythema and Intervention: 35.5(0.7) Estimated Blood Loss mL induration that Control: 35.4(0.6) Control: n=80 mean (SD) responded to treatment P=0.54 Intraop: Pre-oxygenation, Intervention: 230 (180) of infection Temp at extubation ,mean induction, emergence and Control: 200 (190) (SD) °C extubation: FIO2 100% P = 0.03 Perioperative Care: Intervention: 36.2 (0.07) Intraop: 35% Oxygen (FIO2 0.35) Crystalloid L: Anesthesia- general- Control: 36.1 (0.6) Postop Transport from OR: 35% Intervention: 4.5(2.1) heterogeneity in inhalation P=0.20 Oxygen at 4 L/min (nasal Control: 3.8(1.9) agents used: Procedure: Colectomy cannula) P=0.02 Isoflurane (right, left, hemicolectomy In recovery extubated: 35% Blood loss and Crystalloid not Intervention: 68.8% & sigmoid), low anterior Oxygen at 4 L/min via a high- significant on multivariate Control: 75% resection, flow nonrebreathing, analysis Sevoflurane abdominoperineal humidified, aerosol delivery Nitrous oxide 30 min after Intervention: 21.3% resection, gastrectomy, system. incision mean (SD), Control: 17.5% pancreaticoduidenectomy In recovery intubated: 35% %vol/vol Desflurane , exploratory laparotomy, Oxygen through ventilator for 2 Intervention: 5 (10%) Intervention: 10.0% and large gynecologic h, then recovery/ICU team Control: 21 (30%) Control: 7.5% staging/ de-bulking determined therapy P=0.008 Other notes: procedures in which Standard Preventative Preoperative SSI Risk bowel or peritoneum was Measures: Reoperations: Stratification: NNIS M/0/1/2/3 involved. Bowel prep: regimen undertaken Intervention: 4/80 (5.0%) Intervention: 7/32/35/5/2 Indications: night before surgery according Control: 0/80 Control:9/31/34/6/0 Cancer to surgeon’s instructions. AMP P=0.06 P=0.94 Intervention: 36/80 choice and timing recorded. Length of stay: mean days Control: 30/80 AMP: Intravenous antibiotics (SD) NOTE: Initial power analysis Non-Cancer either immediately before Intervention: 8.3 (7.5) does not indicate baseline Intervention: 44/80 arriving or upon arrival to Control: 6.4 (4.7) SSI rate. It determined that Control: 48/80 operating room according to P= 0.07 300 patients were needed for Setting: University Hospital surgeon’s usual practice. SSI: 13.3 (9.9) a detectable treatment effect Location: NYC, USA Received AMP: No SSI. 6.0 (4.2) of 40%. Interim analysis was Dates of Study: September Intervention: 80/80 (100%) P<0.001 planned to be performed after 2001-May 2003 Control: 78/80 (97.5%) 160 patients recruited and Inclusion Criteria: Patients P=.26 Mortality study halted if P≤0.03. This >18 y old undergoing POD#16 1 Control patient study represents that interim © 2017 American Medical Association. All rights reserved. 362

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score major abdominal surgical Admission to hospital: most who developed an analysis, enrollment stopped procedures under general admitted on morning of incisional SSI, later a deep after statistically significant anesthesia. surgery. abscess, had a difference in SSI rates Laparoscopically assisted postoperative myocardial between groups noted. procedures were eligible infarction, followed by a Follow-Up: provided that laparotomy stroke and died 14 days was performed at some Funding Source Conflicts: point during the surgery. Adverse Events: Authors: None Exclusion Criteria: Pulmonary embolus: 1 Institution: None Exclusively laparoscopic Intervention patient had a Study: None procedures, patients pulmonary embolus on Supplies: None whose respiratory status POD#3 but recovered required an FIO2 in without incident excess of 0.35, patients with severe chronic obstructive pulmonary disease (COPD) who were likely to experience respiratory depression at FIO2 of 0.80 (minor COPD acceptable), patients who were hemodynamically unstable prior to surgery (systolic blood pressure <90mmHg or use of vasopressors), patients who had received bleomycin at any time & patients who had an ASA status class 5 or 5E indicating patient is not expected to survive 24 hours regardless of the surgery. Fully laparoscopic procedures were excluded.

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Whitney RCT To determine Number of patients: N=24 Intervention: n=13 Wound complications: Definitions: 2001 101 1, 10 the effects of Patient Characteristics: Postop: 28% Oxygen delivered at Clinical healing (assessed SSI: Retrospective medical (ES) 28% oxygen Subjects compared on rate of 2L/min via nasal through self-report and chart review (documentation given in the coexisting conditions, cannula medical chart review) of wound complications to first 36 hours smoking history, Timing of Intervention: showed no significant include presenting after surgery intraoperative & Postoperative – after discharge differences between symptoms, wound on tissue postoperative variables from recovery and admission groups. appearance, culture results [if oxygen levels, and there were no to surgical unit Self-report: any] and prescribed collagen statistically significant Duration of Treatment: Total Wound Problems treatment. Follow up phone deposition, differences between 36 hours postop Control: 13/ 11 calls with patient questioned and clinical groups. Device: nasal cannula for Intervention: 9/ 13 about wound healing healing Age: 18-80 years; Mean delivery of the 28% Self-report included notation problems including wound outcomes. (SD) supplemental oxygen for of any wound problem, appearance and treatment. Intervention: 41 (9.9) intervention problems with wound Final wound healing Control: 42 (11.5) Monitoring Intervention: drainage, concerns about classification: Gender: m/f Subcutaneous tissue oxygen incision redness, problems Primary: no wound edge Intervention: 69%/31% (PscO2) measured via silastic with incision swelling, separation or other indication Control: 85%/15% tonometer inserted incision opening, treatment of wound healing problems. Obesity: subcutaneously in subject’s sought for wound Secondary: only if patient Body surface area m2:mean dorsal left upper arm after complications, treatment reported partial or complete (SD) anesthetic induction. prescribed for problem, separation of the wound Intervention: 2.00 (0.20) Equilibration and baseline and pain at surgical site edges or other indications of Control:2.05 (0.30) established while patient on that did not decrease over wound healing problems and Comorbidities: Cardiac room air. Second equilibration time. I also confirmed by medical History: Yes (p=0.084) at 30 minutes. PscO2 readings Medical Chart Review (30 record documentation Intervention: 0% recorded at 1, 2, 18, and 36 days) Control: 7.1% hours postoperatively Complication necessitated SSI not defined, but wound Procedure: cervical fusion Wound healing evaluated by clinic visit: complications and infections and/ or excision of hydroxyproline content in a Intervention: 0/13 (at a left or right neck surgical cervical intervertebral disk subcutaneous Control: 1/11 wound and in some cases a (neurosurgery or the polytetrafluoroethylene tube Incision redness thigh skin graft)were orthopedic surgery removed on the 7th post-op day Intervention: 1/12 measured by three services) Control: n=11 Control: 1/8 individuals using the Indications: NR Room air Incision drainage ASEPSIS scoring method Setting: Military regional Standard Preventative Intervention: 0/13 (comparisons of the medical center Measures: NR Control: 1/8 ASEPSIS method with Location: Pacific Northwest, Incision swelling standard clinical definitions of USA Intervention: 0/12 wound infection or Dates of Study: NR (24 Control: 0/8 complications demonstrated © 2017 American Medical Association. All rights reserved. 364

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score month period) Other wound problem: that ASEPSIS was as Inclusion Criteria: Aged 18- Intervention: 1/12 sensitive as and significantly 80 years, male & female, Control: 0/8 more specific than the other able to read & speak Wound Healing Assessment indicators of wound problems English, give informed Histology scores for cellularity Perioperative Care: NR consent, & discharged and presence of Other notes: NR from the post-anesthesia connective tissue or mean Follow-Up: for 30 days post-op care unit without amounts of hydroxyproline via medical record review & supplemental oxygen in the ePTFE implants- No telephone call to the subject Exclusion Criteria: NR significant difference Funding Source Conflicts: between control & Authors: None intervention groups. Institution: None However, only subjects in Study: None intervention group Supplies: None achieved hydroxyproline levels >0.40µg/mm of ePFTE tubing. ASEPSIS Scores- all within satisfactory healing (0-10 out of 20) without significant differences between the mean scores. Wound healing classification: all primary healing Other infections: NR Topic specific outcomes: Tissue oxygen mean (SD) Intervention: 63 mm Hg ±14 Control: 48 mm Hg ±7 P=0.001 No significant effects for time or for an interaction between time and group. Reoperations: NR Length of stay: NR Mortality: NR Adverse Effects: NR

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Greif RCT To test Number of patients: Intervention: n=250 SSI (Follow up 15 days) Definitions: 2000 93 1, 2, 3, hypothesis N=500 Intraop: 80% Oxygen and 20% Note: Follow up evaluations SSI: (ES) 4, 5, 6, that Patient Characteristics: Nitrogen after induction of not completed in 3 patients Likely infected: when pus could 7, 8, 9, supplemental Patient clinical anesthesia and intubation. who withdrew from the be expressed from the 10 administration characteristics, Increased 10 100% during study-they had no known incision or aspirated from a of oxygen diagnoses, surgical extubation. infections and in analysis loculated mass within the during procedures, duration of Postop: 80% Oxygen via were considered wound. perioperative surgery, hemodynamic nonrebreathing mask for 2 uninfected. Infected: Wounds with culture- period values and use of hours, then room air unless Overall incidence was 8% positive pus decreases the anesthetic were recorded additional oxygen required to (6% predicted by NNIS Wound Healing and infection incidence of & analyzed and not found maintain oxyhemoglobin scores) Scoring: ASEPSIS wound to be statistically concentrations of >92%. Intervention: 13/250 (5.2%) Perioperative Care: infections in significant between Timing of Intervention: (95%CI, 2.4-8) Was anesthesia: standardized patients groups except as noted. Intra and Post-operatively Control: 28/ 250 (11.2%) and induced with IV undergoing Baseline: Duration of Treatment: (95%CI, 7.3-15.1) thiopental sodium (3-5mg/kg elective Age (y) (±SD) Intraop and 2 hours P=0.01 of bodyweight), fentanyl (1-3 colorectal Intervention: 57±15 postoperatively. Absolute difference in SSI μg/kg) and vecuronium resection. Control: 57±15 Device: Postop-Nonrebreathing rates: 6% bromide (0.1mg/kg) and Gender (m/f) 280/220 mask sealed to the patient’s (95%CI, 1.2-10.8) maintained with isoflurane Obesity: face and connected to a valved adjusted to keep mean Weight (kg) Mean ±SD manifold and oxygen blender. ASEPSIS Scores mean ±SD arterial blood pressure w/in Intervention: 74±17 Monitoring Intervention: Intervention: 3±7 20% of pre-induction value. Control: 72±17 Intraop: Concentrations of Control: 5±9 Additional fentanyl administered Height (cm) Mean ±SD inspired oxygen and end-tidal P=0.01 to improve analgesia when Intervention: 170±12 isoflurane and carbon dioxide Mixed Effects model: Only patient emerged from Control: 169±12 were measured use of 30% oxygen anesthesia. Comorbidities: Intraop and postop: Oxygen (controls) correlated Other notes: NR Smoker saturation measured with pulse significantly with the risk of Preoperative SSI Risk Intervention: 24% oximeters infection Stratification: NNIS & Control: 29% Arterial blood was obtained 1h OR 2.3 (95%CI, 1.2-4.6) SENIC (modified) Intraop: End-tidal isoflurane after induction of anesthesia SENIC 1/2/3 – No. patients concentration-% and 2h postop to measure Analysis SSI (N=41) vs. No Intervention: 71/158/21 Intervention: 0.90±24 partial pressure of oxygen. SSI (N=459) Control: 65/165/20 Control: 0.84±0.24 Control: n=250 ASEPSIS Scores: P=.86 P=0.005 Intraop: 30% Oxygen and 70% SSI: 25±13 NNISS 0/1/2-No.patients Difference clinically Nitrogen after induction of No SSI: 2±4 Intervention: 132/100/18 unimportant anesthesia and intubation. P<0.001 Control:127/106/17 Procedure: Elective Increased to 100% during WBC (X10-3/mm) mean ±SD P=0.86 colorectal resection extubation. Preop- not statistically © 2017 American Medical Association. All rights reserved. 366

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Colon: Postop: 30% Oxygen via significant difference Initial plan was to study 1000 Intervention: 71% nonrebreathing mask for 2 between groups. patients – evaluate results Control: 63% hours, then room air unless Postop (POD#1, 3, 6, and 9) after 500—750 patients Rectum: additional oxygen required to patients with SSI had enrolled. A priori criterion of Intervention: 29% maintain oxyhemoglobin statistically significant ending the study after Control: 37% concentrations of >92%. higher counts (P value enrollment of 500 patients Subgroup Analysis#1 N=54 (1 range: <0.001-0.02) was a difference in incidence Indications: center) Staples removed (days of SSI between groups with Cancer: Intervention: n=22 postop) one tailed P<0.012. Intervention: 65% Control: n=32 SSI: 11.1±2.4 Control: 55% Wound collagen and protein No SSI: 10.3±1.4 Follow-Up: 15 days postop Inflammatory Bowel Disease deposition: near end of P<0.001 Wounds evaluated daily until (IBS) surgery, 7cm expanded Length of stay- see below discharge then at a clinic Intervention: 20% polytetrafluoroethylene implant visit15 days) Control: 25% inserted in subcutaneous Other infections: NR Funding Source Conflicts: Other tissue a few centimeters to one Topic specific outcomes: Authors: None Intervention: 15% side of and parallel to the Perioperative administration Institution: None Control:20% surgical incision- removed on of oxygen in concentrations Study: None Setting: 3 hospitals (2 POD#7 and assayed for that exceeded those Supplies: None university) hydroxyproline and protein. designated: Location: Austria (2) and Subcutaneous oxygen tension: Intervention: 1/500 Germany (1) oxygen sensor within Control: 38/500 Dates of Study: July 1996- subcutaneous saline-filled Mean ±SD October 1998 tonometer in the lateral upper All patients N=500 Inclusion Criteria: Patients arm. Measurement taken after Arterial oxygen saturation-% 18-80 y undergoing induction of anesthesia and Intraoperative elective open colorectal continued at designated Intervention: 99.1±0.6 resection, including those oxygen concentration intraop Control: 98.7±1.1 undergoing abdominal- and 2 h postop. P=<0.001 peritoneal pull-through Subgroup Analysis#2 N=24 (1 Partial pressure of arterial procedures center) oxygen-mm Hg Exclusion Criteria: Patients Intervention: n=12 Intraoperative undergoing minor colon Control: n=12 Intervention: 348±97 surgery (e.g. polypectomy Intraop: muscle oxygen tension: Control: 121±34 or isolated colostomy), Oxygen electrode inserted into P<0.001 recent history of fever, quadriceps femoris (0.35mm Postoperative infection or both, serious diameter needle inserted 1mm Intervention: 206±91 malnutrition (serum at a time) Oxygen tension Control: 114±35 albumin<3.3g/dl, WBC recorded at each of 200 P<0.001 © 2017 American Medical Association. All rights reserved. 367

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score <2500 cell/ml3 or loss of measurement points, Oxygen saturation-% (pulse >20% bodyweight), and histogram constructed for each oximetry) bowel obstruction. patient. Muscle oxygen tension Postoperative evaluated 90 minutes after Intervention: 99±2 induction of anesthesia at the Control: 97±2 designated FIO2. P=<0.001 Standard Preventative Measures: Subgroup Analysis #1 N=54 Bowel Prep: Night before, patient Subcutaneous oxygen underwent standard tension-mm Hg mechanical bowel prep with an Intraoperative electrolyte solution but no Intervention: 109±43 intraluminal antimicrobials. Control: 59±15 AMP: IV for a mean of 2.7±2.3 P<0.001 days after skin incision. Mostly Postoperative metronidazole combined with Intervention: 73±25 cefazolin, cefamandole, Control: 54±25 amoxicillin, clavulanate or P=0.02 mezlocillin. Types and duration Collagen Deposition-ng/mm of AMP were similar in the two Intervention: 258±118 groups. Fluid-Patients Control: 267±109 aggressively hydrated. P=0.38 Intraop: Crystalloid 15ml/kg/h IV; Protein Deposition-ng/mm Blood loss replacement in Intervention 153±91 solution to blood ratio 4:1 or Control: 163±74 colloid at2:1. P=0.31 Postop: Fluids at 3.5ml/kg/h X Subgroup Analysis#2 N=24 24h then at 2ml/kg/h X24h. Muscle oxygen tension-mm Leukocyte depleted blood Hg transfusions as deemed Intervention: 49±10 necessary by surgeon. Control: 25±6 Surgical wound treatment P<0.001 (intraop): There was no antimicrobial or antiseptic Reoperations: NR irrigation of the wound or Length of stay: peritoneal cavity. Intervention: 12.2±6.1 days Wound closure: standard – all Control: 11.9±4.0 days deep layers including P=0.26 peritoneum were closed with Length of stay © 2017 American Medical Association. All rights reserved. 368

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score continuous sutures. SSI (N=41) vs. No Subcutaneous tissues were SSI(N=459) closed with interrupted sutures SSI: 18.7±8.3 days & the skin was stapled No SSI: 11.4±4.1 days Normothermia: Intraoperative P<0.001 core temp was maintained at 36°C with use of forced air Mortality: Follow up: 15 cover over the patient and days warming of intravenous fluid. Cause of death in most cases Intraoperative core temps was sepsis and multi-organ monitored in the distal failure. esophagus; Infrared aural- Intervention: 1/250 (0.4%) canal temps or axillary temps Control: 6/250 (2.4%) measured throughout p=0.13 hospitalization. Analgesic: Adverse Effects intravenous & intramuscular Admission to ICU: for surgical opioids and administered by a complications such as study blinded nurse blinded to dehiscence, anastomotic treatment group assignment. leak, * peritonitis. Restarting feeding, staple Intervention: 5/250 (2%) removal, patient discharge Control: 12/250 (4.8%) determined by attending p=0.14 surgeon blinded to treatment group assignment. Discharge based on return of bowel function, control of any infections and adequate healing of incision.

Q7. What is the optimal target FIO2 to reduce the risk of SSI; how and when should it be administered? Our search did not identify RCTs or SRs that both evaluated the optimal fraction of inspired oxygen, how and when it should be administered, and included SSI as an outcome. All studies evaluating the use of supplemental increased oxygenation both intraoperative and postoperatively used 80% FiO2 as the target level.

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2.1E3. RISK OF BIAS ASSESSMENTS OF STUDIES: Q6-7 OXYGENATION eTABLE 44. Risk of Bias Assessments of Randomized Controlled Trials for Q6-7 Oxygenation Funding Randomiza- Outco- Attrition source(s) Describ- tion Describ- me smaller than Attrition disclosed and ed as appropriate ed as asses- Study Investiga- Attrition 10-15% of appropriat- no obvious Overa- Author randomiz -ly double- sor participa- tor describ- assigned ely conflict of ll Risk Year Q ed performed blind blinded nt blinded blinded ed patients analyzed interest of Bias Question 6: Oxygenation Belda 91 6          Low 2005 Bickel 92 6          Low 2011 Duggal 99 6        Low 2013 Gardella 98 6           Low 2008 Greif 93 6           Low 2000 Meyhoff 94 6           Low 2009 Pryor 97 6           Low 2004 Scifres 100 6       Low 2011 Staehr 95 6           Low 2011 Stall 96 6           Low 2013 Thibon 90 6         Low 2012 Turtiainen 102 6        Low 2011 Whitney 101 6   High 2001

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2.1F. Q8-10 ANTISEPTIC PROPHYLAXIS 2.1F1. GRADE TABLE: Q8-10 ANTISEPTIC PROPHYLAXIS eTABLE 45. GRADE Table for Q8-10 Antiseptic Prophylaxis Increase Decrease GRADE GRADE

GRADE Overall

Quantity of GRADE and Type Starting Comparison Outcome Findings Evidence of of GRADE for Evidence Evidence response Outcome Base Precision Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Large Magnitude Large Q8. What are the most effective strategies for preparing the patient’s skin prior to surgery to reduce the risk of SSI? Q8A. How safe and effective is preoperative antiseptic bathing or showering? • No difference on meta-analysis of 4 RCTs 104-107 (N=7791) in clean, elective and potentially infected procedures: 356/3906 (9.1%) vs. 389/3885 (10%): RR 0.91 (0.80- 1.04). • No difference on meta-analysis restricted to 2 higher quality RCTs104,106 (N=6302): 293/3167 (9.3%) vs. 305/3135 (9.7%); RR 0.95 (0.82-1.10) SSI* 1 SR 103 • Five months into 1 large study 105 the High 0 0 0 0 0 0 0 0 High placebo was found to have antimicrobial properties and was changed but results Chlorhexidine were not stratified nor excluded. gluconate (CHG) • No difference in each individual trial solution High • Number preoperative baths, amount of vs. antiseptic used per bath, bathing placebo instructions to each group, intraoperative antiseptic skin preparation agent, use of AMP, and follow up varied between studies. • No difference on meta-analysis of 2 RCTs 104, 107 (N=3589) 9/1804 (0.5%) vs. 10/1785 Product- (0.6%); RR 0.89 (0.36-2.19). related • Every study used 4% CHG 103 Adverse 1 SR • Data are driven by the large higher quality High 0 0 0 -1 0 0 0 0 Moderate Reactio- RCT 104 as no allergic reactions were ns reported in either group in the smaller (N=100), lesser quality RCT107. • 1 large study106 (N=1813) not included in the © 2017 American Medical Association. All rights reserved. 371

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• No difference on meta-analysis of 3 RCTs 108, 105, 109 (N=1443): 82/752 (10.9%) vs. 94/691 (13.6%); RR 1.02 (0.57-1.84) • Each study used 4% CHG • Heterogeneity for this comparison was high: P=0.08, I2 =60%. • Only the largest (N=1315) RCT 105 reported reduction in SSI with 4% CHG: 62/689 (9.0%) vs. 80/626 (12.8%); RR: 0.70 (0.57- 0.96); no special showering/bathing instructions were given to the un-medicated CHG solution bar soap group whereas “great care was vs. 103 SSI* 1 SR taken to ensure that the patients using High 0 0 0 0 0 0 0 0 High High Un-medicated [CHG]…complied with the instructions.” bar soap • One (N=66) of the two smaller, lesser quality studies108 suggested higher rate of SSI with CHG: 8/31 (25.8%) vs. 4/35 (11.4%): RR: 2.26 (0.75-6.77) and the other 109 (N=64) showed no difference: 12/32 (37.5%) vs. 10/30 (33.3%); RR 1.13 (0.57- 2.21) • Number preoperative baths, bathing instructions, intraoperative antiseptic skin preparation agent, use of AMP, procedures, and follow up varied between studies. • No difference on meta-analysis (N=1142) of CHG solution 107,109,110 103 3 RCTs : 22/623 vs. 29/519; RR vs. SSI* 1 SR High 0 0 0 -1 0 0 0 0 Moderate Moderate 0.82 (0.26-2.62) No Wash • Each study used 4% CHG © 2017 American Medical Association. All rights reserved. 372

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Quantity of GRADE and Type Starting Comparison Outcome Findings Evidence of of GRADE for Evidence Evidence response Outcome Base Precision Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Large Magnitude Large • Heterogeneity for this comparison was significantly high: P<0.03, I2 = 70%. • Studies included outpatient and inpatient procedures, patients undergoing vasectomy 109, plastic surgery of the trunk 107 and elective biliary tract, inguinal hernia or breast cancer procedures 110, plus differences in SSI definition • Individual study results differed with only the largest (n=978) study 110 favoring 4% CHG: 9/541 (1.7%) vs. 20/437 (4.6%): RR 0.36 (0.17-0.79), the other two suggesting no difference: 12/32 vs. 9/32; RR: 1.33 (0.65- 2.72) 109 and 1/50 vs. 0/50; RR: 3.00 (0.13- 71.92). • Despite instructions to not shower, it is not clear if the “No wash” groups did in fact shower. • Reduced risk of SSI with whole body washing in 1 RCT 110 (N=1093) in elective CHG solution: biliary tract, inguinal hernia or breast cancer Whole body 103 procedures: 9/541 (1.7%) vs. 23/552 (4.1%); SSI* 1 SR High 0 0 0 -1 0 0 0 0 Moderate Moderate vs. RR: 0.40 (0.19-0.85). partial body wash • Whole body wash = entire body + scalp • Partial body wash = restricted to proposed surgical site. • 1 RCT (N=114) in elective, clean plastic Aqueous surgical procedures (thorax or abdomen) iodophor solution reported no infections in either group vs. control (“usual SSI* 1 RCT 111 (Follow up NR). The study was designed to High -1 0 -1 -1 0 0 0 0 Very Low Very Low personal hygiene assess impact of preoperative showering on routine”) skin colonization, not SSI. • Study used 10% povidone iodine solution

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1-step vs. 2-step • In a study 114 of 108 CABG patients, no difference was observed (12% vs. 13%) in sternal infections (6 week follow up) Aqueous Iodophor (1 or 2 step) vs. • No difference on a meta-analysis (N=626) of 5 RCT Iodophor in SSI* 114-118 5 studies: OR: 1.80 (0.50 – 6.52); p=0.37; High 0 -1 0 -1 0 0 0 0 Low Low 2 Alcohol (1 step, I =67% with or without adhesive drape) CHG-alcohol vs. Aqueous Iodophor CHG-alcohol (1 • In a meta-analysis (N=1976) of 5 RCTs, or 2 step) vs. 5 RCT CHG-alcohol was associated with reduced SSI* 116,119-122 High 0 0 0 0 0 0 0 0 High High Aqueous risk for SSI: OR: 0.59 (0.42 – 0.83); Iodophor (1 or 2 p=0.003; I2=0

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Quantity of GRADE and Type Starting Comparison Outcome Findings Evidence of of GRADE for Evidence Evidence response Outcome Base Precision Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Large Magnitude Large step) • One study 120 (N=849) reported 3 (0.7%) drug-related adverse events (pruritus, Product- erythema or both around the surgical related 2 RCT 120,121 wound) in each group (P>0.99) High -1 0 0 0 0 0 0 0 Moderate Adverse • One study 121 (N=500) reported two cases of Events skin irritation in aqueous iodophor group, and no cases in CHG-alcohol group CHG-alcohol vs. Iodophor-alcohol CHG-alcohol (1 or 2 step) vs. • No difference on meta-analysis of 6 RCTs 6 RCT Iodophor- SSI* 116,123-127 (N=1323), OR: 0.64 (0.24 – 1.71); p=0.38; High 0 0 0 0 0 0 0 0 High High 2 alcohol (1 or 2 I =16% step) • No difference among the 743 patients available for follow up at 3-4 days in a large (N=866) general surgery study125: 27/389 (6.9%) vs. 35/354 (9.9%); p=NS. Significance varied by procedure: biliary surgery and “other clean operations” each suggested lower incidence of SSI with CGH- alcohol (p<0.05), in contrast, there was a lower incidence of SSI (not statistically CHG-alcohol significant) with iodophor-alcohol in large (2 step) vs. 3 RCT SSI* 123-125 bowel and other laparotomy procedures. High 0 0 0 0 0 0 0 0 High High Iodophor- 124 • No difference in a study of 250 elective, alcohol (2 step) clean, plastic surgery breast procedures. Only 4 superficial SSIs reported at 30 day follow up, all in the iodophor-alcohol group (p=0.06) • No infections reported in either group in a small (N=50) study123 of foot surgeries. The study was designed to evaluate the products’ efficacy in reducing skin contamination, not SSI (follow up and © 2017 American Medical Association. All rights reserved. 375

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Quantity of GRADE and Type Starting Comparison Outcome Findings Evidence of of GRADE for Evidence Evidence response Outcome Base Precision Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication Large Magnitude Large definition of SSI not reported). • In a study of 80 foot/ankle surgeries126, only 1 SSI reported (CHG-alcohol group). Follow up and definition of SSI not reported. • In a study116 of 100 arthroscopic shoulder CHG-alcohol surgeries, no infections were reported in (1 step) vs. 3 RCT either group at 10-month follow up. SSI* 116,126,127 High 0 0 0 0 0 0 0 0 High High Iodophor- • In a study127 of 100 elective lumbar spinal alcohol (1 step) surgeries, no infections were reported in either group at 6 month follow up • All studies were designed to evaluate the products’ efficacy in reducing skin contamination, not SSI Q8C. How safe and effective is the application of a microbial sealant immediately following skin preparation? • No difference on meta-analysis (N=609) of 4 4 RCT RCTS in cardiac surgery, hernia repair, or SSI* 128-131 High 0 -2 0 0 0 0 0 0 Low scoliosis correction: OR: 0.46 (0.08 – 2.51); p=0.37; I2=68% Cyanoacrylate- • In 4 RCTs there were no significant product based skin related adverse events reported. Low sealant vs. Product- • In one RCT130 surgeons reported difficulty 4 RCT No sealant related 128-131 incising through the clear film in 4/166 High 0 0 0 0 0 0 0 0 High Adverse patients but no difficulty suturing wounds.

Events- There was one report of visible “flaking” of the film at the time of procedure.

Q8D. How safe and effective are plastic adhesive drapes? Non-Iodophor • No difference on meta-analysis of 4 RCTs impregnated 4 RCT SSI* 132-135 (N=1742) (RR: 1.05; 95% CI: 0.81 – 1.35; High -1 0 0 0 0 0 0 0 Moderate Moderate adhesive drape 2 p=0.71; I =0 vs. No drape

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Iodophor- • No difference on meta-analysis of 2 RCTs impregnated 2 RCT SSI* 114,136 (N=1113) RR: 1.03 (0.66 – 1.60); p=0.89; High 0 0 0 0 0 0 0 0 High High adhesive drape 2 I =0 vs. No drape

*Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

Increase Decrease GRADE

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Quantity Overall of and Type Starting GRADE of Comparison Outcome Findings Evidence of GRADE Evidence for Evidence response Base Large Outcome Precision Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication vs. 6/42; p<0.05 but not in contaminated procedures: 1/44 vs. 3/46: p=NS • A subanalysis 138 of peritoneal lavage with normal saline then 100ml PI solution prior to closure in dirty: 4/13 vs. 5/16; p=NS • 1 study 139 peritoneal lavage with 1L of 10% PI solution for 60 sec, repeated 3 times during the procedure, the last time before closure in contaminated and dirty combined suggested no difference: 1/37 vs. 4/34; p=0.12. • In meta-analysis (N=660) of 2 studies of clean spine surgeries 0.35% povidone iodine irrigation (volume not reported) and wound soaking for 3 minutes followed by irrigation with 2L normal saline was associated with reduced risk for deep SSI 2 RCT OR: 0.08 (0.01 – 0.58); p=0.01; I2=0. Deep SSI* 140,141 High 0 0 0 0 -1 0 0 0 Moderate • In both studies, irrigation was completed prior to bone grafting and instrumentation. It was not repeated prior to wound closure. Also, AMP was started preoperatively, redosed intraoperatively as appropriate and continued for 5 days postoperatively. • Of note, 10/12 (83.3%) SSIs were MRSA. • In meta-analysis (N=329) of 2 studies in general surgical clean-contaminated, contaminated, and dirty cases (subpopulations in which both study groups Superficial 2 RCT were reported to have received parenteral 142,143 High 0 0 0 0 0 0 0 0 High SSI* AMP), irrigation of the subcutaneous tissues for 60 seconds with 10% povidone iodine prior to wound closure was associated with reduced risk for superficial SSI OR: 0.21 (0.10 – 0.45); p<0.01; I2=0 © 2017 American Medical Association. All rights reserved. 378

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GRADE

Quantity Overall of and Type Starting GRADE of Comparison Outcome Findings Evidence of GRADE Evidence for Evidence response Base Large Outcome Precision Magnitude Directness Consistency Confounders Study Quality Study Dose - Publication Bias Publication • In meta-analysis (N=149) of clean- contaminated cases, PI associated with reduced risk OR: 0.15 (0.03 – 0.72); p=0.02; I2=0 • In meta-analysis (N=90) of dirty cases, PI associated with reduced risk OR: 0.26 (0.08 – 0.91); p=0.03; I2=0 • One study 137 in 168 laparotomy patients with contaminated peritoneal cavities reported no complications from the use of Adverse povidone iodine were noted. Events - 3 RCT • One study 141 in 414 mixed spine surgery 137,141,143 High 0 0 0 0 0 0 0 0 High Product patients reported no product-related Related adverse event with 0.35% povidone iodine followed by normal saline irrigation • One study 143 in 187 general surgical procedures reported no allergic reactions • One study 140 in posterior spine (no trauma) reported one incidence of wound Wound 2 RCT dehiscence event with 0.35% povidone 140,143 High 0 0 0 -1 0 0 0 0 Moderate Healing iodine followed by normal saline irrigation. • One Study 143 no evidence of delayed wound healing. • One RCT 142: no significant change in serum free iodine Serum • 2 RCT137,139: significant increase in postop 3 RCT 137 Iodine 137,139,142 serum iodine levels at 24h. In 1 RCT the High 0 0 0 0 0 0 0 0 High

Level increase resolved by 72h, 1 RCT139 the increase resolved by 7 days. Both, no signs of iodine toxicity. Q10. How safe and effective is repeat application of an antiseptic skin preparation agent to the surgical site immediately prior to closing the surgical incision? Topical antiseptic agents

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GRADE

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2.1F2. EVIDENCE TABLES: Q8-10 Q8. What are the most effective strategies for preparing the patient’s skin prior to surgery to reduce the risk of SSI? eTABLE 46. Evidence Table for Q8A. How safe and effective is preoperative antiseptic bathing or showering? Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Webster, SR To review the Study types: RCT Intervention: Any type of All results intervention vs. Definitions: SSI definition used 2012 103 1, 2, 3, 4, evidence for N: 7 RCT, 10,157 participants antiseptic solution (any control – RR (95% CI). No by the studies was accepted (RA) 5, 6, 7, 8, preoperative Inclusion criteria: RCTs strength, any regimen, at significant heterogeneity Perioperative care: NR 10, 11 bathing or comparing any antiseptic any time before the surgery) unless specified Other Notes: None showering with preparation used for used for preoperative tub- SSI: Follow-up not reported antiseptics for preoperative full body wash or or bed-bathing or Chlorhexidine 4% vs. Funding Source Conflicts: preventing showering, with non-antiseptic showering. All studies used placebo – all studies (4 Authors: None nosocomial SSI preparations. 4% chlorhexidine gluconate studies, N=7791): Institution: None Exclusion criteria: Quasi-RCTs 0.91(0.80-1.04); Fixed Study: None Databases searched: Cochrane Comparison: Non-antiseptic effects model; I2=0% Supplies: None Wounds Group Specialized soap, non-antiseptic soap Chlorhexidine 4% vs. Register, CENTRAL, solution, no shower or bath placebo – high quality MEDLINE, EMBASE, CINAHL, studies (2 studies, hand searching, reference lists N=6302): 0.95(0.82-1.10); of retrieved articles (searches Fixed effects model; I2=0% ended October-November Chlorhexidine 4% vs. bar 2010) soap (3 studies, N=1443): Quality assessment: Using the 1.02(0.57-1.84); Random Cochrane Collaboration Tool effects model; I2=60% for assessing risk of bias, low Chlorhexidine 4% vs. no risk of bias for: wash (3 studies, N=1142): Random sequence generation – 0.82(0.26-2.62); Random 5/7 studies effects model; I2=70% Allocation concealment – 3/7 Chlorhexidine full wash vs. studies partial wash (1 study, Blinding of investigator and N=1092): 0.40(0.19-0.85) participant – 3/7 studies Allergic reaction: Blinding of outcome assessor – Chlorhexidine 4% vs. 5/7 studies placebo (2 studies, Incomplete outcome data – 6/7 N=3589): 0.89(0.36-2.19); studies Fixed effects model; I2=0% Selective reporting – 7/7 studies Other bias – 4/7 studies Murray RCT To test the Number of patients: N=100 Intervention group: n=50 SSI: Definitions: 2011 112 1, 4, 6, 9 hypothesis that Patient Characteristics Shower with soap and water Total SSI: SSI – NR

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score (ES) the home use ·Age, years, mean±SD the evening before Intervention: 0/50 of 2% Intervention: 49.0±16.2 operation and wipe their Control: 0/50 Perioperative care: NR chlorhexidine Control: 52.0±16.7 entire operative extremity, Other notes: Positive cultures gluconate- P=0.14 including the axilla, Other infections: NR were primary outcome of impregnated ·Gender: M/F shoulder, and ipsilateral Topic-specific outcomes: interest. Study was powered cloths would be Intervention: 36/14 (72% male) chest and back with a 2% Compliance with protocol to detect a difference in more Control: 25/25 (50% male) chlorhexidine gluconate- Intervention: 45/50 (90%) positive cultures. It was efficacious than P=0.04 impregnated cloth 1h after [4 unable to elevate arm underpowered to detect any a standard ·Obesity: NR showering. Then the sufficiently to apply the difference in SSI soap-and-water ·Comorbidities: morning of surgery, cloth, 1 patient showered Follow-up: 2 months post op. shower at Diabetes mellitus: patients were instructed to in between applications of [follow up insufficient for decreasing the Intervention: 4/50 (8%) avoid showering and apply chlorhexidine- implant SSI] preoperative Control: 4/50 (8%) a second 2% chlorhexidine impregnated cloth. Funding Source Conflicts: cutaneous P>0.99 gluconate0-impregnated Control: 50/50 (100%) Authors: NR levels of Immunosuppressive cloth in the same manner P=0.056 Institution: Industry pathogenic medications: as the first within 2h of Study: Industry bacteria on the Intervention: 1/50 (2%) departing for the hospital. Reoperations: NR Supplies: Industry shoulder Control: 0/50 Timing of intervention: Length of stay: NR P=0.99 Preoperative Mortality: NR Shaved axilla Duration of intervention: Adverse events: Intervention: 8/50 (16%) duration of chlorhexidine- No serious adverse events Control: 12/50 (24%) impregnated cloth scrub occurred in any patients P=0.45 Device/agent: 2% Side effects (mild itching or a Took abx prior to surgery chlorhexidine gluconate- feeling of dry skin): Intervention: 1/50 (2%) (for impregnated cloth and/or Intervention: 12/50 (24%) upper respiratory infection) soap Control: 0/50 Control: 0/50 Monitoring intervention: NR P<0.002 P=0.99 Control group: n=50 Patients instructed to shower Procedures: shoulder surgery with soap and water the [no acute trauma surgeries] morning of surgery. Open Standard preventive Intervention: 6/50 (12%) [6 measures: primary total shoulder Antimicrobial prophylaxis: arthroplasties] preop 1g of cefazolin if Control: 8/50 (16%) [6 primary weight was <90kg and 2g if total shoulder arthroplasties, 1 weight was >90kg, or revision total shoulder 900mg clindamycin if arthroplasty & 1 Weaver- allergic to penicillin, was © 2017 American Medical Association. All rights reserved. 382

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Dunn procedure] administered to all patients P=0.77 within 1h of skin incision. Arthroscopic Shoulder arthroplasty Intervention: 44/50 (88%) patients received an Control: 42/50 (84%) additional 1g vancomycin. P=0.77 Antimicrobial drape – antibacterial-impregnated Indications: NR drape used for all cases Setting: 1 university hospital involving implantation of a Location: USA prosthesis. Dates: January 2010 – May Intraoperative skin prep: 2% 2010 chlorhexidine gluconate Inclusion Criteria: Patients and 70% isopropyl alcohol. scheduled for any type of Hair removal: 6 patients shoulder surgery. reported shaving their own Exclusion Criteria: Refusal to hair before surgery but it is participate had an open not reported which group wound, a current infection, or they belonged to. a chronic immunosuppressive condition. Veiga RCT To assess the Number of patients: N=114 Intervention group: n=57 SSI (follow up NR) Definitions: 2008 111 1, 4 influence of Patient Characteristics Patients instructed to shower No SSI seen in either group. NR (ES) povidone- ·Age: mean 38.3 y (range 18-65) with liquid detergent-based iodine ·Gender: m:f: 26:88 povidone-iodine 1-% and Other infections: NR Perioperative care: NR preoperative ·Obesity: NR water 2hours before Topic-specific outcomes: showers on ·Comorbidities: NR surgery. Patients instructed Patients with no Other notes: NR skin Procedures: Plastic surgery to rinse thoroughly, lather microorganism growth colonization in involving the thorax or with detergent, rinse, lather, PVP-I: 33/57 (57.9%) Follow-up: NR elective plastic abdomen: Breast and rinse again. Control: 0/57 Funding Source Conflicts: surgery reconstruction, reduction Timing of intervention: Authors: None procedures mammoplasty, augmentation preop Patients with S. aureus Institution: NR mammoplasty, liposuction, Duration of intervention: growth (13/114 (11.4%) Study: NR gynecomasty, scar revision, duration of shower. PVP-I: 1/57 (1.8%) Supplies: NR supernumerary mammoplasty, Device/agent: Povidone– Control: 12/57 (21.1%) and abdominoplasty. iodine 10% detergent-based P=0.0019 soap Indications: NR Monitoring intervention: Setting: 1 school hospital Samples for quantitative Reoperations: NR Location: Brazil skin sampling obtained in Length of stay: NR © 2017 American Medical Association. All rights reserved. 383

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Dates: September 15, 2004 – the OR. A 5x10cm area on Mortality: NR December 1, 2005 the anterior abdominal wall Adverse events: NR Inclusion Criteria: Patients was swabbed with a sterile older than 18 years scheduled cotton swab pre-moistened for elective and clean plastic with sterile saline. Samples surgery procedures on the were processed within 6h thorax or abdomen after obtainment and plated Exclusion Criteria: Patients onto agar plates. with a history of Control group: n=57 hypersensitivity to povidone- No special instructions for iodine, presence of rashes, showering implemented open sores or skin lesions, and before surgery. Patients antimicrobial use at the time of followed their usual surgery. personal hygiene routine on day of surgery Standard preventive measures: NR

eTABLE 47. Evidence Table for Q8B. How safe and effective are antiseptic skin preparation agents individually and in combination? Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Savage RCT To identify Number of patients: N=100 Intervention group: n=50 SSI : Definitions: 127 2012 1 the common Patient Characteristics: No Skin was prepared with 2% Total SSI: 0/100 SSI - NR (ES) bacterial significant differences chlorhexidine gluconate Superficial SSI Perioperative care: NR flora on the between groups with and 70% isopropyl Intervention: 0/50 Other notes: study was skin regards to Age or BMI. alcohol. Spine was Control: 0/50 designed with Colonization overlying the ·Age: mean, years prepared according to Deep SSI as primary outcome. SSI lumbar spine Intervention: 51 the manufacturer’s Intervention: 0/50 was secondary. and to Control: 54 instructions. Each Control: 0/50 Power was on the basis of the evaluate the ·Gender: NR preparation solution assumption that a 20% efficacy of ·Obesity: BMI mean (kg/m2) allowed to adequately Other infections: NR difference in positive skin two readily Intervention: 231 dry for approximately 3-5 Topic-specific culture rates would be available Control: 175 minutes. outcomes: clinically relevant, the skin- ·Comorbidities: NR Timing of intervention: Superficial wound number of patients required © 2017 American Medical Association. All rights reserved. 384

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score preparation Diabetes mellitus: Pre-operative dehiscence to achieve 80% power at solutions in Intervention: 3/50 (6%) Duration of intervention: Intervention: 1/50 (2%) alpha=0.05 was 50/group the Control: 4/50 (8%) Application + 3-5 min Control: 0/50 Follow-up: minimum of 6 elimination Smoker (>1.5 packs/day): drying time months of bacterial Intervention: 3/50 (6%) Device/agent: with 2% Reoperations: NR Funding Source Conflicts: pathogens Control: 3/50 (6%) chlorhexidine gluconate Length of stay: NR Authors: NR from the Corticosteroid use: and 70% isopropyl Mortality: NR Institution: NR surgical site Intervention: 3/50 (6%) alcohol, or 0.7% Adverse events: NR Study: NR following Control: 2/50 (4%) available iodine and 74% Supplies: Industry skin Immunocompromised: isopropyl alcohol preparation. Intervention: 2/50 (4%) Monitoring intervention: Control: 3/50 (6%) NA Previous Spine Surgery Control group: n=50 Intervention: 10/50 (20%) Skin was prepared with Control: 9/50 (18%) 0.7% available iodine History of alcohol abuse: and 74% isopropyl Intervention: 4/50 (8%) alcohol. Spine was Control: 2/50 (4%) prepared according to History of MRSA: the manufacturer’s Intervention: 0/50 instructions. Each Control: 2/50 (4%) preparation solution Duration of surgery: mean allowed to adequately (min) dry for approximately 3-5 Intervention: 51 minutes. Control: 54 Standard preventive P=0.05 measures: No specific cleansing or shaving Estimated Blood Loss: mean protocol prior to the (mL) surgery. If necessary, Intervention: 388 hair was removed with Control: 175 clippers in the operating P=0.02 room. Procedures: elective lumbar Antibiotic Prophylaxis: all spine surgery including received 1 or 2g of microdisectomy, posterior cefazolin (based on spinal fusion with or without weight) prior to surgery an associated interbody except in cases of fusion, decompression penicillin allergy where alone, kyphoplasty. they received 900 mg of © 2017 American Medical Association. All rights reserved. 385

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Indications: NR clindamycin. Patients Setting: 1 University Hospital who required spinal Location: USA instrumentation followed Dates: February – August the same protocol with 2010 the addition of 1g of Inclusion Criteria: vancomycin. Consecutive patients Drape – same non- undergoing elective lumbar antimicrobial drape was spine surgery used in all cases Exclusion Criteria: If patient had an open wound at the incision site, abrasion in the vicinity of the planned incision, an active infection at or near the surgical site, or an active infection elsewhere in the body. Sistla RCT To compare No. Patients: N=400 Intervention: n=200 SSI- (30days) Definitions: 119 2010 1, 4, 5, the efficacy Patient Characteristics: 2.5% chlorhexidine with Overall SSI: 33/400 Infections: CDC criteria (ES) 6, 7, 9 of povidone Patient characteristics & 70% ethanol applied in (8.3%) Questionnaire: patient self- iodine and a surgical elements were concentric circles Intervention: 14/200 reported on 1 or more of the combination similar between groups. No beginning with the site of (7.0%) following conditions: no of statistically significant incision to the periphery Control: 19/200 (9.5%) problems, redness and pain chlorhexidin difference. and allowed to dry P=0.364 around the wound which e-ethanol in All values given for entire before the surgical site Grade of SSI: settled without treatment, the reduction study group. (N=400) was draped Grade 1: Pus Discharge: redness and pain around the of skin Age≤60 years: 306 (76.5%) Timing of Intervention: 12/400 (3%) wound which required bacterial Age≥60 years: 94 (23.5%) Preoperative Intervention: 5/200 (2.5%) antimicrobials, discharge of counts and Gender (m/f): 391/9 Duration of intervention: Control: 7/200 (3.5%) pus from the wound, wound its effect on Obesity: NR intraoperatively P=0.538 break down, need for wound Side (bilateral/unilateral): Agents: Sterile cotton Grade 2:Erythema, hospitalization. infection 38/362 swabs pre-moistened with induration or cellulitis: Note: patients reported to the rates Comorbidity present: 23 sterile saline, Agent brand 18/400 (4.5%) hospital when they following (5.8%) name for intervention & Intervention: 8/200 (4%) developed infection for hernia ASA 3: 9 (2.3%) control NR Control: 10/200 (5%) confirmation and treatment repair. Preop Stay Monitoring intervention: P=0.605 due to limited free medical <48 h: 229 (57.3%) N/A Grade 3: Wound facilities. >48 h: 171 (42.8%) Control: n=200 dehiscence: 3/400 Perioperative care Duration of Surgery 10% povidone-iodine (0.8%) Shaving of operative site done © 2017 American Medical Association. All rights reserved. 386

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score <55 min: 320 (80%) applied in concentric Intervention: 1/200 (0.5%) the night before surgery on >55 min: 80 (20%) circles beginning with the Control: 2/200 (1%) all patients. Grade of surgeon site of incision to the P=0.619 Admission preop-patients in Resident: 378 periphery and allowed to this series were (94.5%)Procedures: Open dry before the surgical SSI rate in prosthetic predominantly from distant Hernia repair site was draped repair: 10.6% vs. suture regions, admitted and then Herniotomy: 18 (4.5%) Standard preventive repair (NR) despite use operated on next available Herniorrhaphy: 132 (33%) measures of AMP; difference not operating day. Hernioplasty: 250 (62.5%) AMP: Patients undergoing statistically significant. Type of anesthesia Indications: prosthetic repair Spinal Suture repair: 62% (hernioplasty) received a Univariate analysis Risk of Intervention: 172/200 (86%) Prosthetic repair: 33% single dose of cefazolin SSI Control: 169/200 (84.5%) Herniotomy: 5% intravenously an hour Operation Side Local Setting: Academic medical before surgery. Bilateral: 8/38 (21%) Intervention: 28/200 (14%) institute infected Control: 30/200 (15%) Location: India Unilateral: 25/362(7%) General Dates: NR infected Intervention: 0 Inclusion Criteria: Adults RR 3.05 (CI 95%, 1.48- Control: 1/200 (0.5%) undergoing elective open 6.28) Dressing: Sterile dressings inguinal hernia repair P= 0.007 applied after surgery & Exclusion Criteria: Patients Preoperative Stay wounds were left exposed with recurrent or complicated >48 hrs. : 22/171(13%) after 48 hr. inguinal hernia and patients infected Other notes: with a history of allergy to the <48 hrs. : 13/229(6%) NOTE: In Table 1 they indicate antiseptics infected n=250 (62.5%) RR 2.27 (95% CI, 1.17- hernioplasties (prosthetic 4.37) repair) BUT in the results P=0.019 text they state “Sixty-two Duration of surgery percent of patients > 55min: 11/80 infected underwent suture repair < 55min: 22/320 [which should be a RR 2.00 (95%CI, 1.01*- herniorrhaphy]; prosthetic 3.95) repair was performed in 33% P=0.066 of patient s [which is the Multivariate analysis found number of herniorrhaphies in only preoperative stay to table1) unclear which is be a significant risk correct. factor (p<0.001) (not age, They also note that higher © 2017 American Medical Association. All rights reserved. 387

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score gender, side of hernia, infection rates in developing comorbidity, ASA score, countries vs. others is partly procedure, type of due to “certain practices and anesthesia, grade of special problems in these surgeon or length of regions”: shaving, admission surgery) prior to surgery, poor Other infections: NR personal hygiene in some of Topic Specific the patients in lower Outcomes: Not relevant socioeconomic strata and Reoperations: None of not practicing antiseptic the SSIs with pus or showers preop. wound dehiscence Follow up: CDC criteria used necessitated removal of by investigators to record the prosthetic material infections in the (mesh) postoperative period. Length of Stay: NR Patients were given a Readmission: NR questionnaire to record/ Mortality: NR report wound conditions and was returned 30 days after surgery. (72% of 400 completed the questionnaire) Funding Source Conflicts: Authors: NR Institution: NR Study: NR Supplies: NR

Darouic- RCT To compare No. Patients: Intervention: SSI within 30 days Definitions: he 1, 2, 3, the efficacy Intention to treat (ITT) N=849 ITT n=409 ITT N=849 SSI diagnosed on basis of 2010 120 4, 5, 6, of Per protocol N=813 Per protocol: n=391 Any SSI CDC criteria (ES) 7, 8, 9, chlorhexidin Patient Characteristics: Skin at surgical site was Intervention: 39/409 Malnutrition: Defined as > 10% 10 e-alcohol Patients in the two study scrubbed with an (9.5%) decrease in weight in over 2 with that of groups were similar with applicator that contained Control: 71/440 (16.1%) months povidone- respect to demographic 2% chlorhexidine RR 0.59 (95% CI, 0.41- iodine for characteristics, coexisting gluconate & 70% 0.85) p=0.004 Perioperative care preventing illnesses, risk factors for isopropyl alcohol. More Superficial NR surgical-site infection, antimicrobial than one chlorhexidine Intervention: 17/409 Other notes infections exposure, & duration & types alcohol applicator was (4.2%) None or surgery. used if area exceeded 33 Control: 38/440 (8.6%) Follow up: 30 days; Surgical © 2017 American Medical Association. All rights reserved. 388

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score All values given for by 33 cm. RR 0.48 (95% CI, 0.28- site assessed 1x/day during intervention Timing of Intervention: 0.84) p=0.008 hospitalization, on discharge Intention to Treat intervention Preoperative Deep Incisional & at time of follow up & population n=409 Duration of intervention: Intervention: 4/409 (1%) whenever SSI occurred. Age yr.; mean (range): Intraoperatively Control: 13/440 (3.0%) Investigators called patients 53.3±14.6 (18-100) Agents: RR 0.33 (95% CI, 0.11- 1x/week during 30 day Gender: Male Sex (%) 58.9 Intervention: 2% 1.01) p=0.05 follow-up period. Obesity: NR chlorhexidine gluconate & Organ/space Funding Source Conflicts: Gastrointestinal Disease: 67% 70% isopropyl alcohol Intervention: 18/409 Authors: Industry Cardiopulmonary disease: Control: 10% povidone- (4.4%) Institution: NR 33.5% iodine Control: 20/440 (4.5%) Study: NR Neurologic disease: 12/5% Monitoring intervention: RR 0.97 (95% CI, 0.52- Supplies: NR Renal disease: 7.3% N/A 1.80) Immunologic disease: 4.7% P>0.99 Cancer: 58.0% Control: Sepsis from SSI Diabetes mellitus: 15.4% ITT: n=440 RR -.62; (95% CI, 0.30- Liver Cirrhosis: 2.2% Per protocol n=422 1.29) History of Alcohol Abuse: Skin at surgical site was Time to onset of SSI 17.9% scrubbed and painted longer in intervention vs. History of smoking: 37.2% with an aqueous solution control P=0.004 Procedures of 10% povidone-iodine ITT population N=849 (Allowed to dry? NR) Per-protocol analysis Abdominal: yielded similar efficacy Intervention : 72.6% Standard Preventive results. Control : 70.0% Measures Other Infections: NR Colorectal: ITT Population, N=849 Topic Specific Intervention: 45.5% AMP: All patients received Outcomes: Control: 43.4% systemic prophylactic ITT population subgroup Biliary: antimicrobials within 1 analysis Intervention: 10.8% hour before the initial All Infections by Surgery Control: 12.3% incision. No significant type Small Intestine: differences in the type or Abdominal: Intervention: 10.0% number of antimicrobials Intervention: 37/297 Control: 7.7% given. (12.5%) Gastroesophageal: AMP postop Control: 63/308 (20.5%) Intervention: 6.4% Intervention :51.7% 95% CI for absolute Control: 6.6% Control:48.9$ difference, -13.9to-2.1 Non-Abdominal Surgery P=0.41 percentage points Intervention: 27.4% Shower: Colorectal © 2017 American Medical Association. All rights reserved. 389

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Control: 30.0% Preoperative Shower Intervention: 28/186 Thoracic: Intervention: 26.7% (15.1%) Intervention:10.8% Control: 27%p=0.94 Control: 42/191 (22.0%) Control: 13.0% 4% chlorhexidine gluconate Biliary Gynecologic: P=0.32 Intervention: 2/44 (4.6%) Intervention:10.3% 10% povidone iodine Control: 5/54 (9.3%) Control:9.1% P=0.26 Small intestine: Urologic: 6% triclobarban soap bar Intervention: 4/41 (9.8%) Intervention: 6.4% P>0.99 Control: 10/34 (29.4%) Control:8.0% Hair removal- as necessary Gastroesophageal Indications: NR by hair clipping Intervention: 3/26 (11.5%) Setting: 6 University-affiliated Control: 6/29 (20.7%) hospitals Non-Abdominal Location: USA Intervention: 2/112(1.8%) Dates: April 2004-May 2008 Control: 8/132 (6.1%) Inclusion Criteria: Patients 95% CI for absolute ≥18 years undergoing clean- difference, --7.9 to 2.6 contaminated surgery percentage points performed under controlled Thoracic: conditions without Intervention: 2/44 (4.5%) substantial spillage or Control: 4/57 (7.0%) unusual contamination. Gynecologic Exclusion Criteria: A history Intervention: 0/42 of allergy to chlorhexidine, Control: 1/40 (2.5%) alcohol or iodophors; Urologic evidence of infection at or Intervention: 0/26 adjacent to the operative Control: 3/35 (8.6%) site; and the perceived Both the ITT and Per inability to follow the patient’s protocol analyses course for 30 days after showed lower rates of surgery SSI in the intervention group for each of the seven operations included.

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score occurred significantly less often in intervention group for small intestinal (P=0.04), or abdominal surgery (P=0.009) or who did not shower preoperatively (P=0.02) Factors affecting any SSIs Use of Chlorhexidine (vs. PVP-I) Univariate: OR: 0.55; p=0.004 Multivariate: OR: 0.45 p=0.004 Use of Abdominal Surgery (vs. Non-Abdominal Surgery) Univariate: OR: 4.63; p<0.001 Multivariate: OR: 3.21 p=0.001 Alcohol Abuse Univariate: OR: 1.11; p=0.69 Multivariate: OR: 1.12 p<0.001 Liver Cirrhosis Univariate: OR: 3.28; p=0.02 Multivariate: OR: 2.14 p=0.02 Immunologic Disease Univariate: OR: 2.72; p=0.01 Multivariate: OR: 1.79 p=0.05 Cancer Univariate: OR: 2.05; © 2017 American Medical Association. All rights reserved. 391

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score p=0.002 Multivariate: OR: 1.65 p=0.03 Diabetes Mellitus Univariate: OR: 1.90; p=0.01 Multivariate: OR: 1.75 p=0.03 Malnutrition Univariate: OR: 3.02; p=0.003 Multivariate: OR: 2.62; p=0.01 Gastrointestinal Disease Univariate: OR: 2.96; p<0.001 Multivariate: OR: 1.27 p=0.05 Days surgical drain in place Univariate: OR: 1.03; p=0.02 Multivariate: OR1.04 p<0.001 Preop shower with Chlorhexidine (vs. no shower) Univariate: OR: 1.56; p=0.38 Multivariate: OR: 0.95 p=0.19 Preop shower with PVP-I (vs. no shower) Univariate: OR: 0.135; p=0.01 Multivariate: OR; 0.36 p<0.001 Use of Chlorhexidine (vs. PVP-I) © 2017 American Medical Association. All rights reserved. 392

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Univariate: OR: 1.08; p=0.79 Multivariate: OR: 0.96 p=0.72

Reoperation: NR Length of Stay: NR Readmission: NR Mortality: Intervention: 4/391 (1%) None had SSIs Control: 3/422 (0.7%) All 3 died from organ/space SSI related sepsis 0.3% (95%CI -0.9-1.5); p =0.72 Adverse events: Total Serious adverse events: Intervention: 72/409 (17.6%) Control: 70/ 440 (15.9%) 1.7% (95%CI -3.3-6.7); p =0.52 Bloodstream Infection Intervention: 11/409 (2.7%) Control: 23/ 440 (5.2%) -2.5% (95%CI -5.1-0.1); p =0.08 Abscess Intervention: 6/409 (1.5%) Control: 11/ 440 (2.5%) -1.0% (95%CI -2.9-0.8); p =0.33 Pneumonia Intervention: 6/409 (1.5%) Control: 9/ 440 (2%) © 2017 American Medical Association. All rights reserved. 393

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score -0.6% (95%CI -2.3-1.2); p =0.61 Antiseptic Agent Related Adverse Events Includes pruritus, erythema, or both around the surgical wound. Intervention: 3/409 (0.7%) Control: 3/ 440 (0.7%) 0.1% (95%CI -1.1-1.2); p >0.99

No cases of fire or chemical skin burns in the operating room Cheng RCT To compare No. Patients: N=50 Intervention n=25 SSI & Adverse events: Definitions: NR 2009 123 1, 2, 10 the effect of Patient characteristics: No Skin prepared with (Follow up NR) Perioperative care: NR (ES) povidone- Demonstrable difference in chlorhexidine gluconate None of the 50 patients Other notes: None iodine and age, sex or site of operation 0.5% in 70% alcohol) developed any post- Follow up: No follow up chlorhexidin between groups. scrub and paint operative infections or recorded e gluconate The only demographic Timing of Intervention: wound complications Funding Source Conflicts: (both with information given were age Preoperative Other Infections: NR Authors: None isopropyl and gender. Duration of intervention: Topic specific Institution: None alcohol) on Age y, mean±SD intraoperative outcomes: Not relevant Study: None lowering 51.1± 17.4 Agent: Supplies: None bacterial Gender m/f: 12/38 Intervention: 0.5% Reoperation: None load and if Obesity: NR Chlorhexidine gluconate Length of Stay: NR any Procedures: in 70% alcohol Readmission: None additional Metatarsal osteotomies for Control: 10% Alcoholic Mortality: None benefits correction of hallux valgus tincture of povidone- (additional deformity: 23/ 50 (46%) iodine, 1% available lowering of Removal of osteophytes from iodine the bacterial the first metatarsal: 15/ 50 Monitoring intervention: load) were to (30%) NR be gained by Correction of lesser toe Control: n=25 an additional deformities: 12/ 50 (24%) Skin prepared with pre-scrub Indications: See Procedures alcoholic tincture, with a Setting: 1 Hospital povidone-iodine 10% © 2017 American Medical Association. All rights reserved. 394

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score bristled Location: United Kingdom (1% available iodine) surgical Dates: August 2007 – January scrub and paint brush with 2008 Standard Preventive either of Inclusion Criteria: Measures these Undergoing foot surgery AMP: All patients were solutions on Exclusion Criteria: If there given a single dose of a the non- were current open wounds, prophylactic broad surgical foot. skin ulcers and/ or sore, a spectrum antimicrobial history of onychomycosis, prior to their procedure paronychia or nail deformity, but after skin prep. poorly controlled diabetes mellitus or recent antimicrobial use (w/in one week of surgery) Saltzman RCT To examine No. Patients: N=150 Intervention1 n=50 SSI: 10 month minimum Definitions: 2009 116 1, 6, 9 the native Patient Characteristics: 0.7% iodophor and 74% No postoperative infection Not recorded (ES) bacteria Characteristics given isopropyl alcohol had developed in any of Perioperative care around the represent the whole study. Intervention2 n=50 the patients in this study Hair removal: 37/ 150 (25%) shoulder and Age: 17-79 years old 2% chlorhexidine gluconate at a minimum follow-up reported voluntary shaving of axilla, and to Gender (m/f): 84/66 and 70% isopropyl Other Infections: NR axillary hair prior to determine Obesity: NRIntervention1: alcohol Topic specific enrollment. All were women. the efficacy Heavy Smokers (>1.5 pack per Intervention3 n=50 outcomes: Not relevant 12 in control, 9 in of three day): 1/50 Shoulder prepared with Reoperation: NR intervention1, 16 in different Diabetes mellitus: 4/50 povidone-iodine scrub & Length of Stay: NR intervention2 surgical Rheumatoid Arthritis: 0/50 paint 0.75% iodine scrub Readmission: NR Other notes: None skin- History of Alcoholism or and 1.0% iodine paint Mortality: NR Follow up: 10 months preparation hepatitis: 4/50 Timing of Intervention Adverse events: NR Funding Source Conflicts: solutions Intervention2: Preoperative Authors: Industry (2% Heavy Smokers: 0/50 Duration of intervention: Institution: None chlorhexidin Diabetes mellitus: 6/50 Intraoperative Study: Industry e gluconate Rheumatoid Arthritis: 2/50 Agent: Supplies: Industry and 70% History of Alcoholism or Intervention1: 0.7% isopropyl hepatitis: 2/50 iodophor and 74% alcohol; Control: isopropyl alcohol 0.7% Heavy Smokers: 3/50 Intervention2: 2% iodophor Diabetes mellitus: 3/50 chlorhexidine gluconate and 74% Rheumatoid Arthritis: 0/50 and 70% isopropyl isopropyl History of Alcoholism or alcohol alcohol; and hepatitis: 1/50 Control: Povidone-iodine © 2017 American Medical Association. All rights reserved. 395

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score 0.75% iodine scrub (0.75% iodine scrub scrub and Procedures and 1.0% iodine paint) 1.0% iodine Arthroscopic Shoulder Prosthetic implant surgeries paint)on the Surgery= 137/150 (91.3%) utilized antibacterial- eradication Shoulder Arthroplasties barrier (adherent drape) of bacteria (primary) = 4 Monitoring intervention: from the Indications: NR N/A shoulder by Setting: One hospital Standard Preventive evaluating Location: USA Measures: the residual Dates: September 2007 – Shower: All patients were bacteria February 2008 instructed to shower the present Inclusion Criteria: Patients day before the surgery. following undergoing shoulder AMP: Preoperative surgical skin surgery. antimicrobials were preparation. Exclusion Criteria: If patient administered to all 150 had an open wound or a patients. Arthroscopic or current infection or were soft tissue surgeries chronically received cefazolin or immunosuppressed. clindamycin. Arthroplasties: AMP: received the same AMP as above plus vancomycin. Skin Prep: After skin prep used an antibacterial- impregnated barriers (adhesive drapes)

Paochar- RCT To study the No. Patients: N=500 Intervention: n=250 Surgical Wound Definitions: oen 1 efficacy in Patient characteristics: Age, 4% chlorhexidine in 70% Infection: SSI: if the wound drained 2009 121 the reduction operative time and wound isopropyl alcohol scrub (5 1 month purulent material or if the (ES) of bacterial class were all analyzed and minutes) followed by 4% Total: (%) surgeon judges it to be colonization found not to be statistically chlorhexidine in 70% Intervention: 5/250 (2%) infected and opens it. (Dunn and significant. isopropyl alcohol paint. 2/5 arteriovenous shunt 2005) postoperativ Characteristics given Timing of Intervention: 2/5 appendectomy e wound represent the whole study. pre-operatively 1/5 right half colectomy Perioperative care : NR infection Age 10-60 years old Duration of intervention: Follow up: 1 month. Surgical among Age y mean (range) intraoperative Control: 8/250 (3.2%) wounds examined twice a povidone- Intervention: 50.5 (18-79) Agents: 4% chlorhexidine 4/8 arteriovenous shunt week for the first week and © 2017 American Medical Association. All rights reserved. 396

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score iodine and Control: 56.2 (20-79) in 70% isopropyl alcohol 1/8 modified radical every week for 1 month. chlorhexidin Gender (m/f): 297/213 scrub/4% chlorhexidine in mastectomy e antiseptic Obesity: NR 70% isopropyl alcohol 2/8 appendectomy skin Operative time hours paint; povidone-iodine 1/8 gastrectomy Other notes preparations mean (range) scrub solution and paint. Numbers incorrectly reported in general Intervention: 1.45 (45min- Monitoring intervention: For intervention group (transposed) within results surgery 3hr) N/A RR 1.61 (CI 95%, 1.40- table 2. patients Control: 1.43 (40 min-3 h) 1.81) Funding Source Conflicts: Wound Classification Control: n=250 Authors: NR Clean (I) Povidone-iodine scrub Other infections: NR Institution: NR Intervention: 96 (38.4%) solution (5 minutes) Topic Specific Study: NR Control: 87/250 (34.8%) followed by povidone outcomes: Not relevant Supplies: NR Clean contaminated (II) iodine paint (Allowed to Reoperation: NR Intervention: 118/250 (47.2%) dry? NR) Length of Stay: NR Control: 112/250 (44.8%) Standard Preventive Readmission: NR Contaminated (III) Measures: The authors Mortality: NR Intervention: 46/250 (18.4%) allowed other pre- Adverse events: 2 cases Control: 51/250 (20.4%) operative preparations of skin irritation from Procedures: All general under the standard povidone-iodine and no surgery guideline. What these allergies to chlorhexidine Indications: NR were: NR Setting: One university hospital Location: Thailand Dates: June 2006 – November 2008 Inclusion Criteria: Patients aged 18-60 years old, with clean (class 1), clean contaminated (class 2), and contaminated wounds (class 3) and ASA class 1 and 2 scores. Exclusion Criteria: Patient refusal, dirty wounds, uncontrolled diabetes, immunosuppressive drugs, serum albumin levels less than 3.0 mg/dl, and a history © 2017 American Medical Association. All rights reserved. 397

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score of allergic reaction to either study agent. Veiga RCT To compare No. Patients: N=250 Intervention: n=125 SSI: 30 days Definitions: 2008 124 1 povidone- Patient Characteristics: Vigorous scrub with Superficial incisional: SSI: CDC definitions (ES) iodine and Characteristics given antiseptic soap followed Intervention = 0/125 Perioperative care chlorhexidin represent the whole study. by absorption with a Control =4/125 (1.6%) NR e ethanolic Mean operation time: sterile towel. This was P= 0.06 Other notes solutions for Intervention: 97.9 min followed by skin prep. Not statistically significant This paper is a “Viewpoints” in skin Control: 107.9 min Skin was painted with Other infections: NR Plastic & Reconstructive antisepsis Age: >18 years chlorhexidine 0.5% Topic-specific Surgery before Gender: NR ethanolic solution and outcomes: Follow up: 30 days elective, Obesity: NR allowed to dry for 2 Not relevant Funding Source Conflicts: clean, plastic Procedures: Breast minutes Authors: None surgery reconstruction, Timing of Intervention: Adverse events: NR Institution: None procedures. mammoplasty, breast Preoperative Reoperation: NR Study: None prosthesis, abdominoplasty, Duration of intervention: Length of Stay: NR Supplies: None scar revision, zetaplasty, Intraoperative Readmission: NR lipoma exeresis, Agents: Povidone-Iodine Mortality: NR gynecomasty & 10%, or Chlorhexidine supernumerary mamma 0.5% Indications: NR Monitoring intervention: Setting: 1 hospital Patients were followed up Location: Brazil to 30 days to determine Dates: NR postoperative infections Inclusion Criteria: Patients Control group: n=125 >18 years of age, scheduled Vigorous scrub with for elective and clean plastic antiseptic soap followed surgery procedures. by absorption with a Exclusion Criteria: NR sterile towel. This was followed by skin prep. Skin was painted with 10% Povidone-iodine ethanolic solution and allowed to dry for 2 minutes Standard Preventive Measures: NR Ellenhorn RCT To prove the No. Patients: N=234 Intervention: n=119 Wound infection-30 days Definitions: 113 2005 1, 2, 10 equivalency Patient Characteristics: Patients underwent only Intervention: 12/ 119 Infection: defined by clinical © 2017 American Medical Association. All rights reserved. 398

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score (ES) for two Demographic data (mean painting of the operative (10%) criteria as presence of commonly age, obesity, diabetes, site with aqueous Control: 12/115 wound erythema or used preoperative antimicrobial povidone-iodine solution (10%) purulence requiring techniques administration, and Mean (available iodine 1.0%) P=0.078 therapeutic intervention of surgical ASA score) were analyzed only. within the first 30 days after skin site and not found to be Timing of Intervention: Other infections the surgical procedure preparation. statistically significant Preoperative Intra-abdominal infection [The between groups (All P≥10). Duration of intervention- Intervention: 2/ 119 (2%) Perioperative care: techniques Age (mean) Intraoperative Control: 4/115 (3%) Hair Removal: A razor was are 1) a Intervention: 57.7 y Agent: Aqueous povidone- P= 0.14 used to remove hair from the scrub with Control: 60.5 y iodine (1.0%) and operative site. Other notes: povidone- Gender: NR povidone-iodine detergent Topic-specific None iodine soap The following (0.75%) outcomes: NR Follow up: 30 days after followed by characteristics given Monitoring intervention: Reoperation: NR surgery. paint with represent the whole study. NR Length of Stay: NR Funding Source Conflicts: aqueous Obese: 43/234 (18.4%) Control: n=115 Readmission: NR Authors: None povidone- Diabetic: 17/234 (7.3%) Patients underwent a Mortality: NR Institution: None iodine OR 2) ASA score (mean) vigorous 5-minute scrub Adverse events: NR Study: None only Intervention: 2.3 using urethane sponges Supplies: None povidone- Control: 2.4 saturated with povidone- iodine paint.] Procedures: Comparable iodine detergent between groups except as (available iodine 0.75%). noted Detergent was then Colorectal: 79/234 (33.8%) absorbed with a blotting Genitourinary: 38/234 (16.2%) towel before painting the Pancreaticobiliary: 40/234 operative site with (17.1%) aqueous povidone-iodine Upper gastrointestinal: 38/234 solution (available iodine (16.2%) 1.0%) which was allowed Intervention: 24/20 (20%) to air-dry. Control: 14/115 (12%) Standard Preventive Other*: 39/234 (12.3%) Measures: *Includes retroperitoneal Skin Prep: All patients had sarcoma, lymph node all gross foreign material dissection, second-look removed from the skin ovarian cancer using a dry sponge and Clean: 70/234 (29.9%) tape remover, if Clean-contaminated: 164/234 necessary. (70.1%) Shower: Patients were not © 2017 American Medical Association. All rights reserved. 399

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Drain: 67/234 (28.6%) instructed to shower with Indications: malignancy any antibacterial agent Setting: cancer center before the operation. Location: USA Non-Standard Dates: NR Preventative measures: Inclusion Criteria: Patients AMP: Use of perioperative undergoing elective IV antimicrobials left to abdominal operation the discretion of the Exclusion Criteria: Active operating surgeon. infection at the time of AMP given: operation, neutropenia Total: 229/234 (98%) defined as a white blood cell Intervention: 98% count of <2000 or an Control: 97% absolute neutrophil count of <500, history of skin reaction to iodine and anticipated use of prosthetic material as part of the surgical procedure. Bibbo RCT To No. Patients: N=127 Intervention: n=60 SSI (Follow up NR) Definitions: None 2005 122 1, 10 determine Patient characteristics: A 7-minute scrub with No Postoperative wound (ES) the efficacy Patient characteristics were chlorhexidine gluconate infections developed Perioperative care: NR of recorded and analyzed and (4%) and isopropyl Other Infections: NR chlorhexidin they found no differences alcohol (70%) paint. Topic specific Other notes: None e compared between the two groups Allowed to dry before outcomes: Follow up: NR with The following draping. Not relevant Funding Source Conflicts: povidone- characteristics given Timing of Intervention: Reoperation: NR Authors: None iodine as a represent the whole study. Preoperative Length of Stay: NR Institution: None preoperative Mean age (Range): 46 y (16- Duration of intervention: Readmission: NR Study: None skin 85y) intraoperative Reoperation: NR Supplies: None preparation Gender (m/f): 61/66 Agent: Chlorhexidine Mortality: NR agent in Obesity: NR gluconate (4%) and Adverse events: NR reducing Co-morbidities: isopropyl alcohol (70%) bacterial Compromised hosts: 35% paint; a Povidone-Iodine skin (includes smokers, diabetics, scrub (7.5%); and a contaminatio history of steroid use, or povidone-iodine paint n before history of MRSA (10%) clean, colonization) Monitoring intervention: elective foot Procedures: NR Culture swabs taken from and ankle Indications: NR all the toes, all webs © 2017 American Medical Association. All rights reserved. 400

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score surgery. Setting: One Hospital spaces, nail folds, toe Location: USA surfaces, and from the Dates: NR site of the proposed Inclusion Criteria: Patients surgical incision. Patients with intact, uninfected skin having toe surgery had having clean, elective foot the dorsal foot swabbed and ankle surgery as the matching site. Exclusion Criteria: Patients Swabs were sealed and with open wounds, skin immediately transported ulcers and/ or sores, an & processed for aerobic, active acute or chronic anaerobic, acid fast, and infection, or who were on fungal cultures active antimicrobial therapy, Control: n=67 which could alter skin flora. A 7-minute scrub with povidone-iodine (7.5%) and painting of the foot and ankle with a povidone-iodine (10%) solution. Allowed to dry before draping. Standard Preventive Measures: Shower: No special instructions for bathing or showering implemented before surgery. Patients followed their usual personal hygiene on the day of surgery. AMP: Prophylactic intravenous antimicrobials (cefazolin or vancomycin for patients with documented penicillin and/or cephalosporin allergy) were administered in the 20 minute window before incision © 2017 American Medical Association. All rights reserved. 401

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Adhesive drapes were not used. Ostrander RCT To assess No. Patients: N= 120 Intervention1: n=40 Postoperative infection: Definitions: NR 2005 126 1, 7, 8 the efficacy Patient characteristics: 3% chloroxylenol (Follow up-NR) (ES) of three The following Intervention2: n=40 Total: 3/120 (2.5%) Perioperative care: All different characteristics given 2% chlorhexidine gluconate Intervention1 procedures performed by surgical represent the whole study. and 70% isopropyl Chloroxylenol: 2/40 (5%) one surgeon. skin- Age y mean (range):48 (19-78) alcohol (1 polymicrobial SSI after Other notes: Power preparation Gender (m/f): 47/78 Intervention 3 n=40 0.7% open reduction internal calculation not met. solutions Obesity: NR iodine and 74% isopropyl fixation (ORIF) calcaneal Follow up: NR (0.7% iodine Comorbidities: alcohol fracture and 1 atypical Funding Source Conflicts: and 75% Diabetes: Timing of Intervention: mycobacterium SSI after Authors: Industry isopropyl Intervention 1: 0 Preoperative excision of Morton Institution: None alcohol; 3% Intervention 2: 0 Duration of intervention: neuroma) Study: None chloroxyleno Control: 1/ 40 (2.5%) intraoperative Intervention2 Supplies: None l; & 2% Rheumatoid Arthritis Monitoring intervention: Chlorhexidine gluconate chlorhexidin Intervention 1: 2/40 (5%) NR and alcohol: 1/40 (2.5%) e gluconate Intervention 2: 2/40 (5%) Control: Each group (Polymicrobial SSI after and 70% Control: 4/40 (10%) served as its own control excision of large lipoma isopropyl Liver disease: for colonies formed (used at lateral heel-portion of alcohol) in Intervention 1: 2/40(5%) a more proximal tibial large tissue flap eliminating Intervention 2: 0 site) underwent necrosis with potential Control: 2/40 (5%) subsequent bacterial Renal issues Standard Preventive development of SSI) pathogens Intervention 1: 1/40 (renal Measures: Control Iodine-alcohol: from the foot insufficiency) Shower: No home cleaning 0/40 by Intervention 2: 1/ 40 (renal or disinfectant protocols P<1.0 evaluating transplant) utilized prior to surgery. Other infections: NR the residual Intervention 2: 1/40 (end AMP: All patients received Topic Specific bacterial stage renal disease) intravenously Outcomes: NA skin Control : 1/40 (renal failure) administered cefazolin) Adverse events: NR contaminatio Procedures: Foot and ankle within one hour of the Reoperation: NR n following surgery surgical start time. Length of Stay: NR surgical skin Indications: NR Readmission: NR preparation. Setting: One hospital Mortality: NR Location: USA Dates: October 2002 – May 2003 Inclusion Criteria: Patients © 2017 American Medical Association. All rights reserved. 402

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score undergoing foot and ankle surgery Exclusion Criteria: If patients had an open wound, abrasion, or current infection. Segal RCT To evaluate No. Patients: N=209 Intervention1: n=52 Sternal wound Definitions 2002 114 1, 2, 5, the effect of Patient characteristics: Povidone-iodine five-minute Infections: 6 weeks Obesity: BMI>120% of ideal (ES) 9 four different Patient demographics scrub with paint Intervention1: 7/52 weight. skin compared. Intervention2: n=50 (13.5%) SSI: Clinical exam for signs of preparations The following One-step iodophor/alcohol Intervention2: 1/50 (2.0%) drainage, redness, on the characteristics given water insoluble film Intervention 3: 3/51 (5.9%) tenderness, or sternal incidence of represent the whole study. Intervention3: n=51 Intervention 4: 7/56 instability. Sternal surgical sternal SSIs All patients had at least one one-step iodophor/alcohol (12.5%) site exhibiting any of these in patients high-risk factor (the basis of water insoluble film with P=0.117 signs was cultured. Positive undergoing the study). iodine impregnated Infections per treatment cultures were correlated with coronary 39% had 2 risk factors surgical adhesive drape Aqueous Iodine ( clinical evidence according artery 4% had 3 risk factors Intervention 4: n=56 Intervention 1+4) to the CDC guideline to bypass graft (Percentage numbers appear Povidone-iodine paint 14/108 (13.0%) indicate a sternal SSI surgery larger in bar graph within Timing of Intervention: Insoluble Iodine (CABG) paper my copy is difficult to Preoperative (Interventions 2 and 3) Perioperative care who were read) Duration of intervention: 4/101 (4.0%) NR identified as Age (y): Mean Intraoperative P=0.02 Other notes high risk of 60.9 years (no SD given) Agents: Solutions, Χ2=5.3 Impregnated drapes in developing Gender: Over 75% male insoluble film & incise Other infections: NR Intervention 3 shown to be sternal SSI Obesity: NR drapes not specified Topic-specific ineffective as an intervention. Redo sternotomies: 11.5% Monitoring intervention: outcomes: NR Study deemed underpowered Procedures performed using Observation by nurses Reoperation: NR Follow up: 6 weeks the IMA: 88.5 Control: Length of Stay: postoperatively through Uninfected patients had regularly scheduled clinic Mean±SD Standard Preventive a 5-6 day shorter length visits Total OR time: 248 min ±29 Measures of hospital stay than Funding Source Conflicts: Cross clamp time: 42 min±20 Shower infected patients. Authors: NR Last OR Glucose: 434±210 The nurse instructed Mortality: NR Institution: NR Procedures: elective CABG patients to take an Adverse events: NR Study: NR Surgery antimicrobial shower the Supplies: NR Indications: NR evening before and the Setting: 1 tertiary/ teaching morning of surgery, or if hospital they were inpatients, they Location: USA were given a preoperative © 2017 American Medical Association. All rights reserved. 403

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Dates: Oct 1, 1994 – April 30- antimicrobial shower in 1997 the hospital. Inclusion Criteria: Patients Hair removal undergoing elective CABG If necessary, a qualified with one or more of the patient care assistant following conditions: clipped patients’ hair the Diabetes morning of surgery in Obesity patients’ rooms. Chronic Obstructive AMP: All patients received Pulmonary Disease (COPD) a prophylactic Exclusion Criteria: Patients antimicrobial (i.e., with an allergy to topical cefuroxime) or if they had iodine or with a preexisting a documented allergy to infection indicated by a white penicillin, they received blood cell count higher than vancomycin in 10,000 or by a temperature appropriate dosing higher than 100.5oF window to provide (38.06oC) because their adequate coverage at the procedures were performed time of incision. emergently.

Hort RCT To No. Patients: N=49 Intervention: n= 25 feet SSI (Follow up NR) Definitions( e.g., SSI) 2002 118 1, 4, 5 investigate Patient Characteristics: Age, (23 patients[2 received NO patient in either group Not defined (ES) the gender, weight, co- bilateral procedures-]) showed clinical signs of Perioperative care usefulness morbidities: NR Patient was given two wound infection and all NR of standard Bilateral Procedures: chlorhexidine gluconate wounds healed Other notes: If a patient surgical Intervention: 2/23 scrub brushes with uneventfully. underwent a bilateral preparation Control: 6/26 directions to perform two procedure, both feet (with separate self-scrubs Other Infections: NR assigned to the same group. chlorhexidin Procedures: NR several hours apart Topic specific Follow up: NR e gluconate Indications: NR before retiring to bed the outcomes: NR Funding Source Conflicts: home scrubs Setting: 1 Hospital night before the Reoperation: NR Authors: NR and Location: USA operation. In the Length of Stay: NR Institution: NR preoperative Dates: NR operating room, a 10 Mortality: NR Study: NR povidone- Inclusion Criteria: Patients minute scrub with Adverse events: NR Supplies: NR iodine or the undergoing foot or ankle povidone-iodine topical chlorhexidin surgery solution was followed by e gluconate Exclusion Criteria: Total painting of the foot with home scrubs ankle arthroplasties povidone-iodine topical © 2017 American Medical Association. All rights reserved. 404

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score plus pre- solution plus the addition operative of a 3-minute 70% alcohol) preoperative preparation in prevention of the area with 70% of surgical alcohol. site Timing of Intervention: contaminatio Preoperatively n. Duration of intervention: intraoperative Agents: Povidone-Iodine solution; Scrub Brushes Monitoring intervention: NR Control: n=32 feet (26 patients;6 had bilateral procedures) Patient was given two chlorhexidine gluconate scrub brushes with directions to perform two separate self-scrubs several hours apart before retiring to bed the night before the operation. In the operating room, a 10 minute scrub with povidone-iodine topical solution was followed by painting of the foot with povidone-iodine topical solution. Standard Preventive Measures AMP: All patients were given one dose of broad- spectrum intravenous antimicrobial preoperatively (usually © 2017 American Medical Association. All rights reserved. 405

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score cefazolin before tourniquet) Operative irrigation: Wounds were irrigated frequently during surgery with an antimicrobial solution. Roberts RCT To compare Number of patients: n=200 Intervention group: n=104 SSI (30days) Definitions: 1995 117 1, 2, 7, the efficacy Patient Characteristics: no 1step: patients underwent Overall Infection: Infected Wounds: if purulent (ES) 8, 9 of 2 significant differences in 1 step iodophor in water 1step: 10/104 (9.6%) material drained from the commerciall patient characteristics application preop. And 2step: 9/96 (9.4%) incision site. Confirmation of y available between groups. allowed to air dry NS infection by a positive culture skin preps: a ·Age: NR thoroughly for 2-3 min. 1 Chest Infection was not necessary. relatively ·Gender: NR unit was used for each 1step: 4/104 (3.8%) Superficial infected surgical new 1-step, ·Obesity: NR chest, and each leg. 2step: 6/96 (6.3%) wounds: involved the skin, iodophor in ·Comorbidities: NR Timing of intervention: NS subcutaneous tissue or alcohol, film- Procedures: CABG preop Deep Chest Infection muscle located above the forming, Indications: NR Duration of intervention: 1step: 0/104 fascial layer. water- Setting: 1 general hospital NA 2step: 3/96 (3.1%) Deep infected surgical insoluble Location: USA Device/agent: aqueous wounds: involved tissues or skin prep, Dates: NR just mentioned a “1 iodophor Leg Infection: spaces at or beneath the versus the year period” Monitoring intervention: 1step: 6/104 (5.8%) fascial layer including tradition al 5- Inclusion Criteria: consenting NR 2step: 5/96 (5.2%) wounds that spontaneously 10 minute adults undergoing CABG Control group: n=96 NS dehisced or were aqueous Exclusion Criteria: if patients 2step: patient underwent a deliberately opened for iodophor were allergic to iodine or its traditional 2step starting Other infections: no drainage. scrub and compounds with a 5-10min scrub of evidence found for either Elderly: 65yo or older paint. In both operative sites (chest and group Perioperative care: In both groups, an legs) with aqueous Topic-specific groups, an iodophor- iodophor- iodophor solution followed outcomes: NR containing antimicrobial containing by an application of an Reoperations: incise film was also applied antimicrobial iodophor solution. The All 3 deep wounds in on the chest. No incise film incise film sites were then blotted control group required was used on the leg. was also dry with a sterile towel. surgical intervention. Other notes: Small sample applied on Standard preventive Length of stay: NR size. Too small to perform the chest. measures: multivariate analyses. No incise Showers: patients had Mortality: NR Follow-up: 30 days film was antimicrobial (iodophor) Adverse events: NR Funding Source Conflicts: used on the showers on the night prior Authors: NR © 2017 American Medical Association. All rights reserved. 406

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score leg. to surgery Institution: NR AMP: Cefuroxime started in Study: NR OR approx. 30 min prior Supplies: NR to incision and continued every 6h for 36h postop. Hair removal: with clipper. Gilliam RCT To compare No. Patients: N=60 Intervention: n=30 SSI (follow up NR) Definitions: 115 1990 1, 8, 9 the efficacy Patient characteristics: Age, Skin was prepared with a None of the patients NR (ES) of a sex, & duration of operation one-step application of a became infected traditional were not statistically water-insoluble iodophor- Other Infections: No Perioperative care skin significantly different in-alcohol solution applied Infections Hair Removal: All hair was preparation between groups. as paint. Skin was Topic Specific Outcome: removed by dry shave just of an Age (average), y: allowed to dry before Drape Lift: (yes or no prior to preparing the skin. aqueous Intervention: 65y covering the surgical area phenomenon) Other notes iodophor Control: 61y with a sterile, non- Intervention: 0/30 Intervention was found to consisting of Gender (m:f): antimicrobial plastic Control: 12/30 (40%) increase incise drape a five-minute Intervention: 11:19 surgical adhesive drapes. P<0.01 adhesion, particularly at the scrub-and- Control: 8:22 Timing of Intervention: Reoperation: NR wound edges. paint AND a Obesity: NR Preoperative Length of Stay: NR Follow up: NR sterile non- Length of Operation (average), Duration of intervention: Readmission: NR Funding Source Conflicts: antimicrobial Min (range): Intraoperatively Mortality: NR Authors: NR plastic Intervention: 135 (30-310) Agent Water-insoluble Adverse events: NR Institution: NR surgical Control: 130 (160-300) iodophor-in-alcohol Study: NR adhesive solution Supplies: NR drapes. With Procedures: Primary or Monitoring intervention: the efficacy revision total hip or total For liquid skin prep NR of a single knee arthroplasty except for surgical application Indications: NR adhesive drape, where of a water- Setting: 1 hospital adhesion to the skin was insoluble Location: USA evaluated by the iodophor-in- Dates: NR operating surgeon prior to alcohol Inclusion Criteria: Patients wound closure solution undergoing clean total joint Control: n=30 AND a surgery. Skin was prepared with a sterile non- Exclusion Criteria: NR traditional five-minute antimicrobial aqueous iodophor scrub plastic followed by the surgical application of an aqueous adhesive iodophor solution as © 2017 American Medical Association. All rights reserved. 407

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score drapes. paint. Skin was allowed to dry before covering the surgical area with a sterile, non-antimicrobial plastic surgical adhesive drapes. Standard Preventive Measures Preop Shower: All patients showered the night before surgery with chlorhexidine gluconate soap. Environmental: Surgery was conducted under a horizontal unidirectional laminar air-flow system. Berry RCT To compare No. Patients: N=866 Intervention: n=453 SSI – (Follow up: not Definitions: 1982 125 1, 2, 6, the effect of Patient Characteristics: Two applications of 0.5% clear- wound assessed No definitions, wounds were (ES) 7, 8, 9 alcoholic Operative & demographic chlorhexidine alcohol. 3-4 days postop and at judged at evaluator’s povidone- information was deemed Skin preparation solution discharge) discretion as normal, iodine and similar between study was applied with sterile More than one type of erythematous, edematous, alcoholic groups. Details not reported sponges. abnormality reported on discharging or purulent. chlorhexidin Age: Timing of Intervention: some wounds Moist wounds were swabbed e (both as <15 years Preoperative Wound abnormality: Any & cultured for both aerobic skin prep Intervention: 4 (0.9%) Duration of intervention: abnormality agreed by (Cowan 1974) & anaerobic and surgical Control: 4 (1.0%) Intraoperatively both observers at (biochemical tests) scrub) on 15-64 years Agent: povidone iodine discharge, all organisms the Intervention: 338 (74.6%) 10% in alcohol or 0.5% operations Perioperative care : NR incidence of Control: 309 (74.8%) chlorhexidine in spirit Any wound abnormality postoperativ ≥65 years Monitoring intervention: Intervention: 44/453 Other notes: None e wound Intervention: 112 (24.7%) NA (9.7%) Follow up: Wounds were infection in a Control: 100 (24.2%) Control: n=413 Control: 61/413 (14.8%) assessed independently by general Gender: NR Two applications of Χ2(1)= 4.7, P=0.03 one member of the nursing surgical unit Obesity: NR povidone-iodine 10% in Biliary tract staff and one member of the Procedures, No (%): (N=886) alcohol. Skin preparation Intervention: 6/90 (6.7%) medical staff at a “standard” Operations on biliary tract: 167 solution was applied with Control: 15/77 (19.5%) period of 3-4 days post- (18.8%) sterile sponges. Χ2(1)= 5.1, P<0.05 operatively and then at Large bowel operations: 61 Other clean operations discharge (6.9%) Standard Preventive Intervention: 2/105 . If patient was discharged © 2017 American Medical Association. All rights reserved. 408

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Other laparotomy operations: Measures (1.9%) before the 3rd day was 96 (10.8%) Surgical hand Scrub: A Control: 13/99 (13.1%) assessed just prior to leaving 2 Hernia/genitals/varicose veins sterile brush was used to Χ (1)= 7.9, P<0.05 the hospital. 338 (38.1%) scrub the hands, paying Differences in procedures Funding Source Conflicts: Other ‘clean’ non-abdominal: particular attention to the below, not statistically Authors: NR 204 (23.0%) areas under the nails and significant: Institution: NR Indications: NR in the nail folds. The Large Bowel Study: NR Setting: 1 hospital forearms were washed as Intervention: 5/28 Supplies: NR Location: United Kingdom far as the elbow. Skin (17.9%) Dates: May 1978 – February was scrubbed for 4-5 Control: 3/33 (9.1%) 1980 minutes as Other Laparotomy Inclusion Criteria: All elective recommended. Intervention: 15/49 surgical cases Control: Scrub solution (30.6%) Exclusion Criteria: Patients was alcoholic povidone- Control: 9/47 (19.1%) known to be sensitive to iodine (10% available Hernia, genitalia, veins either skin preparation iodine) Intervention: 16/181 utilized in this study. Intervention: Scrub (8.8%) solution was alcoholic Control: 21/157 (13.4%) chlorhexidine with .5% available chlorhexidine. Wound abnormalities: Hair removal: Skin shaving Specific abnormality was routinely performed agreed by both on hairy skin 18-24 hours observers at preoperatively discharge, all Non-Standard Preventive operations Measures: Redness of wound: Antimicrobial Prophylaxis Intervention: 16/453 Only patients undergoing (3.5%) colonic & rectal surgery Control: 21/413 (5.1%) received metronidazole 3 Swelling of Wound: times daily and neomycin Intervention: 12/453 four hourly for 3 days. (2.6%) Bowel Prep: Routine bowel Control: 12/413 (2.9%) prep was used only in Discharge from wound: large bowel surgery. Intervention: 16/453 (3.5%) Control: 21/413 (5.1%) Pus from wound: Intervention: 13/453 © 2017 American Medical Association. All rights reserved. 409

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score (2.9%) Control: 22/413 (5.3%) Any abnormality agreed by both observers 3-4 days postop (Note: *64 intervention and 59 control patients were discharged before 3 days, therefore the total population for results below is: Intervention: n=389 Control: n=354Infection was slightly more common overall in the control group but the difference was not statistically significant: Total wound abnormalities Intervention: 27/389 (6.9%) Control: 35/354 (9.9%) Biliary tract Intervention: 2/90 (2.2%) Control: 8/76 (10.5%) Large Bowel Intervention: 3/28 (10.7%) Control: 0/31 Other Laparotomy Intervention: 7/49 (14.3%) Control: 5/47 (10.6%) Hernia, genitalia, veins Intervention: 13/157 (8.3%) Control: 16/150 (10.7%) Other clean operations Intervention: 2/65 (3.1%) Control: 6/50 (12.0%) © 2017 American Medical Association. All rights reserved. 410

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score

Any abnormality recorded by one or both observers 3-4 day postop (i.e. disagreement between observers) Total wound abnormalities Intervention: 41/389 (10.5%) Control: 44/354 (12.4%) Biliary tract Intervention: 4/90 (4.4%) Control: 11/76 (14.5%) Χ2(1)= 3.9, P<0.05

Overall infection rate for “clean” operations (excluding colonic & biliary): 11.9% Infection/ abnormality rates varied between surgeries and groups. NO overall statistically significant advantage for either group emerged for an all-purpose skin prep solution. Other Infections: NR Topic Specific Outcomes: NA Reoperation: NR Length of Stay: NR; Analysis of the date for each group showed no significant difference between the preparations in the mean length of patients’ stay in © 2017 American Medical Association. All rights reserved. 411

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score the hospital Readmission: NR Mortality: NR Adverse events: NR

eTABLE 48. Evidence Table for Q8C. How safe and effective is the application of a microbial sealant immediately following skin preparation? Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Dromzee RCT To test the Number of patients: Intervention group: n=28 SSI : Definitions: 2012 131 1, 2, 10 hypothesis N=56 Sterile, film-forming cyanoacrylate Total: 6/56 (10.7%) SSI – not defined (ES) that microbial Patient Characteristics liquid application before Intervention: 5/28 Perioperative care: sealant ·Age, year: mean (SD) application of the incise drape (18.2%) Anesthesia: general reduces Intervention: 14.93 (1.7) Timing of intervention: Control: 1/28 (3.6%) anesthesia was used surgical site Control: 15.21 (1.9) Intraoperative P=0.096 Other notes: 50 patients = infection in P=0.570 Duration of intervention: NR There were 3 deep and number of cases required to children and ·Gender: B NR Device/agent: film forming 3 superficial have an 80% chance of adolescent ·Obesity: NR cyanoacrylate liquid infections but it is not detecting an effect of 0.05. patients with ·Comorbidities: NR Monitoring intervention: NA report which group Follow-up: NR scoliosis Number of fused levels, Control group: n=28 they belonged in Funding Source Conflicts: undergoing mean (SD) Incise drape alone. Authors: None scoliosis Intervention: 11.93 Standard preventive measures: All infections resolved Institution: None correction. (2.7) AMP: NR after local wound Study: None Control: 12.54 (3.09) Pre-op bathing: all patients debridement and Supplies: None P=0.440 showered with a povidone iodine antibiotics. Intraoperative blood loss skin antiseptic the day before the (ml) mean (SD) surgery and early in the morning Age as risk factor for Intervention: 539.64 of the surgery. early infection (284.09) Skin prep: in OR using 2 Mean age (SD) Control: 658.93 consecutive applications of one- Infection (n=6): 17.07 (489.15) step 5% povidone-iodine & (0.47) P=0.271 alcohol solution. No infection (n=50): Intraoperative time (min), Drapes: both groups used sterile 14.83 (1.8) mean (SD) incise drapes P<0.0001 Intervention: 196.61 Drains – one to three suction drains

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score (62.76) were placed in the wound before Other infections: NR Control: 234.64 (90.65) closure. Topic-specific P=0.074 Closure: either skin staples or outcomes: NR 4-6 Week preoperative bioresorbable skin sutures at Reoperations: NR halo traction: 6/56 surgeon’s discretion. Length of stay: NR (10.7%) [which group Mortality: NR NR] for stiff and Adverse events: severe deformity No immediate or Procedures: Scoliosis delayed adverse correction effects related to the Indications: 29 had use of sealant were spinal deformities noted. from various neuromuscular causes. 27 had adolescent idiopathic scoliosis. Setting: 1 university hospital Location: France Dates: June 2010 and June 2011 Inclusion Criteria: (1) idiopathic or neuromuscular scoliosis, and (2) indicated for posterior correction and fusion Exclusion Criteria: (1) previous spinal surgery and (2) indicated for anterior or combined procedures.

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score von RCT To determine Number of patients: Intervention group: SSI: (follow up 30 days Definitions: Eckards- 1, 2, 6, if the use of N=293 Intention to treat (ITT): n= 146 postop) SSI: CDC/ NNIS criteria tein 7, 8, 9 cyanoacrylate Patient Characteristics: Per protocol: n=131 Patients may have more Adverse events: any 2011 128 -based skin There was no Surgical sites were prepared with than 1 SSI undesirable clinical (ES) sealant before significant difference commonly used surgical skin For ITT Analysis Below occurrence in a patient that coronary between groups preparations such as povidone- Intervention: n=146 may be attributed to the artery bypass except in occurrence iodine or 0.7% available iodine in Control: n=147 study treatment or to SSI. grafting of obesity (see below) isopropyl alcohol 74%w/w. Total SSIs: Perioperative care: NR (CABG) could ·Age, y: mean (SD) Skin sealant was applied on the 23/293 (7.8%) Other notes: None reduce Intervention: 63.2 surgical sites after surgical skin Intervention: 9/146 Follow-up: For the duration of surgical (8.53) preparations and just before (6.2%) hospitalization and for 30 wound Control: 62.9 (9.97) making the incision. Surgical Control: 14/147 (9.5%) days postop contamination ·Gender (m:f) incise drapes (if used) were p=0.285 Funding Source Conflicts: by skin Intervention: 120/26 applied after all surgical skin The majority were Authors: None microflora and Control: 129:18 preparations had dried superficial SSIs: Institution: None decrease ·Obesity (BMI>30.0 to completely. Skin sealant was Incision site infection Study: None post- ≥37 kg/m2) considered dry when a film Intervention: 6 (2.7%) Supplies: None procedure Intervention: 40 formed on the skin. Control: 10 (6.6%) infections. (27.6%) Timing of intervention: Control: 20 (13.6%) Intraoperatively Although there P=0.003 Duration of intervention: frequency of patients ·Comorbidities Intraoperatively with SSI was similar Diabetes Mellitus, Device/agent: Cyanoacrylate- between groups, the Type I or Type II based skin sealant use of skin sealant Intervention: 49 Monitoring intervention: NR was associated with a (33.6%) Control group: 35% relative risk Control: 49 (33.3%) ITT: n= 147 reduction in the Tobacco Use, Per Protocol: n=138 occurrence of SSI Intervention: 84 Surgical sites were prepared with In the subgroup of (57.5%) commonly used surgical skin obese patients, there Control: 91 (61.9%) preparations such as povidone- was a relative risk Alcohol use iodine or 0.7% available iodine in reduction for SSI of Intervention: 42 isopropyl alcohol 74%w/w. 83.3% associated (28.8%) with use of skin Control: 52 (35.4%) Standard preventive measures: sealant. However, Duration of surgery NR this is based on small (min): Non-standard preventive patient and event Intervention: 227.6 (42.4) measures: numbers: Control: 211.7 (60.6) AMP: administered at the discretion Obesity © 2017 American Medical Association. All rights reserved. 414

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score P=0.469 of the surgeon and according to Intervention: 1/40 Intraaortic balloon pump: hospital protocol (2.5%) Intervention: 9 patients Surgical procedure: dictated by Control: 3/20 (15.0%) Control: 4 patients current practice and not specified P=0.0.015 Procedures: Elective in the study protocol Coronary artery Patients with at least bypass grafting one SSI: (CABG) Sternal Site Infection Indications: NR Intervention: 4 (2.7%) Setting: 5 Centers Control: 7 (4.8%) Location: USA, Europe, P=0.363 Asia and Latin Graft Site Infection America Intervention: 7 (4.8%) Dates: April 2006 - Control: 7 (4.8%) February 2009 P=0.989 Inclusion Criteria: NOTE: Patients aged 18 Left saphenous vein years or older who graft harvest in 74%- were undergoing 78% of patients elective CABG Left radial artery or right surgery with median saphenous vein graft sternotomy and the harvest in 25-30% of use of saphenous patients vein or radial artery as Location and number of 1 of the graft sites. harvest sites did not Exclusion Criteria: appear to affect risk Patients undergoing of SSI “but does add additional procedures, further variation to the known sensitivity or study” allergy to cyanoacrylate, Sternal and/or Graft isopropyl alcohol, Site(s)_ Infection iodine or iodine- Intervention: 9 (6.2%) containing products or Control: 14 (9.5%) tape. Also abnormal P=0.285 skin conditions Both Sternal and Graft around the surgical Site Infection incision site, Intervention: 2 (1.4%) antimicrobial- Control: 0 © 2017 American Medical Association. All rights reserved. 415

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score impregnated incise P=0.247 drapes used during the operation, Infections for Total chemotherapy, Population immunosuppressive Denominators: therapy or steroid Intervention: n= 146 therapy, use of Control: n= 147 antimicrobials for an Arteriovenous graft site active infection, HIV infection infection with CD4 Intervention: 1 (0.7%) count <350mm3, Control: 0 therapeutic radiation Incision site infection or renal dialysis, Intervention: 6 (2.7%) morbid obesity Control: 10 (6.6%) (BMI>37kg/m2); Mediastinitis neutropenia, Intervention: 3 (2.1%) intraaortic balloon Control: 2 (1.4%) pump or mechanical Osteomyelitis assist device in place Intervention: 1 (0.7%) preoperatively, and Control: 1 (0.7%) hospital stay >14 days Postoperative Wound Infection Intervention: 0 Control: 1 (0.7%) Skin graft Infection Intervention: 0 Control: 1 (0.7%) Wound Infection Intervention: 1 (0.7%) Control: 0

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Alcohol Use Intervention: 2/42 (2.7%) Control: 6/52 (4.8%) P=0.291 Tobacco Use Intervention: 3/84 (3.6%) Control: 11/91 (12.1%) P=0.050 Obesity Intervention: 1/40 (2.5%) Control: 3/20 (15.0%) P=0.0.015 Skin sealant associated with a relative risk reduction of 83% for obese patients Alcohol Use or Tobacco Use or Obesity Graft Site Infection Intervention: 2/108 (1.9%) Control: 6/112 (5.4%) P=0.037 Sternal Site Infection Intervention: 4/108 (4.6%) Control: 5/112 (4.5%) P=0.546 Graft and/or Sternal Site Infection Intervention: 5/108 (4.6%) Control: 11/112 (9.8%) P=0.024

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Postoperative re- exploration of sternal incision site Intervention: 5/ 146 (3.4%) Control: 3/ 147 (2.0%) Length of stay: NR Mortality: 4 (1.4%) total (none considered related to study treatment) Intervention: 1/146 (0.7%) Sudden death after spasm of the graft, myocardial infarction, pulmonary embolism, and air embolism Control: 3/ 147 (2.0%) 1/3 excessive bleeding, atrial fibrillation, and global abdominal ischemia 1/3: ventricular fibrillation 1/3: hemorrhagic shock, erosion of the right atrium and mediastinitis P=0.363 Adverse events: Intervention: n= 146 Control: n= 147 Overall fewer than 10% of subjects experienced adverse events during the study and most were related to SSIs © 2017 American Medical Association. All rights reserved. 418

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Erythema Intervention: 1/146 (0.7 Control: 0/ 147 Surgical and medical procedures: Hospitalization Intervention: 0/ 146 Control: 1/ 147 (0.7%) Iyer RCT To determine Number of patients: Intervention group: n= 47 SSI: (follow up: 1 Definitions: 2011 129 1, 3, 4, the effect of N=47 (94 legs) The long saphenous vein grafts month) Infection: if the wound showed (ES) 5, 10 pretreatment Patients served as were taken from the below-knee Total saphenous vein signs of infection, it was with n-butyl their own controls segment in both legs of all harvest site SSI: graded by the Southampton cyanoacrylate Patient Characteristics: patients. Skin was disinfected 13/94 (13.8%) wound grading system -based Baseline using alcoholic povidone-iodine Intervention: 1/ 47 (Bailey 1992) microbial skin characteristics solution & 3 minutes were (2.1%) Grades as follows: sealant to the between the treated allowed for the disinfecting Control: 12/ 47 (25.5%) 0: Normal healing saphenous and untreated legs solution to dry. The sealant was P=0.0011; 95% CI for 1: Normal healing with bruising vein graft were similar because applied to only 1 leg per case difference (-0.374 to - or erythema, subclassified harvest site in the procedure was after the disinfecting solution was 0.0945) as A, B, or C according to a population conducted on the allowed to dry. An applicator was the size of bruising undergoing same individual. used to apply a single even layer Intervention: The leg 2: erythema with other signs of cardiac ·Age y, mean (SD): 67.0 of microbial sealant over an area developed a severe inflammation subclassified surgery and (7.6) overlying the saphenous vein infection and required as A, B, or C according to discuss its ·Gender (m:f): 39:8 harvest site. The sealant was incision and drainage. findings at 1 point around potential use ·Obesity- NR allowed to dry for 2 minutes. In the same patients, the suture or around the in decreasing ·Comorbidities Skin sealant was NOT used at the the untreated leg had whole wound infections in Arterial hypertension: 31 sternal site. no infection. 3: hemoserous discharge other kinds of (65.9%) Timing of intervention: Control: These 12 legs (A<2cm, B>2cm, C=large surgery. Peripheral vascular Intraoperatively showed evidence of volume, d>3 days) disease: 0 (0%) Duration of intervention: infection that ranged 4: purulent discharge (A<2cm, Venous disease in the Intraoperatively from oozing of serous B>2cm) legs: 0 (0%) Device/agent: Cyanoacrylate- fluid which responded 5: deep or severe infection Diabetes Mellitus: 12 based skin sealant to conservative with or without tissue (25.5%) Monitoring intervention: NR therapy (n=7) to breakdown. Hyperlipidemia: 40 Control group: n= 47 severely infected Perioperative care: NR (85.1%) Skin was disinfected using alcoholic wound requiring Other notes: the study was Renal Failure: 4 (8.5%) povidone-iodine solution & 3 incision and drainage terminated after ethical Ejection fraction, mean minutes were allowed for the (n=4) and committee review at the © 2017 American Medical Association. All rights reserved. 419

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score (SD): 47.3 (13.3) disinfecting solution to dry. No debridement (n=1) enrollment of 47 patients Procedures: Coronary skin sealant. Follow-up: 1 month (if the artery bypass graft Standard preventive measures: There were no other general practitioner involved (CABG) requiring 3 or Surgical technique: apart from infections observed at with the care after more lengths of long application of the sealant, the 30 days and discharge detected an saphenous vein to surgical technique in both legs investigators were not infection before the 4-week achieve was identical and the vein was aware of any follow-up, an appointment revascularization. harvested using a single open infections developing was arranged before the Additional internal incision. Endoscopic techniques after this point. stipulated follow-up and the thoracic conduit was were not employed and in most findings were recorded. also routinely used of the patients, the below portion Other infections: NR Funding Source Conflicts: Indications: NR of the vein was harvested. Topic-specific Authors: None Setting: 1 hospital Hair removal: performed using an outcomes: Institution: None Location: Australia electrical clipper the day before Southampton Grade Study: None Dates: Began August surgery. Intervention: 1/1: Grade Supplies: None 2008 - ???? (NR) Shower: patients washed with soap 4B Inclusion Criteria: the morning of surgery Control: 3/12: Grade 5 Patients undergoing Drapes: iodine impregnated drapes 2/12: Grade CABG requiring 3 or were used in all patients. 4B more lengths of long Closure: Closure of the 2/12: Grade saphenous vein to subcutaneous layer was with 2-0 3D achieve absorbable, braided synthetic 4/12: Grade revascularization sutures, and subcuticular closure 3B Exclusion Criteria: If of the skin was with 3-0 synthetic 1/12: Grade the patient required absorbable sutures. A 3A ≤2 segments of vein hydrocolloid dressing was used wherein only 1 leg in all patients Reoperations: was used and any Normothermia: All patients Intervention: The features that would underwent systemic cooling to infected leg required cause dissimilarity 32o to 34oC. incision and drainage. between the legs, Control: 1 severely which included the infected leg required vein in either leg not debridement. being usable, Length of stay: NR unilateral vascular Mortality: NR disease, or skin Adverse events: lesion. Also if there No patients had was a discrepancy in perioperative the length of the infarctions and there © 2017 American Medical Association. All rights reserved. 420

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score incision between the were no adverse treated and untreated intraoperative events. legs. Towfigh RCT To compare Number of patients: Intervention group: n=83 SSI (2 and 4 weeks): Definitions: 2008 130 1, 2, 3, the safety and N=166 (evaluable for (Per Protocol: 68) Total SSI: 3/148 (2%) Signs of infection: swelling, (ES) 4, 5, 7, effectiveness effectiveness of Standard surgical skin preparation Intervention: 0 erythema, drainage, 8, 9, 10 of microbial antimicrobial sealant) including a skin prep of 10% Control: 3/80 (3.8%) warmth. And dehiscence. sealant in Note: 148 (84%) in per povidone-iodine on the operative All 3 SSIs were Perioperative care: NR reducing the protocol analysis field which was allowed to dry. positive for S. aureus Other notes: A patient was incidence of Patient Characteristics: This was followed by a single and 1/3 of these was considered lost to follow up surgical There were no coat application of the a deep infection with after 4 unreturned attempts incision statistically significant cyanoacrylate-based microbial MRSA at contact. bacterial differences between sealant. The sealant was allowed Given the low number of Follow-up: at 2 and 4 weeks contamination the two groups. to dry before the application of events and early postoperatively to access relative to ·Age: mean (SD) y surgical drapes. termination of the the incision surgical skin Intervention: 52.7 study, it is Funding Source Conflicts: preparation (15.9) Timing of intervention: Pre intra, underpowered to Authors: None alone in Control: 54.1 (14.9) and postoperatively detect a difference in Institution: None elective open Values below based on Duration of intervention: Pre intra, SSI. Study: Industry inguinal Total pop: N=177 and postoperatively Supplies: Industry hernia repair. Intervention n=88 Device/agent: Cyanoacrylate- Other infections: NR Control n=89 based microbial sealant Topic-specific ·Gender (male) Monitoring intervention: NR outcomes: Intervention: 84/88 Control group: n=83 Most patients did not (95.5%) (Per Protocol: 80) maintain a sterile Control: 86/89 (96.6%) Standard surgical skin preparation wound throughout ·Obesity: (BMI>30kg/m2) including a skin prep of 10% surgery regardless of Intervention: 27 povidone-iodine on the operative resultant SSI or not. (30.7%) field which was allowed to dry. One surgeon reported Control: 18 (20.2%) Standard preventive measures: visible flaking of the ·Comorbidities Instruction: all principal microbial sealant film Diabetes Mellitus investigators were given hands- during the procedure. Intervention: 2 (2.3%) on instruction in how to use the One patient in the Control: 4 (4.5%) applicator prior to enrollment of microbial sealant 7 patients had comorbid subjects. group had skin clinical characteristics Non-standard preventive irritation (resolved on that have been measures: its own) reported to be Surgeons were allowed to perform Surgeons reported 4 associated with the open inguinal hernia repair incidents of difficulty © 2017 American Medical Association. All rights reserved. 421

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score wound complications based on their personal incising through the such as preference with respect to hair clear film. hyperhidrosis, clipping, perioperative Reoperations: eczema, psoriasis, or antimicrobials, surgical The deep MRSA an autoimmune techniques and use of mesh infection from the disease. One patient Preoperative data: control group required had a previous history Based on Total population N=176 readmission, of SSI. because data missing from 1 debridement, mesh Procedure duration: intervention removal and (min) Antimicrobial shower: intravenous Mean (SD) Intervention: 23/87 (26.4%) antimicrobials. Intervention: 73.7 (28.4) Control: 24/89 (27.0%) Length of stay: NR Control: 75.6 (31.5) Hair removal: 173/176 (98.3%) Mortality: NR Procedures: Open Clipping/shaving Adverse events: inguinal hernia repair. Intervention: 45/35 Serious adverse events Indications: NR Control:47/36 All serious adverse Setting: 6 Teaching AMP: administered to 131/176 events occurred in hospitals (74%) the control group and Location: USA Intervention: 61/87 (70.1%) resolved at final Dates: July 2005 - Control: 70 (78.7%) follow up September 2006 Mesh implanted Admission for SSI due to (Clinical trial Intervention: 71/88 (81.6%) MRSA:1 discontinued in Control: 72/89 (80.9%) Groin hematoma: 1 September of 2006 Closure using sutures Chest pain: 1 when FDA granted Intervention: 87/88 (98.9%) Dyspnea: 1 regulatory approval Control: 88/89 (98.9%) Scrotal edema: 1 for this product as a Wound covered with a dressing Knee pain: 1 class II medical Intervention 77 (87.5%) Non-serious adverse device. Control: 80 (89.9%) events Inclusion Criteria: P=0.62 Scrotal edema, Scheduled for open, hematoma class 1 clean inguinal Intervention: 3 hernia repair; aged 18 Control: 2 or older; able to Wound dehiscence complete mean (SD) Intervention: 1 30 (5) day follow-up.; Control: 0 and able and willing to Incisional pain/ swelling provide informed Intervention: 1 consent Control: 1 © 2017 American Medical Association. All rights reserved. 422

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Exclusion Criteria: Skin irritation Known sensitivity to Intervention: 1 cyanoacrylate Control: 0 formaldehyde or Possibly attributable to acetone products or investigational device iodine or iodine Constipation containing products; Intervention: 1 surgical procedures Control: 0 involving mucous Incisional bleeding membranes or eyes; Intervention: 1 laparoscopic surgical Control: 0 procedures; evidence Urinary frequency of coexistent infection Intervention: 0 at a remote body site; Control: 1 skin rashes or Urinary retention exfoliative condition Intervention: 1 the day of surgery; Control: 1 history of keloid Epigastric hernia formation; currently drainage receiving high-dose Intervention: 1 steroid or Control: 0 immunosuppressive Decreased limb therapy; sensation chemotherapy Intervention: 0 treatment within 30 Control: 1 days of current surgery; diagnoses of diabetes HbA>7.0% obtained within 90 days; use of oral, IV or topical (in expected area of incision) antimicrobials within 20 days prior to the day of surgery; pregnant or nursing; or participation in any other study of an investigational drug or © 2017 American Medical Association. All rights reserved. 423

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score device within 2 week prior to the current procedure.

eTABLE 49. Evidence Table for Q8D. How safe and effective are plastic adhesive drapes? Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Segal RCT To No. Patients: N=209 Intervention1: n=52 Sternal wound Definitions 2002 114 1, 2, 5, evaluate Patient characteristics: Povidone-iodine five-minute scrub Infections: 6 weeks Obesity: BMI>120% of ideal (ES) 9 the effect Patient demographics with paint Intervention1: 7/52 weight. of four were compared. Intervention2: n=50 (13.5%) SSI: Clinical exam for signs of different The following One-step iodophor/alcohol water Intervention2: 1/50 drainage, redness, skin characteristics given insoluble film (2.0%) tenderness, or sternal preparation represent the whole Intervention3: n=51 Intervention 3: 3/51 instability. Sternal surgical s on the study. one-step iodophor/alcohol water (5.9%) site exhibiting any of these incidence All patients had at least insoluble film with iodine Intervention 4: 7/56 signs was cultured. Positive of sternal one high-risk factor (the impregnated surgical adhesive (12.5%) cultures were correlated with SSIs in basis of the study). drape P=0.117 clinical evidence according patients 39% had 2 risk factors Intervention 4: n=56 Infections per to the CDC guideline to undergoing 4% had 3 risk factors Povidone-iodine paint treatment indicate a sternal SSI coronary (Percentage numbers Timing of Intervention: Aqueous Iodine ( artery appear larger in bar Preoperative Intervention 1+4) Perioperative care bypass graph within paper my Duration of intervention: 14/108 (13.0%) NR graft copy is difficult to read) Intraoperative Insoluble Iodine Other notes surgery Age (y): Mean Agents: Solutions, insoluble film & (Interventions 2 and 3) Impregnated drapes in (CABG) 60.9 years (no SD given) incise drapes not specified 4/101 (4.0%) Intervention 3 were shown to who were Gender: Over 75% male Monitoring intervention: P=0.02 be ineffective as an identified Obesity: NR Observation by nurses Χ2=5.3 intervention. as high risk Redo sternotomies: 11.5% Control: Other infections: NR Study deemed underpowered of Procedures performed Topic-specific Follow up: 6 weeks developing using the IMA: 88.5 Standard Preventive Measures outcomes: NR postoperatively through sternal SSI Shower Reoperation: NR regularly scheduled clinic Mean±SD The nurse instructed patients to Length of Stay: visits Total OR time: 248 min take an antimicrobial shower the Uninfected patients Funding Source Conflicts: ±29 evening before and the morning had a 5-6 day shorter Authors: NR © 2017 American Medical Association. All rights reserved. 424

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Cross clamp time: 42 of surgery, or if they were length of hospital stay Institution: NR min±20 inpatients, they were given a than infected patients. Study: NR Last OR Glucose: preoperative antimicrobial Mortality: NR Supplies: NR 434±210 shower in the hospital. Adverse events: NR Procedures: elective Hair removal CABG Surgery If necessary, a qualified patient Indications: NR care assistant clipped patients’ Setting: 1 tertiary/ hair the morning of surgery in teaching hospital patients’ rooms. Location: USA AMP: All patients received a Dates: Oct 1, 1994 – April prophylactic antimicrobial (i.e., 30-1997 cefuroxime) or if they had a Inclusion Criteria: documented allergy to penicillin, Patients undergoing they received vancomycin in elective CABG with one appropriate dosing window to or more of the following provide adequate coverage at conditions: the time of incision. Diabetes Obesity Chronic Obstructive Pulmonary Disease (COPD) Exclusion Criteria: Patients with an allergy to topical iodine or with a preexisting infection indicated by a white blood cell count higher than 10,000 or by a temperature higher than 100.5oF (38.06oC) because their procedures were performed emergently.

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Ward RCT To Number of patients: Intervention group: n=305 SSI: Definitions: 2001 132 1, 2, 3, evaluate N=605 After drying the cleansed area, a Infection: if two of the 3 (ES) 4, 5, 6, the ability Patient Characteristics: plastic adhesive drape was Drape: 34/305 (11.1%) following features were 7, 8, 9 of the new Characteristics were carefully applied to the skin and No Drape: 30/298 present: generation similar between groups. toweling and this remained in (10.1%) 1) Erythematous cellulitis of adhesive situ until the last skin suture or (erythematous induration surgical Procedures: Caesarean staple had been inserted. The P=0.6933 either side of the incision drapes to Section drape was then removed and a line prevent Setting: 1 Regional dressing applied. 2) Seropurulent discharge Post referral hospital Timing of intervention: from the wound. Cesarean Location: South Africa Intraoperatively 3) Positive swab culture Wound Dates: Aug 18, 1992 – Duration of intervention: (organisms and Infection. January 29, 1993 Intraoperatively leucocytes). Inclusion Criteria: Device/agent: plastic adhesive Perioperative care: NR Consecutive patients drape Other notes: None undergoing Caesarean Control group: n=298 Follow-up: 5 days. Section Same standard preventive Funding Source Conflicts: Exclusion Criteria: measures but no drape was Authors: NR Women having applied. Institution: NR coincidental appendix Standard preventive measures: Study: NR ruptured or requesting Skin Prep: preoperatively, Supplies: NR early discharge. abdomen and perineum were washed with 4% chlorhexidine soap. On the Operating table, the abdomen was liberally swabbed with a solution of 0.5% chlorhexidine in 80% alcohol for at least 30s over an area extending from the xiphosternum to the flanks, down as far as the mid-thigh and across to the perineum in the midline. The surgeon then scalpel shaved an area 2cm either side of the proposed incision site. Standard sterile double towel draping followed. The site was padded dry with a sterile swab © 2017 American Medical Association. All rights reserved. 426

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score AMP: At clamping of umbilical cord, patient received 1g of cephazolin intravenously unless antimicrobials were already being administered as therapy or prophylaxis. A 1g metronidazole suppository was inserted preoperatively and repeated after 12h. Chiu RCT To Number of patients: N= Intervention group: n= 65 SSI: Definitions: NR 1993 133 1 investigate 120 Operation site was covered with a Total: 11/120 (9.2%) Perioperative care: NR (ES) the Patient Characteristics: plastic adhesive drape. Drape: 6/65 (9.2%) Other notes: None effectivene The two groups were Timing of intervention: Superficial: 5/65 Follow-up: NR ss of matched for patient Intraoperatively+ (7.7%) Funding Source Conflicts: plastic characteristics. Duration of intervention: Deep: 1/65 (1.5%) Authors: NR adhesive ·Age: NR Intraoperatively No Drape: 5/55 (9.1%) Institution: NR skin drapes ·Gender: NR Device/agent: plastic adhesive Superficial: 4/55 Study: NR in the ·Obesity: NR drape (7.3%) Supplies: NR prevention ·Comorbidities: NR Control group: n= 55 Deep: 1/55 (1.8%) of wound Procedures: Acute Hip Operation site was left uncovered. infection Fracture including Same standard preventive after acute Internal fixation with measures but no drape was hip fracture sliding hip-screw done applied. operations. for trochanteric Standard preventive measures: fractures; Austin-Moore Ultraclean air: there was no femoral head laminar flow, ultraclean air, or replacement inserted exhaust suits in the operating for displaced subcapital room. fracture in older AMP: cephalosporin antibiotic was patients; and for given at induction of anesthesia. undisplaced fractures or Skin prep: Operation site was for displaced fractures prepared with povidone solution in young patients, the then wiped, dried and draped fracture was fixed with with sterile towels. three cancellous lag screws. Setting: 1 University Hospital Location: China © 2017 American Medical Association. All rights reserved. 427

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Dates: January – December 1991 Inclusion Criteria: patients with hip fracture operations done by one of two surgeons done in the same operating theater. Exclusion Criteria: NR Dewan RCT To Number of patients: Intervention group: n=529 SSI: Definitions: 1987 136 1, 2, 4 determine N=1016 Patients with iodophor- Wound infection Infection: present if wound (ES) 7, 8 if skin Patient Characteristics: impregnated drape applied Intervention: 36/529 discharged pus or if the organism satisfactory Timing of intervention: (6.8%) discharge of fluid from the contaminati randomization for the perioperatively. Control: 34/487 (7.0%) wound was as associated on of the non-parametrically Duration of intervention: surgery Not significantly with appositive bacterial wound distributed groups was Device/agent: Iodophor- different culture. Infection was also made confirmed for each of the impregnated drape Other infections: NR diagnosed if the wound through major wound infection Monitoring intervention: NA Topic-specific showed erythema more than iodophor risk factors and excluded Control group: n=487 outcomes: NR 1cm lateral to the wound impregnate a bias from these. Patients where no iodophor- Reoperations: NR margin, and for either one d incise ·Age: NR impregnated drape was used. Length of stay: NR third of the length of the drapes ·Gender: NR Standard preventive measures: Mortality: NR wound or an 8cm length of it. should be ·Obesity: NR Routine skin prep of an iodophor Adverse events: NR Perioperative care: NR reduced ·Comorbidities: NR antiseptic followed by alcohol. Other notes: None and less Procedures: general The operative field was dried Follow-up: 3weeks follow up than when abdominal operations with a sterile swab. Funding Source Conflicts: a standard including inguinal hernia Authors: NR skin repair Institution: NR preparation Indications: NR Study: NR is used. Setting: One university Supplies: NR Thus if hospital contaminati Location: New Zealand on is Dates: August 1983 – May significantly 1985 linked to Inclusion Criteria: infection, a Patients undergoing reduction in abdominal operation, the wound including inguinal hernia infection Exclusion Criteria: © 2017 American Medical Association. All rights reserved. 428

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score rate from patients under 10 years skin of age and patients of organisms one surgeon when he should felt the color of the drape follow. precluded optimal incision placement. Also, patients requiring abdominoplasty and two patients with a strong history of previous iodine allergy. Psaila RCT To assess Number of patients: Intervention group: N=51 SSI Definitions: 1977 135 1, 8, 9 the role of N=144 (n=98 utilized An adhesive plastic drape was Wound infection: Presence of infection: (ES) adhesive here) applied over cloth towels at the All: 26/144 (18.0%) 1) Erythema around the plastic skin Patient Characteristics: abdominal surgery site. Drape: 8/51 (16%) sutures or along the drapes and ·Age: NR Timing of intervention No Drape: 10/47 (21%) wound edge with an plastic ring ·Gender: NR Duration of intervention Other infections: NR accompanying pyrexia wound ·Obesity: NR Device/agent Topic-specific 2) Discharge of exudate protectors ·Comorbidities: NR Monitoring intervention outcomes: NR or pus from the wound in the Procedures: abdominal Control group: n=47 Reoperations: NR 3) Wound breakdown. prevention surgery. Cloth towels were applied to the Length of stay: NR 4) If infection was of wound Indications: NR abdominal wound Mortality: NR considered to be infection Setting: One University Standard preventive measures: Adverse events: NR present, a swab was following hospital Skin prep: 1 in 30, 0.05% taken and sent. abdominal Location: United Kingdom chlorhexidine and cetrimide 0.5% Perioperative care: NR surgery Dates: NR and Chlorhexidine gluconate Other notes: None Inclusion Criteria: 0.5% in alcohol. Follow-up: daily after the 3rd Patients undergoing postoperative day. abdominal surgery Funding Source Conflicts: Exclusion Criteria: Authors: NR Patients receiving Institution: NR preoperative Study: NR antimicrobials (with Supplies: NR exception of non- absorbable sulphonamides used for bowel prep)

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Study Author Design Study Year Risk of Population and Setting Intervention Results Comments Objective (Extractor) Bias Score Jackson RCT To conduct Number of patients; Intervention group: n=473 SSI: Definitions : 1971 134 1, 2 a study to n=921 Patients who had a plastic Wound infection Wound infection: defined in (ES) determine Patient Characteristics: adhesive drape utilized at the Drape: 67/473 (14.2%) terms of the discharge of the Recorded, not reported site of surgery No Drape: 52/448 pus from the wound. effectivene by study group. Timing of intervention: (11.6%) Usually a small amount ss of ·Age: NR Intraoperative P>0.20 (e.g., the so-called stitch plastic ·Gender: NR Duration of intervention: until Other infections: NR abscess), but sometimes a adhesive ·Obesity: NR just after incision. Topic-specific wound abscess developed drapes in ·Comorbidities: NR Device/agent: Plastic adhesive outcomes: NR which required evacuation preventing Procedures: NR drape. Reoperations: NR by removal of a suture and wound Indications: NR Monitoring intervention: NA Length of stay: NR spreading of the wound infection. Setting: 1 hospital Control group: n=448 Mortality: NR edges. Wherever possible, Location: England Patients who had no adhesive Adverse events: NR the infecting organism was Dates: Started December drape utilized. isolated and the cause was 1967 – two years later. Standard preventive measures: assessed. If a swab grew a Inclusion Criteria: All Skin prep: swab soaked in 2.5% microorganism, but no pus suitable cases operated alcoholic solution of iodine BP was produced, the wound on by one of the 3 was used to paint the operation was not regarded as authors or 2 other area. This was wiped dry and infected. The slight surgeons. ether was painted around the moistness at the site of a Exclusion Criteria: area of the incision. drainage tube was not Operations where accepted by itself as an drapes could not be indication of infection. used satisfactorily Perioperative care: NR (mastectomy, perineal Other notes: None operations, amputation, Follow-up: at least 4 weeks. limb arterial surgery, Funding Source Conflicts: etc.); known iodine Authors: NR sensitivity, cases where Institution: NR difficulties with Study: NR adhesiveness of drapes Supplies: NR were present or where drapes were unsatisfactory.

eTABLE 50. Evidence Table for Q9. How safe and effective is antiseptic irrigation prior to closing the surgical incision?

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Chang RCT To evaluate Number of patients: Intervention group: n=120 SSI: Definitions: 2006 140 1, 2, 4, the effect of n=244 Wounds were irrigated with Superficial: no infections Superficial infection: above (ES) 6, 7, 8, wound Patient 0.35%povidone-iodine solution in either group lumbosacral fascia 9, 10 irrigation Characteristics: to soak for 3min, followed by Deep: Deep infections: below with patient characteristics irrigation with 2000cc of normal Intervention: 0/120 lumbosacral fascia & all povidone- were not statistically saline to remove povidone- Control: 6/124 (4.8%) deep infections were iodine on significantly different iodine solution. P=0.29 confirmed by lab wound between groups Timing of intervention: parameters including the healing, ·Age, y: NR intraoperative Other infections: NR erythrocyte sedimentation infection ·Gender: NR Duration of intervention: 3min Topic-specific rate (ESR) and level of C- rate, fusion ·Obesity: NR Device/agent: 0.53% povidone- outcomes: NR reactive protein (CRP) and status and ·Comorbidities: NR iodine solution Reoperations: NR a positive culture of biopsy. clinical Procedures: primary Monitoring intervention: NA Length of stay: NR Perioperative care: NA outcome of instrumented Control group: n=124 Mortality: NR Other notes: none spinal lumbosacral Wound was only irrigated with Adverse events: one Follow-up: every three surgeries posterolateral fusion 2000cc normal saline incidence of wound months until the end of the levels for Standard preventive measures: dehiscence event study. Duration was approx. degenerative spinal Pain control – 3 days postop. with 0.35% povidone 19months. disorder. AMP: preop IV bolus injections of iodine followed by Funding Source Conflicts: Indications: lumbar or cefazolin and gentamicin, normal saline Authors: None lumbosacral additional postop cefazolin and irrigation. Institution: None segmental instability gentamicin injections were Study: None defined by chronic given for 48h postop followed Supplies: None back, buttock and/or by oral cefazolin for 3 days leg pain and postop. degenerative Custom made orthosis immobilized spondylolisthesis, patient whenever out of bed for degenerative 3 months postop. scoliosis, or isthmic spondylolisthesis. Setting: 1 university hospital Location: Taiwan Dates: Jan 2002 – Aug 2003 Inclusion Criteria: patients undergoing primary instrumented lumbosacral © 2017 American Medical Association. All rights reserved. 431

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score posterolateral fusion levels for degenerative spinal disorder. Exclusion Criteria: prior spinal surgery, spinal trauma, malignancy Cheng RCT To evaluate Number of patients: Intervention group: n=208 SSI: Definitions: 2005 141 1, 2, 5, the efficacy N=417 Wound was soaked with povidone Overall Infection: suspected when (ES) 7, 8, 9 of dilute Patient iodine solution for 3min (5mL of Intervention: 0/208 unusual pain, tenderness, 10 betadine Characteristics: povidone-iodine diluted with Control: 7/206 (3.4%) erythema, induration, fever, solution in there were no normal saline to achieve 0.35% P=0.0072 or wound drainage was the statistically significant povidone iodine solution.) The noted. Findings were prevention of differences between wound was then irrigated with Superficial: investigated with infection, groups except with copious amounts of normal Intervention: 0/208 measurement of ESR, CRP, particularly age: saline (2000ml) Control: 1/206 (0.5%) and bacteriological cultures deep ·Age (mean) y Timing of intervention: P=0.4976 from the operative site or infection Intervention: 64 intraoperative Deep: blood. All patients with following Control: 61 Duration of intervention: 3min Intervention: 0/208 highly suspected wound spinal P=0.0682 soak Control: 6/206 (2.9%) infection underwent surgical surgery ·Gender: NR Device/agent: -.35% povidone- P=0.0146 debridement. ·Obesity: NR iodine solution Perioperative care: NR ·Comorbidities: NR Monitoring intervention Other infections: NR Other Notes: none Procedures: spinal Control group: n=206 Topic-specific Follow-up: at 3 month surgery Patients outcomes: NR intervals until study was (decompression, Standard preventive measures: Adverse events: no over. (mean length 15.5 pedicle screw fixation, Basic aseptic technique was product-related months) discectomy, tumor followed. adverse event with Funding Source Conflicts: excision) Skin prep: with povidone iodine. 0.35% povidone Authors: None Setting: 1 university AMP: 1 does parenteral cefazolin iodine followed by Institution: None hospital and gentamicin 1h preop then normal saline Study: None Location: Taiwan Cefazolin every 6h & irrigation Supplies: None Dates: January 2002 – gentamicin every 12 hours for May 2003 48h postop. Oral antimicrobial Inclusion Criteria: doses (cefazolin) were patients undergoing continued for 3 days. spinal surgery. Exclusion Criteria: © 2017 American Medical Association. All rights reserved. 432

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Mortality in follow-up period, also, patients with overt or suspected pyogenic vertebral osteomyelitis, discitis, or any form of preoperative spinal infection; and patients with fever or other suspected sources of infection. Sindelar RCT To evaluate Number of patients: Intervention group: n=37 SSI: Definitions: NR 1985 139 1, 2, 7, the efficacy N=75 Irrigation of the intraperitoneal area Total Infections Perioperative care: NR (ES) 8, 9 and toxicity Patient was performed 3 times during PVP-I LMW: 2/37 (5.4%) Other notes: None of Characteristics: the operation with 1000ml of a [dirty] Follow-up: 7days intraperitone The experimental and 10% solution of PVP-I LMW. Saline: 9/38 (26.7%) [7/9 Funding Source Conflicts: al irrigation control groups did not The Solution was suctioned contaminated; 2/9 Authors: NR with Low statistically differ with from the peritoneal cavity 30- dirty] Institution: NR Molecular respect to patient 60s after installation. In patients Study: NR Weight characteristics. undergoing primary wound Organ/Space Infection Supplies: NR Povidone ·Age, y: NR closure, irrigation of the PVP-I LMW: 1/37 (2.7%) Iodine ·Gender: NR subcutaneous tissue was [dirty] Solution ·Obesity: NR performed prior to skin closure Saline: 6/38 (15.8%) [4/6 (PVP-I ·Comorbidities: NR with 1000ml of PVP-I LMW contaminated; 2/6 LMW) in Procedures: 10%. dirty surgical Contaminated or dirty Timing of intervention: procedures Intra-abdominal intraoperative Deep wound infection performed in surgical procedures Duration of intervention: duration PVP-I LMW: 0/37 the face of Setting: National of lavage. Saline: 1/38 (2.6%) bacterial Institute of Health Device/agent: low molecular [Dirty] contaminatio Location: USA weight povidone iodine solution n (i.e. intra- Dates: NR (10%) Superficial wound abdominal Inclusion Criteria: Control group: n=38 infection: surgical Patients 18yo or Irrigation of the intraperitoneal area PVP-I LMW: 1/37 (2.7%) procedures older, scheduled for was performed 3 times during [dirty] where there elective or emergency the operation with 1000ml of Saline: 2/38 (5.3%) [both was likely to intra-abdominal saline. The Solution was contaminated] be bacterial surgery involving suctioned from the peritoneal © 2017 American Medical Association. All rights reserved. 433

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score contaminatio entry into the cavity 30-60s after installation. CLEAN (No AMP) n of the peritoneal cavity In patients undergoing primary 0/113 vs.7/121 (6%); peritoneal where the surgery wound closure, irrigation of the p<0.01 cavity) was classified as subcutaneous tissue was contaminated or dirty performed prior to skin closure Potentially (esophageal, gastric, with 1000ml of saline. Contaminated (AMP) small intestinal, Standard preventive measures: 1/49 vs. 7/49; p<0.05 colonic, hepatic, AMP: patients received peri- pancreatico-biliary. operative antimicrobials in Contaminated (AMP) Exclusion Criteria: accordance to the practice of 3/44 vs. 12 /46; p<0.05 Patients undergoing the surgeon responsible. clean operative Dirty (AMP) procedures. If there 3/36 vs. 13/42; p<0.001 was a history of iodine sensitivity, Adverse events: thyroid disease, renal Significant increase in insufficiency or postop serum Iodine surgery involving levels at 24h resolved ischemic or necrotic by 72h. No clinical tissues which might signs of iodine toxicity interfere with wound healing either in the presence or absence of infectious complications. Vallance RCT To compare Number of patients: Intervention group: SSI: Definitions: NR 1985 138 1, 7, 8, a Povidone- N=29 PVP-I: n=13 PI: 4/13 (31%) Perioperative care: NR (ES) 9 Iodine Patient Patients who received a saline Saline: 5/16(31%) Other notes: None solution Characteristics: lavage until solutions returned p=NS Follow-up: 30 days against Patient characteristics clear with 100ml PVP-I solution Funding Source Conflicts: saline alone were not statistically inserted before wound closure Authors: None for different between the Timing of intervention: Institution: None peritoneal groups. intraoperatively Study: None lavage in ·Age, y: NR Duration of intervention: NR Supplies: None patients ·Gender: NR Device/agent: PVP-I or saline undergoing ·Obesity: NR Control group: operations ·Comorbidities: NR Saline: n=16 for Procedures: dirty Patients who received a saline generalized laparotomy lavage until solutions returned © 2017 American Medical Association. All rights reserved. 434

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score purulent or procedures clear with inserted before fecal Setting: 1 hospital wound closure peritonitis Location: UK Standard preventive measures Dates: NR Fluid maintenance: all patients Inclusion Criteria: were resuscitated with iv fluids Patients who were before surgery confirmed at AMP: all patients were begun on laparotomy to have broad spectrum antimicrobial generalized purulent postop prophylaxis which were or fecal peritonitis. continued for at least 5 days Exclusion Criteria: postop. Patients dying within 4 days of the operation. Rogers RCT To elucidate Number of patients: Intervention group: n=86 SSI: Definitions: 1983 143 1, 2, 7, further the N=187 After fascial closure, patients Clean (No AMP) Wound infection: any wound in (ES) 8, 9 potential Patient underwent an approximate one P-I: 2/56 (3.6%) which a purulent discharge value of Characteristics: minute irrigation of the Saline: 6/68 (8.8%) occurred during a month of Povidone ·Age, y: NR subcutaneous tissue with p=?? observation after the Iodine ·Gender: NR approximately 60ml of 10% operation. wound ·Obesity: NR Povidone Iodine (1% available Clean-contaminated Perioperative care: NR irrigation as ·Comorbidities: NR iodine) solution. (AMP) Other notes: None an adjunct in Procedures: Clean Timing of intervention: P-I: 1/24 (4.2%) Follow-up: 1 month the (Inguinal hernia intraoperative Saline: 5/27 (18.5%) Funding Source Conflicts: prevention repair, Duration of intervention: approx. p=? Authors: NR postoperativ cholecystectomy, 1 minute Institution: NR ely of wound laparotomy, hiatal Device/agent: PVP-I or saline Dirty (AMP) Study: NR infections. hernia repair, Control group: n=101 P-I: 1/6 (16.6%) Supplies: NR proximal gastric After fascial closure, patients Saline: 1/6 (16.6%) vagotomy, ventral underwent an approximate one p=NS hernia, and other), minute irrigation of the clean contaminated subcutaneous tissue with saline (upper solution. gastrointestinal, colorectal, biliary Standard preventive measure: tract, appendectomy AMP: administered to all patients and other clean perioperatively in both the contaminated clean-contaminated and dirty surgeries), and Dirty categories. © 2017 American Medical Association. All rights reserved. 435

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score (perforated viscus, Bowel Prep: mechanical (cleansing traumatic perforation enema, cathartics & low residue procedures) liquids) and antimicrobial bowel procedures. prep (orally administered Setting: 1 veterans neomycin and erythromycin hospital base) were used for elective Location: USA colorectal surgeries. Dates: July 1, - December 31, 1979 Inclusion Criteria: All patients undergoing operative procedures Exclusion Criteria: operations on the anorectal area; also patients who died or who required reoperation within three weeks of primary operation unless the wounds were obviously infected. Vascular procedures and operations on the head and neck Sindelar RCT To evaluate Number of patients: Intervention group: n=129 SSI: Definitions: 1979 142 1, 7, 8, the efficacy N=266 Patients had subcutaneous tissues Superficial SSI: Infection: if any amount of pus (ES) 9 of povidone- Patient irrigated for 60 seconds with PI: 7/129 was discharged within 12 iodine Characteristics: 10% povidone-iodine solution Saline: 32/137 weeks of operation. Serous irrigations of patient groups were Timing of intervention: drainage from questionable subcutaneou similar in age, sex intraoperative Potentially wounds was cultured and s tissue distribution and types Duration of intervention: 60 Contaminated was considered infected if during of surgery. seconds PI: 1/49 any bacterial growth was wound ·Age, y: NR Device/agent: 1% available Saline: 7/49 recovered. closure in ·Gender: NR iodine, povidone-iodine solution p<0.05 Perioperative care: NR reducing the ·Obesity: NR Control group: n=137 Other Notes: None incidence of ·Comorbidities: NR Patients had subcutaneous tissues Contaminated Follow-up: up to 12 weeks superficial Procedures: both irrigated for 60 seconds with PI: 3/44 postop. © 2017 American Medical Association. All rights reserved. 436

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score wound elective and saline solution Saline: 12 /46 Funding Source Conflicts: infections for emergency surgical Standard preventive measures p<0.05 Authors: NR a variety of procedures including AMP: Parenteral AMP preop and Institution: NR surgical abdominal & for 48h postop Dirty Study: NR incisions. gastrointestinal PI: 3/36 Supplies: NR procedures, oncologic Saline: 13/42 procedures, vascular p<0.001 reconstructions, head and neck operations, Adverse events: no thoracic and significant change in genitourinary free iodine serum procedures and levels trauma operations. Setting: 1 university hospital Location: USA Dates: NR Inclusion Criteria: patients undergoing operative procedures. Exclusion Criteria: Amputations for ischemic disease, drainage of subcutaneous abscesses, skin grafting and anorectal procedures. Also, patients with a history of iodine sensitivity, thyroid diseases and significant renal impairment

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Sindelar RCT To study Number of patients: Intervention group: n=80 SSI: Definitions: 1979 137 1, 5, 7, both the N=168 Prior to closure, the peritoneal Intraabdominal Abscess Intraabdominal abscess: fever, (ES) 8, 9 possible Patient cavity was irrigated for 60 Overall: 10/168 (5.95%) persistent pain, palpable toxicity and Characteristics: seconds with 1L of 1% Intervention: 1/80 mass, abnormal the possible patient groups were povidone-iodine solution, giving (1.3%) roentgenograms, or positive benefit of similar in age, sex 0.1% available iodine in diluted Control: 9/88 (10.2%) ultrasonographic findings. povidone- distribution and types form. Following irrigation, the P<0.05 Patients with suspected iodine of surgery. peritoneum was suctioned and Dirty Procedures: abscesses underwent peritoneal ·Age, y: NR the majority (estimated>90%) of Intervention: 0/36 surgical exploration. irrigations in ·Gender: NR the irrigant was removed. Control: 6/42 (14.3%) Adverse event: iodine toxicity reducing the ·Obesity: NR Timing of intervention: P<0.05 Perioperative care: NR incidence of ·Comorbidities: NR intraoperative Contaminated Other notes: None intra- Procedures: Duration of intervention: 60 Procedures: Follow-up: 3 months or until abdominal Laparotomy: surgical seconds Intervention: 1/44 death. abscess explorations in the Device/agent: 1% povidone-iodine (2.3%) Funding Source Conflicts: formation in presence of solution Control: 3/46 (6.5%) Authors: NR patients with bacterially Monitoring intervention: NA P=NS Institution: NR contaminate contaminated Control group: n=88 Other infections: NR Study: NR d abdomens. peritoneal cavities. Peritoneal cavity was irrigated for Topic-specific Supplies: NR Indications: 60 seconds with 1L of normal outcomes: NR contaminated saline solution followed by Reoperations: NR abdomen suctioning. Length of stay: NR Setting: 1 university Standard preventive measures Mortality: NR hospital Amp: all patients received Location: USA preoperative systemic Adverse events: Dates: NR antimicrobial prophylaxis which Iodine toxicity: Inclusion Criteria: were continued for 48h postop Intervention: 5/80 patients undergoing or longer if clinically indicated (6.25%) laparotomy. by manifestations of sepsis. Control: 0/88 Exclusion Criteria: (Typically clindamycin and patients with a history gentamicin except in allergy or Serum iodine levels of iodine sensitivity, possible renal impairment for were elevated 24 thyroid disease, or which doxycycline was hours after significant renal substituted). intraperitoneal disease. irrigation with PI solution and returned to near normal by 73h postop and no complications from © 2017 American Medical Association. All rights reserved. 438

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score the use of PI

eTABLE 51. Evidence Table for Q10. How safe and effective is repeat application of an antiseptic skin preparation agent to the surgical site immediately prior to closing the surgical incision? Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Harihara RCT To investigate Number of patients: Intervention group: n=54 (23 SSI: (Follow up NR) Definitions: 2006 144 1 whether N=107 gastric and 31 colorectal) Gastric Surgery SSI: JNIS system which is a (ES) incisional (47 Gastric & 60 Before skin closure, skin was Wound Infection: Japanese modification of topical colorectal) irrigated with 500ml saline Intervention: 1/23 the CDC NNIS System. application of Patient solution. Povidone-Iodine was (4.3%) Wound infection: infection Povidone- Characteristics: No applied to the skin around the Control: 0/24 excluding organ/space iodine (PVP-I) significant difference incision twice using swabs in P=0.4894 infection from SSI. just before was observed the same manner as the SSI Perioperative care: NR skin closure between groups. preoperative skin preparation Intervention: 3/23 Other notes: NR can prevent ·Age: after irrigation and just before (13.0%) Follow-up: NR wound Gastric skin closure. Control: 3/24 (12.5%) Funding Source Conflicts: infection or Intervention: Timing of intervention: P=0.6460 Authors: NR SSI. 62.1±11.9y Intraoperatively Colorectal Surgery Institution: NR Control: 65.0±11.9 Duration of intervention: Wound Infection: Study: NR Colorectal Intraoperatively Intervention: 4/31 Supplies: NR Intervention: Device/agent: Povidone-iodine (12.9%) 62.8±12.3 (PVP-I) Control: 4/29 (13.7%) Control: 66.3±11.5 Monitoring intervention: NR P=0.4894 ·Gender: m:f Control group: n= 52 (23 gastric SSI Gastric and 29 colorectal) Intervention: 5/31 © 2017 American Medical Association. All rights reserved. 439

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Intervention: 18:5 Povidone-Iodine was not applied to (16.1%) Control: 20:4 the skin around the incision just Control: 5/29 (17.2%) Colorectal before skin closure. P=0.6460 Intervention: 18:13 Control: 15:14 Standard preventive measures: RISK FACTORS FOR ·ASA Physical Status NR INFECTION (1:2:3:4:5) Gastric Surgery Gastric No significant risk Intervention: factors were identified 13:10:0:0:0 affecting either wound Control: 12:12:0:0:0 infection or SSI rates Colorectal in the univariate Intervention: analysis using the 19:10:2:0:0 logistic regression Control: 10:17:2:0:0 model in gastric surgery. ·Obesity: BMI (only for colorectal) Colorectal Surgery Colorectal Univariate Analysis of Intervention: 23.1±3.4 Risk Factors Control: 21.8±3.2 Wound Infection ·Comorbidities: (only for ASA: OR = 3.4232; colorectal) P=0.0436 Colorectal DM: OR = 5.6400; Diabetes mellitus (DM) P=0.0573 Intervention: 3/31 (9.7%) SSI Control: 5/29 (17.2%) ASA: OR = 3.7093; Smoking >30 years P=0.0206 Intervention: 7/31 DM: OR = 7.6667; (22.6%) P=0.0162 Control: 9/29 (31.0%) Multivariate Analysis of Procedures: Gastric Risk Factors and colorectal Wound Infection: OR surgery. (95% CI) Indications: : NR ASA: 2.9039 (0.752- Setting: 1 medical 11.211) center DM: 3.8966 (0.637- Location: Japan 23.834) © 2017 American Medical Association. All rights reserved. 440

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Dates: July 2004 – P = 0.0452 December 2004. Inclusion Criteria: SSI: OR (95% CI) Patients undergoing ASA: 2.6602 (0.6660- gastric or colorectal 10.725) surgery between DM: 3.8336 (0.574- July 2004 and 25.617) December 2004 Smoking: 2.1090 Exclusion Criteria: NR (0.382-11.644) Wound Class: 1.7113 (0.153-19.185) P = 0.0452

Other infections: NR Topic-specific outcomes: Gastric surgery: No relation was identified between wound infection or SSI rates and skin or subcutaneous tissue positive cultures in gastric surgery. Colorectal surgery: Wound infection and SSI occurred in 2 of 5 skin culture positive cases. Wound infection and SSI occurred in 4 of 7 subcutaneous culture positive cases (2 same as in skin culture) and showed statistical significance: COLORECTAL SURGERY: © 2017 American Medical Association. All rights reserved. 441

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Culture Positive: 7 cases Culture Negative: 53 cases Wound Infection Culture Positive: 4/7 (57.1%) Culture Negative: 4/53 (7.5%) P=0.0042 SSI Culture Positive: 4/7 (57.1%) Culture Negative: 6/53 (11.3%) P=0.0115

Reoperations: NR Length of stay: NR Mortality: NR Adverse events: NR

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2.1F3. RISK OF BIAS ASSESSMENTS OF STUDIES: Q8-10 ANTISEPTIC PROPHYLAXIS eTABLE 52. Risk of Bias Assessments of Systematic Reviews for Q8-10 Antiseptic Prophylaxis Databas- Number of Studies es included/ screened Heterogenei- Characteris- Funding describe Inclusion excluded by two Data Individ- ty between tics of source(s) d and two / studies independ- extracted ual study results included disclosed or more exclusio along with ent by two study assessed studies and no Search database- n criteria reasons of reviewers independ- quality qualitatively Publicati- reported in obvious Overall Author terms es describe exclusion for ent assess- and/or on bias evidence conflict Risk of Year Q describedsearched d described inclusion reviewers ed quantitatively assessed table of interest Bias Key Question 8-10: Antiseptic Prophylaxis Webster 103 8           Low 2012

eTABLE 53. Risk of Bias Assessments of Randomized Controlled Trials for Q8-10 Antiseptic Prophylaxis Funding Attrition source(s) Described Randomizati- smaller than disclosed and as on Described Outcome Study 10-15% of Attrition no obvious Overall Author randomiz- appropriately as double-assessor participant Investigat- Attrition assigned appropriately conflict of Risk of Year Q ed performed blind blinded blinded or blinded described patients analyzed interest Bias Key Question 8-10: Antiseptic Prophylaxis Berry 125 8       Low 1982 Bibbo 122 8   High 2005 Chang 140 9         Low 2006 Cheng Modera- 123 8    2009 te Cheng 141 9        Low 2005 Chiu 133 8  High 1993 Darouiche 120 8           Low 2010 Dewan Modera- 136 8      1987 te Dromzee Modera- 131 8    2012 te Ellenhorn Modera- 113 8    2005 te Gilliam 8    Modera- © 2017 American Medical Association. All rights reserved. 443

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Funding Attrition source(s) Described Randomizati- smaller than disclosed and as on Described Outcome Study 10-15% of Attrition no obvious Overall Author randomiz- appropriately as double-assessor participant Investigat- Attrition assigned appropriately conflict of Risk of Year Q ed performed blind blinded blinded or blinded described patients analyzed interest Bias 1990 115 te Harihara 144 10  High 2006 Hort Modera- 118 8    2002 te Iyer Modera- 129 8      2011 te Jackson 134 8   High 1971 Murray Modera- 112 8     2011 te Ostrander Modera- 126 8    2005 te Paochar- oen 8  High 2009 121 Psaila Modera- 135 8    1977 te Roberts Modera- 117 8      1995 te Rogers Modera- 143 9      1983 te Saltzman Modera- 116 8    2009 te Savage 127 8  High 2012 Segal Modera- 114 8     2002 te Sindelar 139 9      Low 1985 Sindelar Modera- 142 9     1979 te Sindelar Modera- 137 9      1979 te Sistla 119 8       Low 2010 Towfigh 8          Low © 2017 American Medical Association. All rights reserved. 444

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2.2. Prosthetic Joint Arthroplasty Section GRADE, Evidence, and Risk of Bias Assessment Tables

2.2A. Q11 BLOOD TRANSFUSION 2.2A1. Q11 GRADE TABLE: Q11 BLOOD TRANSFUSION eTABLE 54. GRADE Table for Q11 Blood Transfusion Increase Decrease GRADE GRADE

GRADE Overall

Quantity of GRADE Starting Comparison Outcome and Type of Findings Evidence of GRADE Evidence for Evidence response

- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Q11. How do perioperative blood transfusions impact the risk of SSI in prosthetic joint arthroplasty patients? • Meta-analysis of 6 studies (N=8493) shows increased risk with transfusion: OR:1.56 (1.18 – 2.06); p<0.01; I2=0 • Meta-analysis of 4 OBS(N=7484) shows increased risk with transfusion: OR: 1.59 Transfusion 2 RCT 145, (1.15 – 2.18); p<0.01 146 vs. • Both meta-analyses include a high SSI* 147- High 0 0 0 0 0 0 0 0 High High No 4 OBS proportion of infections in patients 150 Transfusion transfused with allogeneic blood only. • Meta-analysis of 2 RCT (N=1009) shows no increased risk of infection in patients transfused with autologous or both autologous plus allogeneic blood transfusion: OR 1.07 (0.39 – 2.89); p=0.90. Q11A. Are specific blood products associated with a risk of SSI? Allogeneic Blood Transfusion • In meta-analysis of 4 OBS (N=5737), Allogeneic combing all allogeneic transfusions without (any) vs. No 4 OBS 147- regard to buffy coat depletion or Low SSI* 150 Low 0 0 0 0 0 0 0 0 Low Transfusion leukoreduction, transfusion associated with increased risk of infection: OR: 1.96 (1.46 – 2.63); p<0.01; I2=0

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Increase Decrease GRADE GRADE

GRADE Overall

Quantity of GRADE Starting Comparison Outcome and Type of Findings Evidence of GRADE Evidence for Evidence response

- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • In a large retrospective OBS (N=28,087) of primary THA, using a propensity score Reoperation 151 matched population (N=4508), reoperations due to 1 OBS due to infection were rarely reported (only 5 Low 0 0 0 -1 0 0 0 0 Very Low wound or 0.2% in each group) and there was no infection* difference between groups OR: 0.57 (0.11 – 2.93) • In a large prospective study (N=3945) of primary (81%) and revision (19%) hip and Allogeneic knee surgeries, subanalysis of 1644 Not WBC 148 patients found allogeneic “not- WBC depleted vs. SSI* 1 OBS Low 0 0 0 -1 0 +1 0 0 Low Low depleted” transfusion was associated with No increased risk of wound infection OR: 2.12 Transfusion (1.13 – 4.00); p=0.02 • Actual WBC content was not reported. • In a large prospective study (N=3945) of primary (81%) and revision (19%) hip and Allogeneic knee surgeries, subanalysis of 1817 WBC 148 patients suggested no difference in risk of depleted vs. SSI* 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low Very Low infection with allogeneic “WBC depleted” No blood: 18/637 (3%) vs. 22/1180 (2%); Transfusion p=0.19 • Actual WBC content was not reported. • In a prospective study of 444 elective primary total hip replacements, PJIs were 149 Allogeneic PJI* 1 OBS very rare (1% of total population) and no Low 0 0 0 -1 0 0 0 0 Very Low “Buffy Coat difference was observed between groups Depleted (both groups 1%) Very Low vs. No • Positive wound cultures were identified in SSI* Transfusion 149 2.3% of population, and no difference was Incisional 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low observed between groups (3.3% vs. 2.0 %);

p=0.47

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Increase Decrease GRADE GRADE

GRADE Overall

Quantity of GRADE Starting Comparison Outcome and Type of Findings Evidence of GRADE Evidence for Evidence response

- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • Allogeneic buffy coat depleted blood transfusion associated with increased risk of Wound- wound healing disturbance (31% vs. 18%; healing 1 OBS 149 p<0.05) Low 0 0 0 -1 0 +1 0 0 Low disturbance • On univariate OR 2.1 (1.2-3.5); p=0.03 and multivariate analyses, transfusion was the only significant risk factor • In a meta-analysis of 2 OBS (N=1637), allogeneic WBC filtered was associated with increased risk OR: 1.92; (1.12 – 3.29); p=0.02; I2=0 • One study147 (N=201) in primary unilateral Allogeneic hip or knee arthroplasty (N=201) no WBC 2 OBS difference with allogeneic WBC filtered Filtered vs. SSI* 147,150 Low 0 0 0 0 0 0 0 0 Low Low transfusion: 3/100 (3%) vs. 1/101 (1%); No p=0.33 Transfusion • In a second larger study150, subanalysis (N=1436) in primary and revision TKA reported increased risk with allogeneic WBC filtered: 32/637 (5.0%) vs. 22/799 (2.8%); p=0.03 • One study148 (N=1101) comparing allogeneic “WBC depleted” and “WBC-not Allogeneic depleted” found no difference between ”lower WBC groups: 18/637 (3%) vs. 18/464 (4%); OR: content” vs. 148, 2 OBS 0.72; 95% CI: 0.37 – 1.40; p=0.33 Allogeneic SSI* 150 Low 0 0 0 0 0 0 0 0 Low Low • One study 150 (N=1243) comparing “higher allogeneic “WBC filtered” to “WBC-not WBC filtered” found no difference between content groups: No difference: 32/637 (5.0%) vs. 43/606 (7.1%); P=0.30 Autologous Blood Transfusion

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Increase Decrease GRADE GRADE

GRADE Overall

Quantity of GRADE Starting Comparison Outcome and Type of Findings Evidence of GRADE Evidence for Evidence response

- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • No difference in a meta-analysis of 2 RCTs (N=970) OR: 1.15 (0.43 – 3.13); p=0.78 • In a small RCT 146 of hip arthroplasties subanalysis (N=58), no infections were observed in either group: 0/49 vs. 0/9, but study was designed to evaluate transfusion induced immunomodulation, not SSI. (7day follow up) • 1 larger RCT 145 in hip arthroplasties, subanalysis (N=912); no difference at 90 2 RCT Autologous 145,146 day follow up: 9/481 (1.7%) vs. 7/431

(Any) vs. No SSI* (1.6%);p>0.05 High 0 0 0 -1 0 0 0 0 Moderate Moderate 2 OBS Transfusion 147,148 • In a large prospective (N=3945) OBS study 148 of primary and revision hip and knee surgeries, subanalysis (N=2491) found autologous transfusion was associated with a reduction in wound infections: 11/1311 (1%) vs. 22/1180 (2%); OR: 0.45 (0.22 – 0.92); p=0.03 • In an OBS study147 (N=186) of primary hip or knee arthroplasty patients: 0/85 vs.1/101- too few events to perform additional analysis. • No difference in a large RCT (N=1089) in THA (regardless of WBC filtration status): • Subanalysis of 657 patients reported no Autologous difference with autologous “no WBC ± WBC 145 filtration” transfusions: 5/226 (2.2%) vs. Filtration vs. SSI* 1 RCT High 0 0 0 -1 0 0 0 0 Moderate Moderate 7/431 (1.6%); p=0.59 No • transfusion Subanalysis of 686 patients reported no difference with autologous WBC filtered blood transfusions: 3/255 (1.2%) vs. 7/431 (1.6%); p=0.64 Autologous SSI* 1 RCT 146 • In a small RCT of THA, subanalysis of 34 High 0 0 0 -2 0 0 0 0 Low Low © 2017 American Medical Association. All rights reserved. 449

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Increase Decrease GRADE GRADE

GRADE Overall

Quantity of GRADE Starting Comparison Outcome and Type of Findings Evidence of GRADE Evidence for Evidence response

- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Whole patients, no infections in either group at 7 Blood vs. day follow up. Whole blood included No autologous donated and perioperative Transfusion salvage blood. • The study was designed to evaluate transfusion induced immunomodulation, not SSI. • In a large prospective (N=3945) study of primary and revision hip and knee surgeries, subanalysis (N=2491) found autologous transfusion (including autologous blood donated whole blood or packed red blood cells, cell saver, acute normovolemic hemodilution, and Autologous postoperative salvage) was associated with “Not WBC 148 a reduction in wound infections: OR: 0.45 depleted” SSI* 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low Very Low (0.22 – 0.92); p=0.03, follow up period was vs. No limited to the patient’s stay in the surgical Transfusion unit. Transfusion trigger for autologous blood transfusion is not reported • Autologous donated blood only: 4/610 (0.66%) vs. 22/1180 (1.86%); p=0.05 • Autologous postoperative salvage blood only: 8/191 (4.19%) vs. 22/1180 (1.86%); p<0.05 • In a small RCT146 of hip arthroplasties (N=33), no infections were observed in Autologous either group at 7 day follow up. The study Buffy Coat 146 1 RCT was designed to evaluate transfusion Depleted SSI* 147 High 0 0 0 -2 0 0 0 0 Low Low 1 OBS induced immunomodulation, not SSI. vs. No • In 1 OBS147 (N=186) of primary hip or knee Transfusion arthroplasty patients: 0/85 vs.1/101- too few events to perform additional analysis.

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Increase Decrease GRADE GRADE

GRADE Overall

Quantity of GRADE Starting Comparison Outcome and Type of Findings Evidence of GRADE Evidence for Evidence response

- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • In a small RCT 146 of hip arthroplasties (N=49), no infections were observed in Autologous either group at 7 day follow up. The study “lower WBC was designed to evaluate transfusion content” vs. induced immunomodulation, not SSI. 2 RCT 145 Autologous SSI* 145,146 • In a large RCT of total hip arthroplasties High 0 0 0 -1 0 0 0 0 Moderate Moderate

”higher (per protocol analysis, (n=481), no WBC difference was observed between groups: content” OR: 0.53 (0.12 – 2.23); p=0.30. Only 1 PJI reported in each group (Intention to treat analysis n=951) • In one large OBS study of elective primary and revision hip and knee arthroplasties, subanalysis in 801 patients showed Post- significantly higher infection rates with operative postoperative salvage recovery only salvage 148 autologous blood versus autologous only vs. SSI* 1 OBS Low 0 0 0 -1 0 +1 0 0 Low Low donated blood only in both hip: 3/69 (4%) Autologous vs. 4/462 (1%); p<0.05 and knee Donated arthroplasties: 5/122 (4%) vs. 0/148 (0%); blood-only p<0.05. Hip and knee arthroplasties combined: 8/191 (4.19%) vs. 4/610 (0.66%) OR: 0.15; (0.04 – 0.51); p<0.01 Allogeneic vs. Autologous blood transfusion • When combining transfusions without Allogeneic regard to buffy coat depletion or (Any) vs. 3 OBS leukoreduction, transfusion with allogeneic SSI* 147,148,152 Low 0 0 0 0 0 +1 0 0 Moderate Moderate Autologous blood was associated with increased risk of (Any) SSI as compared to autologous transfusion OR: 4.53 (2.37 – 8.65); p<0.01; I2=0 Allogeneic ± • Allogeneic NOT WBC Depleted: In a large WBC 2 OBS prospective study 148 of hip and knee SSI* 148,152 Low 0 0 0 0 0 +1 0 0 Moderate Moderate depleted vs. surgeries, subanalysis in 1775 patients Autologous showed increased risk: 18/464 (4%) vs. © 2017 American Medical Association. All rights reserved. 451

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Increase Decrease GRADE GRADE

GRADE Overall

Quantity of GRADE Starting Comparison Outcome and Type of Findings Evidence of GRADE Evidence for Evidence response

- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Not WBC 11/1311 (1%); OR: 4.77 (2.24 – 10.18); depleted p<0.01 • WBC Not Depleted: In one prospective study 148 Allogeneic versus autologous blood donation only: 18/464 (4%) vs. 4/610 (0.66%); p=0.001 • WBC Not Depleted: One prospective study 148 Allogeneic versus postoperative salvage only: 18/464 (4%) vs. 8/191 (4.19%); p=0.85 • WBC depleted: One prospective study 148 Subanalysis in 1948 patients showed allogeneic “WBC depleted” transfusion was associated with increased risk of wound infection: 18/637 (3%) vs. 11/1311 (1%); p=0.01 • WBC Depleted: In one small observational study152 in hip arthroplasties, allogeneic “WBC depleted” blood transfusion was not associated with increased risk of infection as compared to perioperative cell saver shed washed blood: 2/48 (4.17%) vs. 0/49; p=0.28 Allogeneic WBC Filtered vs. 147 SSI* 1 OBS • No difference: 3/100 (3%) vs. 0/85; p=0.23. Low 0 0 0 -1 0 0 0 0 Very Low Very Low Autologous Buffy coat depleted Both Autologous and Allogeneic Blood Transfusion Both • No difference in post-hoc subanalysis145 Autologous 1 RCT 145 (N=470) : 0 of 39 transfused vs. 1.6% of and SSI* 2 OBS 431 not transfused (p=0.82) High 0 0 0 -1 0 0 0 0 Moderate Moderate 147,148 Allogeneic • One study148 No difference: 8/329 (2%) vs. (Any) vs. No 22/1180 (2%) OR: 1.31; 95% CI: 0.58 – © 2017 American Medical Association. All rights reserved. 452

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- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Transfusion 2.97; p=0.52 • No difference in subanalysis 147 (n=123): 0/22 vs. 1/101 (1%)

• In a large OBS study 153 (N=2884) of primary total hip (n=2016) and knee (n=480) arthroplasties and hip revisions (n=388), Both transfusion with both allogeneic (buffy coat Autologous depleted) and autologous (buffy coat and depleted and salvaged blood) was 2 OBS Allogeneic SSI* 148,153 associated with increased risk of wound Low 0 0 0 0 0 0 0 0 Low Low

vs. infection compared with autologous (buffy Autologous- coat depleted-only) blood alone. Statistical only testing was not possible (data presented in graph format). • In 1 study148 SSI= 8/329 (2%) vs. 11/1311 (1%); p=0.02 Q11B. If the risk of SSI is increased, can this effect be isolated from the risk associated with more complex cases? • Increased risk of transfusion among revisions (THA and TKA combined) in a Revision vs. meta-analysis of 2 OBS studies (N=6385): Primary 2 OR 3.81 (1.61 – 9.03); p<0.01; I =95% Arthroplasty 148 2 OBS • In one study Increased risk among (Hip [THA] Transfusion* 148,150 Low 0 -1 0 0 0 +1 0 0 Low Low revisions: 303/362 (84%) vs. 2112/3118 and knee (68%); p<0.001 [TKA] • 150 combined) In one observational study Increased risk among revisions: 274/350 (78%) vs. 969/2555 (38%); p<0.01 Revision • Higher risk of transfusion among revision THA Transfusion* 1 OBS 148 THA: 252/293 (86%) vs. 51/69 (74%); Low 0 0 0 -1 0 0 0 0 Very Low Very Low vs. Revision p=0.02

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- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders TKA Calculated 148 • No difference in median calculated blood 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low blood loss loss: 2875ml vs. 2528ml; p=0.23

• Any blood transfusion 148: Higher risk among revision hip arthroplasties: 252/293 (86%) vs. 1405/2066 (68%); p<0.01 • Allogeneic only148: More allogeneic only transfusions among transfused revision hips as compared to primary hip arthroplasties: 115/252 (46%) vs. 503/1405 (36%); p<0.01 • Autologous only148: More autologous only transfusions among transfused primary hip as compared to revision hip arthroplasties: 2 OBS Transfusion* 148,153 83/252 (33%) vs. 737/1405 (52%); p<0.01 Low 0 0 0 0 0 0 0 0 Low

• BOTH Autologous and additional allogeneic blood transfusion; Higher risk among Revision revision THAs- Meta-analysis (N=4061): OR THA 2.44 (1.77 – 3.36); p<0.01; I2=50% vs. • One OBS148 Higher risk among revision Low Primary THAs: 54/252 (21%) vs. 165/1405 (12%); THA p<0.001 • One OBS 153 Higher risk among revision THAs: 76/388 (20%) vs. 159/2016 (8%); p<0.01 • Meta-analysis 2 OBS studies: significantly higher calculated blood loss in revision hips: mean difference 700 ml (95% CI: 323 ml – 1076 ml); p=0.0003; I2=87% Calculated 2 OBS 148,153 • Low 0 0 0 0 0 0 0 0 Low blood loss Mean calculated blood loss higher for revision hip: 3060 ml vs. 2143 ml; p<0.01148; Mean blood loss significantly higher for revision hip: 1720±460ml vs. 1190±480ml; p<0.01153 © 2017 American Medical Association. All rights reserved. 454

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- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • Significantly longer procedure duration for Procedure 153 revision hip arthroplasty (mean ±SD): 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low duration 183±64 minutes vs. 115±38 minutes; p<0.01 • Any transfusion no difference for revision knee as compared to primary knee: 51/69 (74%) vs. 707/1052 (67%); p=0.25 no difference for revision knee as compared to primary bilateral knees: 51/69 (74%) vs. 11/13 (85%); p=0.42 148 • Allogeneic only: No difference- 23/51 (45%) Revision Transfusion* 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low TKA vs. vs. 245/707 (35%); p=0.13 Very low Primary • Autologous only: No difference -17/51 TKA (33%) vs. 245/707 (49%); p=0.85 • BOTH autologous and additional allogeneic blood transfusion higher risk of transfusion for revision knees: 11/51 (21%) vs. 77/707 (11%); p=0.02 Calculated 148 • Mean calculated blood loss higher for 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low blood loss revision knee: 2634 ml vs. 2072 ml; p<0.01 • Any transfusion 148: No difference- 1405/2066 (68%) vs. 707/1052 (67%); p=0.65 • Allogeneic only 148: No difference- 503/1405 (36%) vs. 245/707 (35%); p=0.60 Primary 148 148, • Autologous only : No difference- 737/1405 THA vs. 2 OBS Transfusion* 153 (52%) vs. 385/707 (54%); p=0.38 Low 0 0 0 0 0 0 0 0 Low Low Primary • TKA Both Autologous and additional allogeneic 148: No difference- 165/1405 (12%) vs. 77/707 (11%); p=0.56 • BOTH autologous and additional allogeneic 153 : No difference-159/2016 (8%) vs. 43/480 (9%); p=0.44

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- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • Meta-analysis 2 OBS: No difference- Mean difference: -19 ml (-176 ml – 137 ml); p=0.81; I2=84% • Mean calculated blood loss no difference: 2143 ml vs. 2072 ml; p=0.24 148 • Mean blood loss higher in primary knee Calculated 2 OBS arthroplasty 1190±480ml vs. 1280±403; 148,153 Low 0 -1 0 0 0 0 0 0 Very Low blood loss p<0.01153 • Median preoperative estimate blood loss was significantly lower than median calculated blood loss for both primary total hip (median 750 vs. 1944ml; p<0.01) and total knee (median, 800 vs. 1934ml; p<0.01) procedures148. • Any transfusion -No difference: 1387/2039 (68%) vs. 18/27 (67%); p=0.88 • Allogeneic only: No difference: 496/1387 Primary (36%) vs. 7/18 (39%); p=0.78 THA: 148 Transfusion* 1OBS • Autologous only: No difference 728/1387 Low 0 0 0 -1 0 0 0 0 Very Low Very Low Unilateral (53%) vs. 9/18 (50%); p=0.83 vs. Bilateral • BOTH Autologous and additional allogeneic blood transfusion: No difference: 163/1387 (12%) vs. 2/18 (11%); p=0.93 • Any transfusion: No difference: 696/1039 (67%) vs. 11/13 (85%); p=0.20 • Allogeneic only: No difference - 242/696 Primary (35%) vs. 3/11 (27%); p=0.61 TKA: 148 Transfusion* 1OBS • Autologous only: No difference 377/696 Low 0 0 0 -1 0 0 0 0 Very Low Very Low Unilateral (54%)vs. 8/11 (74%); p=0.23 vs. Bilateral • BOTH Autologous and additional allogeneic: Only unilateral TKA received both:- 77/696 (11%) vs. 0/11 (0%); p=0.47 Q11C. How does the volume of transfused blood product impact the risk of SSI? Our search did not identify data that evaluated differences in the volume of transfused blood product and their impact on the risk of SSI in prosthetic joint arthroplasty patients. © 2017 American Medical Association. All rights reserved. 456

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- Outcome Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Q11D. How safe and effective is withholding blood transfusion to reduce the risk of SSI? Our search did not identify data that both evaluated the safety and effectiveness of withholding blood transfusions and its impact on the risk of SSI in prosthetic joint arthroplasty patients. *Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

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2.2A2. EVIDENCE TABLE: Q11, Q11A, AND Q11B BLOOD TRANSFUSION Q11. How do perioperative blood transfusions impact the risk of SSI in prosthetic joint arthroplasty patients? Q11A. Are specific blood products associated with a risk of SSI? Q11B. If the risk of SSI is increased, can this effect be isolated from the risk associated with more complex cases? eTABLE 55. Evidence Table for Q11. How do perioperative blood transfusions impact the risk of SSI in prosthetic joint arthroplasty patients? Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Frietsch RCT To determine if No. patients: Intervention Group: SSI (3 months) Definitions: 2008 145 1, 2, 3, 4, leukoreduction of ITT: N=951 Leukodepleted AWB ITT Analysis N=951 Wound Infection: Defined either as (SIBT) 5, 7, 8, 9, autologous whole Per-Protocol=481 (LD-AWB) Wound Infections 1. isolation of bacteria from fluid 10 blood (AWB) ITT n=488 Intervention: 6/488 wound secretions containing pus, reduces the Patient Per Protocol n=255 (1.2%); 2. abscesses (verified by surgical . transfusion- Characteristics: (52.3%) Control: 9/463 (1.9%) drainage or aspiration of pus), or related Baseline Timing of Intervention: OR 0.63 (95% CI, 0.22- 3, arthritis by clinical symptoms immunomodulatio characteristics of Intra and postoperative 1.78); p=0.27 requiring surgical drainage. n (TRIM) effect, the patients were Duration of Other infections Respiratory tract infection (RTI): 1) resulting in similar in the two Intervention: NR Overall, urinary, positive x-ray (chest infiltration) reduced groups (number, Device/ Agent: respiratory, together with fever, 20 dyspnea or perioperative sex, age, height, Intervention (LD-AWB): fungal and Other cough or purulent sputum together infection rate weight, calculated double bag system with (gastrointestinal, with fever, or 3) isolation of bacteria and/or length of blood volume, inline whole-blood WBC pleuritis, vascular in tracheal secretion (only intubated hospital stay. overall estimated filter for pre-storage thrombophlebitis, skin patients) together with fever. perioperative leukoreduction. Blood infection other than ASEPSIS Index: Daily wound blood loss, was leukoreduced after wound, gynecologic) inspections evaluated for the donated storage on cooling none with statistically following wound conditions: clear autologous units plates at 4 to 6°C for 1-4 significant difference exudate, erythema, putrid exudate, per patient, ASA hours. Residual WBC Note: Infections dehiscence of profound tissue layers score, Anesthesia content was consistently occurred while in with size of relative wound area of type, surgery type below 1 X 106 per unit hospital in 87.5% of the total wound concerned. If more [cementless, and mean red blood cell cases. than one wound condition was cemented, hybrid], loss (RBC) was less Per-protocol Analysis existent, only the condition with the duration of than 10%. N=481 highest rating was scored. Wound surgery, Control (non-ND Wound Infections inspection scores were added up anesthesia and AWB): single-bag Intervention: 3/255 (dynamic part). Each of the hypothermia. system. All units stored (1.2%) additional criteria (antimicrobial Age years at 4°C until transfusion Control: 5/226 (2.2%) treatment, abscess drainage [local median (range) or expiry 0.53(0.12-2.23);p=0.30 vs. general anesthesia], bacterial Intervention:63 Both systems contained Other infections growth [positive culture of at least (28-82) 70ml citrate phosphate Overall, urinary, 100,000 colonies of a single © 2017 American Medical Association. All rights reserved. 458

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Control:63 (26-83) dextrose adenine respiratory, organism], and prolonged hospital Gender m/f: (CPDA-1) as storage fungal and Other stay (static part) could be added 470/481 medium. (gastrointestinal, once. mean±SD(median/ Monitoring pleuritis, vascular range) Intervention: thrombophlebitis, skin Perioperative Care Height (cm) Hemoglobin (Hb) levels. infection other than Preop: Intervention: Transfusion Trigger: wound, gynecologic) Patients were scheduled to donate 2 170±8.9 (170/150- Hemoglobin (Hb) none with statistically or 3 units of AWB (500ml each) in 196) concentration significant difference weekly intervals with surgery Control: <8.0±0.5g/L during and planned to take place in weeks 3 to 5 170.3±9.0(170/14 after surgery In both ITT and Per- after the first donation. 0-197) (irrespective of whether Protocol: Weight(kg) autologous or allogeneic Overall infection rate, Hb concentration below 110g/L Intervention: blood was to be ASEPSIS score, during donation period led to 80.1 ±14.1(80/48- transfused) Length of Stay, postponement of following donation 126) antimicrobial by 1 week. Control: Control Group- Non- treatment, multidrug 80.4±14.2(80/50- leukodepleted AWB use, fever>38°C after Patients encouraged to take oral iron 136) (non-LD AWB) postop day 3: No (300mgFe2+ orally per day) ASA1=192/951 ITT n=463 significant difference (20.2%) Per Protocol n=226 RBC loss was calculated as the ASA2=628/951(66 (48.8%) SUBGROUP compensated RBC loss .0%) ANALYSIS 1: (perioperatively transfused RBC ASA3=125/951(13 Standard preventive Not transfused (NOT-T; volume) plus non-compensated RBC .1%) measures AMP (second n=431) vs. loss estimated from pre and •Comorbidities: generation Autologous only postoperative (Day 3) hematocrit NR cephalosporin) , transfused (AUT-T; (Hct) levels correcting large-vessel to Procedure: normothermia, n=481) total body Hct: Primary hip normovolemia, adequate vs. RBC loss= (Hctpre-HctPOD3) X Blood arthroplasty oxygenation Additionally Volume* X 0.86+RBC-Vunits. (cemented n=30, allogeneically transfused RBC-Vunits=RBC volume of cementless (ALL-T; n=39) transfused AWB n=642, hybrid Overall infection rate: *Calculated according to Nadler) n=274) NOT-T: 14.2% Blood loss=RBC loss/(Hctpre- Indications: NR AUT-T: 20.6% HctPOD3)/2 Setting: 2 ALL-T: 13.2% university and 1 p=0.03 Transfusion rates by Center: urban hospital: Wound infections: No transfusion; autologous only; Center A n=696 NOT-T: 1.6% autologous and allogeneic © 2017 American Medical Association. All rights reserved. 459

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score (73.2%); Center B AUT-T: 1.7% A n=696: 43%;52.7%;4.3% n=213 (22.4%) ALL-T: 0% B n=213:56.8%;39.4%;3.8% Center C n=42 p=>0.05 C n=42: 26.2%, 71.4%, 2.4% (4.4%) Urinary tract Infection: Anesthesia Location: NOT-T 11.1% Spinal: Intervention: AWB 297/488 Germany AUT-T 16.8% (60.9%) Dates: NR ALL-T 13.2% Control: Non LD AWB: 312/463 Inclusion criteria: p=0.02 (67.4%) Patients Other infections: General: Intervention: AWB 187/488 scheduled for Respiratory, fungal, and (38.3%) primary hip other infections Control: Non LD AWB: 143/463 arthroplasty and (gastrointestinal, (30.9%) preoperative pleuritis, vascular Epidural: Intervention: AWB 2/488 donation of at thrombophlebitis, skin (0.4%) least 2 units of infection other than Control: Non LD AWB: 1/463 (0.2%) AWB wound, gynecologic) all Other Intervention: AWB 2/488 Exclusion p=>0.05 (0.4%) criteria: Subjects Length of Stay days: Control: Non LD AWB: 3/463 (0.6%) with mean±SD (median) contraindications NOT-T 13.0±2.3 (13) for preoperative AUT-T 13.8±3.6 (14) Follow up: Phone, letter or an autologous blood ALL-T 14.3±4.2 (14) outpatient visit 3 months post op. donation p=≤0.01 Wound inspection: daily during the according to the first 14 postoperative days and German Note: significant discharge, not on weekends guidelines, difference in infection Funding Source Conflicts: immune rate and length of stay Authors: None deficiency, steroid was paralleled by Institution: None therapy and significantly longer Study: None intended use of anesthesia and surgery Supplies: Industry cell salvage. duration (NR), suggesting dependency from the complexity level of surgery rather than transfusion.

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score blood product at bedside at Centers A and C. Subgroup analysis to exclude any influence of these microfilters on overall infections rate showed no statistical significant difference (p=0.63, two-sided).

Topic specific outcomes: N/A

Reoperation: In both ITT and Per- Protocol: antimicrobial treatment, multidrug use: No significant difference In ITT protocol: Wound infection requiring revision or hospitalization: Intervention: 1/488 (0.2%) Control: 3/463 (0.6%) Delayed wound healing requiring revision or hospitalization: Intervention: 7/488 (1.4%) Control: 7/463 (1.5%) Surgical wound revision: Intervention: 3/488 (0.6%) Control: 8/463 (1.7%) Prosthesis infection: Intervention: 1/488 (0.2%) © 2017 American Medical Association. All rights reserved. 461

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Control: 1/463 (0.2%) Re-surgery - prosthesis exchange: Intervention: 1/488 (0.2%) Control: 1/463 (0.2%)

Length of stay: Median (range) ITT Intervention (LD AWB): 14 days (7-36) Control (Non-LD AWB):14 days (8-55) P=0.17 Per-Protocol Intervention (LD AWB): 14 days (7-34) Control (Non-LD AWB):14 days (9-55) P=0.71 Mortality: none

Adverse events: In ITT protocol: not significantly different between groups Total: Intervention: 1/488 Control: 1/463 Relation to LD: Possible /unlikely unrelated Intervention: 3/7/3 Control: 2/2/8 Myocardial infarction, bradycardic arrhythmia, transient cerebral, ischemic attack, © 2017 American Medical Association. All rights reserved. 462

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score respiratory insufficiency (sleep apnea), deep venous thrombosis, dyesthesia foot Frietsch RCT To address Number of Intervention group: SSI (follow up 7 days) Definitions: NR 2001 146 1, 2, 5, 7, Transfusion- patients N=58 n=2 None of the patients Perioperative care: (ES) 8, 9, 10 induced Patient Transfused Autologous presented clinical signs Anesthesia: spinal/general immunomodulatio Characteristics Blood: of infection. Authors WB: 17/8 n (TRIM) caused WB=Whole Blood Blood was donated at indicate “This study is RCP: 20/4 by autologous RCP=buffy coat- weekly intervals (450ml not expected to have the NT: 8/1 blood – stored poor packed Red each). Surgery was statistical power to either as Whole Cells and fresh- scheduled for the 5th discriminate between the Analytical methodology: Shapiro- Blood (WB) or as frozen Plasma week after the first two types of storage Wilk test used to probe for normality buffy coat-poor NT-NO donation. regarding outcome of distribution (P>0.4). For repeated packed red cells Transfusion RCP: Buffy coat-poor criteria of measurements, baseline corrected and fresh-frozen ·Age: mean±SD packed red cells (RC) immunomodulation, area under curve (AUC) was plasma (RCP) – WB: 58±10 years and fresh-frozen plasma such as wound or calculated. T-test and Wilcoxon rank in patients RCP: 59±10 (FFP): n=24 donated systemic infection rates sum test for independent variables undergoing hip years blood was separated or LOS, as the infection were used to determine statistical arthroplasty. NT: 61±8 years into RC and FFP(80- rate in this type of significance. Monocyte and ·Gender: m/f 90% of leukocytes and surgery is generally low” Other notes: Small sample size neutrophil WB: 9/16 >98% platelets were Follow-up: 7 days observation phagocytic RCP: 10/14 eliminated) period activities, rate of NT: 7/2 Timing of intervention: Other infections: None Funding Source Conflicts: systemic and ·Obesity: intra or postoperatively occurred in either group. Authors: None wound infection, Weight Duration of Topic-specific Institution: None se of WB: 71±16 kg intervention: Intra outcomes: Study: None antimicrobials RCP: 74±15 kg and/or postoperatively. Supplies: None and length of NT: 84±10 kg Agent: Autologous No allogeneic hospital stay Height blood. Either Whole transfusions were (LOS) were WB: 166±9 cm blood (WB) or buffy-coat required in any group. evaluated. RCP: 168±7 cm poor packed red cells NT: 171±5 cm (RC) Total Blood loss: median ·Comorbidities: - Oldest blood was used (Range) NR first. WB: 1740 (820-3170) 3Units Monitoring ml Predeposited intervention: RCP: 1760 (880-3290) WB: 22/25(88%) hemoglobin count and ml RCP: 22/24 leucocyte counts were NT: 1530 (1120-2320) © 2017 American Medical Association. All rights reserved. 463

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score (91.2%) determined by routine ml NT: 9/9 (100%) automated laboratory Transfusion of 2 Units methods. Differential predeposited units Predeposited blood cell count was 3 units WB: 3/25 (12%) measured by WB: 3/25 RCP: 2/24 depolarized orthogonal RCP[(RC/FFP)/n]: (8.8%) light scattering (9/7)/24 NT: 0 Control group: n=32 NT: 0 Storage period WB Whole Blood n=25 2 units (days) donated blood units WB: 8/25 WB: 27.9±2.9 stored as whole blood RCP[(RC/FFP)/n]: RCP: 28.4±2.0 Non-transfused patients (6/6)/24 NT: 28.2±1.6 (NT) NT: 0 Length of Surgery NT 7 had donated blood 1 unit WB: 102±17 stored as WB vs. 2 as WB: 14/25 minutes RCP. RCP[(RC/FFP)/n]: RCP: 89±21 Standard preventive (9/4)/24 minutes measures NT: 0 NT: 92±25 Thromboembolic P≤0.05 for all transfusion minutes Prophylaxis: 40mg of unit values (3, 2, 1) for subcutaneous WB vs. RC Procedures: Hip enoxaparin administered Volume replacement arthroplasty 1/day starting 12h prior (ml) Indications: NR to surgery. Modified Ringer’s Setting: 1 AMP: cefuroxime Solution university hospital administered WB: 4376±802 Location: intravenously prior to RCP: 4604±642 Germany surgery. NT: 4422±1190 Dates: NR Cemented, cementless, Colloid Solution Inclusion and hybrid prostheses WB: 1540±628 Criteria: patients were implanted. RCP: 1333±602 who had donated Volume replacement: NT: 1417±530 autologous blood modified ringer’s solution and were and gelatin solution were Patients with Cell scheduled for hip used. Salvage arthroplasty Postop_ autologous WB: 12/25 (48%) Exclusion plasma was re- RCP: 8/24 (33.3%) Criteria: transfused for volume NT: 1/9 (11.1%) contraindication replacement primarily in Volume transfused: © 2017 American Medical Association. All rights reserved. 464

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score for autologous the RCP group. median(range) blood donations Analgesic: diclofenac & WB: 510 (240-1200) ml and diseases prirtarmid. RCP: 610 (4-1600) ml associated with Cell salvage: performed NT: 360 ml impaired immune in all groups if a patient defense. had <3 units and/or Laboratory Analysis: presented for surgery Regarding hemoglobin with Hb concentration concentration, <12g/dl. Blood collected neutrophils, monocytes, was processed and phagocytic activity, and retransfused with drain oxidation activity: blood measured and There were no sponged blood significant differences in estimated values between the Transfusion Triggers: three groups. Hb, 9g/dl or clinical signs of myocardial ischemia. Reoperations: NR Length of stay: (mean±SD) WB: 15.3±0.8 days RCP: 15.3±0.6 days NT: 15.0±1.0 days

Mortality: NR Adverse events: NR Pedersen Retrosp- To determine Number of Intervention group: SSI (Follow Up 90 Definitions 2009 151 ective whether patients: Receiving Transfusion Days) Outcomes (within 90 days of index (ES) concur- allogeneic red N=28,087 Intervention1: n=9063 (Adjusted) procedure): ent blood cell Matched group (32.3%) Reoperation due to 1. Death, control transfusion was N=4508 Patients received ≥1 unit infection 2. Hospitalization with cardiovascular 1, 2, 3, 4, associated with Patient red blood cell (RBC) Intervention2: 5/2254 events including myocardial 5, 6, 7, 8 increased odds of Characteristics: transfusion within 8 days (0.2%) infarction, congestive heart failure, complications For total group, of surgery Control2: 5/2254 peripheral vascular disease, or following primary Transfused Intervention2: n=2254 (0.2%) cerebrovascular events, total hip patients were Patients receiving ≥1 OR (95%CI): 0.57 (0.11- 3. hospitalization with venous replacement older & had more unit RBC allogeneic 2.93) thromboembolism, including deep (THR). comorbid transfusion within 8 days venous thrombosis and/or pulmonary Complications conditions. They of surgery (matched by Other infections: embolism, included also were more propensity scoring to the Pneumonia: adjusted 4. hospitalization with pneumonia © 2017 American Medical Association. All rights reserved. 465

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score hospitalization likely to be female, control2 group Intervention2: 36/2254 and with receive a (1.6%) 5. reoperation due to infection. cardiovascular cemented Timing of intervention: Control2: 17/2254 and/or prosthesis, and to intraoperative &/or (0.8%) Perioperative care: cerebrovascular have a THR Postoperative OR (95%CI): 2.1 (1.2- Regional Anesthesia: events, venous procedure of more 3.8) Intervention2: 1753/2254 (77.8%) thromboembolis than 2 hours. Duration of Control2: 1757/2254 (78.0%) m, pneumonia, For the intervention: within 8 Topic-specific SMD=0.18378 reoperation due propensity- days of surgery outcomes: to infection of matched Median (range) number Analytical methodology: To primary THR, and population, there Agent: Allogeneic red of units transfused: overcome bias due to confounding, mortality within were no blood cells. Intervention1: 2 (1-20) they matched patients not receiving 90 days of substantial Intervention1: Control: 0 transfusions with patients receiving primary THR differences for any Median: 2units/patient transfusion with a 1:1 ratio using of the Range: 1-20 units Duration of operation: propensity score matching. The characteristics Similar between propensity score for each patient related to the risk Monitoring matched groups except was calculated using logistic of transfusion intervention: NA for Longer surgeries: regression. Patients were matched Standardized >121 minutes: for baseline characteristics. mean difference Control group: Intervention2: 151 Information on blood lost during (SMD)>0.1 is No Transfusion (6.7%) surgery was not available for this indicative of Control1: n=19024 Control2: 157 (7.0%) dataset. significant Patients who received SMD: 0.20997 They adjusted for hemoglobin imbalance no transfusion Preoperative concentration 1-7 days postoperative between groups Control2: n=2254 Hemoglobin as a surrogate measure of blood Patients who received concentration w/in 3 loss. ·Age: Age no transfusion and were months prior to surgery: Information on smoking status, groupings were matched by propensity <138.5 g/L obesity/BMI, prior history of similar between scoring to Intervention2 Intervention2: 1410 transfusion, and preoperative history groups except for (62.6%) of increased perioperative bleeding 80+ years Standard preventive Control2: 1362 (60.4%) and pre-operative history of chronic Intervention2: measures: NR SMD: 0.25041 anemia was also not available and 404/2254 (17.9%) not included in propensity matching Control2: Non-standard score. 411/2254 (18.2%) preventive measures: SMD= 0.18397 Anti-rheumatic drug Length of stay: NR Other notes: Data utilized in this Prophylaxis for study is from ·Gender: female n heterotropic bone Mortality: (within 90 1) The Danish Hip Arthroplasty (%) formations: days of primary THR) - Registry (DHR). This registry of all © 2017 American Medical Association. All rights reserved. 466

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Intervention2: Intervention2: 195/2254 adjusted primary THR consists of data 1490/2254 (8.7%) Intervention2: 39/2254 recorded prospectively by the (66.1%) Control2: 208/2254 (1.7%) operating surgeons using Control2: (9.2%) Control2: 18/2254 standardized forms. (pre-, peri- and 1439/2254 SMD=0.06109 (0.8%) postoperative data). Reoperation (63.8%) OR (95%CI) 2.17 (1.24- data was also obtained here. SMD=0.11293 3.80) 2) The Danish Transfusion Database. Data included all ·Obesity: NR Adverse events: allogeneic red blood cell transfusions ·Comorbidities: Deep venous administered to included patients Diabetes thrombosis/ pulmonary within 8 days of primary THR Intervention2: embolism –adjusted surgery. Patients were classified as 134/2254 (5.9%) Intervention2: 28/2254 having received either no or one or Control2: (1.2%) more units. 115/2254 (5.1%) Control2: 23/2254 3) The Civil Registration System was SMD=0.05238 (71.0%) utilized for data on mortality. Preoperative OR (95%CI): 1.17 (0.67- 4) The Danish National Registry of Hemoglobin 2.06) Patients was used for hospitalization <138.5g/L within 3 data. Diagnoses were classified mo. before Cardiovascular or according to the Danish version of surgery cerebrovascular disease the International Classification of Intervention2: – adjusted Diseases (ICD. The ninth edition 1410/2254 Intervention2: 54/2254 (ICD-8) was used from 1977 to 1993 (62.6%) (2.4%) and the tenth edition (ICD-10) has Control2: Control2: 39/2254 been used hereafter. The physician 1362/2254 (1.7%) who diagnosed the patient assessed (60.4%) OR (95%CI): 1.42 (0.93- all discharge codes. SMD=0.25041 2.15) Odds estimates may partly reflect Procedures: Composite outcome – unmeasured bias due to blood loss Primary Total Hip adjusted Replacement OR (95% CI): 1.67 Limitation: No information on (THR) (1.23-2.26) intraoperative blood loss which may Indications: have impacted postop transfusions. Primary arthrosis Subanalysis of Information on pre/post-operative Intervention2: composite outcome risk hemoglobin concentration used as a 1647/2254 by Number of surrogate measure of blood loss. (73.1%) transfusions/ patient: Control2: Adjusted OR (95%CI) Follow-up: until the occurrence of © 2017 American Medical Association. All rights reserved. 467

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score 1633/2254 ≥6 transfusions:3.4 (1.3- death, hospitalization for (72.5%) 9.2) cardiovascular or cerebrovascular SMD=0.23293 3-4 transfusions: 1.5 events, venous thromboembolism, Trauma (0.8-2.9) pneumonia, reoperation due to Intervention2: 2-3 transfusions: 1.2 infection or 90 days after surgery. 323/2254 (14.3%) (0.8-1.9) Funding Source Conflicts: Control2: 1 transfusion: 2.7 (1.2- Authors: None 319/2254 (14.2%) 5.7) Institution: None SMD=0.28662 Study: None Other Subgroup analysis for Supplies: None Intervention2: history of cardiovascular 284/2254 (12.6%) events Control2: With History (matched) 302/2254 (13.4%) Intervention2: 407/2254 SMD=0.00682 (18.1%) Control2: 407/2254 Setting: Multi- (18.1%) center 20 - Red blood cell hospitals in North transfusion was Jutland, Aarhaus, associated with odd of Funen, and the composite adverse Copenhagen). outcome within 90 days These 20 of surgery: 1.2 (0.8-1.9) orthopaedic departments serve Without History ~45% of the (matched) Danish population Intervention2: (nearly 2.3 million 1834/2254 (81.4%) people). Control2: 1834/2254 Location: (81.4%) Denmark In THR patients without Dates: January 1, cardiovascular events 1999 – December prior to surgery, OR of 31, 2007 composite outcome: 1.7 Inclusion (1.1-2.7) Criteria: Patients with primary THR Subgroup analysis procedures postoperative registered in the hemoglobin (matched) © 2017 American Medical Association. All rights reserved. 468

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Danish Hip Hemoglobin Arthroplasty concentration <105g/L Registry (DHR) Intervention2: 729/2254 and performed at (32.3%) the hospitals Control2: 729/2254 reporting to the (32.3%) Danish - Adjusted OR: for Transfusion composite adverse Database during outcome w/in 90 days of the study dates. surgery: 1.1 (0.5-2.7) for This includes transfused vs. non patients who transfused sustained right and left THR Hemoglobin during the study concentration>105g/L period as long as Intervention2: surgery was not 1505/2254 (66.8%) performed on the Control2: 1505/2254 same day (those (66.8%) were treated as - Adjusted OR: for independent composite adverse operations) outcome w/in 90 days of Exclusion surgery: 1.6 (1.0-2.5) for Criteria: Patients transfused vs. non without possibility transfused for follow up and bilateral primary THR procedures performed during the same surgery.

Monte del Prospect- To prospectively Number of Intervention group: SSI (Follow up - NR) Definitions: Trujillo ive evaluate the patients N=108 n=60 Unadjusted: Postoperative Infectious 2008 152 concurre utility of a new Patient Utilization of the blood Total Infection: Complications (urinary tract, (ES) nt control device that Characteristics: processing device Intervention: 1 (2%) respiratory tract, and wound 1, 3, 4, 5, automatically There were no designed to wash Control: 5 (10%) infections): CDC definitions. 6, 7, 8 provides washed differences in autologous blood and re- P=0.086 Adverse reactions to WSB salvaged blood to characteristics infuse the blood. Wound Infection reinfusion: Shivers, fever, reduce exposure between groups Intervention: 0 (0%) bradycardia, hypotension © 2017 American Medical Association. All rights reserved. 469

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score to Allogeneic except age and Timing of intervention: Control: 2 (4%) Estimated blood volume: calculated Blood Hypertension. intraoperative and/or Infection Rate using gender and body weight Transfusions Data expressed as postoperative ABT: 12.2% (4/32) [Gross1983] (ABT) in elective mean ±SD or n Duration of No ABT: 2.6% (2/76) Total Perioperative Blood Loss (CBL Total Hip (%) intervention: duration of p=0.046 (ml)) = [Uncompensated RBC loss Replacement ·Age (y): transfusion (ml) = Compensated RBC loss (THR) patients. Intervention: Other infections: (ml)]/0.35 End-points 62±14 Agent: Perioperatively Urinary Infection Uncompensated RBC loss (ml)= include the Control: 67±9 salvaged WSB. The Intervention: 1 (2%) (preoperative Hct – postoperative impact of P= 0.027 blood was collected with Control: 2 (4%) day 4 Hct) x Estimated Blood Washed ·Gender: f/m non-fractionated heparin Volume (EBV) Salvaged Blood Intervention: and was re-infused Respiratory Infection: Compensated RBC Loss (ml) = (WSB) return on 27/33 within the first 6h from Intervention: 0 (0%) [Packed allogeneic red cell units x both the rate of Control: 31/17 the beginning of blood Control: 1 (2%) 165 (ml/unit) = [washed autologous postoperative ·Obesity: weight salvage. blood volume x washed autologous infection and the (kg) Device: A blood Topic-specific blood Hct] length of hospital Intervention: processing device outcomes: Acute Anemia: hypotension, stay. 79±9 designed specifically to Intervention: Enough tachycardia, tachypnea, dizziness, Control: 80±11 adapt to the intermittent WSB blood volume fatigue. ·Comorbidities blood loss of orthopedic obtained to be returned: Diabetes surgical patients. 49/60 (82%) Perioperative care: Intervention: 7 Mean: 336±205 Anesthesia: standard general or (12%) Monitoring Hct: 63±5% regional Control: 12 intervention: NR RBC: 205±151ml Cemented THR: Regional/General (25%) RBC/patient: 1.3±0.9 Anesthesia Anemia Control group n=48 Intervention: 6/6 (Hb<130g/l) Patients received normal **Calculated and total Control: 8/9 Intervention: 4 allogeneic blood perioperative blood loss P=0.876 (7%) transfusions (ABT) if was not significantly Uncemented THR: Regional/General Control: 2 (4%) necessary, one unit of different between groups Anesthesia Hypertension leukodepleted packed according to age, Intervention: 27/21 Intervention: 16 red blood cell was gender, anesthesia type Control: 13/18 (27%) considered to have a or hypertension. P=0.119 Control: 32 RBC mass of 165ml. (67%) Calculated Blood Loss Cemented components: 73% of P=0.001 Standard preventive (ml) patients (79 patients) measures: Cemented THR: Patient distribution Surgical Team: All Intervention: 1943±906 Oral Iron Supplement according to patients were operated Control: 2091±747 Intervention: 32 (53.3%) © 2017 American Medical Association. All rights reserved. 470

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score preoperative Hb on by the same surgical P=0.634 Control: 24 (50%) levels, team (senior surgeons) Uncemented THR: P=0.338 perioperative Hb and each attending Intervention: levels, and surgeon performed two 2336±1015 calculated total operations in each Control: 2347±971 Analytical methodology: Chi- blood loss were no surgical session (1 P=0.966 square or Fisher’s Exact test for different in both intervention and 1 qualitative variables. Parametric one- groups. control) ABT rate, way ANOVA or non-parametric Preoperative Hb Approach: All patients Total Mann-Whitney for quantitative (g/dl) were positioned supine Intervention: 15% (n=9) variables. Cemented THR: and anterolateral Control: 48% (n=23) Intervention: approach was used to RR:0.31; P=0.001 Other notes: none 14.4±1.2 the hip. Preoperative Hb≥13g/dl Control: 13.6±1.2 Antimicrobials: surgery RR: 0.32; P=0.003 Follow-up: NR P=0.067 performed under Preoperative Hb3g/dl Funding Source Conflicts: Uncemented THR: antimicrobial prophylaxis RR: 1.47; P=0.091 Authors: None Intervention: Anticoagulant: surgery Age<60yo Institution: None 14.5±1.6 performed under RR: 0.47; P=0.021 Study: None Control: 14.6±1.4 antithrombotic Age≥60yo Supplies: None P=0.823 prophylaxis (low RR: 0.17; P=0.027 (note: p<0.05 molecular weight within control heparin) ABT rate n (%) group) Analgesia: Postop. Cemented THR: Procedures: Components: Same Intervention: 1 (8%) Unilateral Total acetabular and femoral Control: 10 (59%) Hip Replacement components were used P=0.008 (THR) in all hips. Uncemented THR: Drains: 2 suction drains Intervention: 8 (17%) Indications: NR were used in all Control: 13 (42%) procedures. Removed P=0.013 Setting: 1 Center on POD 2. Location: Spain Transfusion was Total ABT units Dates: January indicated when patient’s Cemented THR: 2005 – June 2006 Hb level decreased to Intervention: 2 Inclusion less than 8g/dL or when Control: 20 Criteria: Patients the patient had P=0.017 undergoing THR symptoms of acute Uncemented THR: anemia (hypotension, Intervention: 13 Exclusion tachycardia, tachypnea, Control: 28 © 2017 American Medical Association. All rights reserved. 471

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Criteria: Patients dizziness, fatigue, etc.) P=0.005 with hematological Transfusion Index (ml diseases or RBC/ transfused patient) coagulation Allogeneic disorders, hepatic Overall or renal diseases, Intervention: 53±117 those receiving Control: 371±154 anticoagulant P=0.001 therapy or with Cemented THR: known infection or Intervention: 49±129 malignancy. Also, Control: 378±142 patients with any P=0.001 other blood-saving Uncemented THR: strategy (e.g. Intervention: 54±118 preoperative Control: 366±168 autologous blood P=0.001 donation or Autologous erythropoietin Cemented THR: treatment). Intervention: 163±77 Control: 0 Uncemented THR: Intervention: 218±153 Control: 0 Overall Total Intervention: 263±189 Control: 371±154 P=0.022 Cemented THR: Intervention: 212±167 Control: 378±142 P=0.049 Uncemented THR: Intervention: 272±192 Control: 366±168 P=0.001 Reoperations: NR Length of stay (days): Intervention: 10.1±3.1 © 2017 American Medical Association. All rights reserved. 472

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Control: 11.6±7.4 P=0.201 ABT:13.5±7.9days No ABT: 9.6±3.1 days Difference 3.9 days; 95%CI (1.8-6.0); P=0.001 Mortality: NR Adverse events: DVT Intervention: 0 (0) Control: 1 (2%) Ability to walk (days) Intervention: 4.6±1.4 Control: 5.1±3.4 NoABT:4.4±1.6 days ABT: 5.7±3.5 days Difference 1.3d; 95%CI (0.3-2.3) P=0.013 Innerhof- Prospect- To determine that Number of Intervention group: SSI (Follow up- Definitions: er ive the use of White patients: N=308 Allogeneic (WBC- discharge) Urinary Tract Infection (UTI): 2005 147 concur- Blood Cell (WBC) Preoperative filtered)n=100 Wound infection (total=4 diagnosed by orthopedic surgeon, (ES) ent filtered blood Autologous Blood (1.2%) established from positive results of control components Donation (PAD): Allogeneic: 3/100 (3%) microbiologic cultures and clinical 1, 2, 3, 4, should cause n=143 Timing of intervention: No RBC: 1/101 (1.0%) signs of UTI 5, 6, allogeneic No PAD: n=165 Intraoperative and/or Autologous: 0 Pneumonia: when signs of fever, recipients to No transfusion: postop Both: 0 leukocytosis, and chest infiltrate exhibit n=101 were observed postoperative Autologous: n=85 Duration of Wound infection: clinically in the infection rates Allogeneic, WBC intervention: duration of Other infections: case of purulent secretion and similar to those of filtered= n=100 transfusion Total infections (UTI, painful erythema. patients receiving Both, n=22 pneumonia, wound, Purulent Dermatitis (bacterial dermal autologous blood Patient Agent: all blood purulent dermatitis): infection distinct from operation site): during elective Characteristics: components produced 22/308 (6.82%) resulting confirmed by positive microbiologic primary hip or ·Age: median by hospital in antimicrobial therapy results. knee arthroplasty (IQR) Autologous or Allogeneic for treatment using the No RBC: 66y (54- whole blood was Allogeneic: 12/100 Perioperative care: NR incidence of 73) collected in top and (12%) postoperative Autologous: 64y bottom bags; citrate No RBC: 7/101 (6.9%) Analytical methodology: Chi- © 2017 American Medical Association. All rights reserved. 473

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score infection as an (55-70) phosphate dextrose Autologous: 1/85 (1.2%) square and U test to compare endpoint Allogeneic: 74y adenine-1 was used as Both: 1/22 (4.6%) baseline data of patients. (67-78) anticoagulant. WBC P=0.03 Univariate analysis was performed Both: 72y (65-77) reduction was provided Allogeneic compared for factors associated with P<0.0001 by pre-storage inline with Autologous postoperative infection and ·Gender: f/m WBC filtration of whole transfusions: P=0.0053 transfusion supply. No RBC: 43/58 blood. Separated RBCs No transfusion Chi-square and Kruskall-Wallis test Autologous: 44/41 were stored in 100ml of compared with were applied to analyze predictive Allogeneic: 73/27 saline-ademine-glucose- compared to autologous: factors of infection after allogeneic Both: 15/7 mannitol additive P=0.06 transfusion. P=0.0001 solution and kept at 4oC Allogeneic + Both: Logistic regression model for ·Obesity: BMI and plasma was frozen 10.7% (13/122) evaluating risk factors for No RBC: 28 (25- (to -30oC core temp) Autologous + None: postoperative infection. 31) within 2 hour of 4.3% (8/186) Autologous: 27 separation. P=0.03 Other notes: As expected, Fresh (24-30) Autologous blood was Frozen Plasma (FFP) was seldom Allogeneic: 26 donated by means of **Incidence of infection necessary to correct coagulopathy (23-29) apheresis, at 400ml of increased significantly (15/308 patients) and Both: 26 (24-32) RBCs 3-4 weeks before with the number of intraoperatively salvaged blood was P=0.009 surgery. It was divided transfused allogeneic processed for 44/308 (14%) of ·Comorbidities: into 2 units re- WBC-filtered RBCs patients only and therefore was not Existing Disease suspended in 100ml (p=0.01, data not analyzed further. (including saline-adenine-glucose- shown) Coronary artery mannitol each. RBCs Follow-up: Discharge disease, were not WBC filtered Statistically significant Funding Source Conflicts: congestive heart and the WBC content Multivariate analysis of Authors: NR failure, COPD, was 2,000-30,000 variables predicting Institution: NR Diabetes mellitus, WBCs/μL postop infection Study: NR renal and liver Allogeneic WBC-filtered Supplies: NR disease, chronic Monitoring RBCs polyarthritis, intake intervention: NR OR (95%CI): 23.66 of corticosteroids, (1.33-422.06) P=0.02 malignant Control group: n=208 disease) Control1: n=101 Foley catheter (days) No RBC: 37.6% No RBCs/ no OR (95%CI): 1.23 (1.1- (n=38) Transfusion 1.4) Autologous: Control2: n=85 P=0.002 29.4% (n=25) Autologous UTI Allogeneic: 58% Control 2: n=22 Allogeneic: 7/100 © 2017 American Medical Association. All rights reserved. 474

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score (n=58) Both Autologous and (7.0%) Both: 36.4% Allogeneic RBCs No RBC: 5/101 (5.0%) (n=8) Autologous: 1/85 (1.2%) P=0.0007 Standard preventive ·Hb at admission measures: Both: 0/22 (g/dl): Transfusion trigger: bHb Pneumonia No RBC: 14.3 levels below 8g/dl and/or Allogeneic: 3/100 (13.7-15.1) physiologic signs of (3.0%) Autologous: 12.8 anemia No RBC: 0/101 (12.3-13.9) Warming: all patients Autologous: 0/85 Allogeneic: 13.1 were actively warmed (12.1-13.8) with fluid warmer and a Both: 1/22 (4.5%) Both: 12.2 (11.4- convective warming Purulent Dermal 12.5) system. infection P<0.0001 Transfusions: fluid Allogeneic: 0/100 ·Hb at discharge warmers and 40-μm No RBC: 1/101 (1.0%) (g/dl): blood filters were used Autologous: 0/85 Not significantly AMP: single dose of different between second-generation Both: 0/22 groups. cephalosporin before Procedures: incision. Topic-specific Primary Hip Anticoagulant: outcomes: Replacement: 189 Enoxaparin administered ·Total RBCs (units Primary Knee 12h before operation. transfused): Replacement: 119 Catheters: all patients Allogeneic: 2 (2-4) Indications: NR received Foley catheters No RBC: 0 Setting: 1 center on the morning of the Autologous: 2 (1-2) Location: Austria day of surgery. Dates: 10 months Non-standard Both: 4 (3-4) Inclusion preventive measures: P<0.0001 Criteria: Patients Blood Aspiration: blood undergoing was aspirated into a cell- ·Shed Blood (ml): primary hip or saver system and Allogeneic: 500 (300- knee replacement processed when 700) surgery appropriate (>1000ml of No RBC: 550 (500-900) Exclusion blood in the reservoir. Autologous: 500 (450- Criteria: Any Postoperatively 1000) infection (including unwashed shed blood UTI), medical was also re-transfused Both: 500 (300-1000) © 2017 American Medical Association. All rights reserved. 475

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score reason for not within 6h P=NS donating FFP: was only used to Reoperations: NR autologous blood, treat coagulopathy Length of stay: surgery for 15/308 (4.9%) With Infection: 16.8±4.2d metastatic No Infection: 14.0±2.1d process, or P=0.0004 stabilization of Mortality: NR acute fractures. Adverse events: ·Foley Catheter (days) Allogeneic: 3 (3-4) No RBC: 3 (2-4) Autologous: 3 (2-3)

Both: 4 (3-5) P=0.006 Weber Prospect- To determine the Number of Intervention group: SSI (follow up 6 weeks) Definitions: 2005 149 ive effects of patients: N=444 n=92 Unadjusted results. Wound and urinary tract infections: (ES) concur- allogeneic blood Received allogeneic Deep Infection defined by the presence of a positive ent transfusion on Patient blood transfusion. (mean(SEM)) culture. Wounds were examined control length of hospital Characteristics: Intervention: 1% (10%) daily by orthopedic surgeons who 1, 2, 3, 4 stay in patients mean (SEM) or n Timing of intervention: Control: 1% (8%) were trained to the assessment undergoing (%) Intraoperative and P=NS protocol but not blinded to elective total hip ·Age: years postoperative transfusion. arthroplasty by Intervention: 64.2 Positive Wound Culture Deep infection: requires joint examining the (14.5) Duration of (mean(SEM)) involvement frequency of Control: 63.1 intervention: Intervention: 3.3% Wound-healing disturbance: allogeneic blood (11.2) Intraoperative with (18%) erythematous inflammation of >1cm, transfusion, ·Gender: %male different triggers either Control: 2.0% (14%) wound fluid discharge, purulent wound-healing Intervention: 13% before or after 4 hours P=NS suture, wound dehiscence, blister, or disturbances, (34) postop. any degree of wound necrosis. superficial and Control: 39% (49 Wound Disturbance deep wound P<0.01 Agent: Packed red (mean(SEM)) Perioperative care: NR infections, and ·Obesity blood cells were Intervention: 31% (47%) length of hospital Height (cm) supplied by local blood Control: 18% (39%) Analytical methodology: admission. Intervention: 167 bank and consisted of P<0.05 Occurrence of wound disturbance (8.6) buffy coat-depleted cells, To determine impact of factors in relation to blood Control: 171 (8.9) mean vol. 320ml, Hb perioperative blood loss, transfusion and other potentially P<0.05 17.8g/dl, Hct=0.58, and they divided the group related factors were calculated using Weight (kg) Leukocytes 0.4x109/L into 3 subgroups: logistic regression © 2017 American Medical Association. All rights reserved. 476

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Intervention: 72 Blood loss 1-700mL Risk variables were calculated using (15.4) Monitoring Blood loss 101-1000mL stepwise conditional backward and Control: 79 (13.8) intervention: Blood loss >1000mL. forward selection to perform P<0.001 Info collected For each subgroup they multivariate analysis. 1. At POD 0 - all routine observed “essentially the Effect of variables on Length of stay ·Comorbidities: clinical postop same proportion in the was calculated with linear regression Diabetes mellitus assessments, name of incidence of wound analysis. Then log-normalized. Intervention: 2/92 surgeon, Hb level. disturbances as was (2.2%) 2. POD1 - blood loss, found for the groups as Other notes: None Control: 18/352 transfusion data a whole.” (Study not (5.1%)Pulmonary (including units and type powered for this analysis Follow-up: at least 6weeks disease of blood products given so correlation between postoperatively. Intervention: 9/92 and Hb before transfusion and wound Funding Source Conflicts: (9.8%) transfusion) any blood- disturbances did not Authors: NR Control: 29/352 saving techniques used, reach significance in Institution: NR (8.2%)Steroids and medications used these subgroups)_ Study: NR Intervention: 1/92 3. POD4 – serum Supplies: NR (1.1%) prealbumin and pre- Control: 12/352 transfusion Hb (only if Unadjusted predictors of (3.4%) transfused) Wound healing Rheumatoid 4. Discharge – blood disturbances: OR Arthritis loss, transfusion data (95%CI) Intervention: 6/92 (number of units and Blood Transfusion (6.5%) type of blood product) OR: 2.1 (1.2-3.5); Control: 16/352 and length of P=0.03 (4.5%) hospitalization. All other variables not Procedures: significant Elective primary Control group: n=352 total hip No transfusion received **Blood transfusion was arthroplasty also the only significant Standard preventive variable using Indications: NR measures: multivariate analysis All patients received Setting: 1 hospital standard care acceding Other infections: to standard protocol by Urinary Tract Infection Location: The using active body (mean(SEM)) Netherlands warming and so on. Intervention: 3.3% Therefore, fraction of (18%) Dates: October inspired oxygen, body Control: 3.7% (19%) © 2017 American Medical Association. All rights reserved. 477

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score 29, 1998 – temperature, and so on P<0.01 October 27, 1999 was comparable between groups. Topic specific Inclusion Because of the length of outcomes: Criteria: Patients study period, group of Preop ESR (mm 1st h) undergoing surgeons was limited Intervention: 18.3 (13.8) planned elective and their distribution was Control: 14.5 (11.1) primary total hip comparable between P<0.05 arthroplasty, groups. Preop prealbumin ≥18yo, living in (mmol/L) The Netherlands, Non-standard Intervention: 266 (51.4) or otherwise preventive measures Control: 285 (56.2) available for follow Transfusion Trigger: P<0.05 up for at least 6 Hb<8.1 g/dl (5.0mmol/l) Preop Hb (mmol/L) wk. postop during surgery and until Intervention: 8.0 (0.8) 4h postop and Hb<8.9 Control: 8.6 (0.7) Exclusion g/dl (5.5mmol/l) more P<0.001 Criteria: Any than 4h postop. For Operation time (min) infection of any patients with Intervention:80 (31.6) body-system at cardiovascular disease, Control: 71 (19.5) screening, as all triggers were P<0.05 determined by increased by 0.8g/dl Perioperative blood symptoms or (0.5mmol/l) loss (mL) erythrocyte Intervention: 789 (551) sedimentation rate Gentamycin cement Control: 540 (274) (ESR)>20mm used (%) (SEM) P<0.001 (unless known to Intervention: 21% (41) Total Blood Loss (mL) be preexistent); Control: 14% (34) Intervention: 1185 (716) any blood P=NS Control: 922 (431) transfusion P<0.001 received within Reoperations: NR 6wk before Length of stay: mean surgery; and any (SEM) d other operation Intervention: 12.3 (5.3) within 6wk preop. Control: 9.8 (3.5) Also, patients who P<0.001 donated Evaluation to determine autologous blood if length of stay was preoperatively. affected by perioperative © 2017 American Medical Association. All rights reserved. 478

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score blood loss showed that duration of hospitalization was essentially unaffected by blood loss and a similar difference in hospitalization duration between transfused and nontransfused was maintained among the subgroups. (Study not powered to detect significant differences in sub-analysis but did reach significance in patients who lost more than 700mL of blood perioperatively) Regression model to predict length of stay (days) (β (95%CI) (How much each variable adds to length of stay) Age (days per 10yr) 0.9 (0.6-1.2); P<0.001 Operation time (days per 10 min) 0.2 (0.1-0.4); P=0.011 Wound disturbance (days if present) 1.3 (0.4-2.1); P=0.006 Transfusion (days if given) 2.2 (1.3-3.1); P<0.001 Mortality: NR © 2017 American Medical Association. All rights reserved. 479

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Adverse events: NR Llewelyn Prospect- To conduct a Number of Intervention group: SSI (Follow Up 90 Definitions: 2004 150 ive Pre- two-cohort patients: N=3942 Received Transfusions days) 2 primary outcomes of interest “ (ES) Post prospective evaluable n= 2095 Surgical wounds Length of stay and Infections” 1, 2, 3, 4, study in patients Total Orthopaedic Length of Stay (LOS): the days 8 undergoing Patient received transfusion: Orthopedic between the operation and discharge elective coronary Characteristics: 1243 Intervention1: 43/606 form the acute care ward. (Days on artery bypass using evaluable Intervention1: n=997 (7.1%) intensive care unit and/or high graft or total hip populations: (Orthopaedic I1 n=606) Intervention2: 32/637 dependency unit plus orthopedic or and/or knee Transfusions: n= Patients receiving (5.0%) cardiac ward) replacement Before ULR: n= transfusions before Control1: 31/871 Infections: new suspected and surgery before 997 mandatory ULR. These (3.6%) proven postop infections for which and after Ortho before transfusions were Control2: 22/799 antimicrobial s were prescribed universal n=606 intended to be (2.8%) (excluding topical antimicrobials and leukoreduction After ULR: unmodified RBC, but antimicrobials given as perioperative (ULR) to examine n=1098 cohort included patients Proven Infections antimicrobial prophylaxis) plus local the effects of Ortho after: who received BC-RBC Orthopedic signs and symptoms as follows: ULR on a large n=637 and/or WBC reduced Intervention1: 50/606 UTI: two or more of following: group of surgical No Transfusion RBCs ONLY IF they also (8.3%) 1) fever with no other recognized patients who Before ULR: received at least 2 u Intervention2: 26/637 cause received n=956 unmodified RBC. (4.1%) 2) urgency transfusion(s). Ortho before: Intervention2: n=1098 AOR:0.45 (0.28-0.74); 3) frequency n=871 (Orthopaedic I2 n- p=0.002 4) dysuria After ULR: n=891 637)Patients receiving Control1: 21/871 Lower Respiratory Tract Infection: Ortho after: transfusions after (2.4%) LRTI: new or increased production of n=799 mandatory ULR (Full Control2: 29/799 sputum and/or fever (>38oC) with ·Age: years cohort2 is WBC reduced (3.6%) appropriate chest signs including Transfusions: allogeneic RBCs) consolidation and/or chest x-rays Before Other infections showing new or progressive infiltrate ULR:68.6±11.1 Timing of intervention: Wound infections: with purulent After intraoperative and Lower Respiratory discharge in or exuding from the ULR:69.2±10.2 postoperative Infections wound. No Transfusion Orthopedic Secondary outcomes: Before ULR: Duration of Intervention1: 21/606 Hospital proven postop infections: 68.0±10.4 intervention: (3.5%) required clinical symptoms above After intraoperative and Intervention2: 26/637 leading to antimicrobial prescription ULR:68.1±10.3 postoperative (4.1%) PLUS positive microbio culture ·Gender: male Control1: 20/871 (except physician’s diagnosis of (%) Agent: (2.3%) pneumonia sufficed as confirmation © 2017 American Medical Association. All rights reserved. 480

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Transfusion: Cohort1: Unmodified Control2: 22/799 of LRTI) Before ULR: 471 RBCs or unmodified (2.8%) Major non-infectious postop (47.2%) RBC and RBCs with complications: one or more of the After ULR: 600 Buffy coat removal (BC- Urinary Tract Infections following: cardiac arrest, infarction, (54.6%) RBCs), or WBC-reduced Orthopedic renal impairment requiring dialysis, P = 0.001 RBCs only if they Intervention1: 22/606 confirmed deep vein thrombosis No Transfusion received at least 2u (3.6%) and/or pulmonary embolism, Before ULR: 422 unmodified Intervention2: 16/637 respiratory failure, and return to (44.1%) RBCCohort2: all blood (2.5%) operating room for bleeding from After ULR: 423 was WBC-reduced Control1: 19/871 surgical wound site. (47.5%) within 48 hours of (2.0%) ·Obesity (weight collection by filtration Control2: 26/799 Perioperative care: NR (kg)) either of whole blood or (3.3%) Transfusion: of BC-RBCs. Analytical methodology: 80% Before ULR: Bacteremia/ Septicemia power and 5% significance, a 75.1±15.7 Monitoring Orthopedic sample size of 400-500 patients After ULR: intervention: Intervention1: 3/606 receiving transfusion was adequate 75.7±14.8 Transfusion recorded. (0.5%) to allow the study to detect an effect No Transfusion Control group: Intervention2: 1/637 size of 0.125. Before ULR: No Transfusions n= (0.2%) T-test or chi square. 79.6±15.6 1847 Control1: 4/871 (0.5%) Binary outcomes required logistic After ULR: Total Orthopaedic No Control2: 0 regression 80.6±16.0 Transfusion: n=1670 Time-dependent variables were ·Comorbidity (%) Control1: n=956 Other Site Infections analyzed by Cox proportional Transfusion: Orthopaedic C1 n=871 Orthopedic hazards method Before ULR: 318 Patients not receiving Intervention1: 17/606 (31.8%) transfusions before (2.8%) Other notes: Data were collected by After ULR: 341 mandatory ULR Intervention2: 13/637 research nurses or audit staff by (31.1%) Control2: n=891 (2.0%) review of hospital notes and No Transfusion Orthopaedic C2:n=799 Control1: 13/871 computer information systems after Before ULR: 309 Patients not receiving (1.5%) the patient’s discharge. (32.3%) transfusions with Control2: 13/799 After ULR: 249 leukocyte reduction (1.6%) Follow-up: 90 days after discharge (28.0%) (after mandatory ULR) Funding Source Conflicts: Infection (%) Topic-specific Authors: None Transfusion: Standard preventive outcomes Institution: None Before ULR: 65 measures Drain Losses (mL) Study: None (6.5%) Non-standard Unchanged in Supplies: None After ULR: 45 preventive measures: orthopaedic patients © 2017 American Medical Association. All rights reserved. 481

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score (4.1%) Transfusion Triggers; who received P=0.013 Each hospital followed transfusions vs. those No Transfusion its own transfusion who did not Before ULR: 29 protocols Lowest Hb Level (g/dL) (3.0%) Data not stratified by After ULR: 32 procedure type (3.6%) Discharge Hb level Hb level (g/dl) (g/dL) Transfusion: Data not stratified by Before ULR: procedure type 13.2±1.4 After ULR: Subgroup analysis: of 13.3±1.4 storage age and dose of No Transfusion blood on primary Before ULR: outcomes before and 13.7±151.2 after ULR (including After ULR: postop infections, and 13.8±1.2 postop LOS) found no Procedures: Non- statistically significant emergent comparisons. Coronary Artery Bypass Grafting TRANSFUSION DATA (CABG) and Number RBC elective total hip units/patient replacement and/ or total knee Orthopedic replacement Before ULR: 2.7±1.5 (Primary and After ULR: 2.9±2.0 revisions) P=0.115 Primary Number of patients (%) Procedure: receiving – THIS IS Orthopedic CABG+ORTHO Procedures 1 unit of RBCs Redoes (includes Before ULR: 114/997 bilateral and THR (11.4%) plus TKR) After ULR: 78/1098 Transfusion: (7.1%) Before ULR: 145 2-3 units of RBCs (23.9%) Before ULR: 476/997 © 2017 American Medical Association. All rights reserved. 482

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score After ULR: 129 (47.7%) (20.2%) After ULR: 540/1098 P=0.118 (49.2%) No Transfusion >3 units RBCs Before ULR: 58 Before ULR: 407/997 (6.7%) (40.8%) After ULR: 26 After ULR: 480/1098 (3.3%) (43.7%) P=0.001 P=0.003 TKR (%) FFP/cryoprecipitate Transfusion: Before ULR: 84/997 Before ULR: 194 (8.4%) (32.0%) After ULR: 108/1098 After ULR: 242 (12.1%) (38.0%) P=0.008 P=0.027 PLTs No Transfusion Before ULR: 75/997 Before ULR: 443 (7.5%) (50.9%) After ULR: 110/1098 After ULR: 408 (12.3%) (51.1%) P=0.0004 P=0.934 Indications: Reoperations: NR variable Setting: Length of stay: postop Multicenter (CABG LOS: mean (SD) days at 4 hospitals and Received Transfusions Arthroplasty at 7 Orthopedic hospitals) Before ULR: 2.8±1.56 Location: After ULR: 3.3±2.98 England AR 1.16 (1.04-1.30); Dates: p=0.010 Cohort1 (pre- No Transfusions ULR): Began Orthopedic January –May Before ULR: 8.3±3.4 1999 and After ULR: 7.9±3.8 continued until AR 1.11 (1.00-1.22); enough patients p=0.042 were recruited © 2017 American Medical Association. All rights reserved. 483

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score (approx. 5 Mortality (in hospital months) and up to 90 days after Cohort2 (Post discharge home): ULR): Began January –May Orthopedic 2000 and Intervention1: 7/606 continued until (1.2%) enough patients Intervention2: 7/637 were recruited (1.1%) (approx. 5 Control1: 5/871 (0.6%) months) Control2: 3/799 (0.4%) Inclusion Adverse events: Criteria: CABG Major Complications patients Orthopedic undergoing Intervention1: 40/606 nonemergency, (6.6%) whether primary or Intervention2: 39/637 redo procedures, (6.1%) with or without AOR: 0.85 (0.28-2.61); aortic or mitral P=0.775 valve replacement Control1: 34/871 or (3.9%) endarterectomy. Control2: 15/799 Orthopedic (1.9%) patients AOR: 0.44 (0.24-0.82); undergoing p=0.010 elective THR or TKR whether primary or redo operations. Bilateral procedures were included if performed during the same operation Exclusion Criteria: Patients receiving © 2017 American Medical Association. All rights reserved. 484

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score previously donated autologous transfusions Cohort1: patients receiving BR-RBC & WBC-reduced transfusions unless they had also received at least 2 units of unmodified RBCs. Rosenc- Prospect- To examine Number of Intervention group: SSI (Follow up Definitions: her ive blood patients: N=3996 Received discharge from Infection: Determination of infection 2003 148 Concurr- management Transfusions: 2762 Surgery Department) was made using physical clinical (ES) ent practices before, Patient Allogeneic Only Unadjusted: judgment. Cohort during and after Characteristics (±WBC filtration) Overall wound infection Overall Infection Rates: includes 1, 3, 4, 5 elective total ·Age mean±SD =1024/2762 (37%) rate: 81/3996 (2%) wound infections, urinary tract knee and total hip 69±11.2 years Autologous Only Allogeneic-only: 36/999 infection, respiratory tract infection, arthroplasties in Allogeneic-only: =1393/2762 (50%) (4%) septicemia, and “other” infections Europe (including 71±10.7 Autologous Blood Autologous-only: Estimated blood Loss: Physician’s revisions and Autologous-only: Donation (ABD) = 11/1311 (1%) estimates of EBL were recorded bilateral 66±11.6 1290/1393 (93%) Χ2(1) = 19.26; p<0.001 before the surgery. procedures) and P<0.001 Acute Normovolemic (allogeneic only vs. Baseline Hb level: Hb level collected to determine ·Gender: m/f Hemodilution=82/1393 autologous only) during the assessment office visit factors predictive 1393/2431 (sex (6%) Allogeneic & when the surgery was planned - of the risk data missing for Cell saver=329 Autologous: 8/329 (2%) 21±7 days before surgery. associated with 172 patients) Postop salvage=264 No Transfusion: 22/1180 allogeneic ·Obesity: NR Allogeneic and (2%) Perioperative care: NR transfusion. ·Comorbidities: Autologous: ABD Transfusions only: Factors Hypertension: n=345/2762 (13%) 4/615 (1%) Analytical methodology: Logistic examined 1631 (41%) Allogeneic Transfusion regression was used for modeling included blood Coronary Artery Timing of intervention: WBC-Depleted: the probability of transfusion based wastage; pre- Disease: 469 Intraoperative/postopera 18/637 (3%) on selected predictor variables. and (12%) tive Not WBC-Depleted: Otherwise, descriptive statistics or postoperative Hb Significant 18/464 (4%) Parametric and nonparametric evolution; differences Duration of No statistically statistical tests after consideration of transfusion between intervention: significant difference distributional characteristics and associated transfusion Intraoperative/postopera between WBC depleted statistical test assumptions were © 2017 American Medical Association. All rights reserved. 485

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score complications; method groups: tive and non WBC depleted utilized. and predictors of χ2(3)=13.82; allogeneic transfusions allogeneic P<0.001 Device/agent: Other notes: The tables and data transfusion. Diabetes: 382 Transfused blood Knee Patients only were not uniformly presented. (10%) ABD only: 0/148 Numbers & % were frequently COPD: 317 (8%) Monitoring Postop salvage only: mislabeled leading to problems Rheumatic: 149 intervention: 5/122 (4%) interpreting the data. Missing data (4%) CRF=case report forms Χ2(1) = 5.97; p<0.05 from every table resulted in Significant were utilized to report, (Knee ABD vs. Postop “apparent discrepancies” in the differences scan then analyze the Salvage) counts adding to the problem of between perioperative data Hip Patients Only interpretation. transfusion including transfusion ABD only: 4/462 (1%) method groups: type and amount. Postop salvage only: Follow-up: Until discharge from χ2(3)=13.29; 3/69 (4%) Surgery Department P<0.001 Control group: n=1234 Χ2(1) = 5.60; p<0.05 Funding Source Conflicts: Hematologic: 106 No transfusions (Hip ABD vs. Postop Authors: NR (3%) Salvage) Institution: NR Standard preventive Study: NR Procedures: measures: NR Overall Infection Rates: Supplies: NR Elective total hip Allogeneic-only: 110/999 and total knee (11%) arthroplasties. Autologous-only: Primary unilateral 93/1311 (7%) hip: 2027 (51%) Allogeneic & Primary bilateral Autologous: 30/329 (9%) hip: 27 (1%) No Transfusion: 94/1180 Primary unilateral (8%) knee: 1036 (26%) ABD transfusion only: Primary bilateral 25/615 (4%) knee: 13 (0%) Allogeneic Transfusion Hip revision: 292 WBC-Depleted: (7%) 82/637 (13%) Knee revision: 69 Not WBC-Depleted: (2%) 42/464 (9%) Knee Patients only Indications: ABD only: 6/148(4%) Variable Postop salvage only: 13/122 (11%) Setting: 225 Hip Patients Only © 2017 American Medical Association. All rights reserved. 486

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Centers ABD only: 19/462 (4%) Postop salvage only: Location: Europe 12/69 (17%) --France, Germany, Greece, Other infections: SEE Italy, the ABOVE Netherlands, and Topic-specific Spain outcomes: Donated Blood: n= Dates: NR Baseline Hb Level was linearly regressed with Inclusion the probability of Criteria: All allogeneic transfusion: patients WOMEN: undergoing total Base Hb level of 8.0 = hip or total knee 75% prob of transfusion replacement. Base Hb level of Enrollment of 16.0=12% prob of consecutive transfusion patients was MEN: requested with a Base Hb level of 8.0 = limit of 20 patients 70% prob of transfusion per center. Base Hb level of 16.0=8% prob of Exclusion transfusion Criteria: NR Reoperations: NR Length of stay: days Allogeneic: 13.0±8.1 Autologous: 12.3±10.5

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score autologous): 13.5±10.2 P<0.001 Mortality: NR Adverse events: Fluid volume overload: Ranged from 3-4% across transfusion methods: NS

Suspected Clinical DVT: Ranged from 2-3% across transfusion methods including no transfusion. NS

Transfusion Reactions: Recorded not reported Borghi Prospect- To evaluate the Number of Intervention group: n= SSI (follow up: Definitions 2000 153 ive incidence and patients N=2884 278 discharge from Perioperative care: (ES) concur- risk factors for Patient Patients receiving orthopedic ward) MSBOS: the actual number of blood ent allogeneic blood Characteristics allogeneic concentrated All infection data was units transfused in 90% of patients control transfusion (after ·Age: (mean±SD) red blood cell (ARBC) presented in bar graph receiving one individual surgical 1, 2, 3, 4, autologous blood years transfusions after all form. The below procedure. 5, 8 transfusion) in THA: 61±12 autologous blood (both numbers are Anesthesia: either balanced general, patients TKA: 68±8 pre-donations and blood percentages inferred. regional or integrated scheduled for HR: 64±11 recovered intra and epidural/general anesthesia. The primary hip, ·Gender m/f postoperatively. Statistical Significance type was freely decided by the primary knee or THA: 726/1290 Timing of intervention of difference between attending anesthesiologist with no revision hip TKA: 125/355 Duration of ARBC PLUS randomization. arthroplasties HR: 124/264 intervention Autologous and No Analytical methodology: and receiving an ·Obesity Agent: ARBC across each Continuous variables: Analysis of aggressive Weight (kg) Autologous Blood group is as follows variance autotransfusion THA: 68±11 Collected: According to GROUP THA: p=0.0005 Post hoc comparisons: Tukey’s test regimen TKA: 70±10 the Maximum surgery GROUP TKA: p=0.008 and student’s t-test with Bonferroni’s HR: 68±10 blood order on GROUP HR: p=0.005 correction. Height (cm) Schedule, 2 units of pre- Infection: Categorical variables: χ2-square or THA: 162±9 donated blood were THA: Fisher’s exact test. Multivariate TKA: 160±8 collected for THA and ARBC plus autologous: analysis of variance for repeated HR: 161±8 TKA and 3 units for 1% measures with Wilks’ λ-test for © 2017 American Medical Association. All rights reserved. 488

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score ·Comorbidities: Revision of Hip No ARBC: 0.5% changes over time NR Arthroplasty. Autologous TKA: After univariate analysis, partial risk Duration of blood was separated ARBC plus autologous: factors associated with the response Surgery (min) into RBC and FFP. FFP 2% were further evaluated by multiple THA: 115±38 re-infused at end of No ARBC: 0.5% logistic regression analyses. TKA: 117±44 surgery or within 24h; HR: Other notes: None HR: 183±64 pre-donated RBCs ARBC plus autologous: Follow-up: Discharge from P (THA vs. transfused during 3d 1% orthopedic ward HR)=0.0005 postop. No ARBC: 0.5% Funding Source Conflicts: P (TKA vs. Monitoring Authors: None HR)=0.0005 intervention: NR Wound Hematoma Institution: None Control group: n=2606 THA: Study: None Procedures: Patients receiving ARBC plus autologous: Supplies: None Total hip autologous blood 11% arthroplasty: transfusion (pre- No ARBC: 2% 2016/2884 donation separated into TKA: (69.9%) RBC and FFP) plus ARBC plus autologous: Total knee intraoperative re-infused 11% arthroplasty: cell-salvage and No ARBC: 5% 480/2884 (16.6%) postoperative closed HR: Hip revision of system drain(see details ARBC plus autologous: arthroplasty: below) 8% 388/2884 (13.5%) Standard preventive No ARBC: 2% Indications: measures variable Iron Supplement: during Other infections: NR Setting: 1 each pre-donation of Topic-specific orthopedic autologous blood and outcomes: institute the first 4 POD, all Perioperative Blood Location: Italy patients received Losses (ml) Dates: NR (5 year intravenous iron THA: 1190±480 period) (200mg/day) TKA: 1280±403 Inclusion Perioperative Blood HR: 1720±460 Criteria: Patients Return: P (THA vs. HR)=0.0005 undergoing Total Intraoperatively, P (TKA vs. HR)=0.0005 Hip Arthroplasty uncoagulated blood was (THA) Total Knee collected from wound Intraoperative Blood Arthroplasty (TKA) into a reservoir using an recovery (ml) or Hip Revision of aspirator and collection THA: 267±168 Arthroplasty (HR) bag connected to the TKA: 162±92 © 2017 American Medical Association. All rights reserved. 489

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score Exclusion inferior edge of the HR: 524±387 Criteria: NR surgical wound in order P (THA vs. TKA)=0.0005 to concentrate, wash P (THA vs. HR)=0.0005 and infuse red cells. P (TKA vs. HR)=0.0005 These were immediately returned to the patient. Postoperative Blood Postoperatively, recovery (ml) uncoagulated blood lost THA: 387±237 from the surgical wound TKA: 541±294 was monitored and HR: 465±287 collected using a closed P (THA vs. TKA)=0.0005 recovery system P (THA vs. HR)=0.0005 connected to the P (TKA vs. HR)=0.0005 surgical drains. If blood losses exceeded 200ml Patients receiving ABRC during 1st 8h postop, the plus autologous units of fresh frozen Transfusion plasma were re-infused THA: 159 (8%) at the end or within the TKA: 43 (9%) first 24h of surgery. HR: 76 (20%) Autologous P (THA vs. HR)=0.0005 Transfusion Trigger: if P (TKA vs. HR)=0.0005 Hb <11g/dl (number of patients Allogeneic receiving ABRC concentrated Red transfusions was not Blood cells significantly different Transfusion Trigger: across anesthesia types presence of for each surgery type) asymptomatic anemia (vertigo, dizziness, Hb concentration: postural hypotension, Baseline Hb headache, insomnia, concentration was confusion, tachycardia, significantly lower for HR angina, dyspnea) or than for THR and TKR at when Hb<6g/dl (10g/dl 1st and 3rd in patients with POD(p<0.0005 vs. THA cerebrovascular or & P<0.001 vs. TKA) coronary artery disease) Main Risk factors © 2017 American Medical Association. All rights reserved. 490

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score associated with An increased incidence of Perioperative transfusion of Allogeneic blood: Preoperative Hb<10g/dl: OR: 8.8 (6.5-16.8); p=0.004 Hip Revision Arthroplasty OR: 5.8 (3.9-8.5); p=0.0001 No MSBOS pre- donation: OR: 3.4 (2.7-4.1); p- 0.0001

Reoperations: NR Length of stay: Patient Discharge (days after Surgery) THA: 12±5 TKA: 16±6 HR: 15±7 P (THA vs. TKA)=0.0005 P (THA vs. THR)=0.0005

Patients not receiving ARBC’s log-rank curve showed significantly shorter durations of stay than the log-rank curve for patients receiving ARBC plus autologous transfusion (p=0.0005)

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score effects were reported during either preoperative collection of autologous blood or iv iron administration

Statistical Significance of difference between ARBC plus autologous blood and No ARBC across each group is as follows GROUP THA: p=0.0005 GROUP TKA: p=0.008 GROUP HR: p=0.005

Dysrhythmia THA: ARBC plus autologous: 3% No ARBC: 0.5% TKA: ARBC plus autologous:9% No ARBC: 1% HR: ARBC plus autologous: 7% No ARBC: 1.5%

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score HR: ARBC plus autologous: 4% No ARBC: 1%

Myocardial Ischemia THA: ARBC plus autologous: 6% No ARBC: 0.5% TKA: ARBC plus autologous: 0 No ARBC: 0.5% HR: ARBC plus autologous: 4% No ARBC: 0.5%

Pulmonary Embolism THA: ARBC plus autologous: 1% No ARBC: 0.5% TKA: ARBC plus autologous: 2% No ARBC: 0 HR: ARBC plus autologous: 5% No ARBC: 0.5%

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Study Author Design Year Population and Risk of Study Objective Intervention Results Comments (Data Setting (N) Bias Extractor) Score ARBC: 2% No ARBC: 1.5% HR: ARBC plus autologous: 0% No ARBC: 0.5%

Q11C. How does the volume of transfused blood product impact the risk of SSI? Our search did not identify data that evaluated differences in the volume of transfused blood product and their impact on the risk of SSI in prosthetic joint arthroplasty patients. Q11D. How safe and effective is withholding blood transfusion to reduce the risk of SSI? Our search did not identify data that both evaluated the safety and effectiveness of withholding blood transfusions and its impact on the risk of SSI in prosthetic joint arthroplasty patients.

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2.2A3. RISK OF BIAS ASSESSMENTS OF STUDIES: Q 11 BLOOD TRANSFUSION eTABLE 56. Risk of Bias Assessments of Randomized Controlled Trials for Q11 Blood Transfusion Funding Attrition source(s) Described Randomizati- Describe- smaller than disclosed and as on d as Outcome Study 10-15% of Attrition no obvious Overall Author randomiz- appropriately double- assessor participant Investiga- Attrition assigned appropriate- conflict of Risk of Year Q ed performed blind blinded blinded tor blinded described patients ly analyzed interest Bias Question 11: Blood Transfusion Frietsch 145 11          Low 2008 Frietsch 146 11        Low 2001

eTABLE 57. Risk of Bias Assessments of Other Controlled Studies for Q11 Blood Transfusion Attrition not Statistical Funding All study groups significantly Investigator Potential adjustment for source(s) derived from similar different Measure of Measure of blinded to confounde- potential disclosed and no Overall Author source/reference across study exposure is outcome is endpoint rs confounders obvious conflict Risk of Year Q populations groups valid valid assessment identified done of interest Bias Question 11: Blood Transfusion Borghi 153 11       Low 2000 Del Trujillo 152 11        Low 2008 Innerhofer 147 11       Low 2005 Llewelyn 150 11      Low 2004 Pedersen 151 11         Low 2009 Rosencher Moder- 148 11     2003 ate Weber Moder- 149 11     2005 ate

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2.2B. Q12-16 SYSTEMIC IMMUNOSUPPRESSIVE THERAPY 2.2B.1 GRADE TABLE: Q12-16 SYSTEMIC IMMUNOSUPPRESSIVE THERAPY eTABLE 58. GRADE Table for Q12-16 Systemic Immunosuppressive Therapy Increase Decrease GRADE GRADE

Overall

Quantity GRADE of

GRADE and Type Starting Evidence Comparison Outcome Findings of of GRADE for Evidence Evidence Outcome response

- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Systemic Immunosuppressive Therapy: Biologic Agents (Non-Tumor Necrosis Factors [TNF] and Anti-TNFs) and Disease Modifying Antirheumatic Drugs- (DMARD) Q12. How does systemic corticosteroid or other immunosuppressive therapy impact the risk of SSI in prosthetic joint arthroplasty patients? Q12A. Does the type of agent impact the risk of SSI? • In meta-analysis of 2 OBS studies (N=528) , biologic agents were associated with a higher risk for SSI: OR: 5.90 (2.68 – 12.99); 2 OBS 2 SSI* 154,155 p<0.01; I =0 Low 0 0 0 0 0 0 +1 0 Moderate

• In each of these studies154,155 multivariate logistic regression analysis identified biologic agents as a significant risk factor SSI. • In a meta-analysis of 2 OBS (N=528), biologic agents were not associated with a higher risk for PJI: OR: 3.59 (0.52 – 24.88); Biologic- 2 p=0.20; I =0 agents 154 2 OBS • In one study , 3 (0.7%) total organ/space (non-TNF PJI* 154,155 Low 0 0 0 -1 0 0 0 0 Very Low SSIs among 420 RA patients undergoing Very and anti- THA or TKA: 1/48 (2.08%) vs. 2/372 (0.54%); Low TNF) p=0.27 vs. • 155 DMARDs In the other study , 1/54 (1.85%) vs. 0/54 (0%); p=0.50 • In a meta-analysis of 2OBS (N=528), biologic agents associated with increased risk for superficial SSI OR: 5.80 (2.55 – 13.18); p<0.01; I2=0 Superfic- 2 OBS 154 154,155 • 1 OBS study = 24 (5.7%) total superficial Low 0 0 0 0 0 +1 0 0 Moderate ial SSI* SSIs among 420 RA patients undergoing THA or TKA: 9/48 (18.75%) vs. 15/372 (4.03%); p<0.01 • 1 OBS Study155= 7/54 (12.96%) vs. 1/54 © 2017 American Medical Association. All rights reserved. 496

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GRADE and Type Starting Evidence Comparison Outcome Findings of of GRADE for Evidence Evidence Outcome response

- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders (1.85%); p=0.06 • 1 small study (N= 113): 2/39 (5.1%) vs. 5/74 (6.8%); OR 0.7459 (0.14-4.03); p=1.00 (results include 4 ankle fusions) Adverse • No difference on subanalysis (30 THAs and events of 156 1 OBS 65 TKAs- THA: none in either group; TKA: Low 0 0 0 -1 0 0 0 0 Very Low surgical 4/51 (7.8%) vs. 1/14 (7.1%); OR 0.90 (0.09- wounds 8.80). 92.3% of all patients on biologic agents (infliximab and etanercept) were also on methotrexate (DMARD). • 1 small (N=90) retrospective 1:1 pair- matched case-control study of deep venous thrombosis (DVT) in joint arthroplasty (96%) Adverse and other joint procedures (4%): increased events- 155 1 OBS incidence of DVT with biologic agents 23/45 Low 0 0 0 -1 0 0 0 0 Very Low drug (51%) vs. 12/45 (26%); p=0.02. related • On multivariate logistic regression analysis biologic agents (anti-TNF) were the only risk factor for DVT: OR 2.83 (1.10-7.25); p=0.03 • No difference in 1 study (N=202) total joint replacements in RA patients: 3/92 (3.26%) 157 vs. 2/110 (1.81%); p=0.66 at 6m follow-up PJI* 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low • Revision total joint replacements: 1/9 DMARD: (11.1%) vs. 0/16; p=0.26 methotrex- • Bilateral TKA: 0/3 vs. 1/11 (9.09%); p=1.00 ate vs. Very Deep No 157 • No difference: 0/92 vs. 1/110 (0.91%); Low wound 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low DMARD p=0.57 therapy abscess* Infected • No difference: 2/92 (2.2%) vs. 1/110 (0.9%); Hemat- 1 OBS 157 p=0.47 Low 0 0 0 -1 0 0 0 0 Very Low oma* • Bilateral TKA 1/3 (33%) vs. 0/11; p=0.14

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- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders

Necrotic 157 • No difference: 2/92 (2.17%) vs. 0/110; 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low eschar p=0.24

Serous 157 • No difference: 1/92 (1.09%) vs. 1/110 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low drainage (0.91%)

Q12B. Does the preoperative duration of the therapy impact the risk of SSI? • In a study154 comparing RA patients on biologics (anti-TNF) and DMARDs undergoing arthroplasty surgery, multivariate logistic regression analysis comparing infected to non-infected patients showed years of disease duration was a risk factors for SSI: OR 1.09 (1.04-1.14); p<0.01. • Disease duration for the cohort154 was a Disease 2 OBS SSI* 154,155 median of 14.5 years (interquartile range 8.9- Low 0 0 0 0 0 0 0 0 Low Low duration 21) but these results were not stratified by biologic agents vs. DMARDs. • In a study155 comparing RA patients on biologic (anti-TNF) and DMARDs undergoing arthroplasty surgery multivariate logistic regression analysis also suggested disease duration as a risk factor for SSI: OR 1.17 (1.03-1.33); p=0.02. Q12C. Does the agent dose impact the risk of SSI? • In a retrospective 1:1 matched pair case Biologic- 155 control study 64 rheumatoid arthritis agents patients on biologic agents (anti-TNF) were (anti-Tumor 2 OBS Very 155,154 matched to 64 patients on DMARDs. 0 -1 0 0 0 0 0 0 Very Low necrosis SSI* Low Low Patients in the biologic agent (anti-TNF) factors) vs. group were on significantly higher daily DMARDs doses of prednisone (5mg/day; range 2-7) © 2017 American Medical Association. All rights reserved. 498

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- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders than the DMARD patients (3mg/day, range 0- 5); p<0.01. Multivariate logistic regression analysis showed that prednisone dose OR 1.43 (1.01-2.04); p=0.05 was a risk factor for SSI. • In a retrospective study154 of 420 THAs and TKAs in RA patients, multivariate logistic regression analysis comparing infected to non-infected patients did not show prednisone dose to be a risk factor for SSI. Both patients with SSI (n=27) and those without SSI (n=393) were on prednisone doses of 3mg/day, (range 0-5); p=0.27. Results were not stratified by biologic agents vs. DMARDs. Q13. What are the most effective strategies in managing systemic corticosteroids or other immunosuppressive therapy perioperatively to reduce the risk of SSI in prosthetic joint arthroplasty patients? Q13A. How safe and effective is the discontinuation of these agents preoperatively and when should they be resumed? • In a meta-analysis (N=180) of 3 small observational studies, the data suggests that stopping methotrexate is associated with lower risk for PJI, but the result is not DMARD: significant (OR: 0.20 (0.04 – 1.03); p=0.05; 2 Methotrex- I =0 ate • 1 small OBS study159, overall SSI: 3/41 4 OBS stopped vs. 157-160 (7.3%) PJI* 159 Low 0 0 0 0 0 0 0 0 Low Low continued • 1 OBS study , no difference: 0/26 y

perioperat- vs.3/15; p=0.08. 1y follow up. Methotrexate 2 ively weeks perioperatively • In each of these studies157 - No difference: 1/47 (2.1%) vs. 2/45 (4.44%); p=0.54; 6m follow up. Methotrexate stopped indefinitely • No difference in one small (N=47) study158: 0/32 vs.1 /15 (6.67%); p=0.25. No PJIs © 2017 American Medical Association. All rights reserved. 499

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- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders reported among 32 patients who stopped methotrexate therapy 4 or more weeks preoperatively as compared to 1 among the 15 patients who were one methotrexate within 4 weeks of surgery: • In 1 OBS study160 (N=462) in RA patients undergoing 657 THAs and TKAs, patients were receiving at least 1 DMARD within 3 months of surgery in 336 of those 657 procedures. DMARD therapy was withheld in 192/336 (57%) of these procedures. Stopping DMARD therapy at the time of surgery lowered the risk of subsequent PJI: OR 0.65 (0.09-4.95) but this was not statistically significant. • “No patient in either group experienced a RA Flare 1 OBS 159 postoperative flare of their rheumatoid Low 0 0 0 -1 0 0 0 0 Very Low arthritis”

Infected Hemato- 1 OBS 157 • No difference: 2/47 (4.25%) vs. 0/45; p=0.30 Low 0 0 0 -1 0 0 0 0 Very Low ma

Necrotic 157 1 OBS • No difference: 2/47 (4.25%) vs. 0/45; p=0.30 Low 0 0 0 -1 0 0 0 0 Very Low eschar

Non- communicating 1 OBS 157 • No difference: 0/47 vs. 1/45 (2.22%);p=0.48 Low 0 0 0 -1 0 0 0 0 Very Low serous drainage Biologic • Subanalysis of 50/462 RA patients on 160 Very agent: Anti- PJI* 1 OBS biologic agent (anti-TNF) therapy Low 0 0 0 -1 0 0 0 0 Very Low Low tumor (etanercept, adalimumab, infliximab, or © 2017 American Medical Association. All rights reserved. 500

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GRADE and Type Starting Evidence Comparison Outcome Findings of of GRADE for Evidence Evidence Outcome response

- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders necrosis anakinra) who underwent hip or knee factor (anti- arthroplasties, suggested an increase in TNF): incidence of PJIs among those in whom anti- Stopped TNF therapy was continued perioperatively, vs. but the findings were not statistically continued significant: 0/12 (0%) vs. 3/38 (7.9%). perioperatively Q13B. Should the agent dose be adjusted, and if so, for how long? Our search did not identify data that evaluated perioperative immunosuppressive therapy dose adjustment and its impact on the risk of SSI in prosthetic joint arthroplasty patients. Q14. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty patients who are on systemic corticosteroid or other immunosuppressive therapy? Our search did not identify data that specifically evaluated differences in duration of postoperative AMP in prosthetic joint arthroplasty patients who were on systemic corticosteroids or other immunosuppressive agents and its impact on the risk of SSI. However, multiple procedures examined in the Core section, Q1.E: Postoperative AMP duration that included patients on immunosuppressive therapy showed no benefit of continuing AMP after closing the surgical incision in the operating room. Therefore, the broader recommendation for duration of postoperative AMP should be applied to prosthetic joint arthroplasty procedures irrespective of use if systemic corticosteroid or other immunosuppressive therapy. Intra-articular Corticosteroid Injections Q15. How do preoperative intra-articular corticosteroid injections impact the risk of SSI in prosthetic joint arthroplasty patients? History of corticoster- 161- • Meta-analysis (N=1146) 5 OBS studies; OR: oid 5 OBS 2 SSI* 165 1.91 (1.01 – 3.61); p=0.05; I =13% Low 0 0 0 0 0 0 0 0 Low Low Injection • 35/476 (7.4%) vs. 26/670 (3.9%) vs. no injection • In a meta-analysis of 2 studies (N=414), no 2 OBS SSI* 161,162 difference between groups OR: 1.89 (0.53 – Low 0 0 0 -1 0 0 0 0 Very Low 2 6.76); p=0.33; I =50% TKA: Injection • In a meta-analysis of 2 studies (N=414), no Very vs. No difference between groups OR: 12.30 (0.62 – Low Injection 2 OBS 242.88); p=0.10 PJI* 161,162 Low 0 -1 0 -1 0 0 0 0 Very Low • 1 study161 (N=144) reported significant risk of PJI for TKA patients injected prior to surgery: 3/54 (5.6%) vs. 0/90 (0%); p<0.03 at 1yr © 2017 American Medical Association. All rights reserved. 501

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GRADE and Type Starting Evidence Comparison Outcome Findings of of GRADE for Evidence Evidence Outcome response

- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders follow up. All 3 had received a steroid injection within 11mo of surgery; mean (range): 9.6mo (8-11) • One study162 (N=270) matched 90 injected patients to 180 patients not injected prior to TKA and reported no infections in either group at 1 year follow up: 0/90 vs. 0/180. Half were injected within 1yr prior to surgery. • In a meta-analysis of 2 studies (N=414): no difference between groups OR: 1.71 (0.68 – 4.31); p=0.26; I2=16% • One study161 (N=144) reported 22 (15.3%) total superficial SSIs and no difference at 30 Superfic- 2 OBS 161,162 day follow up: 12/54 (22.2%) vs. 10/90 Low 0 0 0 0 0 0 0 0 Low ial SSI* (11.1%); p=0.1 • One study162 (N=270) reported 7(2.6%) total superficial SSIs and no difference at 30 day follow up: 2/90(2.2%) vs. 5/180 (2.7%); RR 0.80 (0.16-4.03); p=1.0 • In a meta-analysis of 3 studies (N=732), no difference between groups: 18/332 vs. 163- 11/400; p=0.07; OR: 1.70 (0.58 – 4.96); 3 OBS 2 SSI* 165 p=0.34; I =13% Low 0 0 0 -1 0 0 0 0 Very Low 163 • 1 OBS Study , SSI= 0/68 vs. 2/136 • 1 OBS Study164, SSI= 14/224 vs. 9/224 THA: 165 • 1 OBS Study , SSI= 4/40 vs. 0/40 Injection Very • vs. No In a meta-analysis of 3 studies (N=732), no Low Injection difference between groups7/332 (2.1%) vs. 2/400 (0.5%); OR: 2.95 (0.61 – 14.18); 3 OBS 163- p=0.18; I2=0% PJI* 165 Low 0 0 0 -1 0 0 0 0 Very Low • One study163 (n=202) found 66 injected patients (68 THAs) to 136 not-injected patients (136 THAs): no difference: 0/68 (0%) vs. 1/136 (0.73%); p=0.80. © 2017 American Medical Association. All rights reserved. 502

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- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Methylprednisolone 40mg/dL injections were administered an average of 14 months before surgery (median, 11months) • One retrospective matched cohort study164 (N=4448) in THA reported no difference: 3/224 (1.33%) vs. 1/224 (0.44%) at 2y follow up. Hazard ratio: 3 (0.3-29.8). Cumulative risk of deep infection at 5yr was 3% (95% CI, 0-7%) for the injection group and 0.6% (95%CI, 0-1.7%) for the no-injection group. Steroid dose average 20.47mg (range, 6-40) • 1 small (N=80) study165 in joint infections requiring revision THA reported no difference: 4/80 (5%); 4/40 (10%) vs. 0/40 (0%); p=0.13 at 1y follow up (used methylprednisolone 80mg/dL)

• In a meta-analysis of 3 studies (N=732), no difference between groups OR: 1.32 (0.54 – 3.22); p=0.55; I2=0 • One study163 found no difference: 0/68 (0%) vs. 1/136 (0.73%); p=0.80. (30 day follow up) • One study164 found no difference: 11/224 163- Superfic- 3 OBS (4.9%) vs. 8/224 (3.6%) 2 year follow up; 165 Low 0 0 0 0 0 0 0 0 Low ial SSI* Hazard ratio 1.5 (95% CI, 0.6-3.6); Cumulative risk of superficial SSI at 5 years: 4.5% (95% CI, 2.4-8.4) vs. 3.7% (95% CI, 1.1-6.1) • One study165 found no infections: 0/40 vs. 0/40 (1 year follow up).

Q16 What are the most effective strategies for managing the preoperative use of intra-articular corticosteroid injections to reduce the risk of SSI in prosthetic joint arthroplasty patients? Q16A. Does the length of time between intra-articular corticosteroid injection and prosthetic joint arthroplasty impact the risk of SSI? © 2017 American Medical Association. All rights reserved. 503

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- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders THA: • In a small (N=80) matched, cohort (injected: not injected) study: neither the total number of injections (p=0.89) before THA nor the time interval between the injection and the operation (p=0.88) differed. For this Length of particular measure, the study was time underpowered (0.052 and 0.053, between respectively) most • No association between the average time recent SSI* 2 OBS 164,165 from intra-articular corticosteroid injection to Low 0 0 0 0 0 0 0 0 Low Low injection primary THA and the development of and superficial SSI or PJI surgery • Mean time between injection and THA: 112

days (SD=81days).

• Mean time between injection and THA for 3 patients who developed PJI was less than half the length of time for those who developed superficial SSI (n=11): 44 days (SD=23) vs. 112days (SD=94d). Q16. What are the most effective strategies for managing the preoperative use of intra-articular corticosteroid injections to reduce the risk of SSI in prosthetic joint arthroplasty patients? Our search did not identify data that evaluated preoperative strategies for managing the use of intra-articular corticosteroid injections in prosthetic joint arthroplasty patients and their impact on risk of SSI. Q16A. Does the length of time between intra-articular corticosteroid injection and prosthetic joint arthroplasty impact the risk of SSI? Our search did not identify data that evaluated different lengths of time between preoperative intra-articular corticosteroid injection administration and its impact on the risk of TKA. Q16B. Does the corticosteroid injection dose impact the risk of SSI? Our search did not identify data that evaluated different doses of preoperative intra-articular corticosteroid injections and their impact on the risk of SSI. *Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

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2.2B.2: EVIDENCE TABLES: Q12-16 SYSTEMIC IMMUNOSUPPRESSIVE THERAPY Q12. How does systemic corticosteroid or other immunosuppressive therapy impact the risk of SSI in prosthetic joint arthroplasty patients? Q12A. Does the type of agent impact the risk of SSI? Q12B. Does the preoperative duration of the therapy impact the risk of SSI? Q12C. Does the agent dose impact the risk of SSI? Q13. What are the most effective strategies in managing systemic corticosteroids or other immunosuppressive therapy perioperatively to reduce the risk of SSI in prosthetic joint arthroplasty patients? Q13A. How safe and effective is the discontinuation of these agents preoperatively and when should they be resumed? eTABLE 59. Evidence Table for Q12-13 Systemic Immunosuppressive Therapy Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Bridges Retrospe- To compare the Number of patients: N=38 Intervention group: n=19 SSI (6 weeks) Definitions: 1991 158 ctive surgical patients (6 patients in (6 patients in both groups) PJI Complications: (ES) concurre- outcomes of both groups) and 47 [19 procedures] MTX-on: 1/15 procedures prosthetic joint infection nt control patients with procedures MTX-On - Patients who (6.7%) or would dehiscence or 1, 2, 3, 4, Rheumatoid Patient Characteristics: received MTX within 4 MTX-off: 0/32 infection documented in 6, 7, 8 Arthritis (RA) in no statistically significant weeks of surgery P=0.25 the medical record within whom differences between the Timing of intervention: NA 6 weeks after surgery methotrexate patients in control and Duration of intervention: Other infections: NR Perioperative care: NR (MTX) was intervention groups with NA Topic-specific outcomes: Analytical stopped more regard to any of the Device/agent: NA Flares NR methodology: student’s than 4 weeks characteristics examined. Monitoring intervention: Reoperations: NR t test, chi-square test, or preoperatively ·Age: NA Length of stay: NR Fisher’s exact, 2-tailed with those in ·Gender: Control group: n=25 (6 Mortality: as appropriate. whom MTX ·Obesity: patients in both groups) MTX-on: 6/19 (31.6%) Other notes: none was stopped ·Comorbidities: [34 procedures] MTX-off: 4/25 (16.7%) Follow-up: 6 weeks less than 4 Procedures: n/N MTX-Off – patients in whom One (1) patient death postop weeks procedures MTX was discontinued 4 or overlapped both groups. Funding Source preoperatively. TJA of hip or knee (n) more weeks before the Conflicts: All orthopedic MTX-on: 12/19 (63.2%) surgery, and those in whom Adverse events: NR Authors: NR surgeries were MTX-off: 32/34 (94.1%) surgery was performed Institution: NR included. MCP arthroplasty before or after the MTX Study: NR MTX-on: 2/19 (10.5%) treatment period and who Supplies: NR MTX-off: 0/34 were taking no disease Metatarsal head resection modifying anti rheumatic MTX-on: 1/19 (5.3%) drugs (DMARDs) for at least MTX-off: 1/34 (2.9%) 3 months prior to surgery. Shoulder arthroplasty Standard preventive MTX-on: 1/19 (5.3%) measures: NR MTX-off: 0/34 © 2017 American Medical Association. All rights reserved. 505

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Other MTX-on: 3/19 (15.8%) MTX-off: 1/34 (2.9%) Indications: Rheumatoid Arthritis (RA) Setting: 1 University hospital Location: USA Dates: 1981-1989 Inclusion Criteria: Patients with RA who began MTX therapy and who underwent elective primary orthopedic surgery before January 1990. Exclusion Criteria: Patients undergoing revision Total Joint Arthroplasty. Carpen- Prospecti- To Number of patients: N=32 Intervention group: n=19 SSI (1 year) Definitions: none ter ve prospectively patients (41 procedures) (26 procedures) PJI Perioperative care: NR 1996 159 Concurre- follow all Patient Characteristics: Patients assigned to MTX-on: .3/15 procedures Analytical (ES) nt control rheumatoid no significant differences in discontinue MTX the week (20%) methodology: two- 1, 2, 3, 4, arthritis (RA) patient characteristics prior and during the week of MTX-off: 0/26 procedures sample t test. Bonferroni 6, 7 patients between groups surgery (total of 2 weeks) p=0.08 correction was used for receiving Procedures: Timing of intervention: NA Other infections: NR multiple comparisons. Methotrexate THA: Duration of intervention: Topic-specific outcomes: Fisher’s exact test. (MTX) who MTXon – 8/26 (30.8%) NA Flares: no flares reported in Other notes: none underwent total MTXoff – 4/16 (25%) Device/agent: Methotrexate either group Follow-up: at least 1 joint TKA: Monitoring intervention: Reoperations: NR year postop arthroplasty to MTXon – 7/26 (26.9%) NA Length of stay: NR Funding Source determine if MTXoff – 3/16 (18.8%) Control group: n=13 (15 Mortality: NR Conflicts: continuing or TWA: procedures) Adverse events: NR Authors: NR stopping MTX MTXon – 3/26 (11.5%) Patients assigned to Institution: NR during the MTXoff – 3/16 (18.8%) continue MTX through the Study: NR perioperative TMCPA: perioperative period. Supplies: NR period MTXon – 7/26 (26.9%) Standard preventive influenced the MTXoff – 4/16 (25%) measures: NR rate of TEA postoperative MTXon – 0/26 © 2017 American Medical Association. All rights reserved. 506

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score infections. MTXoff – 1/16 (6.25%) Indications: Rheumatoid Arthritis Setting: 1 army medical center Location: USA Dates: January 1982 – December 1991 Inclusion Criteria: All RA patients receiving MTX at the time they were to undergo total joint arthroplasty or joint fusion during study dates. Exclusion Criteria: patients on azathioprine concurrently Perhala Retrospe- To assess Number of patients: Intervention Group: n=60 SSI (6 months) Definitions: NR 1991 157 ctitve whether the N=121 patients (202 patients (92 procedures) PJI Perioperative care: NR (ES) concurre- risk of local procedures) Patients who had taken MTX vs. NO MTX Analytical nt control infectious Patient Characteristics: MTX: All Total Joint methodology: Student’s 1, 2, 3, 4, complications unless listed below, no Intervention group1: Replacements t test, Chi square 6, 7 or poor wound statistically significant MTXoff: Patients who had MTX: 3/92 (3.26%) analysis. healing is differences in taken MTX but stopped NoMTX: 2/110 (1.81%) Other notes: None increased characteristics existed more than 4 weeks prior to p=0.66 Follow-up: 6 months during the between groups. the surgery Revision total joint Funding Source postoperative ·Age: mean (Y) Intervention group2: replacements: MTX: 1/9 Conflicts: course in MTX: 54.6 MTXon: patients who had (11.1%) Authors: None Rheumatoid NoMTX: 59.0 taken MTX but who took NoMTX 0/16 Institution: None arthritis (RA) P=0.03 MTX within 4 weeks of p=0.26 Study: None patients treated ·Gender: surgery Bilateral TKA Supplies: None with ·Obesity: Timing of intervention: NA MTXon 0/3 Methotrexate ·Comorbidities: Duration of intervention: NoMTX: 1/11 (9.09%) (MTX) Daily prednisone dose: NA p=1.00 mean(mg) Device/agent: Methotrexate Continuous MTX vs. MTX: 4.87 Monitoring intervention: Pausing MTX NoMTX: 3.69 NA PJI P=0.08 Control group: n=61 MTXon: 2/45 (4.44%) Procedures: THA And TKA Patients who had never MTXoff: 1/47 (2.12%) Indications: Rheumatoid taken MTX p=0.54 © 2017 American Medical Association. All rights reserved. 507

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Arthritis Standard preventive Setting: 1 hospital measures: All patients Other infections: Location: USA received antimicrobial s MTX vs. No MTX Dates: January 1, 1978 – perioperatively (Cefazolin or Deep Wound Abscess December 31, 1987 vancomycin) MTX: 0/92 Inclusion Criteria: Patients NoMTX: 1/110 (0.91%) who underwent Total hip or p=0.57 total knee replacement at Infected Hematoma the center during the study MTX: 2/92 (2.17%) dates. And who were NoMTX: 1/110 (0.91%) classified by the American p=0.47 Rheumatism Association Bilateral TKA criteria as having classic or MTX: 1/3 (33%) definite RA (30). NoMTX 0/11 Exclusion Criteria: p=0.14 Patients who had Necrotic eschar undergone apheresis or MTX: 2/92 (2.17%) total lymphoid irradiation or noMTX: 0/110 had been treated with p=0.24 azathioprine, Serous Drainage cyclophosphamide, or MTX: 1/92 (1.09%) chlorambucil concurrently NoMTX: 1/110 (0.91%) Continuous MTX vs. Paused MTX Infected Hematoma MTXoff: 2/47 (4.25%) MTXon: 0/45; p=0.30 Necrotic eschar MTXoff: 2/47 (4.25%) MTXon: 0/45 p=0.30 Serous Drainage MTXoff: 0/47 MTXon: 1/45 (2.22%) p=0.48 Topic-specific outcomes: NR Reoperations: NR Length of stay: NR © 2017 American Medical Association. All rights reserved. 508

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Mortality: NR Adverse events: NR

Momoh- Retrospe- To analyze the Number of patients: Intervention group: n= 48 SSI (Follow Up NR) Definitions: ara ctive risk ratios of N=420 Biologic DMARDS TOTAL INFECTIONS SSI: diagnosed by 2011 154 concurre- SSI after total THA = 81 (19.3%) THA = 11 27 total Postop surgeon according to (ES) nt control hip arthroplasty TKA = 339 (80.7%) TKA= 37 Complications (6.4%) CDC SSI Guideline 1, 2, 3, 4, (THA) or total Patient Characteristics: IFX: 19 (4.5%) Superficial incisional SSI: 1999. 5, 6, 7, knee given for total population ETN: 23 (5.5%) 24 (5.7%) – [treated with arthroplasty given as n (%) or median ADA: 2 (0.5%) antimicrobials] Perioperative care: (TKA) in (IQR) TCZ: 4 (1.0%) Organ/Space SSI: 3 (0.7%) General, lumbar and/or Rheumatoid ·Age: 61 (54.8-68) y – [required surgical epidural anesthesia Arthritis (RA) ·Gender % female: 382 Timing of intervention: For treatment to remove the were all utilized patients treated (91.0%) TNF-blockers was artificial joint prosthesis] with biologic ·Obesity: 21.4 (19.4-23.8) performed in accordance Non-biologic DMARDs: Analytical DMARDs BMI with British Society for 2/3 (66.7%) methodology: (mainly TNF ·Comorbidities: Rheumatology and Japan IFX: 1/3 (33.3%) Multivariate logistic blockers) Diabetes: 34 (8.1%) College of Rheumatology regression to test the compared with Smoking (ever): 67 (16.0%) Guidelines.: That TNF- Statistically significant risk association of SSI with RA patients Surgical history: 193 blocker treatment should be factors putative risk factors and treated with (46.0%) withheld 2-4 weeks prior to Disease Duration (years) with the use of non- non-biologic Disease Duration: 14.5 major surgical procedures: SSI: 23.3 (17.6-26.4) biologic DMARDs and DMARDs. (8.9-21.0)y specifically No-SSI: 14.1 (8.1-19.6) biologic DMARDs. Also to Preop CRP: 0.98 (0.25- ETN & ADA: 2-4 weeks OR: 1.09 (1.04-1.14); determine 2.19) IFX & TCZ: 4 weeks (TCZ p=0.003 Other notes: NR whether Preop Hb: 10.9 (10.2-11.8) was restarted 4 weeks after Biologic DMARDs Follow-up: NR perioperative Preop WBC: 7.25 (6.1-9.0) surgery) SSI: 10/27 (37.0%) Funding Source interruption of Revision: 16 (3.8%) Duration of intervention: No-SSI: 38/393 (9.7%) Conflicts: TNF blockers variable OR: 5.69 (2.07-15.61); Authors: Industry decreases SSI. Procedures: Total Hip Agent: biologic Disease p=0.0007 Institution: NR Arthroplasty (THA) or Total Modifying Antirheumatic Prednisone dose not a Study: NR FROM Knee Arthroplasty (TKA) Drugs (bDMARDS) statistically significant risk Supplies: NR DISCUSSION Indications: Rheumatoid Monitoring intervention: factor © 2017 American Medical Association. All rights reserved. 509

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score The aims of Arthritis (RA) NR SSI: 3 (0-5 this study were Setting: 1 Medical Control group: n=372 No-SSI: 3 (0-5 to assess the University Institute of THA=70 OR: 1.09 (0.93-1.28); influence of Rheumatology TKA=302 p=0.27 non-biologic Location: Japan DMARDs and Dates: January 2005 and Non-biologic DMARDs. As a biologic December 2009 rule were continued DMARDs, as Inclusion Criteria: Patients perioperatively but were Statistically significant well as the who full the 1987 revised administered cautiously in Medications as SSI risk withholding of American College of individual patients if there factors (where n>10 TNF-blocker Rheumatology (ACR) were comorbidities or were administered patients) therapy on the criteria for RA who elderly. IFX incidence of underwent THA or TKA Patients in this group SSI: 4/27 (14.8%) SSI. between January 2005 and received one or more No-SSI: 15/393 (3.8%) December 2009 and were immunosuppressive and/or OR: 9.8 (2.41-39.82); treated with biologic or non- immunomodulatory Non- p=0.001 biologic DMARDs biologic medication ETN Exclusion Criteria: NR IMMUNOSUPPRESIVE SSI: 6/27 (22.2%) AGENTS No-SSI: 17/393 (4.3%) MTX: 279 (66.4%) OR: 9.16 (2.77-30.25); Leflunomide: 4 (1%) p=0.0003 Tacrolimus: 31 (7.4%) Mizoribine: 15 (3.6%) Other infections: NR Cyclophosphamide: 3 (0.7%) Topic-specific outcomes: IMMUNOMODULATORY NR AGENTS Reoperations: Salazosulfapyridine: 93 3 Organ/Space SSI (0.7%) (22.1%) required removal of artificial Bucillamine: 52 (12.4%) joint prosthesis Minocycline: 7 (1.7%) Length of stay: NR Actarit: 9 (2.1%) Mortality: NR Auranofin: 4 (1.0%) Adverse events: No cases Gold Sodium Thiomalate: 1 of sever delayed wound (0.2%) healing requiring additional ᴅ-penicillamine: 16 (3.8%) sutures were observed. Glucocorticoids: 296 (70.4%) at average dose of 3.0mg/day

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score measures: All surgeries were performed with protective clothing against infection, in a bioclean room. AMP: cefazolin or ampicillin/cloxacillin were given intravenously twice before surgery and 2h after the start of surgery. AMP was not administered regularly after the day of surgery.

Hirano Retrospe- To investigate Number of patients: Intervention group: n=39 SSI (follow-up NR) Definitions: 2010 156 ctive the influences N=113 INF: 24/39 (61.5%) Infection Adverse events (AEs) of (ES) Concurre- of anti-Tumor Patient Characteristics: ETA: 15/39 (38.5%) TNF: 1 (2.6%) TKA surgical wounds nt Cohort Necrosis Factor mean ± SD (Range) or n Tumor Necrosis Factor Agents administered – included wound 2, 3, 4, 5, 8 (TNF) agents (%) (TNF) group: patients INF, MTX and oral dehiscence and on the ·Age: year (range) treated with anti-TNF agents prednisone continuation of postoperative TNF: 58.9±9.0 (31-73) from both centers Non-TNF: 5 (6.8%) discharge that were recovery in Non-TNF: 62.6±9.1 (30- Administration of agents OR: 0.7459 (0.138-4.0336) healed by conservative patients with 77) were stopped prior to P=0.7459 treatment Rheumatoid P=0.0308 surgery and restarted after Wound dehiscence: Arthritis (RA) ·Gender: Female (%) complete wound healing: Other infections: NR wound which is not and the effects TNF: 32 (82.1%) Timing of intervention: Pre Topic-specific outcomes: completely healed in 14 of biologics on Non-TNF: 65 (87.8%) and postoperatively Subanalysis: influence of POD or which requires wound healing. ·Obesity: NR anti-TNF on wound secondary suture. ·Comorbidities: Duration of intervention: healing Infection: positive culture RA Duration: years variable THA N=30 total results (Range): INF: agent stopped 3-4 TKA N= 65 total Time for complete TNF: 13.5±7.8 (4-32) weeks prior to surgery. TNF n=13 wound healing: the Non-TNF: 16.5±11.7 (1- (mean 29.8 days preop) TNF n=14 period from the date of 51) ETA: agent stopped 1-2 Non-TNF n=17 operation to the removal Steinbrocker Stage III vs. IV weeks prior to the surgery. Non-TNF=51 of surgical staples. TNF: 18.8% vs. 81.2% (mean 9.6 days preop) Postop Febrile periods: Non-TNF: 52.7% vs. AE Occurrence rate for body temp≥37.5oC 47.3% Agents: Anti-TNF surgical wounds: % recovery of P=0.0249 Infliximab (INF) or THA = 0 .0% in both TNF hemoglobin (%Hb), % %MTX use etanercept (ETA) and non-TNF groups. recovery of total protein © 2017 American Medical Association. All rights reserved. 511

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score TNF: 92.3% (%TP), and % recovery Non-TNF: 50.0% Monitoring intervention: TKA of serum albumin P=0.001 NR TNF: 1 (7.1%) (%Alb): Control group: n=74 Non-TNF: 4 (7.8%) Perioperative care: NR Procedures: Ankle Non-TNF Group (traditional OR= 0.9038 (0.0928- arthrodesis and total DMARDs) consisting of 8.7992) p=NS Analytical arthroplasty of the hip, patients only from the methodology: knee, elbow, shoulder and University Hospital. Febrile Period Continuous variables ankle. Only the first THA evaluated with Mann operation for each patient Standard preventive TNF: 3.5±2.0 days Whitney U Test. Or was included. measures: NR Non-TNF: 3.1±1.9days Fisher’s exact test to TKA OR= 0.9038 (0.0928- evaluate the difference TNF: 14 (35.9%) 8.7992) p=NS in Proportions. Non-TNF: 51 (68.9%) TKA Other notes: Data was THA TNF: 2.6±2.5 days collected from medical TNF: 13 (38.2%) Non-TNF: 2.9±1.7 days records. Non-TNF: 17 (23.0%) Follow-up: NR TEA %Hb, %TP, %Alb: The only Funding Source TNF: 8 (20.5%) statistically significant Conflicts: Non-TNF: 4 (5.4%) difference between TNF Authors: None AD and non-TNF groups Institution: None TNF: 3 (7.7%) occurred in the THA Study: None Non-TNF: 1 (1.4%) subgroup for %Hb Supplies: None TSA TNF: 101.0±14.4% TNF: 1 (2.6%) Non-TNF: 83.8±10.0% Non-TNF: 0 P=0.0016 TAA Reoperations: TNF: 0 TNF infection was treated Non-TNF: 1 (1.4%) with surgical debridement without implant removal; Indications: Rheumatoid antimicrobials were Arthritis (RA) administered for 4 weeks. Setting: 1 University Length of stay: NR Hospital and 1 medical Mortality: NR center Adverse events: Location: Japan Adverse Events (AEs) of Dates: April 2004 – July surgical wounds 2007 TNF: 2 (5.1%) Inclusion Criteria: Patients Non-TNF: 5 (6.8%) with RA undergoing Ankle OR: 0.7459 (0.138-4.0336) © 2017 American Medical Association. All rights reserved. 512

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score arthrodesis and total P=0.7459 arthroplasty of the hip, Time to Complete Wound knee, elbow, shoulder and Healing ankle TNF: 10.9±1.2 days Exclusion Criteria: Non-TNF: 10.8±1.3 days revision surgery and other Postop Febrile Periods: minor operations such as TNF: 2.6±2.2 days foot operations and wrist Non-TNF: 2.9±1.7 days operations %Hb TNF: 96.3±14.3% Non-TNF: 90.1±11.5% P=0.0156 %TP TNF: 100.8±9.5% Non-TNF: 100.8±9.2% %Alb TNF: 98.9±13.5% Non-TNF: 98.0±11.3% Kawak- Retrospe- To validate that Number of patients: Intervention group: n=64 SSI (follow up If using Definitions: ami ctive perioperative N=128 surgeries (112 surgeries (49 patients) CDC criteria then all SSI: CDC SSI Guideline 2010 155 Concurre- interruption of patients) Anti-TNF group superficial 30d and criteria (1999) (ES) nt control Tumor Patient Characteristics: IFX = 35 anything with an implant Flare-ups: Arthralgia 1, 2, 3, 4, Necrosis Factor Patients were matched for ETN = 29 wound be 1yr for deep was evaluated using 5, 6, 7 (TNF) blocker type of surgery and gender NOTE: 56 (87.5%) of TNF and organ/space) subjective patient therapy between groups. group was also on MTX and Superficial SSI assessments. decreases ·Age: years 53 (82.8%) were on TNF: 7/64 (10.9%) Serological markers like complications TNF: 57.0 (51.8-64.0) prednisone 5mg/day (range requiring the use of CRP and ESR have not utilizing the DMARDs: 57.0 (47.0-64.0) 2-7) (see patient antimicrobials been deemed suitable British Society ·Gender: male/female characteristics) DMARDs: 1/64 (1.6%) for measuring the for TNF: 13/51 Timing of intervention: P=0.016 disease activity during Rheumatology DMARDs: 13/51 ETN was withheld 2-4 weeks the perioperative period. guidelines and ·Obesity (BMI) before surgery infliximab Deep SSI: Recurrences of the Japanese TNF: 21.2 (20.3-22.7) (IFX) was withheld 4 weeks TNF 1/64 (1.6%) – IFX Arthralgia were College of DMARDs: 21.2 (20.1-23.9) before surgery. and required prosthesis considered Flare-ups. Rheumatology ·Comorbidities Both were restarted after removal Venous recommendatio Disease Duration (y) there was no evidence of DMARD: 0 thromboembolism of ns for TNF: 10.6 (8.0-19.8) infection and once wound lower extremities: withholding DMARDs: 13.4 (8.9-19.1) healing was satisfactory. Multivariate analysis of diagnosed by 3 infliximab (IFX) Methotrexate (MTX) Duration of intervention: putative risk factors for SSI: experienced medical and etanercept TNF: 56 (87.5%) Pre and postoperative OR (90%CI) technologists using © 2017 American Medical Association. All rights reserved. 513

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score (ETN) for 2-4 DMARDs: 48 (75%) Agent: Disease duration (y): 1.169 ultrasonography week prior to P=0.06 Anti-Tumor Necrosis Factor (1.030-1.326); P=0.015 Perioperative care: major surgical DMARDs (TNF) agents: Infliximab TNFα-blocker: 21.8 (1.231- All surgery was procedures TNF: 8 (12.5%) (INF) or etanercept (ETN) 386.1) p=0.036 performed under general then restarting DMARDs: 31 (48.4%) Monitoring intervention: PSL dosage: 1.433 (1.007- or epidural anesthesia treatment once P=7.99E-06 NR 2.040) p=0.046 Analytical there is no Prednisone (PSL) Control group: n=64 methodology evidence of TNF: 53 (82.8%) surgeries (63 patients) Other infections: Multivariate logistic infection and DMARDs: 40 (62.5%) Patients treated with non- Urinary Tract Infection: regression was once wound P=0.008 biologic DMARDs. Some TNF: 1/64 (1.6%) performed to test the healing is PLS, dose, mg/day patients took more than 1 DMARD: 0 association of SSI & satisfactory. TNF: 5 (2-7) DMARD Respiratory Inflammation DVT with putative risk Wound DMARDs: 3 (0-5) Methotrexate (MTX): n=48 TNF: 0 factors complications, P=0.006 Salazosulphapyridine: n=18 DMARD: 1/64 (1.6%) Baseline characteristics Deep Venous Bycillamine: n=6 were compared using Thrombosis Baseline characteristics for ᴅ=penicillamine: n=4 Topic-specific outcomes: Mann-Whitney U-test or and flare-ups DVT Subanalysis (Listed NOTE: 40 (62.5%) of Flare-ups due to Fisher’s exact test. following joint below are only those DMARD patients were on interruption of anti-TNF: Other notes surgery were factors that demonstrated prednisone 3mg/day (range Arthralgia (+): Follow-up: If using CDC assessed. statistically significant 0-5) (see patient IFX: 2/35 (5.7%) criteria then all differences between groups characteristics) ETN: 9/29 (31.0%) superficial 30d and Methotrexate (MTX) Standard preventive P=0.009 anything with an implant TNF: 39 (86.7%) measures: None The ETN patients wound be 1yr for deep DMARDs: 32 (71.1%) experienced difficulty for a and organ/space P=0.06 while during post-op rehab, Funding Source DMARDs but recovered after Conflicts: TNF: 7 (15.6%) resumption of ETN Authors: Industry DMARDs: 24 (53.3%) Treatment. Institution: None P=1.54E-04 Majority of IFX patients Study: None Prednisone (PSL) underwent surgery in the Supplies: None TNF: 38 (84.4%) middle of an 8-week DMARDs: 29 (64.4%) infusion treatment. P=0.026 Reoperations: PLS, dose, mg/day 1 deep SSI (TNF group TNF: 5 (2-7) (IFX)) required removal of DMARDs: 3 (0-5) artificial joint prosthesis. P=0.041 Length of stay NR Procedures: Mortality NR 1:1 pair-matched case Adverse events: control study so numbers Postoperative complication © 2017 American Medical Association. All rights reserved. 514

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score below are number of of delayed wound healing procedure PER STUDY was absent in both groups. GROUP DVT Subgroup analysis Arthroplasty procedures: DVT Positive n=54 (84%) TNF: 23/45 (51%) Shoulder Arthroplasty (SA): DMARDs: 12/45 (26%) 1 P=0.015 Unilateral, elective elbow Multivariate logistic arthroplasty: 2 regression showed that Implant replacement TNF blockers were the only arthroplasty of the MCP statistically significant risk joints: 2 factor for DVT. Wrist arthroplasty:6 OR= 2.83 (1.10-7.25) Unilateral, Elective THA: 8 p=0.03 Unilateral, elective TKA: 33 Total ankle arthroplasty (TAA): 1 Bipolar hip hemiarthroplasty: 1 Non Arthroplasty procedures: n=10 (16%) Arthroscopic synovectomy of the knee: 3 Foot surgery: 5 Ankle arthrodesis:1 Open reduction and internal fixation (ORIF): 1 Indications: Rheumatoid Arthritis Setting: 1 medical university Location: Japan Dates: May 2004 – March 2009. Inclusion Criteria: Patients in matched pairs either treated with anti-TNF agents or conventional DMARDS and who underwent joint surgery for © 2017 American Medical Association. All rights reserved. 515

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score RA. All patients fulfilled the 1987 revised ACR Criteria for RA Exclusion Criteria: Surgery in which TNF agent adalimumab (ADA) was used

Bongar- Retrospe- To determine Number of patients: Intervention group: n=462 SSI (mean follow up 4.3 Definitions tz ctive the cumulative N=924 patients with 657 years) RA Diagnosis: verified 2008 160 concurre- and 1-year Patient Characteristics surgeries. PJI in matched cohorts at 5 by using validated RA (ES) nt cohort incidence of ·Age: mean±SD y Patients with RA undergoing years classification criteria. 1, 2, 3, 4, prosthetic joint RA: 63.6±13.3 either THA or TKA. RA: 15/462 (4.2%) According to the 5, 6, 7 infection (PJI) OA: 67.2±10.8 Timing of intervention: Pre OA: 4/ 462 (1.4%) American College of in total hip P<0.001 or post operatively Log rank p=0.005 Rheumatology arthroplasty ·Gender: n% female Duration of intervention: If HR: 4.08 (1.35-12.33) classification criteria. (THA) and total RA: 363 (78.6%) DMARD therapy was After adjusting for previous OA Diagnosis: verified knee OA: 338 (73.2%) withheld around the time of infection in the index joint: during chart review arthroplasty P=0.06 surgery, the stop and start HR: 3.74 (1.23-11.33) using physician’s (TKA) in a ·Obesity: NR dates were abstracted based [age, sex, functional class, diagnosis of hip and/or modern cohort ·Comorbidities: on pharmacokinetic half-life and comorbidity were not knee OA and absence of of patients with At least 1 comorbidity and/or data on the biologic significant predictors of RA RA and to RA: 337 (73.0%) activity of each DMARD. infection) PJI: diagnosed when at further explore OA: 383 (83.0%) According to the information PJI in matched cohorts at 1 least 1 of the following potential risk P<0.0001 below, the DMARD use was year were present: factors for Mean disease Duration: judged as either withheld or RA: 10/462 (2.3%) 1. Isolation of the same these 21.1 years maintained. OA: 1/ 462 (1.4%) organism from ≥2 infections. Previous PJI in index joint Duration of days medication p=deemed statistically cultures of joint aspirates Additionally, RA: 43 (9.3%) was withheld: significant, but P=NR or intraoperative tissue the frequency OA: 24 (5.2%) Methotrexate:8 OR: 10.30 (1.31-80.26) specimens. of this Steinbrocker functional Leflunomide: 85 days or 14 2. Acute inflammation complication of classification at time of days with cholestyramine PJI in RA population consistent with infection patients with surgery (p<0.0001) wash-out RA: 23/657 (3.7%) on histopathologic RA as Class1 (patient normally Oral gold: 8 (14[2.2%] infected w/in first examination (as compared with active): Intramuscular gold: 29 year) determined by the patients with RA: 4 (0.9%) Sulfasalazine: 8 Revision: 15/255 (5.9%) pathologist). OA who OA: 6 (1.3%) Hydroxychloroquine: 85 Primary: 8/402 (2.0%) 3. Cutaneous sinus tract undergo the Class2 (patient able to Azathioprine: 8 THA: 12/328 (3.7%) communicating with the © 2017 American Medical Association. All rights reserved. 516

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score same type of maintain occupation but Cyclosporine: 8 TKA: 11/329 (3.3%) joint prosthesis surgery was less active): Cyclophosphamide: 8 Previous PJI: 7/67 (10.4%) 4. Purulence in the joint assessed. RA: 183 (39.6%) ᴅ-penicillamine: 15 space (as determined by OA: 338 (73.2%) Etanercept: 8 Statistically significant risk the surgeon). Class3 (unable to maintain Adalimumab: 15 factors for SSI (univariate) Perioperative care occupation): Infliximab: 57 HR (95%CI) [p=NR] RA: 184 (39.6%) Anakinra:8 Revision arthroplasty: 2.99 Analytical OA: 108 (23.4.2%) (1.02-8.75) methodology: Class4 (largely or wholly Agent: See above Previous infection of index Proportion of surgeries incapacitated): joint: 5.49 (1.87-16.14) complicated by a PJI RA: 86 (18.6%) Monitoring intervention: Operation Time: 1.36 per was estimated by OA: 8 (1.7%) NR 60-min increase (1.02-1.81 Kaplan-Meier Unknown: Techniques. RA: 6 (1.3%) Control group: n=462 ** NOTE** - Patients in this Cox proportional OA: 2 (0.4%) patients study who had a previous hazards models were Matched cohort of patients PJI had a risk of another used to examine the Procedures: Total knee with OA instead of RA. infection of only 3.5% as association between the arthroplasty (TKR) or total Patients were listed in the compared with 29.2% after risk of prosthetic joint hip arthroplasty (THA) registry as having a revision of the previously inspection for Primary THA: 164 (25.0%) diagnosis of OA and no infected joint. explanatory variables. Revision THA: 164 (25.0%) diagnosis of RA. Matching Also used to compare Primary TKA: 238 (36.2%) was performed according to DMARD the risk of infection Revision TKA: 91 (13.8%) age (±5 years), site (hip or Stopping DMARD therapy between the RA and OA Indications: Rheumatoid knee), type (revision or at the time of surgery cohorts. Arthritis (RA) or primary arthroplasty), and lowered the Risk of Osteoarthritis (OA) time point of first surgery. subsequent PJI: HR 0.65 Other notes: None (0.09-4.95) but not Setting: 1 hospital Standard preventive statistically significant. Follow-up: measures: Patients who did not stop Length of FU. mean±SD Location: USA AMP: Preop AMP: 656 anti-TNF therapy before (years) (99.9%) surgery:3/38 (7.9%) RA: 3.1±2.4 Dates January 1, 1996 – infections OA: 3.8±2.6 June 30, 2004 Nonstandard preventive Patients who stopped measures: Anti-TNF therapy before All patients were Inclusion Criteria: All Antimicrobial impregnated surgery: 0/12 infections. followed up by surgeon patients with a diagnosis of cement: 209 (31.8%) P=NS examination at least RA or OA who underwent surgeries were performed twice in the first THA or TKA during the with antimicrobial Perioperative cortisone was postsurgical year and study dates. impregnated cement not associated with then at least every 5 increased risk of prosthesis years thereafter. If in- © 2017 American Medical Association. All rights reserved. 517

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Exclusion Criteria: NR infections person follow up was not Other infections: NR possible, patients were Topic-specific outcomes: contacted by letter NR and/or phone and asked Reoperation : to complete a 16/23 (69.6%)infections standardized form were treated with For outstanding or prosthesis removal. 6/16 unclear issues as well as had subsequent for a follow-up <1 year, reimplantation primary physicians were 7/23 (30.4%) were treated contacted. with debridement and long- Funding Source term antimicrobial Conflicts: suppression therapy. Authors: Industry Length of stay: NR Institution: None Mortality: NR Study: None Adverse events: NR Supplies: None

Q13B. Should the agent dose be adjusted, and if so, for how long? Our search did not identify data that evaluated perioperative immunosuppressive therapy dose adjustment and its impact on the risk of SSI in prosthetic joint arthroplasty patients.

Q14. What is the optimal duration of postoperative AMP to reduce the risk of SSI in prosthetic joint arthroplasty patients who are on systemic corticosteroid or other immunosuppressive therapy? Our search did not identify data that specifically evaluated differences in duration of postoperative AMP in prosthetic joint arthroplasty patients who were on systemic corticosteroids or other immunosuppressive agents and its impact on the risk of SSI. However, multiple procedures examined in the Core section, Q1.E: Postoperative AMP duration that included patients on immunosuppressive therapy showed no benefit of continuing AMP after closing the surgical incision in the operating room. Therefore, the broader recommendation for duration of postoperative AMP should be applied to prosthetic joint arthroplasty procedures irrespective of use if systemic corticosteroid or other immunosuppressive therapy.

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eTABLE 60.Evidence Table for Q15. How does preoperative intra-articular corticosteroid injection impact the risk of SSI in prosthetic joint arthroplasty patients? Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Desai Retrospe- To compare the Number of patients: Intervention group: n=90 SSI (Follow up at least 1 Definitions: 2009 162 ctive incidence of N=360 knees (250 knees (80 patients) year) Superficial Infections: (ES) Concurr- infection in patients) Patients who had an Unadjusted Results cases which had ent patients who injection prior to undergoing Superficial Infection (All discharge from Control had an intra- Patient Characteristics knee replacement surgery. treated with antimicrobials superficial layers within 1, 2, 3, 4, articular steroid ·Age: mean (Range) years 45/80 (56.3%) patients had a & no further complications) one moth of surgery; 5 infiltration prior Injection: 68 (49-87) TKR within 12 months after Injection: 2/90 (2.2%) patients who received to a knee No Injection: 72 (51-88) the injection [both patients received antimicrobial cover for replacement, ·Gender: m/f Timing of intervention: injections 18 months prior more than 1 week with those who Injection: 26/54 preoperative to surgery as an outpatient delayed wound healing hadn’t. SSI and No Injection: 74/96 Duration of intervention: procedure] and cases which had Knee of TKR: right/left Variable No Injection: 5/180 (2.7%) positive cultures form Injection: 42/48 Agent: (40mg/dL RR 0.80 (0.16-4.03) P=1.0 superficial layers which No Injection: 82/98 methylprednisolone and settled and did not ·Obesity: NR 5mg/mL levobupivacaine) 6/7 Infections occurred in require further surgery ·Comorbidities: NR intra-articular steroids. patients with Osteoarthritis. for the knee Infiltration was conducted in Deep Infection: cases Procedures: Total Knee the operating theater as a Deep Infection: No Cases with positive swab Arthroplasty (TKR) day-case procedure in either group cultures or tissue biopsy (patients were discharged from the deep tissues, Indications: later the same day). Injection Other infections: NR patients who under-went Osteoarthritis was conducted under strict Topic-specific outcomes: exploration and wash Injection: 58/80 (72.5%) aseptic precautions. None out of the wound with No Injection: 133/170 30 knees (the earlier Reoperations: None positive culture report (78.2%) surgeries) were performed Length of stay: NR and cases which Rheumatoid arthritis as out-patient procedures Mortality: NR underwent revision Injection: 22/80 (27.5%) with strict aseptic Adverse events: NR surgery for infection. No Injection: 37/170 precautions. Perioperative care: NR (21.7%) Monitoring intervention: Analytical Setting: 1 hospital NR methodology: Normal Location: England Control group: n=180 approximation method Dates: 1997 - 2005 knees (170 patients) was utilized to assess Inclusion Criteria: Patients Knees undergoing TKR that non-inferiority of who had total knee had no injection prior to TKR injection on risk of replacement within the surgery. Knees were infection. study dates with a minimum matched two control knees Other notes: Patients 1-year follow-up including to one Intervention knee. were retrospectively © 2017 American Medical Association. All rights reserved. 519

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score patients with diabetes Matching was done on the identified by analysis of mellitus and a history of basis of age, sex and year of the notes in a smoking. operation. Age selection was prospective database of Exclusion Criteria: A done by 10 yearly intervals TKRs performed by the history of malignancy, and year of operation was primary author. immune-suppressive drugs, done by 3-yearly intervals Cohort matching was sero-negative inflammatory Standard preventive done prior to any arthropathy or a previous measures: evaluation of patient infection in the ipsolateral Prosthesis: All TKR were notes with respect to knee. cemented, fixed bearing infection rates. knee systems. Authors estimate that Approach: midvastus given low infection rate, approach under tourniquet sample size of ~2000 Suction: usage was kept to a patients per group minimum and only used needed to rule out (with during pulsed lavage 95% CI) a 50% increase irrigation prior to in infection rate among cementation. those injected. Irrigation: prior to wound Follow-up: At least 1 closure and with 0.05 year follow up. Mean chlorhexidine. follow-up was 48 Hemostatis: meticulously months. Range 1- achieved before closure over 6years) drains Funding Source Tourniquet was released Conflicts: after wound closure Authors: NR AMP: 3 doses of Cefuroxime Institution: NR postoperatively in addition to Study: NR the loading dose to ensure Supplies: NR cover for 24 hours Postop

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Sreeku- Retrosp- To determine if Number of patients: Intervention group: n=66 SSI (F-U at least 1 year) Definitions: None mar ective intra-articular N=202 patients (68 hips) Infection at most recent 2007 163 Concurr- steroid injection Patient Characteristics Injection Cohort: received follow up Perioperative care: NR (ES) ent prior to joint ·Age: avg. (range) median, intra-articular injection of Total Infections: Control (hip) y steroids prior to hip Injection: 0 Analytical 1, 2, 3, 4, replacement Injection: 62.2 (32-89) replacement surgery No Injection: 2/136 (1.4%) methodology: 5 increases the 62.62 Timing of intervention: Difference in incidence: Statistical analysis was risk of injection No-injection: NR (39-89) Pre-operatively 1.4% (-0.5%-3.3%) performed using Stata. in replaced 64.09 Duration of intervention: 95%CI was obtained by joints relative to ·Gender: m/f variable Superficial: the normal patients who Injection: 15/51 Agent: 40mg/dL Injection: 0 approximation method had no intra- No-injection: 32/104 methylprednisolone and No Injection: 1/136 (0.7%) articular ·Obesity: Any patient 5mg/mL levobupivacaine noticed at 4 weeks postop Other notes: All injection prior considered overweight were injected. Patients were and responded to procedures performed to the same (BMI>35) was advised to discharged the same day. antimicrobials. by single surgeon surgery. lose weight prior to surgery. Monitoring intervention: Deep Infection The operation was deferred NR Injection: 0 Follow-up: at least 1 until the patient achieved Control group: n=136 No Injection: 1/136 (0.7%) year target weight. patients (136 hips) who presented 2 months postop Average Follow Up: ·Comorbidities received no intra-articular with pyrexia and severe Injection: 25.33 months Infections: patients were injection prior to surgery pain. Patient was 75yo. Hip No Injection: 22.28 critically assessed for any Each hip in the intervention was aspirated and months focus of sepsis, including was matched to two hips in antimicrobials were started. Funding Source form the bladder, skin and the control (non-injection) Other infections: NR Conflicts: lungs. group Topic-specific outcomes: Authors: NR Time between injection and Matching was done on the NR Institution: NR operation for Injection basis of age (10-year Reoperations: Study: NR Cohort: Mean 14 months intervals), gender, and year Reattachment of trochanter Supplies: NR (median 11 months) of operation (3-year Injection: 1/66 (1.5%) Procedures: Hip intervals). When exact occurred at 2 years Postop replacement matches were unavailable, due to persisting pain Right/left the next closest match was No Injection: 0 Injection: 41/27 chosen. Length of stay: NR Bilateral Procedure: Standard preventive Mortality: Injection: 2/66 measures: Injection: 0 Indications: NR Surgeon: all surgeries were No Injection: 1/136 (0.7%) Setting: 1 Tertiary Referral performed by the senior Patient with joint infection Hospital author presented at 2 months Location: England Approach: by the trans- postop developed acute © 2017 American Medical Association. All rights reserved. 521

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Dates: 1997 - 2004 trochanteric. Trochanteric renal shutdown and died of Inclusion Criteria: Patients osteotomy was done and the multi-organ system failure who underwent hip hip was exposed. at 3 months. replacement surgery after Suction: kept to a minimum Adverse events: steroid filtration. A matched used only during pulsed Aching hip postop cohort of patients was lavage to reduce the suction Injection: 3/66 (4.5%) created of patients who catheter sucking air towards [had absence of infection underwent hip replacement the patient. confirmed by ESR, CRP without steroid infiltration Irrigation: regular washing of Levels & isotope scans] prior to surgery. the wound was done with Exclusion Criteria: chlorhexidine 0.05%. Patients who had previous Hemostatis: meticulous operations on the same hip hemostasis was achieved and patients who had before closure of the drains malignancy or were on AMP: 3 doses of cefuroxime, immune-suppressive drugs. postoperatively, in addition Patients with a previous to the loading dose to infection in the same hip ensure coverage for 24h were excluded. postop.

McIntosh Retrosp- To determine if Number of patients: Intervention group: n=224 SSI (follow-up minimum 2 Definitions: 2006 164 ective the N=448 Patients who received intra- years) Superficial Infection: any (ES) Concurr- administration Patient Characteristics articular steroid injection Superficial Infections wound infection that did ent of an intra- ·Age: mean (SD) years within 1 year prior to total hip Injection: 11 (4.9%) not penetrate the deep Control articular steroid Injection: 70 (9.8) arthroplasty No Injection: 8 (3.6%) fascia and included any 1, 2, 3, 4, injection into an No Injection: 69 (9.6) Timing of intervention: Hazard Ratio: 1.5 (0.6-3.6) patients with persistent 5, 8 osteoarthritic ·Gender m/f Preoperative Cumulative Risk of postoperative wound hip within 1 Injection: 93/131 Duration of intervention: superficial infection at 5 drainage, superficial year of No Injection: 92/132 Variable years: wound dehiscence, or subsequent ·Obesity: Calculated from Agent: (Agent-Not Injection 4.5% (2.4-8.4) suture abscess primary THA mean height/weight standardized) Steroids No Injection: 3.7% (1.1- formation. would increase reported: delivered via intra-articular 6.1) Perioperative care: NR the rate of Injection: 30.1 injection. All injections were 15/19 superficial infections superficial and No injection: 29.8 performed by members of were treated with local Analytical deep Height: mean (SD) cm the radiology department wound care and 7/15 were methodology: periprosthetic Injection: 167 (24) within 1 year prior to the also treated with a course Kaplan-Meier method infection when No Injection: 168 (9.7) THA using standard aseptic of oral antimicrobial was used to estimate the compared with Weight: mean (SD) kg protocols. Hip penetration prophylaxis cumulative risk of a matched Injection: 84 (19.9) was confirmed Deep infections (developed infections. © 2017 American Medical Association. All rights reserved. 522

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score control group No Injection: 84 (19.9) fluoroscopically by the at a mean of 1.69 years) Cox proportional hazard who did not ·Comorbidities: NR installation of radiopaque Injection: 3 (1.3%) model was used to receive a Time from injection to THA: dye before steroid No Injection: 1 (0.4%) assess the difference in preoperative mean (SD) days administration. Type and Hazard Ratio: 3 (0.3-29.8) survivals between intra-articular Injection: 112 (81) amount of steroid dispensed Cumulative Risk of deep groups. Taking into steroid No Injection: NA was left to the discretion of infection at 5 years: account the timing of injection. Operative Time: mean (SD) the performing radiologist. Injection: 3% (0-7%) injection and the length minutes: Monitoring intervention: No Injection: 0.6% (0- of follow-up. Injection: 182 (47) NR 1.7%) Other notes: No Injection: 182 (48.1) Control group: n=224 None of the superficial Follow-up: at 3 months, Procedures: Total Hip Patients who did not receive infections had deep 1 year, 2 years, and 5 Arthroplasty intra-articular steroid infections develop. years. Or until THA Indications: Osteoarthritis injections prior to Total Hip 2/4 deep infections were revision for instability, Setting: I Research Arthroplasty. Patients were preceded by multiple loosening, implant Hospital matched to the Injection recurrent dislocations (both resection for deep Location: USA Group (intervention) in injection group) infection, or death. Dates: January 1998 – May Standard preventive 2/4 deep infections also Minimum 2 years 2002 measures: NR had a chronic medical Average follow up Inclusion Criteria: Patients condition (years) with OA of the hip during 1/2 had a tracheostomy Injection: 2.7 (1.4) the study dates. for sever obstructive sleep No Injection: 2.6 (1.6) Exclusion Criteria: apnea and was on chronic Funding Source Diagnosis of inflammatory anticoagulation for atrial Conflicts: arthritis, connective tissue fibrillation & DVT and/or Authors: None disorders, any history of pulmonary embolism. Institution: None acetabular or femoral 1/2 had type II diabetes Study: None fracture, any previous mellitus Supplies: None surgery on the index hip, or tumor of the acetabulum or No association was found femur. between the average time from intraarticular injection to primary THA and the development of Superficial or Deep Infections Overall average time between steroid injection and THA for injection group: 112 (SD 81) days © 2017 American Medical Association. All rights reserved. 523

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Superficial: 112 (SD 94) days Deep: 44 (SD 23) days Probability value could not be calculated because of limited number of patients with deep infections

Other infections: NR Topic-specific outcomes: NR Reoperations: Superficial infections 2/15 had surgical removal of retained drains 2/15 had wounds incised followed by irrigation and debridement with documentation of fascial integrity Deep Infections 3/3 treated with two-stage exchange 1/3 treated by debridement with prosthesis retention and chronic suppression with oral antimicrobial therapy Length of stay: NR Mortality: Unrelated to THA: Injection: 12 (5.4%) No Injection: 13 (5.8%) Adverse events: Revision for aseptic loosening: Injection: 5 (2.2%) No Injection: 4 (1.8%) Dislocations © 2017 American Medical Association. All rights reserved. 524

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Injection: 6 (2.7%) No Injection: 5 (2.2%) Mean time to dislocation: (yr.) Injection: 1.41 (0.02-3.13) No Injection: 1.54 (0.02-5) 4/11: demonstrated hip stability with conservative treatment 7/11: reoperations Injection: 4 (1.8%) No Injection: 3 (1.3%) Papavas- Retrosp- To determine Number of patients: Intervention group: n=54 SSI Definitions: iliou ective the rate of N=144 Patients who had received Superficial: 30 days Superficial incisional 2006 161 Concurr- infection in Patient Characteristics: one or more intra-articular Superficial wound infection: infection: an SSI which (ES) ent patients who ·Age: NR injection of steroid in their Injection: 12/54 (22.2%) occurred within 30 days Control had undergone ·Gender: NR operated knee No injection: 10/90 of surgery and involved 1, 2, 3, 4, TKR and to ·Obesity: NR (11.1%) only the skin or 5, 8 correlate this ·Comorbidities: NR Timing of intervention: P=0.1 subcutaneous tissue rate with the Procedures: Total knee variable preoperatively around the incision. pre-operative replacement Deep wound infection: 1 One of the following use of intra- Indications: See exclusion Duration of intervention: year criteria had to be met: articular criteria variable Injection: 3/54 (5.6%) 1) purulent drainage steroids. Setting: 1 hospital No injection: 0 from the incision Location: England Agent: Methylprednisolone- P<0.025 2) cultured organisms Dates: February 2002 – Steroid delivered via intra- from a swab or tissue October 2004 articular injection in an All 3 deep infections were biopsy from the orthopedic clinic, treated with long-term superficial wound layers. Inclusion Criteria: All rheumatology clinic, or antimicrobial therapy and Deep Incisional patients who underwent general practice setting revision surgery. infection: an SSI which TKR during the study dates before surgery. All 3 deep infections had occurred within 30 days Monitoring intervention: injections within 12 months. of surgery and involved Exclusion Criteria: If NA only the skin or records were incomplete, No relationship was found subcutaneous tissue patients who had previous Control group: n=90 between the number or around the incision. surgery on the affected Patients with no record of timing of injections and the One of the following knee (other than having received an intra- risk of postoperative criteria had to be met: arthroscopy), a diagnosis of articular injection of steroid infection 1) purulent drainage inflammatory arthritis, before surgery. from the depths of the © 2017 American Medical Association. All rights reserved. 525

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score immunosuppression, and a Other infections: NR incision previous history of infection Standard preventive Topic-specific outcomes: 2) microbiological culture around the knee, smoking measures: Recorded but NR from aseptically- and diabetes. not reported. Reoperations: aspirated fluid, a swab Revision surgery for deep or a tissue biopsy from infection the deep-tissue layers or Injection: 3/54 (5.6%) pus cells present on No injection: 0 microscopy P<0.025 3) a deep incision which Length of stay: NR spontaneously dehisced Mortality: NR or was deliberately Adverse events: opened by a surgeon Postoperative when the patient had a investigations for deep temperature >38oC, infection due to symptoms localized pain, or of persistent pain or tenderness swelling. 4) an abscess or other Injection: 5/54 (9.3%) evidence of infection No injection: 0 involving the deep incision which was found by direct examination, during re-operation, or by histopathological or radiological examination 5) Diagnosis of a deep incisional SSI by an attending physician

Perioperative care: NR Analytical methodology: Chi- squared test Other notes: A pilot study of 420 patients who had received a TKR was performed by reviewing the records looking for incidences of deep © 2017 American Medical Association. All rights reserved. 526

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score infection: 6/420 (1.4%) deep infections occurred. 5/6 infections had received an intra- articular injection of steroid prior to surgery. Follow-up: NR Funding Source Conflicts: Authors: None Institution: None Study: None Supplies: None Kaspar Retrosp- To determine Number of patients: N=80 Intervention group: n=40 SSI (mean follow up 29.8 Definitions 2005 165 ective the influence of (entire database 979) Received intra-articular months) Perioperative care (ES) Concurr- intra-articular Patient Characteristics steroids prior to THA. Details Deep Infection Analytical ent steroid injection ·Age mean ±SEM (Range) of injections were found from Injection: 4/40 (10%) methodology: Control on the rate of y an examination of patients No Injection: 0 Descriptive statistics, 1, 2, 3, 4, surgical site Injection: 71.03±1.53 (45- receiving injections in the P=0.01 unpaired t-test, Fisher’s 5, 8 infection in 87) fluoroscopy suite. exact test for categorical patients with No Injection: 70.55±1.50 Timing of intervention: Overall rate of established data, Kaplan-Meier osteoarthritis (46-87) Preoperatively infections and possible survival analysis, and undergoing ·Gender: m/f infections comparison of survival subsequent Injection: 25/15 Duration of intervention: Injection: 12/40 (30%) plots by Mantel-Cox type THA ·Obesity: BMI variable No Injection: 3/40 (7.5%) log-rank testing. Injection: 28.58±0.72 (17- Other infections: NR Power analysis 39) Agent: Methylprednisolone Topic-specific outcomes: performed by univariate No Injection: 29.94±0.77 80mg with 1-5ml of Time between most recent modeling. (21-43) bupivacaine. Steroids injection and THA: mean Other notes: Study was ·Comorbidities: Mean ASA delivered via intra-articular ±SEM (95%CI) underpowered score for both groups was injection. Injections were Infection and/or infection 2.2 indicating most patients performed in a fluoroscopy test: 11.38±3.03 (5.6-17.2) Follow-up: had few comorbidities suite under aseptic No Infection/ no infection Mean length of follow Problems with the spine technique Test: 10.86±1.74 (7.2-14.5) up: 29.8±0.4 months were present in P=0.878 Injection: 33.2±2.1 approximately half of the Monitoring intervention: Power: 0.053 months population evenly NR No Injection: 30.2±1.6 distributed across groups. Total number of injections months Control group: n=40 before THA mean ±SEM Funding Source © 2017 American Medical Association. All rights reserved. 527

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Study Author Design Year Study Risk of Population and Setting Intervention Results Comments (Data Objective Bias Extractor) Score Procedures: Total hip Did not receive intra-articular Infection and/or infection Conflicts: arthroplasty steroid injections prior to test: 1.43±0.25 Authors: None Cemented: 19 in each THA. Matched cohort. No Infection/ no infection Institution: None group Patients were matched in Test: 1.46±0.11 Study: None Non-Cemented: 21 in each descending order of priority P=0.891 Supplies: None group by gender, cemented or Power: 0.052 cementless THA, age, BMI, Indications: ASA pre-op score, year of Reoperations: Osteoarthritis operation, and surgeon. Overall rate of revision Injection: 1/40 (2.5%) Injection: 5/40 (12.5%) No Injection: 1/40 (2.5%) Standard preventive No Injection: 1/40 (2.5%) Inflammatory Arthritis measures: Recorded but Note: Authors report Injection: 39/40 (97.5%) not reported revision rate of 1.02% No Injection: 39/40 (10/979) for all unmatched (97.5%) controls/primary THAs performed at their hospital Setting: 1 hospital over the study time period Location: USA (excludes those with Dates:1995 - 1998 primary THA performed Inclusion Criteria: Patients elsewhere or before the undergoing THA during the database was established). study dates. Length of stay: Exclusion Criteria: Injection: 6.58±0.49 (2-18) prostatic malignancy, No Injection: 7.26±0.96 (4- previous ipsilateral fracture 36) of the hip or earlier surgery Mortality: NR on the affected side. Also Adverse events: NR patients who were immunocompromised, previously or presently infected, affected with cancer in the hip or suspected tumors around the hip or who had been given an initial diagnosis of osteoarthritis.

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Our search did not identify data that evaluated preoperative strategies for managing the use of intra-articular corticosteroid injections in prosthetic joint arthroplasty patients and their impact on risk of SSI. A. Does the length of time between intra-articular corticosteroid injection and prosthetic joint arthroplasty impact the risk of SSI? Our search did not identify data that evaluated different lengths of time between preoperative intra-articular corticosteroid injection administration and its impact on the risk of TKA. B. Does the corticosteroid injection dose impact the risk of SSI? Our search did not identify data that evaluated different doses of preoperative intra- articular corticosteroid injections and their impact on the risk of SSI.

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2.2B.3 RISK OF BIAS ASSESSMENTS: Q12-16 SYSTEMIC IMMUNOSUPPRESSIVE THERAPY eTABLE 61. Risk of Bias Assessments of Other Controlled Studies for Q12-16 Systemic Immunosuppressive Therapy Attrition not Funding All study groups significantly Statistical source(s) derived from different Measure Investigator Potential adjustment for disclosed and similar across of Measure of blinded to confounde- potential no obvious Overall Author source/reference study exposure outcome is endpoint rs confounders conflict of Risk of Year Q populations groups is valid valid assessment identified done interest Bias Questions 12 – 16: Immunosuppressive Therapy Bongartz 160 13        Low 2008 Bridges 158 13        Low 1991 Carpenter 159 13       Low 1996 Desai 162 15      Low 2009 Hirano 156 12      Low 2010 Kaspar 165 15       Low 2005 Kawakami 155 12        Low 2010 McIntosh 164 15       Low 2006 Momohara 154 12        Low 2011 Papavasil- iou 15       Low 2006 161 Perhala 157 12       Low 1991 Sreekum- ar 15      Low 2007 163

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2.2C. Q17 ANTICOAGULATION 2.2C.1 GRADE TABLE: Q17 ANTICOAGULATION eTABLE 62. GRADE Table for Q17 Anticoagulation Increase Decrease GRADE GRADE

Overall

Quantity GRADE of

GRADE and Type Starting Evidence Comparison Outcome Findings of of GRADE for Evidence Evidence Outcome response

- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Q17. What are the most effective strategies for managing perioperative venous thromboembolism (VTE) prophylaxis to reduce the risk of SSI? Q17A. Does the risk of SSI differ by individual VTE prophylaxis agent? • No difference in a meta-analysis of 4 RCTs 167-170 166 (N=7237) in primary or revision THA, SSI* 1 SR High -1 0 -1 0 0 0 0 0 Low Enoxaparin TKA, or hip fracture surgery: group: 29/3621 vs. (0.8%) vs. 37/3616 (1.0%). (11 day follow up) Low Fondapari- nux Drug related 166 • No episode of decreased platelet count was 1 SR High -1 0 -1 0 0 0 0 0 Low adverse reported in either group events • No difference in a meta-analysis of 4 RCTs (N=12,383): 28/6200 (0.5%) vs. 27/6183 (0.4%); OR: 1.03 (0.60 – 1.76); p=0.92; I2=0; 30-35 day follow up 4 RCT 171- • Two studies171,172 found no difference in THA SSI* 174 High 0 0 0 0 0 0 0 0 High (n=6890): 14/3453 (0.41%) vs. 16/3437 (0.47%). SSIs were rare (30 or 0.40%) • Two studies173,174 found no difference in TKA Enoxaparin (n=5493): 14/2747 (0.51%) vs. 11/2746 vs. High (0.40%). Infections were rare (25 or 0.46%) Rivaroxaban • No difference in 4 RCTs (THA and TKA combined data) composite of excessive Hemor- wound hematoma and reported surgical site rhagic 171- 4 RCT bleeding: 105/6200 (1.7%) vs. 100/6183 wound 174 High 0 0 0 0 0 0 0 0 High (1.6%); p=NS complic • Two studies171,172 found no difference in ations THA: 59/3453 (1.7%) vs. 54/3437 (1.6%); p =NS © 2017 American Medical Association. All rights reserved. 531

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Increase Decrease GRADE GRADE

Overall

Quantity GRADE of

GRADE and Type Starting Evidence Comparison Outcome Findings of of GRADE for Evidence Evidence Outcome response

- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • Two studies173,174 found no difference in TKA: 46/2747 (1.7%) vs. 46/2746 (1.7%); p=NS • No difference in 4 RCTS modified intention to treat analysis: 970/6200 (15.6%) vs. Drug 171- 971/6183 (15.7%) related 4 RCT 171,172 174 • Two studies found no difference in High 0 0 0 0 0 0 0 0 High adverse THA: 15% both 514/3453 vs. 515/3437 events • Two studies173,174 found no difference in TKA: (17% both) 456/2747 vs. 456/2746 • 1 large OBS study (N=2437) Logistic regression analysis showed that enoxaparin (started 12-24 hours postoperatively) was not SSI* 1 OBS 175 associated with increased risk of SSI in Low 0 0 0 -1 0 0 0 0 Very Low primary THA; OR 2.11 (0.24-18.5); p=0.499; or primary TKA: OR 1.07 (0.23-4.95); p=0.932. Enoxaparin • Logistic regression analysis showed that vs. ASA and Very enoxaparin (started 12-24 hours mechanical Low postoperatively) was associated with longer prophylaxis Time time until wound was dry for primary THA until 175 (p<0.01) but not for primary TKA (p=0.62) 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low wound • Patients on enoxaparin had longer time until was dry wound was dry as compared to those on ASA or those on warfarin; this difference was significant on the 5th (p<0.01) but not by the 8th postoperative day. Enoxaparin • In a nested case-control study of TKA vs. patients (n=36 infections, 106 controls) Bemiparin specific anticoagulation agents were not 176 Very vs. Fraxiparin PJI* 1 OBS associated with increased risk of SSI: p=0.97 Low 0 0 0 -1 0 0 0 0 Very Low Low vs. • Only 50 of 5496 (0.91%) patients developed Fondaparin- an SSI; (95% CI, 0.68%-1.20%). ux • Hematoma identified as an independent risk © 2017 American Medical Association. All rights reserved. 532

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Increase Decrease GRADE GRADE

Overall

Quantity GRADE of

GRADE and Type Starting Evidence Comparison Outcome Findings of of GRADE for Evidence Evidence Outcome response

- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders factor for PJI. Adjusted OR 4.2 (1.1-16.6)

• No difference in retrospective study Enoxaparin, (N=41,917) using administrative data from a dalterparin, national sample of primary TKAs: tinzaparin or 4366/37,198 (12%) vs. 559/4719 (12%); 177 Very fondaparinux SSI* 1 OBS adjusted OR 1.08 (0.95-1.24). Low 0 0 0 -1 0 0 0 0 Very Low Low vs. ASA ± • Authors indicated that subtherapeutic dosing mechanical and/or inappropriate timing of the LMWHs or prophylaxis synthetic Factor Xa inhibitor may have impacted the results. • In a large (n=1742) study in primary unilateral TKA, infections were rare 14/1742 (0.8%) and did not differ between groups: 9/957 (0.9%) vs. 5/785 (0.6%) SSI* 1 OBS 178 • Goal INR: 1.6-2.2 for 6 weeks. Follow up was Low 0 0 0 -1 0 0 0 0 Very Low Warfarin vs. 3 months. No • Study excluded patients already on pharmacolo- preoperative anticoagulation therapy for Very gic or other conditions. Low mechanical Deep • Deep SSIs were rare 8/1742 (0.5%) and did prophylaxis Incision 1 OBS 178 not differ between groups: 6/957 (0.6%) vs. Low 0 0 0 -1 0 0 0 0 Very Low al SSI 2/785 (0.3%) Superfic • Superficial SSIs were rare 7/1742 (0.4%) and ial 178 1 OBS did not differ between groups: 3 (0.3%) vs. 3 Low 0 0 0 -1 0 0 0 0 Very Low Incision (0.4%) al SSI • In a large OBS study175 (n=2437) of primary Warfarin vs. THA (n=1211) and TKA (n=1226), logistic ASA ± 2 OBS SSI* 175,177 regression analysis among THAs showed Low 0 0 0 0 0 0 0 0 Low Low mechanical that warfarin with a target INR of 2.0, started prophylaxis on the day of surgery, was not associated © 2017 American Medical Association. All rights reserved. 533

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- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders with an increased risk of wound infection OR 7.47 (0.62-89.3); p=0.112. On logistic regression analysis, warfarin does not appear as one of the variables influencing wound infection after TKA. Follow up was not reported • In a large OBS study177 (N=93, 840) of administrative data on primary TKA, subanalysis (n=56,642), showed no difference; 6349/51923 (12%) vs. 559/4719 (12%); adjusted OR: 1.10 (0.96-1.26). Target INR not reported. SSIs were detected at the time of admission or on readmission within 30 days of index procedure. • Warfarin was not associated with longer time with wound drainage after neither THA Time (p=0.834) nor TKA (p=0.197) until 175 • Patients on enoxaparin had longer time until 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low wound wound was dry as compared to those on was dry SAS or those on warfarin; this difference was significant on the 5th (p<0.01) but not by the 8th postoperative day. • In a 2:1 case control study (N=154) of 78 cases who underwent revision THA or TKJA for septic failure compared to 156 non- infected controls who underwent the same procedure, all on postoperative warfarin Higher vs. 179 (target INR=1.5) found that while the mean Very Lower Mean 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low PJI* INR at all time-points was higher in the Low INR infected group, it was not statistically significant (p=0.06). • INR level was significantly higher in patients with wound-related problems who later developed infection (p=0.03)

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- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • Twice as many infected patients with mean INR >1.5 as compared to controls: 22% vs. 11%; p=0.05 • Infected patients were more likely to have INR>1.5 at time of hospital discharge; 17% vs. 8%; p=0.04 • INR>1.5 at time of hospital discharge was more prevalent in group with wound complications vs. those with uncomplicated postoperative wound healing; 22% vs. 8%; p=0.005 • Multivariate logistic regression analysis showed the following were significant risk factors for PJI: • Wound complications including development of hematoma: OR 27.02 (11.04-91.59); <0.01 • Persistent wound drainage: OR 32.20 (8.7- 119.17); p<0.01 • ASA comorbidities: OR 2.07 (1.08-0.97); p=0.03 • Postoperative transfusion: PR 1.63; (1.14- 2.33); p<0.01 • 13/78 (17%) of patients in the PJI cohort were on anticoagulation therapy preoperatively for another condition. These patients were heparinized postoperatively until fully coagulated with warfarin (target INR = 2-3). 9/13 (69%) developed wound complications including hematoma (n=3), persistent wound drainage (n=5) and delayed wound healing (n=1) Wound • Infected patients had a higher incidence of hemato 1 OBS 179 wound hematomas: 11 (14%) vs. 2 (1%); Low 0 0 0 -1 0 0 0 0 Very Low ma p=0.0001. © 2017 American Medical Association. All rights reserved. 535

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- Base Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Wound draina- • Infected patients had a higher incidence of ge- 1 OBS 179 wound drainage: 24 (31%) vs. 4 (3%); Low 0 0 0 -1 0 0 0 0 Very Low persist- p<0.01 ent Q17B. What is the optimal timing and duration of perioperative VTE prophylaxis that also reduces the risk of SSI? • In a nested case-control study of TKA patients (n=36 infections, 106 controls), infected patients received the first dose of anticoagulant within 12 hours (before or Prophylaxis after) of surgery more frequently than those started not infected: OR 1.5 (0.73-3.0). preoperative- 176 Very PJI* 1 OBS • After adjusting by main risk factors, no Low 0 0 0 -1 0 0 0 0 Very Low ly vs. Low statistical association was found between Postoperati- close perioperative timing of the first dose of vely anticoagulant and risk of PJI. • Hematoma formation identified as an independent risk factor for PJI. Adjusted OR 4.2 (1.1-16.6) Q17C. How safe and effective is modifying the dose of the perioperative VTE prophylaxis agent to reduce the risk of SSI? Our search did not identify data that evaluated the safety and effectiveness of modifying perioperative VTE prophylaxis and its impact on the risk of SSI. *Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

2.2C.2 EVIDENCE TABLE: Q17 ANTICOAGULATION Q17. What are the most effective strategies for managing perioperative venous thromboembolism (VTE) prophylaxis to reduce the risk of SSI? Q17A. Does the risk of SSI differ by individual VTE prophylaxis agent? Q17B. What is the optimal timing and duration of perioperative VTE prophylaxis that also reduces the risk of SSI? eTABLE 63. Evidence Table for Q17. What are the most effective strategies for managing perioperative venous thromboembolism (VTE) prophylaxis to reduce the risk of SSI? Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score © 2017 American Medical Association. All rights reserved. 536

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Turpie RCT To assess the Number of patients: Intervention group: SSI (follow up 41-50 days) Definitions 2009 174 1, 2, 3, 4, 5, efficacy and N=3034 n=1584 Postoperative wound SSI-NR (ES) 7, 8, 9 safety of oral Patient Characteristics Rivarox: Patients assigned infection: Perioperative care: NR rivaroxaban ·Age: mean (SD) y to receive 10 mg 1x/day Rivarox: 4/1526 (0.3%) Other notes: None (Rivarox) 10mg Rivarox: 64.4 (9.7) rivaroxaban PO.in the Enox: 3/1508 (0.2%) Follow-up: for 30-35 RECORD once daily Enox: 64.7 (9.7) evening beginning 6-8h days after last dose of 4 compared with ·Gender: Female n (%) after wound closure or Other infections: NR anticoagulant. (41-50 30mg Rivarox: after adequate hemostasis Topic-specific outcomes days postop) enoxaparin 1007/1526(66.0%) was achieved. Plus Hemorrhagic wound Funding Source (Enox) given Enox: 1508/1508 (64.1%) placebo injection complications: Conflicts: subcutaneously ·Obesity: mean (SD) kg/m2 Timing of intervention: Rivarox: 21/1526(1.4%) Authors: NR every 12h for Rivarox: 30.9 (6.2) Preop Enox: 22/1508 (1.5%) Institution: NR the prevention Enox: 30.7 (6.0) Duration of intervention: Study: Industry of venous ·Comorbidities Postop until the evening Reoperations: NR Supplies: NR thromboemboli History of VTE: before venography on Length of stay: days mean sm after Rivarox: 38/1526(2.5%) POD 11-15 (SD) elective total Enox: 28/1508 (1.9%) Device/agent: Rivarox: 8.0 (6.1) knee Rivaroxaban Enox: 7.9 (6.3) arthroplasty. Procedures: Total Knee Monitoring intervention: Arthroplasty: n (%) NA Mortality: Primary: Control group: n=1564 Rivarox: 6/1526 (0.4%) Rivarox: 1488/1526 Enox: patients assigned to Enox: 6/1508 (0.4%) (97.5%) receive 30mg Enox: 1479/1508 (98.1%) subcutaneously every 12h Adverse events: Revision: beginning 12-24h post Drug related Adverse Rivarox: 37/1526 (2.4%) wound closure. Plus Events: Enox: 28/1508 (1.9%) placebo tablet Rivarox: 310/1526 None or missing data Standard preventive (20.3%) Rivarox: 1/1526 (0.1%) measures: NR Enox: 295/1508 (19.6%) Enox: 1/1508 (0.1%) Indications: NR Setting: Multi-Center Location: Bulgaria, Canada, Denmark, India, Israel, Lithuania, Pakistan, Poland, Sri Lanka, Sweden, USA, Dates: June 2006 – October 2007 Inclusion Criteria: Patients © 2017 American Medical Association. All rights reserved. 537

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score 18 and older scheduled for total knee arthroplasty Exclusion Criteria: Patients with active bleeding or a high risk of bleeding, or any disorder contraindicating the use of enoxaparin or that might necessitate enoxaparin dose adjustment. Also disorders preventing bilateral venography, clinically significant liver disease, severe renal impairment (creatinine clearance <30ml/min), concomitant use of drugs that strongly inhibit cytochrome P450 such as protease inhibitors or ketoconazole, pregnancy or breastfeeding, planned intermittent pneumatic compression or the requirement for ongoing anticoagulant therapy. Eriksson RCT To assess the Number of patients: Intervention group: SSI (follow up 66-77 days) Definitions: 171 2008 1, 2, 3, 4, 5, efficacy and N=4433 n=2266 Postoperative wound SSI - none (ES) 7, 8, 9 safety of a Patient Characteristics Patients who received infection Perioperative care: NR postoperative ·Age: mean (range) y 10mg oral rivaroxaban Rivarox: 8/2209 (0.4%) Other notes: None RECORD 10-mg dose of Rivarox: 63.1 (18-91) 1x/day. Rivaroxaban was Enox: 8/2224 (0.4%) Follow-up: 30-35 days 1 rivaroxaban Enox: 63.3 (18-93) started 6-8h after wound after the last dose of the (Rivarox) given ·Gender: female n (%) closure and administered Other infections: NR study drug. (60-77 days) once daily as Rivarox: 1220/2209 every 22-26h in the Funding Source compared with (55.2%) evening. Plus placebo Topic-specific outcomes: Conflicts: a 40mg Enox: 1242/2224 (55.8%) injection Hemorrhagic wound Authors: Industry subcutaneous ·Obesity: BMI mean (range) Timing of intervention: complications: Institution: NR dose of Rivarox: 27.8 (16.2-53.4) Postop for Rivaroxaban & Rivarox: 34/2209 (1.5%) Study: Industry enoxaparin (a Enox: 27.9 (15.2-50.2) pre and postop for Enox: 38/2224 (1.7%) Supplies: NR low-molecular ·Comorbidities Enoxaparin © 2017 American Medical Association. All rights reserved. 538

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score weight History of VTE Duration of intervention: Reoperations: NR heparin), with Rivarox: 47/2209 (2.1%) 36 days postop (range 30- the first Enox: 55/2224 (2.5%) 42) until patient had a Length of stay [Enox]dose Procedures: Total Hip mandatory bilateral Mortality: given the Arthroplasty venography. Although Death possibly related to evening before Primary further thromboprophylaxis study drug surgery and Rivarox: 2127/2209 was continued at the Rivarox: 3/2209 (0.01%) subsequent (96.3%) investigator’s discretion. Enox: 1/2224 (0.04%) doses given Enox: 2118/2224 (95.2%) Device/agent: 10mg oral once daily, for Revision rivaroxaban or 40mg Adverse events: extended Rivarox: 66/2209 (3.0%) subcutaneous injections of Drug related adverse thromboprophyl Enox: 86/2224 (3.9%) enoxaparin. events axis after Total Missing Data Monitoring intervention: Rivarox: 270/2209 Hip Rivarox: 16/2209 (0.7%) NA (12.2%) Arthroplasty Enox: 20/2224 (0.9%) Control group: n=2224 Enox: 265/2224 (11.9%) Patients who received Indications: NR 40mg subcutaneous Setting: Multi center injections of enoxaparin Location: International: administered 1x/day. It Argentina, Australia, was initiated 12h before Austria, Belgium, Brazil, surgery and restarted 6-8h Canada, Chile, Colombia, after wound closure then Czech Republic, Denmark, administered every 22-26h France, Finland, Germany in the evening. Plus Greece, Hungary, Israel, placebo tablet Italy, Lithuania, the Standard preventive Netherlands, Norway, measures: NR Poland, Slovakia, South Africa, Spain, Sweden, Turkey, United States. Dates: February 2006 – March 2007 Inclusion Criteria: men and women at least 18 years of age who were scheduled to undergo elective total hip arthroplasty. Exclusion Criteria: Those scheduled to undergo © 2017 American Medical Association. All rights reserved. 539

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score staged bilateral THA, were pregnant or breast-feeding, had active bleeding or a high risk of bleeding, or had a contraindication for prophylaxis with enoxaparin or a condition that might require an adjusted dose of enoxaparin. Also conditions preventing bilateral venography, substantial liver disease, severe renal impairment (creatinine clearance <30ml/min), concomitant use of protease inhibitors for the treatment of human immunodeficiency virus infection, planned intermittent pneumatic compression, or a requirement for anticoagulant therapy that could not be stopped.

Lassen RCT To conduct a Number of patients: Intervention group: SSI (follow up 40-49 Definitions: 2008 173 1, 2, 3, 4, 5, multicenter, N=1459 n=1220 days): SSI – postoperative (ES) 7, 8, 9 randomized, Patient Characteristics Rivarox: Patients who Postoperative infection of infection of wound was double-blind ·Age: mean (Range) y received once daily oral wound classified according to trial that Rivarox: 67.6 (28-91) rivaroxaban in a 10-mg Rivarox: 7/1220 (0.6%) the Medical dictionary RECORD compares the Enox: 67.6 (30-90) tablet. Treatment was Enox: 11/1239 (0.9%) for Regulatory Activities 3 efficacy and ·Gender: female n (%) initiated 6-8h after wound (MEdDRA a registered safety of oral Rivarox: 857/1220 closure. Then Other infections: NR trademark of the rivaroxaban (70.2%) administered every 24h Topic-specific outcomes: International Federation (Rivarox) 10mg Enox: 821/1239 (66.3%) until POD10-14. Further Hemorrhagic Wound of Pharmaceutical once daily ·Obesity: BMI Mean thromboprophylaxis was Complications Manufacturers and administered (RANGE) given at investigator’s Rivarox: 25/1220 (2.0%) Associations) postoperatively, Rivarox: 29.5 (16.3-51.1) discretion according to Enox: 24/1239 (1.9%) Hemorrhagic wound with those of Enox: 29.8 (16.0-54.3) local practice. complication: excessive enoxaparin ·Comorbidities Timing of intervention: Reoperations: NR wound hematoma or © 2017 American Medical Association. All rights reserved. 540

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score (Enox), 40mg History of VTE Postop Length of stay: bleeding at the surgical given Rivarox: 48/1220 (3.9%) Duration of intervention: Rivarox: 48/1220 (3.9%) site. subcutaneously Enox: 42/1239 (3.4%) from 6-8h after wound Enox: 42/1239 (3.4%) Perioperative care: NR once daily closure until POD10-14 Other notes: None administered Procedures: Elective total Device/agent: Mortality: Follow-up. 30-35 days preoperatively, knee arthroplasty Rivaroxaban 10mg tablets Death after the last dose of for the Primary: Monitoring intervention: Rivarox: 0/1201 (3.9%) medication. (POD 40- prevention of Rivarox: 1176/1220 NA Enox: 6/1217 (3.4%) 49?) venous (96.4%) Control group: n=1239 Funding Source thromboemboli Enox: 1186/1239 (95.7%) Enox: Patients who Adverse events: Conflicts: sm after Revision received a once-daily Drug related adverse Authors: Industry elective total Rivarox: 24/1220 (2.0%) subcutaneous injection of events: Institution: NR knee Enox: 30/1239 (2.4%) 40mg enoxaparin sodium. Rivarox: 146/1220 Study: Industry arthroplasty None/Missing data This was initiated 12h (12.0%) Supplies: NR Rivarox: 20/1220 (1.6%) before surgery and was Enox: 161/1239 (13.0%) Enox: 23/1239 (1.9%) given again 6-8h after Indications: NR wound closure, then Setting: Multi-center administered every 24h. Location: Austria, Belgium, Study medications were Canada, China, Colombia, continued until at least Czech Republic, Denmark, POD 10 and up to POD France, Germany, Israel, 14. Further Italy, Mexico, the thromboprophylaxis was Netherlands, Poland, Peru, given at investigator’s South Africa, Spain, discretion according to Sweden. local practice. Dates: February 2006 – Standard preventive November 2006 measures: NR Inclusion Criteria: Patients who were 18 years of age or older and scheduled for Total knee arthroplasty. Exclusion Criteria: Patients with active bleeding or a high risk of bleeding that contraindicated the use of low-molecular-weight- heparin and patients with any contraindication © 2017 American Medical Association. All rights reserved. 541

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score necessitating adjustment of its dose. Also, conditions preventing bilateral venography, clinically significant liver disease, concomitant use of protease inhibitors of the human immunodeficiency virus or fibrinolytic agents, planned intermittent pneumatic compression, requirement of ongoing anticoagulation therapy, and pregnancy or breastfeeding.

Kakkar RCT To assess the Number of patients: Intervention group: SSI (follow-up 30-35 days) Definitions: 2008 172 1, 2, 3, 4, 5, efficacy of N=2457 (Safety n=1228; Postoperative wound Deep vein thrombosis (ES) 6, 7, 8, 9 extended population) VTE= 961; Primary infections was assessed and thromboprophyl N=1923 – population for Efficacy=864 RivaRox: 8/1228 (0.7%) confirmed by ascending axis with an major VTE RivaRox: Patients Enox: 6/1229 (0.5%) bilateral venography. RECORD oral factor Xa N=1733 – ITT population receiving extended In cases of suspected 2 inhibitor, for Primary Efficacy duration rivaroxaban as Other infections: pulmonary embolism, rivaroxaban Patient Characteristics: thromboprophylaxis for 5 Infections and infestations: pulmonary angiography, (RivaRox), for this information is for the weeks. Starting 6-8 hours RivaRox: 88/1228 (7.2%) perfusion/ventilation lung 31-39 days, safety population: after wound closure and Enox: 87/1229 (7.1%) scintigraphy with chest compared with RivaRox: n=1228 continued for 31-39 days. radiography or spiral a short-term Enox: n=1229 In addition, they received Topic-specific outcomes: computed tomography LMWH ·Age: mean (SD, IQR) placebo injections for 10- Non-Fatal Pulmonary was done. enoxaparin years 14 days starting 12h Embolism n (95%CI) Major bleeding: bleeding (Enox) regimen RivaRox: 61.4 (13.2, 53- before surgery. RivaRox: 1/864 (0.1%, that was fatal, into a for 10-14 days 71) Timing of intervention: <0.1-0.6) critical organ (e.g. followed by Enox: 61.6 (13.7, 54-72) pre and postoperative Enox: 4/869 (0.5%, 0.1- retroperitoneal, placebo in ·Gender: female (%) Duration of intervention: 1.2) intracranial, intraocular, patients RivaRox: 667 (54.3%) begun 6-8 hours after Absolute Risk Reduction: intra-spinal), required re- undergoing Enox: 651 (53.0%) wound closure and (95%CI) operation, or clinically total hip ·Obesity: BMI mean (SD, continued for 31-39 days. 0.3% (-0.2-1.1), p=0.37 overt extra-surgical-site arthroplasty IQR) Agent: Oral rivaroxaban bleeding associated with (THA) RivaRox: 26.8 (4.8, 23.5- (10mg) once daily Deep vein thrombosis in a fall in hemoglobin of This is known 29.4) Monitoring intervention: Safety Population 20g/L or more, © 2017 American Medical Association. All rights reserved. 542

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score as the Enox: 27.1 (5.2, 23.6- Liver biochemistry and RivaRox: 37/1228 (3.0%) calculated from the RECORD 2 30.0) cardiovascular adverse Enox: 86/1229 (7.0%) POD1 baseline value or study ·Comorbidities: events were monitored requiring infusion of two “Regulation of Previous history of VTE throughout the treatment Deep-vein Thrombosis in or more units of whole Coagulation in RivaRox: 10 (0.8%) and follow-up periods. ITT population: n (95%CI) blood or packed cells. Orthopaedic Enox: 20 (1.6%) Mandatory bilateral RivaRox: 14/864 (1.6%, On-treatment non-major surgery to Duration of surgery: median venography the day after 0.9-2.7) bleeding – any on- prevent Deep- (IQR) (min) the last dose of the study Enox: 71/869 (8.2%, 6.4- treatment bleeding event vein thrombosis RivaRox: 95.0 (72-125) mediation (day 32-40) 10.2) not adjudicated as major and pulmonary Enox: 93.0(73-126) Control group: n=1229; Absolute Risk Reduction: bleeding embolism) VTE: 962; Primary (95%CI) Hemorrhagic wound Procedures: Elective Hip Efficacy=869 6.5% (4.3-8.5), p<0.0001 complications: Arthroplasty (THA) Enox: Patients receiving composite of excessive Previous Orthopedic the heparin-based Proximal DVT: n (95%CI) wound hematoma and Surgery thromboprophylaxis RivaRox: 5/864 (0.6%, surgical-site bleeding RivaRox: 225 (18.3%) Enoxaparin for 2 weeks. It 0.2-1.3) Any post-operative Enox: 232 (18.9%) was initiated 12h before Enox: 44/869 (5.1%, 3.7- bleeding: bleeding Primary surgery and restarted 6-8 6.7) starting after the first RivaRox: 1160 (94.5%) hours after wound closure. Absolute Risk Reduction: tablet intake and ending Enox: 1157 (94.1%) And continued for 10-14 (95%CI) up to 2 days after the Revision POD. Patients also 4.5% (2.9-6.0), p<0.0001 last intake of study RivaRox: 52 (4.2%) received placebo tablets Distal DVT: n (95%CI) medication. Enox: 50 (4.1%) for 31-39 days starting 6- RivaRox: 9/864 (1.0%, Safety Analysis: patients Missing/no surgery 8h after surgery. 0.5-2.0) who received at least 1 RivaRox: 16 (1.3%) Standard preventive Enox: 27/869 (3.1%, 2.1- dose of medication Enox: 22 (1.8%) measures: NR 4.5) Modified ITT population: Nonstandard preventive Absolute Risk Reduction: patients who were valid Indications: NR measures: (95%CI) for safety analysis, had Setting: Multicenter (123 Use of cement 2.0% (0.7-3.3), p=0.0025 undergone planned centers) RivaRox: 621 (50.6%) surgery, and had Location: Multinational (21 Enox: 608 (49.8%) Major venous adequate assessment of countries worldwide) thromboembolism: n thromboembolism. Dates: February 2006 – (95%CI) Patients valid for April 2007 RivaRox: 6/961 (0.6%, assessment of major Inclusion Criteria: Patients 0.2-1.4) venous enrolled during the study Enox: 49/962 (5.1%, 3.8- thromboembolism – dates aged 18 years or 6.7) those valid for safety older, scheduled to undergo Absolute Risk Reduction: analysis and in whom elective THA. (95%CI) the venograms were Exclusion Criteria: Those 4.5% (3.0-6.0), p<0.0001 evaluable for the © 2017 American Medical Association. All rights reserved. 543

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score scheduled to undergo proximal veins, staged bilateral hip Symptomatic venous irrespective of whether arthroplasty, who had thromboembolism: n they were valid for distal active bleeding or a high (95%CI) veins risk of bleeding, or had any RivaRox: 3/1212 (0.2%, Perioperative care: NR condition contraindicating <0.1-0.7) Analytical the use of enoxaparin, or Enox: 15/1207 (1.2%, 0.7- methodology: that might require 2.0) Mantel-Haenszel enoxaparin dose Absolute Risk Reduction: weighting stratified by adjustment, including (95%CI) country with severe renal impairment. 1.0% (0.3 -1.8), p=0.0040 corresponding Also including significant asymptotic two-sided liver disease, pregnancy or Symptomatic venous 95%CI and two-sided p breastfeeding, concomitant thromboembolism in follow- value. Unweighted RR use of HIV protease up period: n (95%CI) reduction calculated with inhibitors, use of fibrinolytic RivaRox: 1/1212 (0.1%, an asymptotic method. therapy or planned <0.1-0.5) Sensitivity analysis: 1) intermittent pneumatic Enox: 2/1207 (0.2%, <0.1- included all randomized compression during the 0.6) patients with evaluable study period, conditions Absolute Risk Reduction: bilateral venography preventing bilateral (95%CI) (irrespective of whether venography, or the 0.1% (-0.2-0.4), p=0.62 it was in the time requirement for an window) or a confirmed anticoagulant that could not Major on-treatment symptomatic/asymptoma be discontinued. bleeding tic event/death RivaRox: 1/1228 (<0.1%) irrespective of the time [hemorrhagic diarrhea and window. 2) All hematemesis and resulted randomized participants in discontinuation of included in Sensitivity rivaroxaban; patient analysis 1. Plus those received acetylsalicylic acid who had evaluable w/o gastric protection bilateral venography/ before surgery] ultrasonography as done Enox: 1/1229 (<0.1%) by the investigator, [Blood in cerebrospinal irrespective of the time fluid. Deemed not related to window, or a study drug but enoxaparin symptomatic/ was discontinued] asymptomatic event/ Non-Major on-treatment death, irrespective of the bleeding: time window, provided © 2017 American Medical Association. All rights reserved. 544

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score RivaRox: 80/1228 (6.5%) the symptomatic event Enox: 67/1229 (5.5%) was not adjudicated. To Clinically relevant non- be a non-event by the major bleeding committee. RivaRox: 40/1228 (3.3%) Other notes: Sample Enox: 33/1229 (2.7%) size based on event rate Any bleeding after initiation of 11% in Enoxaparin of placebo or Rivaroxaban: group. And a RR of 40% RivaRox: 56/1197 (4.7%) in rivaroxaban. Thus 914 Enox: 49/1193 (4.1%) patients per group would be enough to Patients receiving blood demonstrate a transfusion: Reduction in RR with a RivaRox: 485/1228 power of 90% (39.5%) Enox: 514/1229 (41.8%) Follow-up: 30-35 days after the last dose of medication Reoperations: No major Funding Source bleeding events leading to Conflicts: reoperation in either group Authors: Industry Length of stay: NR Institution: NR Mortality up to day 30-42: Study: Industry Death: n (95%CI) Supplies: NR RivaRox: 2/864 (0.2%, <0.1-0.8) (both of cardiovascular cause) Enox: 6/869 (0.7%, 0.3- 1.5) (one of pulmonary embolism, 4 unrelated to venous thromboembolism, one unexplained) Absolute Risk Reduction: (95%CI) 0.5% (-0.2-1.1), p=0.29 Death in follow-up period: n (95%CI) RivaRox: 0/1228 (0.0%, 0.0-0.3) Enox: 2/1229 (0.2%, <0.1- © 2017 American Medical Association. All rights reserved. 545

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score 0.6)[one to pulmonary embolism, one unexplained] Absolute Risk Reduction: (95%CI) 0.2% (-0.1-0.6), p=0.50

Adverse events Any on treatment adverse event: RivaRox: 768/1228 (62.5%) Enox: 807/1229 (65.7%)

Drug related adverse events: RivaRox: 245/1228 (20.0%) Enox: 249/1229 (20.3%)

Drug related serious on- treatment adverse events RivaRox: 13/1228 (1.1%) Enox: 17 (1.4%)

Serious on-treatment adverse events: RivaRox: 90/1228 (7.3%) Enox: 131/1229 (10.7%)

Adverse events leading to discontinuations: RivaRox: 46/1228 (3.8%) Enox: 64/1229 (5.2%)

Edema peripheral RivaRox: 55/1228 (4.5%) Enox: 48/1229 (3.9%)

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Turpie Meta- To perform a Study types and number: Intervention group: SSI: Definitions 2002 166 Analysis meta-analysis N=4 n=3668 Wound infection (by day VTE: deep vein (ES) 3, 4 of 4 Phase III clinical trials: 4/5 Efficacy population: = 11) thrombosis, pulmonary randomized, 2682 Fond: 37/3616 (1.0%) embolism or both up to double-blind Number of total patients Fond: Patients Enox: 29/3621 (0.8%) day 11. trials using the in the review: N=7344 administered Bleeding index: the sum same Efficacy Population: Fondaparinux as an Complications at surgical of the number of units of comparative N=5385 anticoagulant site leading to prolonged packed red blood cells drug 4/4 studies: fondaparinux hospitalization or re- or whole blood (Enoxaparin Inclusion criteria: 4 was administered at2.5mg hospitalization: transfused and the [Enox] and multicenter, randomized, qd with the time of first Fond: 52/3616 (1.4%) difference of the Fondaparinux double blind studies. injection 6h±2h postop and Enox: 52/3621 (1.4%) hemoglobin values [Fond]), end Exclusion criteria: NR the time to second (g/dL) before and after points (venous Databases searched: NA injection ≥12h after first the bleeding occurrence thromboemboli – Studies were all dose. Other infections: NR (i.e. bleeding sm, and conducted as a part of the Timing of intervention: Topic-specific outcomes: index=units of proximal deep Phase 3 studies in a clinical Postoperatively Patients treated for VTE by transfusion + vein trial program. Eriksson: 2001 if surgery day 11: hemoglobin before thrombosis), Aggregate summary was delayed 24-48h after Fond: 199/3616 (5.5%) bleeding – hemoglobin and score: NR admission, fondaparinux Enox: 351/3621 (9.7%) after bleeding) adjudication was initiated 12±2h P<0.001 Fatal bleeding: bleeding committee and Eriksson 2001– Hip preoperatively (68/626 Venous thromboembolism: that was retroperitoneal, to report the Fracture (19.9%)). Omission of Fond: 182/2682 (6.8%) intracranial, intraspinal results of the Lassen 2002– Hip preop injections was Enox: 371/2703 (13.7%) or involved any other meta-analysis. Replacement recommended in both Any deep vein thrombosis critical organ, Turpie 2002 – Hip cohorts if a spinal or Fond: 174/2677 (6.5%) Perioperative care: NR Replacement epidural anesthesia, or Enox: 363/2698 (13.5%) Bauer 2001 – Major Knee catheterization was Any Proximal Deep Vein Other notes: None Surgery planned. Thrombosis Eriksson 2003 – Hip Lassen: Fondaparinux was Fond: 35/2756 (1.3%) Follow up: Fracture initiated a mean of 6.25h Enox: 81/2775 (2.9%) wound infection: 11 days after surgery in 86% of Distal Deep Vein (wound infection and patients Thrombosis VTE) Turpie: Fondaparinux was Fond: 141/2704 (5.2%) entire study: 49 days initiated a mean of 6.5h Enox: 293/2709 (10.8%) (PE) after surgery in 92% of patients. All odds ratios favor Funding Source Bauer: Fondaparinux was Fondaparinux regarding Conflicts: initiated a mean of 6.25h Surgery type, Obesity, age, Authors: Industry in 94% of patients gender, type of anesthesia, Institution: NR © 2017 American Medical Association. All rights reserved. 547

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Duration of intervention: use of cement or duration Study: NR for 5-9 days of surgery with no Supplies: NR postoperatively or until a significant difference seen mandatory bilateral in odds ratios for variations venography was in these factors. performed to assess for a Common Odds Ratio new VTE after a minimum between studies favors 5-day hospital stay Fondaparinux with regards Agent: Fondaparinux to VTE: -55.2 (-63.1 to -45.8); Monitoring intervention: p<0.001 NR

Control group: n=3676 Post-hoc analysis of Efficacy population = timing of Fondaparinux 2703 injection: Enox: Patients A statistically significant administered enoxaparin relationship was shown as an anticoagulant. between the timing 2/4 Studies: enoxaparin in (between 3-9 hours postop) 40mg qd with time of 1st of the first fondaparinux injection 12h±2h injection and major preoperatively bleeding (p=0.008) 2/4 studies: enoxaparin in A statistically significant 30mg qd with time of 1st relationship also existed injection 12-24h between the incidence of postoperatively overt bleeding associated 1/4 studies: Time to with a bleeding index ≥2 second injection 12-2h and the timing of the first postop fondaparinux injection 3/4 studies: time to second (p=0.008) injection NR Efficacy was not affected by Standard preventive this timing: p=0.67 measures: Other thromboembolic Re-operations: See prophylaxes: Intermittent Infections pneumatic compression, Length of stay: See dextran and thrombolytic infections or anticoagulant agents Mortality were prohibited; centers Fatal bleeding © 2017 American Medical Association. All rights reserved. 548

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score were instructed to avoid Fond: 0/3616 the use of aspirin or Enox: 1/3621 (0.0%) nonsteroidal anti- Death from any cause inflammatory drugs when Fond: 15/3616 (0.4%) possible; other antiplatelet Enox: 21/3621 (0.6%) agents were prohibited Death from any cause up to Graduated compression 49 days stockings: use was Fond: 48/3616 (1.3%) allowed and physiotherapy Enox: 52/3621 (1.4%) was recommended Length of administration: Adverse events: investigators could extend Adjudicated bleeding prophylaxis during follow- events up to day 11: up with any currently Fond: 96/3616 (2.7%) available therapy, but only Enox: 63/3621 (1.7%) after a venography was P=0.008 performed. VTE: after occurrence, Bleeding into critical organ treatment was left to the Fond: 0/3616 surgeon’s discretion. Enox: 1/3621 (0.0%) Bleeding leading to another operation Fond: 12/3616 (0.3%) Enox: 8/3621 (0.2%) Bleeding with a bleeding index≥2 Fond: 84/3616 (2.3%) Enox: 53/3621 (1.5%) Any Transfusions Fond: 1950/3616 (53.9%) Enox: 1864/3621 (51.5%) P=0.04

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Asenio Prospective To investigate Number of patients: Intervention group: n=36 SSI (Follow up 6 months Definitions: 2010 176 concurrent the N=5496 Patients who underwent postop) Prosthesis infection: (ES) control with independent Nested Case Control: TKA and developed a For total population of CDC definitions – an a nested effect of Low N=142 prosthetic joint infection. 5496: infection involving the case Molecular Patient Characteristics: Timing of intervention Prosthetic infection periprosthetic tissues control Weight Heparin for case control patients First Dose of LMWH incidence rate: 0.91 and 1, 2, 3, 4, 5, (LMWH) timing ·Age: mean±SD y Preoperatively cases/100 patients Infection: Occurring 6, 7, 8 for Deep Intervention: 71.3±6.1 ≥48h operated (95%CI 0.68-1.2) within the first 6 months Venous Control: 71.4±8.5 Intervention: 0 Infection rate ranged from postop and meeting at Thrombosis ·Gender male n (%) Control: 2 (1.9%) 0.25%-2.34% by center least 1 of the following (DVT) Intervention: 13 (36.1%) 24-48h (p=0.14) criteria: prophylaxis Control: 30 (28.3%) Intervention: 0 1. an organism was related to the ·Obesity Control: 1 (1%) 68% of infections were isolated from a culture of start of surgery Intervention: 23 (63.9%) 13-24h identified post-discharge. fluid or tissue aseptically on the risk of Control: 66 (62.3%) Intervention: 12 (33.3%) Time from procedures to obtained from an prosthesis ·Comorbidities Control: 31 (29.8%) infection median: 37 days incision deliberately infection Diabetes mellitus 7-12h (IQR: 16-63) opened by the surgeon among patients Intervention: 10 (27.8%) Intervention: 3 (8.3%) Early Postoperative 2. an abscess or other undergoing Control: 13 (12.3%) Control: 6 (5.8%) Infection: 46% evidence of infection Total Knee OR:2.83 (1.08-7.38) ≤6h was detected on direct Arthroplasty p=0.03 Intervention: 0 Adjusted OR for examination, either (TKA). Other Hypertension: Control: 1 (1%) independent risk factors for during reoperation or by objectives were Intervention: 27 (75%) POSTOPERTIVELY infection: histopathological or to establish the Control: 64 (60.4%) ≤6h Diabetes: 3.2 (95%CI:1.2- radiographic risk of OR: 2.07 (0.86-5.0); Intervention: 3 (8.3%) 8.8) examination, prosthesis p=0.10 Control: 6 (5.8%) Hematoma formation: 4.2 3. prosthesis infection infection and 7-12h 95%CI (1.1-16.5) was diagnosed by a their Procedures: Total knee Intervention: 10 (27.8%) surgeon or attending microbiological arthroplasty (TKA) Control: 29 (27.9%) Other infections: NR physician. characteristics Non-Primary Arthroplasty 13-24h Topic-specific outcomes: Early prosthesis and to evaluate Intervention: 2 (5.7%) Intervention: 4 (11.1%) Bleeding infection: an the relative Control: 4 (4.0%) Control: 17 (16.4%) Intervention: 12 (33.3%) organ/space wound effect of other Surgery duration 24-48h Control: 32 (30.2%) infection that developed potential risk Intervention: 112.8±34.2 Intervention: 4 (11.1%) within 1 month factors. Control: 121.4±43.1 Control: 11 (10.6%) Wound Hematoma postoperatively. Timing of any dose of Intervention: 19 (52.8%) Late Prosthesis Indications: NR LMWH Control: 50 (47.6%) infection: a prosthesis Within 24h preop OR:3.58 (0.96-13.40) infection that developed Setting: Multicenter (13 Intervention: 15(41.7%) p=0.06 between 1-6 months Spanish hospitals) Control: 41 (38.7%) postop. © 2017 American Medical Association. All rights reserved. 550

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Within 24h postop Reoperations: NR Perioperative care: NR Location: Spain Intervention: 31 (86.1%) Length of stay: NR Analytical Control: 89 (84.0%) Mortality: NR methodology Univariate Dates: January 1, 2005 – Adverse events: NR logistic regression, December 31, 2006 Duration of intervention: paired t-test, multiple variable conditional logistic Inclusion Criteria: All Agent: Low Molecular regression modal was patients undergoing primary Weight Heparin (LMWH). developed from a TKA or total knee Doses received were saturated model replacement in 13 Spanish stratified related to the containing all non- traumatology surgical units time of surgery, and the correlated risk factors during the study dates. time interval relative to that were significant at Exclusion Criteria: surgical time. the .1 level. Only cases Patients with infected Enoxaparin that could be matched to prostheses. Intervention: 19 (52.8%) controls were included in Control: 50 (47.6%) the risk factor analysis. Bemiparin Other notes: None Intervention: 8 (22.2%) Follow-up: Active Control: 26 (24.8%) surveillance by surgeons Fraxiparin and/or hospital Intervention: 7 (19.4%) epidemiologists during Control: 23 (21.9%) the 6 months post-op When clinical records Fondaparinux- NOT a did not provide enough LMWH; synthetic information to rule out pentasaccharide factor Xa infection during the first inhibitor 6 months, patients were Intervention: 2 (5.6%) interviewed by Control: 6 (5.7%) telephone. Investigators P=0.97 extracted all information Monitoring intervention: from medical records NA Funding Source Control group: n=106 Conflicts: For every intervention Authors: None patient who developed an Institution: None infection, 3 control patients Study: None were chosen who did not Supplies: None develop an infection within the first 6 postoperative months. Patients were © 2017 American Medical Association. All rights reserved. 551

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score matched by medical center and date of index case procedures ±2 weeks. Standard preventive measures: AMP: AMP were given across patients, however, timing was not standard and breaks down as follows: >2h preop Intervention: 2 (5.6%) Control: 12 (11.3%) ≤2h preop Intervention: 29 (80.6%) Control: 84 (79.2%) Postop Intervention: 5 (3.9%) Control: 10 (9.4%) Non-Standard preventive measures: Hair Removal P=0.07 between groups Shaving not done Intervention: 6 (22.2%) Control: 25 (28.7%) Blade Razor Intervention: 8 (29.6%) Control: 12 (13.8%) OR:3.3 (0.26-42.1) Electrical Clipper Intervention: 13 (48.1%) Control: 50 (57.5%) OR: 0.18 (0.02-2.24) Normothermic Blanket Intervention: 8 (22.2%) Control: 38 (35.8%) OR: 0.30 (0.09-1.01) p=0.05

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Bozic Retrospect- To utilize Number of patients: Intervention group: SSI (30 days) Definitions: 2010 177 ive administrative N=93,840 Aspirin (n=4719): Patients Wound infection TKA – ICD-9-CM (ES) concurrent data from a Patient Characteristics who received aspirin ± Aspirin: 559/4719 (12%) procedure code 81.45 cohort large national ·Age: mean (SD) y mechanical prophylaxis Injectable: 4366/37.198 Postoperative 1, 2, 3, 4, 5, sample of Aspirin: 66.4 (10.7) and no other (12%) complications, including 6, 7, 8 patients Injectable: 66.5 (10.5) pharmacologic VTEP Warfarin: 6349/51,923 venous undergoing Warfarin: 67.3 (10.4) agent (12%) thromboembolism (any primary total P<0.001 Timing of intervention: thromboembolic event knee ·Gender: male n (%) NR SSI population: n=1037 including proximal or arthroplasty Aspirin: 1679 (36%) Duration of intervention: Adjusted ORs (95%CI) distal DVT as well as (TKA) to Injectable: 12,505 (34%) NR Aspirin as referent PE), proximal DVT and compare the Warfarin: 18,085 (35%) Agent: Aspirin, Warfarin, Injectable: 1.08 (0.95- PE only; surgical site risk of venous ·Obesity: or Injectable VTEPs 1.24) bleeding; and surgical thromboemboli Aspirin: 833 (18%) (LMWH Enoxaparin] or Warfarin: 1.10 (0.96-1.26) site infection were sm (VTE), Injectable: 5105 (14%) fondaparinux [Factor Xa defined using ICD-9-CM surgical site Warfarin: 6454 (12%) inhibitor] Other infections: NR diagnosis codes recoded bleeding, ·Comorbidities Monitoring intervention: Topic-specific outcomes: during the index surgical site Diabetes: NA Any thromboembolism admission as well as infection (SSI), Aspirin: 754 (16%) Control group: Aspirin: 110 (2.3%) principal diagnosis and mortality Injectable: 6561 (18%) Warfarin (n=51,923): Injectable: 1152 (3.1%) associated with any between Warfarin: 8839 (17%) patients who received Warfarin: 2009 (4%) readmissions occurring patients who Deficiency anemia Warfarin as the VTEP P<0.01 for all w/in 30 days of received Aspirin: 456 (10%) Injectable (n=37,198): comparisons discharge. aspirin, Injectable: 5056 (14%) Patients who received Adjusted ORs (95%CI) Perioperative care: NR warfarin, or Warfarin: 5824 (11%) VTEP with injectable n=3271 injectable Aspirin patients had lower agents (e.g. LMWHs or Aspirin as referent Analytical (LMWH and baseline VTE risk score fondaparinux) Injectable: 1.03 (0.76- methodology fondaparinux) than warfarin or Standard preventive 1.39) Alternating logistic VET LMWH/fondaparinux measures: NR Warfarin: 1.36 (1.02 -1.82) regression models were Prophylaxis patients (p<0.001) P<0.01 for all used to assess the (VETP) Aspirin Patients had fewer comparisons independent association medical comorbidities than between the 3 VTEP Injectable (p<0.001) but Proximal DVT or PE strategies and the risk of similar to Warfarin Patients Aspirin: 77 (1.6%) complications or death. (p=0.69) Injectable: 901 (2.4%) A Propensity score was Aspirin patients less likely Warfarin: 1632 (3%) used in all models due to to have a charge for P<0.01 for all the threat of bias from sequential compression comparisons group allocation. The devices in perioperative Adjusted ORs (95%CI) resultant c-statistic was period: n=2610 0.725 which was © 2017 American Medical Association. All rights reserved. 553

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Aspirin 38% Aspirin as referent included in all core LMWH/fondaparinux 48% Injectable: 0.99(0.76-1.28) multivariable models as Warfarin 55% Warfarin: 1.34 (1.05 -1.70) a covariate intended to (p<0.001) P<0.01 for all adjust for allocation bias. Procedures: Total knee comparisons In a secondary analysis, arthroplasty (TKA) 3 propensity scores, Indications: NR Bleeding related to wound including assignment to Setting: Multicenter (307 site injectable VTEP vs. Hospitals participating in a Aspirin: 30 (0.6%) other VETP, etc. These proprietary database Injectable: 459 (1%) scores did not developed for measuring Warfarin: 548 (1%) substantially nor quality and healthcare use P<0.01 for all directionally alter the in hospitalized patients) comparisons results, thus the first The centers are Adjusted ORs (95%CI) propensity score was predominantly small to n=1037 used. midsize nonteaching Aspirin as referent Other notes: None facilities serving a largely Injectable: 1.11 (0.77- Follow-up: 30 days urban patient population. 1.60) Funding Source Location: USA Warfarin: 0.97 (0.65 -1.47) Conflicts: Dates: October 2003 - Authors: None September 2005 Ultrasound or venogram Institution: None Inclusion Criteria: Patients any time after operative day Study: None admitted during the study (n, %) Supplies: None dates, were ≥18 years old, Aspirin: 1 (0.02%) and had primary TKA as Injectable: 73 (0.20%) their principal procedure Warfarin: 28 (0.05%) during their hospitalization Exclusion Criteria: Use of pneumatic Patients with no charges for compression any VTEP treatments, and devices those who had charges for Aspirin: 1795 (38%) VTEP treatments in Injectable: 17,756 (48%) formulations representing Warfarin: 28,757 (55%) therapeutic rather than prophylactic Reoperations: NR anticoagulation. Length of stay: median (IQR) Aspirin: 1 (3-4) Injectable: 4 (3-4) Warfarin: 3 (3-4) © 2017 American Medical Association. All rights reserved. 554

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score P<0.001 Patients on Aspirin also more likely to be discharged home (vs. an extended care facility) Aspirin 30% LMWH/fondaparinux 23% Warfarin: 21% P<0.001 Mortality: Aspirin: 9 (0.2%) Injectable: 45 (0.1%) Warfarin: 54 (0.1%) Adjusted ORs (95%CI) n=109 Aspirin as referent Injectable: 0.63 (0.30- 1.34) Warfarin: 0.54 (0.25-1.15) Adverse events: NR Parvizi Retrospect- To determine Number of patients: Intervention group: n=78 SSI (adjusted results Definitions: 2007 179 ive Case whether N=234 Cases: Patients who when possible; Periprosthetic infection: (ES) Control patients Patient Characteristics developed periprosthetic unadjusted otherwise) patient has at least 3 of 1, 2, 3, 5, 6, receiving ·Age: mean±SD (years) infection Mean duration between 5 of the following criteria: 7, 8 excessive Cases: 66±10 index joint arthroplasty and 1) abnormal serology anticoagulation Controls: 66±10 Timing of intervention: development of infection (erythrocyte (an ·Gender: female (%) pre-and postoperatively was 256 days (range 4- sedimentation rate of international Cases: 36 (46%) 1890 days) >30mm/h; C-reactive normalized Control: NR Duration of intervention: protein level of >1mg/dL) ratio [INR] of ·Obesity: BMI >30 kg/m2 given on the day of Multivariate analysis: 2) Strong clinical and greater than Cases: 44 (56%) surgery and continued for Risk factors for radiographic suspicion clinically Control: 80 (51%) a period of 6 weeks. periprosthetic infection for periprosthetic intended level) BMI 9kg/m2 (mean±SD) If patient a) was on (OR (95%CI) infection were at risk for Cases: 32±9 anticoagulation before ASA score 3) positive joint developing Controls: 32±7 surgery for other 2.07 (1.08-0.97); p=0.03 aspiration culture for wound-related ·Comorbidities: conditions b) had known Postoperative Transfusions: infection problems, ASA Score (mean±SD) allergy to warfarin, or c) 1.63 (1.14-2.33); P=0.007 4) evidence of purulence which in turn, Cases: 2.6±0.57 developed Postoperative wound during the subsequent predisposes Controls: 2.4±0.56 thromboembolism in the complications including surgical intervention them to P=0.01 postoperative period; the development of hematoma: 5) Positive intraoperative © 2017 American Medical Association. All rights reserved. 555

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score periprosthetic Diabetes mellitus patient was given either 27.02 (11.04-91.59); culture. infection. Cases: 14 (18%) subcutaneous and/or p=0.0002 Wound discharge Ultimately, this Control: 22 (14%) intravenous heparin as the Wound Drainage: beyond POD 7 was study is to Steroid Therapy sole or the bridging agent 32.20 (8.7-119.17); deemed clinically examine the Cases: 8 (10%) until adequate and full p<0.0001 significant and correlation Control: 5 (3%) anticoagulation (goal INR- abnormal. between P=0.03 2-3) with oral agent could Other infections: NR Perioperative care: NR anticoagulation NNIS≥1 be established Topic-specific outcomes: and Cases: 50 (64%) Wound Hematoma Analytical periprosthetic Control: 73 (47%) Agent: All patients in both Cases: 11 (14%) methodology: infection. P=0.01 groups were given low- Control: 2 (1%) Wilcoxon procedure: to SURGICAL DATA dose warfarin (goal P=0.0001 perform unadjusted Total Transfusion: INR=1.5) unless indicated Wound Drainage analysis to compare mean±SD otherwise Cases: 24 (31%) means across Cases: 0.78±1.15 Control: 4 (3%) continuous variables. Controls: 0.39±0.79 Monitoring intervention: P=0.0001 Fisher exact test: P=0.002 INR Other Complications compare proportions Allogeneic Transfusion (including PE, DVT & UTI) across categorical Cases: 10 (13%) Control group: n=156 Cases: 18 (23%) variables. Control: 3 (2%) Controls: Patients Control: 18 (12%) T-statistics for P=0.0006 undergoing TKA or THA P=0.02 continuous variables Autologous Transfusion who underwent same Received injectable Χ2 for categorical Cases: 47 (60%) index procedure but did anticoagulant in addition to variables Control: 111 (71%) not develop a subsequent oral Multivariate stepwise P=0.09 infection. Cases: 13/78 (16.7%) logistic regression was (including 1 LMWH) used to perform adjusted Procedures: Standard preventive Received intravenous analysis Primary TKA: measures heparin: Other notes: None Cases: 33/78 (%) AMP: Cephalosporin or an Cases: 13/74 (16.7%) Follow-up: NR Controls: NR alternative for patients with 9/13 heparinized resulted in Funding Source Revision TKA: penicillin allergies was would complications Conflicts: Cases: 10/78 (%) administered within 60 Hematoma: 3/9 Authors: None Controls: NR minutes of arthroplasty Persistent wound Institution: None Primary THA: procedure and continued drainage: 5/9 Study: None Cases: 12/78 (%) for 24h postop. Delayed wound healing: Supplies: None Controls: NR Antimicrobial was 1/9 Revision THA administered at a mean of Cases: 23/78 (%) 39 min pre-incision. INR Controls: NR Mean INR>1.5 Cases: 16 (21%) © 2017 American Medical Association. All rights reserved. 556

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Indications: Degenerative Control: 17 (11%) joint arthritis was the most P=0.05; χ2=3.97 common diagnosis in both INR at day of groups. Discharge>1.5 Posttraumatic arthritis: Cases: 13 (17%) 4/234 (1.7%) Control: 12 (8%) Inflammatory arthropathy: P=0.04; χ2=4.39 2/234 (0.9%) INR>1.5 on day of Setting: 1University discharge Hospital Wound complications:22% Location: USA No Wound Complications: 8% Dates: 2000 - 2005 P=0.005 Inclusion Criteria: All INR level was statistically patients undergoing primary higher in patients with or revision total knee (TKA) wound-related problems or total hip arthroplasty who later developed (THA) for an aseptic infection compared with diagnosis. patients who did not Exclusion Criteria: NR develop infection (p=0.03) Reoperations: Cases: 14 (18%) Control: 3 (2%) OR: 11.2; p<0.0001 Indications for reoperations included: CASES: Evacuation of hematoma: 9/14 (64.3%) Debridement and wash out of draining wound: 3/14 (21.4%) Debridement and closure for wound dehiscence: 2/14 (14.3%) CONTROLS Evacuation of hematoma: 2/3 (66.7%) Delayed wound healing: 1/3: (1%) © 2017 American Medical Association. All rights reserved. 557

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Length of stay: Cases: 6 (Range 1-11) days Controls: 4 (range 2-6) days P=0.006 Mortality: NR Adverse events Wound dehiscence developed in 2 patients both of whom later developed infection Patel Retrospect- The purpose of Number of patients: Intervention group: n=25 SSI (unadjusted Follow Definitions: 2007 175 ive this study is to N=2437 Patients undergoing Up NR) Normal Weight: BMI (ES) concurrent identify Patient Characteristics THR(n=15) or TKR (n=10) Overall: 25/2412 (1.0%) ≤24.9 kg/m2 control pharmacologic ·Age: mean (years) assigned to receive THA: 15/1211 (1.2%) Overweight: BMI 25-29.9 1, 2, 3, 5, 6, factors Infected THA: 59.1 Warfarin, LMWH or aspirin [5/15 had cellulitis which kg/m2 7, 8 (prophylaxis Uninfected THA: 60.1 at the surgeon’s resolved with Obese: BMI 30.0-39.9 against deep Infected TKA: 63.1 preference who developed antimicrobials. 10/15 had kg/m2 venous Uninfected TKA: 66.5 a postoperative wound persistent drainage despite Morbidly Obese: BMI thrombosis), ·Gender: m/f infection 3 days IV antimicrobials ≥40 kg/m2 surgical factors Infected THA: 0.6%/1.2% and underwent operative Length of stay: time/date (estimated Infected TKA: 0.3%/1.0% Timing of intervention: irrigation and debridement] of admission to blood loss and ·Obesity: NR postoperative TKA: 10/1226 (0.8%) time/date of discharge surgical time), ·Comorbidities: NR [7/10 had cellulitis which (as determined by the and patient Duration of intervention: resolved with surgeon) either to home specific factors Procedures: variable antimicrobials; 2/10 or to a rehabilitation (BMI and drain Total Hip Arthroplasty required component setting. output) that are (THA):1211 Agent: removal due to persistent The surgical wound was associated with Total knee arthroplasty Warfarin: target infection; 1/10 underwent inspected daily with the time until (TKA): 1226 international normalized operative irrigation and notation made of when postoperative ratio (INR)= 2.0 debridement due to infected the wound appeared dry wound is dry Indications: NR Low-Molecular-Weight- hematoma but joint according to the following Heparin(LMWH): started components were retained] definition of Weiss and primary total Setting: 1 tertiary care between 12-24 hours Logistic regression analysis Krackow. Wound was joint teaching hospital. postop of variables influencing considered actively arthroplasty, Aspirin (ASA): 325mg in wound infection after THA: draining if a ≥2x2-cm and to Location: USA conjunction with OR(95%CI) area of gauze covering determine pneumatic compression Time until wound dry: the wound was wet or if whether Dates: January 1997 – July devices started the 1.42 (1.18-1.71); p<0.001 fluid was noted to be © 2017 American Medical Association. All rights reserved. 558

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score prolonged 2004 morning after surgery. Coumadin vs. aspirin and originating from the site. wound pneumatic compression (spotting on gauze was drainage Inclusion Criteria: Primary Monitoring intervention: devices: not considered to be results in a unilateral total hip and total NA 7.47 (0.62-89.3); p=0.112 actively draining) longer hospital knee arthroplasties in who LMWH vs. aspirin and Perioperative care: NR stay or closed suction drains had Control group: n=2412 pneumatic compression Analytical increases the been utilized and who had Patients undergoing THR devices: methodology: Multiple risk of early a normal coagulation (n=1196) or TKR (n=1216) 2.11 (0.24-18.5); p=0.499 linear regression postoperative profile. assigned to receive analysis was used to wound Exclusion Criteria: NR Warfarin, LMWH or aspirin Logistic regression analysis model the effects of infection. at the surgeon’s of variables influencing prophylaxis against deep preference who developed wound infection after TKA: venous thrombosis a postoperative infection OR(95%CI) (DVT), BMI, age, & type BMI: 1.08 (1.01-1.16); of anesthesia on time to Standard preventive p=0.018 a dry wound. measures: LMWH vs. aspirin and Multiple logistic Drains: were removed at pneumatic compression regression analysis was 36 hours postop or devices: used to calculate the OR whenever drain output 1.07 (0.23-4.95); p=0.932 between postop infection during any 8-h shift fell Other infections: NR and the time to a dry below 25mL. Topic-specific outcomes: wound while controlling AMP: routine preoperative Regression Analysis of for DVT prophylaxis, and postoperative variables influencing Time BMI, surgical time, EBL prophylactic antimicrobials until wound was dry after 7 Drain output. (cefazolin if patient was THA: Other notes: None not allergic to penicillin, LMWH: Coefficient = 0.318 Follow-up: NR otherwise, clindamycin) P=0.027 (compared with Funding Source including at least 30min aspirin group) Conflicts: prior to initial incision. Morbidly Obese: Coefficient Authors: None = 0.667; P=0.001 Institution: None Drain Output: Coefficient – Study: None 0.002; P=<0.001 Supplies: None Statistically Significant variables influencing Time until wound was dry after TKA: Drain Output: coefficient = 0.0003; P=0.023 Drain output: THA group: every additional © 2017 American Medical Association. All rights reserved. 559

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score 100-mL increase in postop drain output resulted in an additional 0.20 day of wound drainage time. TKA group: every additional 100-mL increase in postop drain output resulted in an additional 0.03 day of wound drainage time. Reoperations: THA: 10/1211 (0.8%) 10/15 underwent operative irrigation and debridement TKA: 3/1226 (0.2%) 2/3 required component removal due to persistent infection; 1/3 underwent operative irrigation and debridement due to infected hematoma but joint components were retained Length of stay: There was a strong positive correlation between the length of hospital stay and the number of days until surgical wound was dry: r=0.29; p<0.001 THA: r=0.34; p<0.001 TKA: r=0.26; p<0.001 Mortality: NR Adverse events: NR

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score Sachs Retrospect- To determine Number of patients: Intervention group: SSI (follow-up 3 months) Definitions: NR 2003 178 ive the safety and N=1742 n=957 Overall: (ES) concurrent efficacy of 6 Patient Characteristics Received low-dose Warfarin: 9/957 (0.94%) Perioperative care: control weeks of low- ·Age: Median Age for both warfarin as No Prophylaxis: 5/785 Patients were 1, 2, 3, 4, 5, dose warfarin groups was 70 years. thromboprophylaxis (0.64%) encouraged to undergo 6 when ·Gender: both groups Superficial infection spinal anesthesia compared with included approximately Timing of intervention: Warfarin: 3 (0.4%) [two no 44% men and 56% women Postoperative required readmission and Analytical thromboprophyl ·Obesity: NR IV antimicrobial therapy; methodology: Chi- axis in total ·Comorbidities: NR Duration of intervention: one treated with an oral square analysis, Mann- knee 6 weeks antimicrobial and Whitney test arthroplasty Procedures: Unilateral, developed wound necrosis using infection Primary Total Knee Agent: low-dose warfarin and required readmission Other notes: None and Arthroplasty (TKA) maintained at an and plastic surgery] complication international normalized No Prophylaxis: 3 (0.3%) Follow-up: 3 months rates as the Indications: NR ration (INR) from 1.6-2.2 [two required readmission postop primary for 6 weeks and IV antimicrobials] outcome Setting: Multicenter Deep Wound Infection Funding Source measures Monitoring intervention: Warfarin: 6 (0.6%) [6 Conflicts: Location: USA NR required surgery, 5 with Authors: None Dates: 1995 - 2000 successful resolution; 1 Institution: None Control group: n=785 required 5 subsequent Study: None Inclusion Criteria: Patients Patients received no surgeries without Supplies: None who were treated with thromboprophylaxis. While resolution; 1 developed postoperative warfarin as in the hospital, this group necrosis requiring recorded in the records of did not receive any aspirin readmission and surgery for the “warfarin clinic” during or NSAIDs and were not wound coverage and the study dates. Patients placed on any type of closure] underwent total knee venous compression No Prophylaxis: 2 (0.3%) arthroplasty and were device. [both required readmission operated on by one of 4 and surgery] surgeons who were using Standard preventive Wound Necrosis(described warfarin on an unselected measures: above) basis for several years. Postoperative protocol: Warfarin: 2 (0.2%) Controls were identified Continuous passive No Prophylaxis: 0 (0%) who were treated without motion (CPM), physical any chemical or mechanical therapy, and weight Total Complication Rate thromboprophylaxis and bearing, as well as most (including infections) were operated on by 1 of 3 orders for pain control and Warfarin: 17 (2.2%) surgeons whose routine nausea were essentially No Prophylaxis: 45 (4.7%) © 2017 American Medical Association. All rights reserved. 561

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score was to avoid the same for all patients. P<0.01 thromboprophylaxis during Both groups received One or more complication TKA initial wound care from a Warfarin: 5% Exclusion Criteria: small group of orthopedic No Prophylaxis: 2% Patients undergoing “special care nurses” who Other infections: bilateral or revision TKA, performed dressing Pneumonia patients on warfarin changes, suture removal Warfarin: 5 (0.5%) prophylaxis for previous and wound observations No Prophylaxis: 1 (0.1%) chronic arterial fibrillation or for the first month after Topic-specific outcomes: thromboembolic events surgery. DVT Warfarin: 2 (0.2%) [two calf vein DVTs] No Prophylaxis: 0 (0%) PE Warfarin: 1 (0.1%) [required readmission] No Prophylaxis: 2 (0.3%) [ these two events were non- fatal occurring within initial hospitalization and resolved with treatment Reoperations: Subsequent surgeries Warfarin: 11 (1.1%) No Prophylaxis: 2 (0.3%) Χ2=4.66; P<0.01 Length of stay- NR Mortality: Deaths (within 90 days) Warfarin: 1 (0.1%); patient admitted 1w postop with GI bleed, unsuccessful attempts to control resulted in myocardial infarction and death No Prophylaxis: 2 (0.3%); 1 in 91yo patient who sustained a fata myocardial infarction 5w postop; 1 in a 73yo patient without prior © 2017 American Medical Association. All rights reserved. 562

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Author Study Year Design Study Population and Setting Intervention Results Comments (Data Risk of Objective Extractor) Bias Score history of cardiac disease readmitted in congestive heart failure 11 days postoperatively, contracted pneumonia and expired None due to thromboembolic disease Adverse events: New Arrhythmia Warfarin: 6 (0.6%) No Prophylaxis: 1 (0.1%) All recovered Angina Warfarin: 5 (0.5%) No Prophylaxis: 0 (0%) MI Warfarin: 3 (0.3%) No Prophylaxis: 2 (0.3%) TIA Warfarin: 1 (0.1%) No Prophylaxis: 1 (0.1%) CVA Warfarin: 2 (0.2%) No Prophylaxis: 1 (0.1%) GI Bleeding Warfarin: 3 (0.3%) No Prophylaxis: 0 (0%) Other Warfarin: 7 (0.7%) No Prophylaxis: 4 (0.5%)

Q17C. How safe and effective is modifying the dose of the perioperative VTE prophylaxis agent to reduce the risk of SSI? Our search did not identify data that evaluated the safety and effectiveness of modifying perioperative VTE prophylaxis and its impact on the risk of SSI.

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2.2C.3. RISK OF BIAS ASSESSMENTS OF STUDIES: Q17 ANTICOAGULATION eTABLE 64. Risk of Bias Assessment of Systematic Reviews for Q17 Anticoagulation Database Number of Studies Funding s included/ screened Heterogenei- Characterist- source(s) described excluded by two Data Individ- ty between ics of disclosed and two studies independe- extracted ual study results included and no Search or more Inclusion/ along with nt by two study assessed studies obvious terms database- exclusion reasons of reviewers independe- quality qualitatively Publicati- reported in conflict Overall Author describe es criteria exclusion for nt assess- and/or on bias evidence of Risk of Year Q -ed searched described described inclusion reviewers ed quantitatively assessed table interest Bias Question 17: Anticoagulation Turpie 166 17   High 2002

eTABLE 65. Risk of Bias Assessments of Randomized Controlled Trials for Q17 Anticoagulation Funding Outco- Attrition source(s) Described Randomizat- Describ- me smaller than disclosed and as ion ed as assess- Study 10-15% of Attrition no obvious Overall Author randomiz- appropriately double- or participant Investiga- Attrition assigned appropriate- conflict of Risk of Year Q ed performed blind blinded blinded tor blinded described patients ly analyzed interest Bias Question 17: Anticoagulation Eriksson 171 17         Low 2008 Kakkar 172 17          Low 2008 Lassen 173 17         Low 2008 Turpie 174 17         Low 2009

eTABLE 66. Risk of Bias Assessments of Other Controlled Studies for Q17 Anticoagulation Attrition not Funding All study groups significantly Investigator Statistical source(s) derived from different Measure blinded to Potential adjustment for disclosed and similar across of Measure of endpoint confoun- potential no obvious Overall Author source/reference study exposure outcome is assessme- ders confounders conflict of Risk of Year Q populations groups is valid valid nt identified done interest Bias Question 17: Anticoagulation Asensio 176 17         Low 2010 Bozic 17         Low © 2017 American Medical Association. All rights reserved. 564

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Attrition not Funding All study groups significantly Investigator Statistical source(s) derived from different Measure blinded to Potential adjustment for disclosed and similar across of Measure of endpoint confoun- potential no obvious Overall Author source/reference study exposure outcome is assessme- ders confounders conflict of Risk of Year Q populations groups is valid valid nt identified done interest Bias 2010 177 Parvizi 179 17         Low 2007 Patel 175 17        Low 2007 Sachs 178 17       Low 2003

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2.2D. Q18 ORTHOPAEDIC SPACE SUIT 2.2D.1. GRADE TABLE: Q18 ORTHOPAEDIC SPACE SUIT eTABLE 67. GRADE Table for Q18 Orthopaedic Space Suit Increase Decrease GRADE GRADE

Quantity GRADE of Overall

and Type Starting Evidence GRADE of Comparison Outcome Findings of GRADE for Evidence Evidence Outcome Base response - Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Q18. How safe and effective are orthopaedic space suits in reducing the risk of SSI in prosthetic joint arthroplasty patients and then which healthcare personnel should wear them? • One retrospective study (N=8288) in TKA using Medicare claims data, found no difference in risk of deep SSI requiring reoperation within 90 days of surgery: Deep 0.28% (0.11-0.46) vs. 0.38% (0.20-0.55); SSI RR 0.75 (0.34-1.62) require- 180 • Deep Infections identified through ICD9- 1 OBS Low 0 0 0 -1 0 0 0 0 Very Low ng CM diagnosis codes for multiple joint/bone reopera- infection, debridement, and implant tion* removal codes (not revision total joint arthroplasty codes). In this study deep infection might be referring to PJI. • Use of laminar flow varied between Space Suit groups. Very Low vs. No suit • One study large joint registry study (N=88,311) with multiple subgroup analyses, found use of space suits was associated with an increased number of deep SSIs requiring revision surgery within Deep 6 months of THA or TKA (P<0.01) but this SSI evidence is limited in size (only 96 events require- 1 OBS 181 Low 0 0 0 -1 0 0 0 0 Very Low or 0.109%): ng • The results did not differ in the presence revision* or absence of laminar flow • Deep SSI in this study might be referring to PJI. • 60% of primary procedures used antimicrobial impregnated cement.

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Increase Decrease GRADE GRADE

Quantity GRADE of Overall

and Type Starting Evidence GRADE of Comparison Outcome Findings of GRADE for Evidence Evidence Outcome Base response - Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders • One small study (N=62) evaluating contamination using space suit or conventional gowns with single hood plus surgical mask, during THA or hip hemiarthroplasty reported only 1 deep SSI in the exhaust suit group (11 days postop) but this evidence is limited in size: 1/31 Deep 182 1 OBS (3.2%) vs. 0/31. (24 month follow up). Low 0 0 0 -1 0 0 0 0 Very Low SSI* • Statistical significance was not reported. • HEPA filtration was present in both study groups. • Deep SSI was not defined-in this study might be referring to incisional SSI • Study was designed to evaluate contamination • One study (14,484) found no difference in risk of superficial SSI for patients undergoing THA or hip hemiarthroplasty: 1 (3.2%) superficial SSI in each group at 16 Superfi- 182 1 OBS and 15 days postoperatively, respectively. Low 0 0 0 -1 0 0 0 0 Very Low cial SSI Follow up 24 months. • Statistical significance was not reported. • HEPA filtration was present in both study groups. *Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

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2.2D.2. EVIDENCE TABLE: Q18 ORTHOPAEDIC SPACE SUIT eTABLE 68. Evidence Table for Q18. How safe and effective are orthopaedic space suits in reducing the risk of SSI in prosthetic joint arthroplasty patients and then which healthcare personnel should wear them? Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting Extractor) Bias Score Hooper Retrospe- To review Number of Intervention group: SSI (Follow up: ≥ 6 Definitions: 2011 181 ctive the New patients: N=88,311 Intervention1: Space Suit months) SSI- deep (joint (ES) concurre- Zealand Primary THR: n=20,385 Unadjusted results: space) nt control Joint 51,485 THR: 21% (n=10,811) THR Revision due to 1, 2, 3, 4, Registry to Primary TKR: TKR: 26% (n=9,574) Early revision for deep early infection: any 5, 6, 8 determine if 36,826 Intervention2: Laminar infection: such procedure the use of Patient Flow Theater: n=30,983 46/51485 (0.089%) performed within laminar flow Characteristics: THR: 33% (n=16,990) Intervention1- Space 6months of the and recorded, not TKR: 38% (n=13,993) Suit: 0.186% initial operation protective reported but Note: Authors only Control1-No Space Suit: Perioperative suits with narrative details that provide percentages; “n” 0.064% care: NR hoods and there were no was calculated. P<0.0001 Analytical self- significant Intervention3: Both Space Intervention2- Laminar methodology: contained differences in clinical Suit and Laminar Flow- Flow theater: 0.148% Percentages with exhaust details between the Numbers not reported Control2-conventional revision for deep systems groups and there (See Other Notes) theater: 0.061% infection were (space suits) was similar duration Timing of intervention: P<0.003 compared between would of operations intraoperative Intervention3-BothSpace groups using the reduce the ·Age: NR Duration of suit + laminar flow: Chi-squared test or rate of early ·Gender: NR intervention: 0.198% Fisher’s exact test deep ·Obesity: NR intraoperative Control3 -Neither No when expected infection ·Comorbidities: NR Device: either laminar air Space suit in a frequencies were requiring a Procedures: Total flow or protective suits conventional OR: 0.053% low. A p-value of revision Hip replacement with hoods and self- P<0.001 <0.05 was procedure (THR) and total contained exhaust From Figure 1c (Bar considered following knee replacement systems (space suits) or Graph- details not reported significant total hip (TKR) and revisions both. in text) Other notes: (THR) and due to early Laminar Flow: All Conventional OR: There was a steady knee (TKR) infections. hospitals confirmed that Suit: ~0.15% increase in the use replacement Indications: they had a regular No Suit: 0.053% of intervention s at 10 Osteoarthritis: 94% maintenance program for Laminar Flow OR: procedures and In years for both THR and filters. There were no Suit: 0.198% 2008 almost half of TKR hospitals which used No Suit:~ 0.10% all procedures were Inflammatory laminar flow combined P values for above NR performed in Arthritis: with a complete surgical SURGEON SPECIFIC laminar-flow THR: 3% enclosure. SURGICAL PRACTICE theaters with space TKR: 4% Space Suits: All the suits INFECTION RATES suits © 2017 American Medical Association. All rights reserved. 568

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting Extractor) Bias Score Setting: Multi-center were contemporary in 33 surgeons did or did not The registry (64 hospitals) design and no surgeon wear space suits captures 98% of Location: New worked in a fully-enclosed Intervention1 (with space both primary and Zealand space. No surgeon suit): 0.082% revision Dates: 1999-2008 worked with all staff in the Control1 (without space arthroplasties Inclusion Criteria: theater. suit) :0.057% performed in New All primary THR & Monitoring intervention: P=0.755 Zealand and TKR and revisions NR 43 surgeons performed records revision due to early Control group: n=NR more than 50 operations in procedures infections with full Control1: (n=67,926) both operating secondary to deep information on THR or TKR performed environments infection. theater environment without Space Suit Intervention2(Laminar and a minimum THR: 79% (n=40,674) Flow): 0.110% Surgeon follow up of 6 TKR: 74% (n=27,252) Control2 (Conventional Questionnaire: months. Control2: (n=57,328)THR OR): 0.028% They compared Specifically or TKR performed In P<0.03 rates for surgeons surgeons who had Conventional theater 30 surgeons used both who used space experience in both THR: 67% (n=34,495) space suit AND laminar suits in both conventional and THR:62% (n=22,833) flow or neither operating room laminar-flow Control3: in conventional Intervention3 (space suit settings (laminar operating theaters theater with no space suit AND laminar flow): flow and and who had Standard preventive 0.1035% conventional) and performed at least measures: Control3 (NO space suit completed at least 50 procedures in Non-standard AND conventional OR): 50procedures in both. Also surgeons preventive measures: 0/3598 procedures each (similar who had used AMP: in New Zealand, P=0.09 surgical practices). space-suits in both prophylactic TKR Questionnaire settings and who antimicrobials are given Early revision for deep requested had completed at for most THR and TKR infection: information on least 50 procedures procedures. (Registry 50/36826 (0.136%) frequency of suit in each shows 96%) Intervention1- Space use, members of Exclusion Criteria: Antimicrobial agent in Suit: 0.243% the team who wore NR cement: Registry data Control1-No Space Suit: them, whether shows 60% utilization 0.098% practice changed rate P<0.001 depending on OR Intervention2- Laminar team and whether Flow theater: 0.193% they wore full suits Control2-conventional or just theater: 0.100% hood/exhaust P<0.019 system. © 2017 American Medical Association. All rights reserved. 569

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting Extractor) Bias Score Intervention3-Both Space suit AND Laminar Flow: Discussion 0.25% comments Control3-Neither (No regarding potential Space suit AND reasons for Conventional OR): 0.087% increased rate of P<0.001 infection with use of From Figure 2c (Bar space suit include: Graph- details not reported Observers in OR in text) have noted Conventional OR: surgeons often Suit: ~0.25% adjust suit or hood No Suit:0.087 % during procedure Laminar Flow OR: and subsequently Suit: 0.25% unknowingly No Suit:~0.12 % contaminate their P values for above NR gloves. SURGEON RELATED Exhaust system – INFECTION RATES there is no 23 surgeons ± space suits: information as to Intervention1 (Space the flow of the suit): 0.251% expelled air from Control1 (No Space exhaust systems suit):0.028% and whether air is P=0.016 concentrated with 32 surgeons performed debris and more than 50 operations in significant numbers both operating of colony forming environments units close to the Intervention2 (Laminar surgical site. Flow): 0.147% Control2 (Conventional Follow-up: OR): 0.189% Minimum 6 months P=0.597 Funding Source Conflicts: NOTE: One hospital of 64 Authors: None was identified as having a Institution: None significantly increased rate Study: None of revision for early deep Supplies: None infection when the use of a © 2017 American Medical Association. All rights reserved. 570

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting Extractor) Bias Score conventional theater and no space suit was compared with laminar flow with a space suit. The hospital contributed only a small number to the database and when these were removed from the analysis, there was no change in the significance of the results. Other infections: NR Topic-specific outcomes: Surgeon Questionnaire 35/60 (58.3%) response rate Space suit used in all replacement procedures: 35/35 Surgical technique the same regardless of laminar flow vs. conventional OR: 35/35 Full space suit: 28/31 OR team members wearing full suit: surgeon, assistant and scrub nurse. OR team members NOT wearing space suit: anesthetist or technician Reoperations: All infections were reoperations Length of stay: NR Mortality: NR Adverse events: Surgeon Questionnaire: Spatial awareness limited by hood (space suit) © 2017 American Medical Association. All rights reserved. 571

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting Extractor) Bias Score “Easier to contaminate themselves while wearing space suit since there was an apparent false sense of security within it”

Miner Retrospe- To assess Number of Intervention group: SSI (follow up 90 days) Definitions: 2007 180 ctive the current patients: N=8288 Intervention1: n=3538 Unadjusted results SSI-deep prosthetic (ES) concurre- effects of procedures Patients in Hospitals Overall 90-day cumulative joint infection nt control laminar which used exhaust suits incidence of deep infection Infection: 1, 2, 3, 5, 8 airflow Patient in more than 75% of requiring reoperation: International systems and Characteristics: procedures 28/8288 TKR Classification of body NR Intervention2: n=3513 (0.34%)BODY EXHAUST Diseases, Ninth exhaust ·Ag: NR Patients in Hospitals SUIT revision (ICD-9) suits on the ·Gender: NR which used laminar air Intervention1: 10/3538 diagnosis and risk of ·Obesity: NR flow in more than 75% of (0.28% (95%CI: 0.11- procedures codes postoperativ ·Comorbidities: NR procedures 0.46)) for evidence of e infections Control1: 18/4750 (0.38 postoperative deep via a Procedures: Timing of intervention: (95%CI: 0.20-0.55)) infection that secondary Unilateral primary Intraoperative required additional analysis of total knee Risk Ratio (95%CI) for operation. data replacement (TKR) Duration of Body Exhaust Suit: 0.75 Reoperations within collected for intervention: (0.34-1.62) 90 days a larger Indications: NR Intraoperative Perioperative study of LAMINAR AIR FLOW care: NR hospital Setting: 256 centers Device: Laminar air flow Intervention2: 15/3513 Analytical characteristi in Illinois, Ohio, or Exhaust suits. (0.43% (95%CI: 0.21- methodology: c and North Carolina and Laminar air flow: 0.64)) None patient Tennessee that horizontal and vertical Control2: 13/4750 (0.27 Did not adjust for outcomes submitted a claim for laminar airflow systems (95%CI: 0.12-0.42)) clustering of events after total TKR during 2000 were combined into a within hospitals knee single group that 28 TKR were performed in bb/c 22/25 replacement Location: USA represented regular use 25 hospitals. hospitals with (TKR) of laminar air flow. infections reported Dates: January 1 – Exhaust Suit: Not Other infections: NR only a single August 30, 2000 indicated: who wore Topic-specific infection and © 2017 American Medical Association. All rights reserved. 572

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting Extractor) Bias Score exhaust suits, specifics of outcomes: because no Inclusion Criteria: design. OR Flow or traffic 30% of hospitals in hospital reported Data from Medicare Monitoring intervention: analysis reported regular more than 2 claims parts A and B NR use of laminar airflow infections. to identify unilateral systems Other notes: primary TKRs. For Control group: 41% of hospitals in this UV Light use- patients with a Control1: n=4750 analysis reported regular collected data on second TKR during Patients in Hospitals use of body exhaust suits. use of UV lights but a separate which used exhaust suits Reoperations: All this was used only hospitalization, only at frequencies of “not at incidences of infection at 13/256 hospitals the first procedure all”, “used in less than were reoperations within and did not allow was considered. 26% of procedures,” 90 days. analysis of effect “used in 26%-75% of Length of stay: NR on infectious procedures”Control2: Mortality: NR outcomes. Hospitals had to n=4775 Adverse events: NR Low number of meet the following Patients in Hospitals events (n=28) criteria: 1. The which used Laminar Air yielded low power orthopedic Flow at frequencies of to exclude potential administrator “not at all”, “used in less benefits. Also returned the survey than 26% of procedures,” precluded analysis on use of laminar “used in 26%-75% of of subgroups and airflow systems procedures” interactions (horizontal or between infection vertical) and body Standard preventive control techniques. exhaust suits during measures: Also potential for TKR in year 2000, 2. Use of laminar air flow misclassification of The survey and exhaust suit was individual contained distributed roughly procedures (focus information independently among on hospital regarding use of hospitals. Most hospitals standard practice)- laminar airflow reported that these infections systems and body methods were either part associated with exhaust suits as of their standard infection hospitals classified infection control control practices as using measures, and 3. (used>75% of time) or intervention There was evidence not at all. technique most of of at least 1 the time, could Medicare claim for a have occurred in TKR performed patients for whom during January 1 the technique was © 2017 American Medical Association. All rights reserved. 573

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting Extractor) Bias Score and August 1, 2000 not use. Follow-up: 90 Exclusion Criteria: days Bilateral TKR during Funding Source the same Conflicts: hospitalization. Authors: None Institution: None Study: None Supplies: None Pasquar- Prospecti- To evaluate Number of Intervention group: SSI (follow up 24 Definitions: ella ve the effect on patients: N=62 n=31 months) Deep and 2003 182 Concurre- aerobic operations Body exhaust suits were Unadjusted: superficial wound (ES) nt control bacterial Patient worn by one surgeon, the Total: 3/61 (4.8%) infections not 1, 2, 3, 4, sedimentatio Characteristics first assistant and the Deep: 1/61 (1.6%) defined but 5, n of a mixed ·Age: mean 70.80 scrub nurse who Superficial: 2/61 (3.2%) recorded. operating years range= 30-95 remained seated Perioperative theater years SD=12.39 throughout the whole Intervention (Exhaust suit): care: ventilation ·Gender: m/f: 33/29 operation. The circulating Deep: 1/31 (3.2%) Anesthesia: either with ·Obesity: NR nurse wore a postop day 11 general or spinal. separate ·Comorbidities: NR conventional gown. Superficial: 1/31 (3.2%) Analytical operating Procedures: Total Operation was conducted postop day 16 methodology: and hip replacements in a diluted airflow system Control (conventional Settle plate results anesthetic (THR) or with separation zones. gown): were compared areas and to hemiarthroplasties Timing of intervention: Deep: 0/31 between patient compare the Indications: Intraoperative Superficial: 1/31 (3.2%) and anesthetist contaminatio Hemiarthroplasties: Duration of postop day 15 areas and between n using either coxoarthrosis intervention: conventional gowns body or fracture (trauma) Intraoperatively Other infections: NR and body exhaust exhaust THR: NR Device: Topic-specific suits using Mann- gowns or Setting: Orthopedic Diluted airflow system outcomes: NA Whitney U tests conventional department in 1 with separation zones: after normality clothing hospital Unidirectional airflow Reoperations: NR checking to during hip Location: system where the air is Length of stay: NR establish significant joint Switzerland forced through a 0.3μm Mortality: NR differences Arthroplasty Dates: December H14 99.995% HEPA Adverse events: NR between variables. (THR and 1997-January 1998 (high efficiency Other notes: None hemiarthropl Inclusion Criteria: particulate air) filter and Follow-up: 24 asty) Patients scheduled supplied through eight air months for THR or ceiling diffusers located Funding Source hemiarthroplasties over the operating table Conflicts: © 2017 American Medical Association. All rights reserved. 574

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting Extractor) Bias Score for either and the instrument table. Authors: NR coxoarthrosis or The air is extracted by Institution: NR fracture between the means of two floor-level Study: NR study dates return air grilles in the Supplies: Industry Exclusion Criteria: walls of the anesthetic NR area. Air turnover rate ≈24 air changes /h with a positive pressure of 2 Pa. A plexiglass barrier separates the OR into the patient area and the anesthetic area. The Patient’s head and the anesthesiologist remain outside the patient area during the operation. Body exhaust suit: Manufacturer named but suit not described. Conventional Gowns: 65% polyester 35% cotton with the head cover consisting of a single hood plus surgical mask and the neck remaining partially exposed. Monitoring intervention: NA Control group: n=31 Conventional gowns worn by all surgical staff during operation in diluted airflow system with separation zones Standard preventive measures: AMP: IV injection of cefamandole 30min before anesthesia © 2017 American Medical Association. All rights reserved. 575

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Author Study Year Design Study Population and Intervention Results Comments (Data Risk of Objective Setting Extractor) Bias Score followed by a second dose of cefamandole in operations lasting longer than 2h. Operating Room Traffic: Operating Team (1 surgeon, 2 assistants, 2 nurses) same for all procedures. Surgeon first assistant and scrub nurse remained seated entire operation (second assistant stood at opposite end of room and circulating nurse moved around). Extraneous personnel were excluded from the OR. Swing doors were closed to all personnel after the final preparation of the patient on the operating table.

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2.2D.3. RISK OF BIAS ASSESSMENTS: Q18 ORTHOPAEDIC SPACE SUIT eTABLE 69. Risk of Bias Assessments of Other Controlled Studies for Q18 Orthopaedic Space Suit Attrition not Funding All study groups significantly Investigator Statistical source(s) derived from different Measure blinded to Potential adjustment for disclosed and similar across of Measure of endpoint confound potential no obvious Overall Author source/reference study exposure outcome is assessme- -ders confounders conflict of Risk of Year Q populations groups is valid valid nt identified done interest Bias Question 18: Surgical Attire Hooper 181 18        Low 2011 Miner 180 18      Low 2007 Pasquarel- la 18      Low 2003 182

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2.2E. Q20 BIOFILM 2.2E.1. GRADE TABLE: Q20 BIOFILM eTABLE 70. GRADE Table for Q20 Biofilm Increase Decrease GRADE GRADE

Quantity GRADE of Overall

and Type Starting Evidence GRADE of Comparison Outcome Findings of GRADE for Evidence Evidence Outcome Base response - Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Q20. What are the most effective strategies to reduce the risk of biofilm formation and SSI in prosthetic joint arthroplasty patients? Q20A. How effective are cement modifications (i.e., antimicrobial and nanoparticle loading)? • Meta-analysis 2 RCTs (N=418), reduced risk for deep SSI in primary hybrid TKA (cemented tibial and patellar components) with cefuroxime 2g in 40g polymethylmethacrylate loaded cement: OR: 0.08 (0.01 – 0.59); p=0.01; I2=0 • 1 study183 in 350 TKAs, non-diabetics: 0/178 vs. 5/162 (3.1%); p=0.02 184 • 1 study in 78 TKAs, all diabetics: 0/41 Deep 2 RCT 183,184 vs. 5/37 (13.5%); p=0.02 High 0 0 0 0 -1 0 0 0 Moderate Cefuroxime SSI* loaded • Based on definition deep SSI included PJI cement vs. • All TKAs performed by same surgeon, in plain operating rooms without ultraviolet light, cement; laminar flow, or orthopaedic space suit Moderate both • AMP included parenteral cefazolin and groups with gentamycin preoperatively then every 6 perioperat- and 12 hours, respectively postop for 36 ive AMP hours followed by cefazolin orally for 7 more days. • Meta-analysis 2 RCT (N=418), no difference OR: 0.91 (0.18 – 4.55); p=0.90; I2=0 Superfi- 2 RCT • In one study183 of 350 TKAs for 183,184 High 0 0 0 -1 -1 0 0 0 Low cial SSI osteoarthritis with no diabetes mellitus: 2/178 vs. 2/162; p=1.00 • In one study184 of 78 TKAs all with diabetes mellitus: 1/41 vs. 1/37; p=0.84

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Increase Decrease GRADE GRADE

Quantity GRADE of Overall

and Type Starting Evidence GRADE of Comparison Outcome Findings of GRADE for Evidence Evidence Outcome Base response - Study Quality Study Consistency Directness Precision Bias Publication Magnitude Large Dose Confounders Q20B. How effective are prosthesis surface modifications (i.e., antimicrobial coating, galvanic couples, “printing” technologies, and nanotechnology)? Our search did not identify in vivo studies that evaluated the safety and effectiveness of prosthesis modifications and their impact on biofilm formation and the risk of SSI. Q20C. How effective are vaccines? Our search did not identify in vivo studies that evaluated the safety and effectiveness of vaccines and their impact on biofilm formation and the risk of SSI. Q20D. How effective are other biofilm control agents (e.g., biofilm dispersants, quorum-sensing inhibitors, novel antimicrobial agents)? Our search did not identify in vivo studies that evaluated the safety and effectiveness of biofilm control agents and their impact on biofilm formation and the risk of SSI *Critical outcome; OR: Odds Ratio; RR: Risk Ratio; CI: Confidence Interval

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2.2E.2. EVIDENCE TABLE: Q20 BIOFILM Q20. What are the most effective strategies to reduce the risk of biofilm formation and SSI in prosthetic joint arthroplasty patients? eTABLE 71. Evidence Table for Q20A. How effective are cement modifications (i.e., antimicrobial and nanoparticle loading)? Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score Chiu RCT To Number of patients: Intervention group: SSI: (range 26-80 months) Definitions: (McQueen 2002 183 1, 5, 10 evaluate N=285 patients n=178 knees Early Superficial Infections: 1990) (ES) the efficacy (340 knees) Cefuroxime-impregnated Intervention: 2/178 (1.1%) Superficial Infection – of Patient cement ( 2g of cefuroxime Control: 2/162 (1.2%) infection superficial to cefuroxime Characteristics: Age, in 40 g cement) was P=1 the deep fascia with - tourniquet time, utilized for fixation of the Early or Intermediate Deep positive or negative impregnate operative time, amount tibial an patellar Infections: cultures and no delays in d cement in of blood transfusion, components only Intervention: 0/178 wound healing. the The Hospital for Special Timing of intervention: Control: 5/162 (3.1%) Deep Infection – prevention Surgery Knee Score Intra and postoperatively Early: 3/5 (60%) Infection extending deep of deep (pre & post operatively), Duration of intervention: Intermediate: 2/5 (40%) to the deep fascia, with infection sex, side of operation, The duration of P=0.0238 persistent wound after and preoperative implantation (indefinitely). No deep infections in bilateral discharge or joint pain, primary diagnosis were all Device: Cefuroxime- procedures positive or negative total knee analyzed and were impregnated cement; pure cultures from deep arthroplasti found to be similar cement without Other infections: NR tissues and delays in es between groups. cefuroxime; prosthetic Topic-specific outcomes: NR wound healing. performed Age: Mean ±SD knee Re-operations attributable to SSI: Deep Infections also without Intervention :70±7.4yr Monitoring intervention: All four early superficial wound confirmed by laboratory clean-air Control:68±6.9yr Radio graphic evaluation infections were treated with wound parameters (the measures Gender: (m/f) at every visit & functional debridement & intravenous erythrocyte such as Intervention evaluation (Hospital for antimicrobials for 1 week then oral sedimentation rate & laminar :69%/31% Special Surgery score) antimicrobials for another week. level C-reactive protein) flow and Control:70%/30% performed at every visit & positive culture of joint body- Obesity: NR starting with the 3rd postop Length of stay: Mean Stay, days fluid. exhaust Comorbidities: NR visit. (range): Early Infections: suits. Operation Side: Control group: n= 162 8 days (5-15 days) Developing <2 months (left/right) knees Mortality: NR after operation Intervention Cement did not contain Adverse events: Intermediate Infections: :51%/49% cefuroxime. Only tibial and Loose femoral component at 2 Developing 2-24 months Control:55%/45% patellar components were years: after operation Procedures: Primary fixed with cement. Intervention: 1/178 (0.6%) – Late Infections: total knee arthroplasties Bilateral TKAs: n=55 underwent revision of the femoral Developing >24 months with cementless fixation patients ; one knee treated component after operation. of the femoral with intervention, the other Not significant statistically with (Rand 1993)

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score component and cement with controls available numbers Follow-up: at 3 weeks, fixation (mixing method Standard preventive 8 weeks, and 6 months of cement NR) of the measures: Patellar fracture after traumatic then every 6 months patellar and tibial Environmental: No episode: thereafter. Average was components. ultraviolet light for Control: 1/162 (0.6%) – treated with 49 months (Range 26-80 Indications: disinfection; no laminar ORIF with tension band wiring months) Osteoarthritis: flow nor body-exhaust Perioperative care: NR Control: 146/162 suits were used. Other notes: (90.1%) AMP Preop: intravenous All surgeries performed Intervention: 154/178 bolus injections of by 1 surgeon (86.5%) cefazolin & gentamicin. The authors report the Rheumatoid Arthritis AMP Postop: Intravenous operating room was not Control: 6/162 (3.7%) injections of cefazolin modern like more Intervention: 10/178 every 6hrs for 36 hours; developed countries with (5.6%) Intravenous injections of better facilities. This Posttraumatic arthritis: gentamicin every 12hrs for study was an effort to Control: 6/162 (3.7%) 36 hours; and oral show that antimicrobial Intervention: 10/178 cefazolin every 6hrs for 7 impregnated cement (5.6%) days. could be utilized as part Gouty arthritis Drain: Used routinely and of a bundle to reduce Control: 2/162 (1.2%) removed on the 2nd day. SSI without clean air Intervention: 1/178 Continuous passive facilities. (0.6%) motion: used every day Funding Source Osteonecrosis: until discharge Conflicts: Control: 1/162 (0.6%) Weight bearing: on the Authors: None Intervention: 3/178 involved knee was allowed Institution: None (1.7%) form the second Study: None Setting: 1 Hospital postoperative day and Supplies: None Location: Taiwan, crutches were used as China needed Dates: 1994-1998 Inclusion Criteria: Patients undergoing primary total knee arthroplasty Exclusion Criteria: Patients with diabetes mellitus, peripheral arterial occlusive © 2017 American Medical Association. All rights reserved. 581

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score disease, psoriasis, prior knee surgery, any kind of lower-extremity infection, osteomyelitis, or a malignant tumor who were being treated with immunosuppressive agents. Chiu RCT To Number of patients: Intervention group: n=41 SSI: (range 26-88 months) Definitions: 2001 184 1, 5, 10 evaluate N=78 knees (35 patients-6 Early superficial wound infection: SSI (ES) the effect Patient Bilateral TKA) Intervention: 1/ 41 (2.4%) Classified according to of Characteristics: Age; Cefuroxime-impregnated Control: 1/37 (2.7%) (McQueen et al 1990) antimicrobi sex; side of operation; cement (2g of cefuroxime P= 0.835 and confirmed by al type of diabetes; type of in 40 g cement) was Deep infection measurement of the (cefuroxim diabetic treatment; utilized for fixation of the Intervention: 0/41 ESR & level of C- e) duration of diabetes tibial and patellar Control: 5/37 (13.5%) reactive protein and impregnate mellitus; tourniquet components only. P=0.021 culture of joint fluid. d cement time; operation time, Timing of intervention: Relative probability of not developing Perioperative care: on the volume of blood Intra and post-operatively a deep infection in intervention group Authors report patients prevention transfusion; Duration of intervention: 0.865 (95%CI 0.769-0.973) had poor control of blood of deep preoperative fasting The duration of All deep infections were in unilateral glucose and the infection blood sugar; implantation (indefinitely). TKAs operating room was “not after preoperative “2 hours Device: Cefuroxime- All deep infections were considered modern”. Also used 7 primary post meal” blood sugar; impregnated cement; pure late (1-6mo postop) and were day course of a systemic total knee postoperative fasting cement without deemed healing satisfactorily until antimicrobial because arthroplast blood sugar, cefuroxime; prosthetic after the first follow-up visit. operating environment y (TKA) in postoperative “2 hours knee No deep infections occurred in was poor and patients patients post meal” blood sugar; Monitoring intervention: bilateral surgeries. were in poor state of with preoperative knee Patients were examined at hygiene. They report diabetes score; and 3 weeks, 8 weeks & 6 Other infections: NR trying to shorten regimen mellitus postoperative knee months post-operatively. Topic-specific outcomes: by using antimicrobial (DM). score were all analyzed Then every 6 months Deep infections impregnated cement and found to be similar there-after. Radio graphic Type 1 Diabetes: Other notes: All between groups except evaluation at every visit & 1/5 6mo postop 70yoMale surgeries performed by postoperative knee functional evaluation 1 surgeon score (HHS-functional) (Hospital for Special Type 2 Diabetes: Follow-up: Patients Age: mean (range) Surgery score) performed 4/5 (1,2,3 and 6 mo. postop in 67- were examined at 3 Intervention: 72y (56- at every visit starting with 73yo Males) weeks, 8 weeks & 6 © 2017 American Medical Association. All rights reserved. 582

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score 90) the 3rd postop visit. months post-operatively. Control: 69y (54-81) Control group: n= 37 Infecting organism in deep Then every 6 months Gender: m/f (%) knees (32 patients-5 infections: there-after Mean follow Intervention: 80/20 Bilateral TKA) Staphylococcus aureus: 3/5 up was 50 months Control: 67/33 Cement did not contain Staphylococcus epidermis: 2/5 (Range 26-88 months) Obesity: NR cefuroxime. Only the tibial Comorbidities: and patellar components Postoperative knee score (HHS- Funding Source NIDDM/IDDM: were fixed with cement. functional) Conflicts: Intervention: 32/3 Bilateral TKAs: Intervention: 91 (SD 2.8) Authors: None Control: 28/4 cefuroxime-impregnated Control: 86 (SD 9.2) Institution: None Duration of Diabetes: y cement used on one side P= 0.0093 Study: None (SD) (Intervention n=6) and not Caused by five cases of deep Supplies: None Intervention: 12y (8.7) the other (Control n=5). All infection in control group Control: 10y (7.8) undertaken in sequence Left/right: (%) under difference Re-operations: Both early Intervention: 80/20 anesthetics superficial wound infections were Control: 52/48 Standard preventive successfully treated with Procedures: Total measures: debridement and intravenous knee arthroplasty with Environmental: No antimicrobials administered for 1 cementless fixation of ultraviolet light for week and orally for another week. the femoral component disinfection; no laminar Deep Infections and cement fixation flow nor body-exhaust 3/5 – radical debridement was (mixing method of suits were used. followed by four weeks of cement NR) of the AMP Preop: intravenous intravenous antimicrobials and then patellar and tibial bolus injections of two months of oral antimicrobials components. cefazolin & gentamicin. 2/5 –deep SSIs underwent two stage Indications: AMP Postop: Intravenous re-implantation procedures. Osteoarthritis injections of cefazolin Length of stay: Mean lengths was 8 Setting: 1 hospital every 6hrs for 36 hours; days (Range 5-14 days) Location: Taiwan, Intravenous injections of Mortality: NR China gentamicin every 12hrs for Adverse events: NR Dates: 1993-1998 36 hours; and oral Inclusion Criteria: cefazolin every 6hrs for 7 Patients with diabetes days. mellitus undergoing Drain: (not vacuum) Were total knee arthroplasty used for 36 hours Exclusion Criteria: Continuous passive Patients with motion: Prescribed rheumatoid arthritis, immediately and used © 2017 American Medical Association. All rights reserved. 583

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Study Author Design Year Study Population and Risk of Intervention Results Comments (Data Objective Setting Bias Extractor) Score psoriasis, previous every day until discharge knee surgery, any type Weight bearing: on the of infection of the lower operated knee was limb, osteomyelitis, allowed immediately & malignant tumor or crutches used as needed. those who were undergoing immunosuppressive therapy.

Q20B. How effective are prosthesis surface modifications (i.e., antimicrobial coating, galvanic couples, “printing” technologies, and nanotechnology)? Our search did not identify in vivo studies that evaluated the safety and effectiveness of prosthesis modifications and their impact on biofilm formation and the risk of SSI.

Q20C. How effective are vaccines? Our search did not identify in vivo studies that evaluated the safety and effectiveness of vaccines and their impact on biofilm formation and the risk of SSI.

Q20D. How effective are other biofilm control agents (e.g., biofilm dispersants, quorum-sensing inhibitors, novel antimicrobial agents)? Our search did not identify in vivo studies that evaluated the safety and effectiveness of biofilm control agents and their impact on biofilm formation and the risk of SSI.

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2.2E.3. RISK OF BIAS ASSESSMENTS: Q20 BIOFILM eTABLE 72. Risk of Bias Assessments of Randomized Controlled Trials for Q20 Biofilm Funding Outco- Attrition source(s) Described Randomizat- Describ- me smaller than Attrition disclosed and as ion ed as assess- Study 10-15% of appropria- no obvious Overall Author randomiz- appropriately double- or participant Investiga- Attrition assigned tely conflict of Risk of Year Q ed performed blind blinded blinded tor blinded described patients analyzed interest Bias Question 20 Biofilm Chiu Mode- 183 20    2002 rate Chiu Mode- 184 20    2001 rate

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3. EVALUATION OF THE RISK OF BIAS OF AN INDIVIDUAL STUDY

3.1. Instructions Check off each item in the appropriate checklist if it is present in the study Divide the total number of checked items by the total number of questions on the checklist Rate the risk of bias as follows: • If < 25% of checklist items were present in study, the Risk of Bias was rated as High • If > 25% and ≤ 50% of checklist items were present in study, the Risk of Bias was rated as Moderate • If >50% of checklist items were present in study, the Risk of Bias was rated as Low

3.2. Checklist for Systematic Reviews 1) Search terms described 2) Databases searched described and two or more databases searched 3) Inclusion/exclusion criteria described 4) Number of included/excluded studies along with reasons of exclusion described 5) Studies screened by two independent reviewers for inclusion 6) Data extracted by two independent reviewers 7) Individual study quality assessed 8) Heterogeneity between study results assessed qualitatively and/or quantitatively 9) Publication bias assessed 10) Characteristics of included studies reported in evidence table 11) Funding source(s) disclosed and no obvious conflict of interest

3.3. Checklist for Randomized Controlled Trials 1) Described as randomized 2) Randomization appropriately performed (e.g. random number table, computerized scheme) 3) Described as double-blind 4) Outcome assessor blinded 5) Study participant blinded (e.g. interventions identical in appearance) 6) Investigator blinded (e.g. opaque sealed envelopes) 7) Attrition described 8) Attrition smaller than 10-15% of assigned patients 9) Attrition appropriately analyzed (e.g. intention to treat analysis) 10) Funding source(s) disclosed and no obvious conflict of interest

3.4. Checklist for Observational Studies 1) All study groups derived from similar source/reference populations 2) Attrition not significantly different across study groups 3) The measure of exposure is valid 4) The measure of outcome is valid 5) Investigators blinded to endpoint assessment 6) Potential confounders identified © 2017 American Medical Association. All rights reserved. 586

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7) Statistical adjustment for potential confounders done 8) Funding source(s) disclosed and no obvious conflict of interest

3.5. Translating Risk of Bias into GRADE Tables When the risk of bias was rated as “High” for >50% of studies making up the evidence base for a given outcome, one point was deducted for Study Quality in the GRADE table.

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4. EVIDENCE TABLE EXTRACTION TEMPLATES

eTABLE 73. Systematic Review (SR) Extraction Template Author Study Year Design Study Population and (Data Intervention(s) Results (by intervention) Comments Quality Objective Setting Extrac- Score tor) SR Narrative Study types and Intervention group: SSI: Definitions: Quality number: Timing of intervention: Other infections: Perioperative Score Number of total Duration of intervention: Topic-specific care: patients in the Device: outcomes: Other notes: review: Monitoring intervention: Re-operations: Follow up: Inclusion criteria: Control group: Length of stay: Funding source Exclusion criteria: Standard preventive Mortality: conflicts: Databases searched: measures: Adverse events: Aggregate summary score:

eTABLE 74. Randomized Controlled Trial (RCT) Extraction Template Author Study Year Design Study Population and (Data Intervention Results Comments Quality Objective Setting Extrac- Score tor) RCT Narrative Number of patients: Intervention group: SSI: Definitions: Quality Patient Timing of intervention: Other infections: Perioperative Score Characteristics: Duration of intervention: Topic-specific care: ·Age: Device/agent: outcomes: Other notes: ·Gender: Monitoring intervention: Reoperations: Follow-up: ·Obesity: Control group: Length of stay: Funding source ·Comorbidities: Standard preventive Mortality: conflicts: Procedures: measures: Adverse events: Indications: Setting: Location: Dates: Inclusion Criteria: Exclusion Criteria:

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eTABLE 75. Other Observational Studies (OBS) Extraction Template Author Study Year Design Study Population and (Data Intervention Results Comments Quality Objective Setting Extract- Score or) Study Narrative Number of patients: Intervention group: SSI: Definitions: Design Patient Timing of intervention: Other infections: Perioperative Quality Characteristics: Duration of intervention: Topic-specific care: Score ·Age: Device/agent: outcomes: Analytical ·Gender: Monitoring intervention: Reoperations: methodology: ·Obesity: Control group: Length of stay: Other notes: ·Comorbidities: Standard preventive Mortality: Follow-up: Procedures: measures: Adverse events: Funding source Indications: conflicts: Setting: Location: Dates: Inclusion Criteria: Exclusion Criteria:

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5. STUDY TYPE DETERMINATION

eFIGURE A. STUDY TYPE DETERMINATION ALGORITHM (Adapted from: Hartling et. al. 2010185)

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6. REFERENCES

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