Intensive Care Med DOI 10.1007/s00134-012-2769-8 GUIDELINES

R. P. Dellinger Surviving Sepsis Campaign: International Mitchell M. Levy Andrew Rhodes Guidelines for Management of Severe Sepsis Djillali Annane Herwig Gerlach and Septic Shock, 2012 Steven M. Opal Jonathan E. Sevransky Charles L. Sprung Ivor S. Douglas Roman Jaeschke Tiffany M. Osborn Mark E. Nunnally Sean R. Townsend Konrad Reinhart Ruth M. Kleinpell Derek C. Angus Clifford S. Deutschman Flavia R. Machado Gordon D. Rubenfeld Steven Webb Richard J. Beale Jean-Louis Vincent Rui Moreno The Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup*

of Hospital Medicine, Surgical Infection R. P. Dellinger ()) Received: 4 June 2012 Society, World Federation of Critical Care Cooper University Hospital, Accepted: 12 November 2012 Nurses, World Federation of Pediatric Camden, NJ, USA Intensive and Critical Care Societies; World e-mail: [email protected] Ó SCCM and ESICM 2013 Federation of Societies of Intensive and Critical Care Medicine. Participation and Sponsoring organizations: American endorsement: The German Sepsis Society M. M. Levy Association of Critical-Care Nurses, and the Latin American Sepsis Institute. Warren Alpert Medical School of Brown American College of Chest Physicians, University, Providence, RI, USA American College of Emergency * Members of the 2012 SSC Guidelines Physicians, American Thoracic Society, Committee and Pediatric Subgroup are A. Rhodes Asia Pacific Association of Critical Care listed in Appendix 1 at the end of this St. George’s Hospital, London, UK Medicine, Australian and New Zealand article. Intensive Care Society, Brazilian Society of D. Annane This article is being simultaneously Critical Care, Canadian Critical Care ˆ ´ Society, Chinese Society of Critical Care published in Critical Care Medicine and Hopital Raymond Poincare, Medicine, Chinese Society of Critical Care Intensive Care Medicine. Garches, France Medicine—China Medical Association, Emirates Intensive Care Society, European For additional information regarding this H. Gerlach Respiratory Society, European Society of article, contact R.P. Dellinger (Dellinger- Vivantes-Klinikum Neuko¨lln, Clinical Microbiology and Infectious [email protected]). Berlin, Germany Diseases, European Society of Intensive Care Medicine, European Society of S. M. Opal Pediatric and Neonatal Intensive Care, Memorial Hospital of Rhode Island, Infectious Diseases Society of America, Pawtucket, RI, USA Indian Society of Critical Care Medicine, International Pan Arabian Critical Care J. E. Sevransky Medicine Society, Japanese Association for Emory University Hospital, Acute Medicine, Japanese Society of Intensive Care Medicine, Pediatric Acute Atlanta, GA, USA Lung Injury and Sepsis Investigators, Society for Academic Emergency Medicine, C. L. Sprung Society of Critical Care Medicine, Society Hadassah Hebrew University Medical Center, Jerusalem, Israel I. S. Douglas Abstract Objective: To provide shock (1C) as the goal of therapy; Denver Health Medical Center, an update to the ‘‘Surviving Sepsis reassessment of antimicrobial therapy Denver, CO, USA Campaign Guidelines for Manage- daily for de-escalation, when appro- R. Jaeschke ment of Severe Sepsis and Septic priate (1B); infection source control McMaster University, Shock,’’ last published in 2008. with attention to the balance of risks Hamilton, ON, Canada Design: A consensus committee of and benefits of the chosen method 68 international experts representing within 12 h of diagnosis (1C); initial T. M. Osborn 30 international organizations was fluid resuscitation with crystalloid Barnes-Jewish Hospital, convened. Nominal groups were (1B) and consideration of the addition St. Louis, MO, USA assembled at key international meet- of albumin in patients who continue M. E. Nunnally ings (for those committee members to require substantial amounts of University of Chicago Medical Center, attending the conference). A formal crystalloid to maintain adequate mean Chicago, IL, USA conflict of interest policy was devel- arterial pressure (2C) and the avoid- oped at the onset of the process and ance of hetastarch formulations (1B); S. R. Townsend enforced throughout. The entire initial fluid challenge in patients with California Pacific Medical Center, guidelines process was conducted sepsis-induced tissue hypoperfusion San Francisco, CA, USA independent of any industry funding. and suspicion of hypovolemia to K. Reinhart A stand-alone meeting was held for achieve a minimum of 30 mL/kg of Friedrich Schiller University Jena, Jena, all subgroup heads, co- and vice- crystalloids (more rapid administra- Germany chairs, and selected individuals. tion and greater amounts of fluid may Teleconferences and electronic-based be needed in some patients (1C); fluid R. M. Kleinpell discussion among subgroups and challenge technique continued as long Rush University Medical Center, among the entire committee served as as hemodynamic improvement is Chicago, IL, USA an integral part of the development. based on either dynamic or static D. C. Angus Methods: The authors were advised variables (UG); norepinephrine as the University of Pittsburgh, to follow the principles of the Grad- first-choice vasopressor to maintain Pittsburgh, PA, USA ing of Recommendations Assessment, mean arterial pressure C65 mmHg Development and Evaluation (1B); epinephrine when an additional C. S. Deutschman (GRADE) system to guide assessment agent is needed to maintain adequate Perelman School of Medicine at the of quality of evidence from high blood pressure (2B); vasopressin University of Pennsylvania, (0.03 U/min) can be added to nor- Philadelphia, PA, USA (A) to very low (D) and to determine the strength of recommendations as epinephrine to either raise mean F. R. Machado strong (1) or weak (2). The potential arterial pressure to target or to Federal University of Sao Paulo, drawbacks of making strong recom- decrease norepinephrine dose but Sao Paulo, Brazil mendations in the presence of low- should not be used as the initial quality evidence were emphasized. vasopressor (UG); dopamine is not G. D. Rubenfeld Recommendations were classified recommended except in highly Sunnybrook Health Sciences Center, selected circumstances (2C); dobuta- Toronto, ON, Canada into three groups: (1) those directly targeting severe sepsis; (2) those tar- mine infusion administered or added S. Webb geting general care of the critically ill to vasopressor in the presence of Royal Perth Hospital, patient and considered high priority in (a) myocardial dysfunction as sug- Perth, Western Australia severe sepsis; and (3) pediatric con- gested by elevated cardiac filling siderations. Results: Key pressures and low cardiac output, or R. J. Beale recommendations and suggestions, (b) ongoing signs of hypoperfusion Guy’s and St. Thomas’ Hospital Trust, despite achieving adequate intravas- London, UK listed by category, include: early quantitative resuscitation of the septic cular volume and adequate mean J.-L. Vincent patient during the first 6 h after rec- arterial pressure (1C); avoiding use of Erasme University Hospital, ognition (1C); blood cultures before intravenous hydrocortisone in adult Brussels, Belgium antibiotic therapy (1C); imaging septic shock patients if adequate fluid studies performed promptly to con- resuscitation and vasopressor therapy R. Moreno firm a potential source of infection are able to restore hemodynamic sta- UCINC, Hospital de Sa˜o Jose´, Centro bility (2C); hemoglobin target of Hospitalar de Lisboa Central, E.P.E., (UG); administration of broad-spec- Lisbon, Portugal trum antimicrobials therapy within 7–9 g/dL in the absence of tissue 1 h of the recognition of septic shock hypoperfusion, ischemic coronary (1B) and severe sepsis without septic artery disease, or acute hemorrhage (1B); low tidal volume (1A) and blood glucose management com- bolus of 20 mL/kg of crystalloids (or limitation of inspiratory plateau mencing insulin dosing when two albumin equivalent) over 5–10 min pressure (1B) for acute respiratory consecutive blood glucose levels are (2C); more common use of inotropes distress syndrome (ARDS); applica- [180 mg/dL, targeting an upper and vasodilators for low cardiac out- tion of at least a minimal amount of blood glucose B180 mg/dL (1A); put septic shock associated with positive end-expiratory pressure equivalency of continuous veno- elevated systemic vascular resistance (PEEP) in ARDS (1B); higher rather venous hemofiltration or intermittent (2C); and use of hydrocortisone only than lower level of PEEP for patients hemodialysis (2B); prophylaxis for in children with suspected or proven with sepsis-induced moderate or deep vein thrombosis (1B); use of ‘‘absolute’’’ adrenal insufficiency severe ARDS (2C); recruitment stress ulcer prophylaxis to prevent (2C). Conclusions: Strong agree- maneuvers in sepsis patients with upper gastrointestinal bleeding in ment existed among a large cohort of severe refractory hypoxemia due to patients with bleeding risk factors international experts regarding many ARDS (2C); prone positioning in (1B); oral or enteral (if necessary) level 1 recommendations for the best sepsis-induced ARDS patients with a feedings, as tolerated, rather than care of patients with severe sepsis. PaO2/FiO2 ratio of B100 mm Hg in either complete fasting or provision Although a significant number of facilities that have experience with of only intravenous glucose within aspects of care have relatively weak such practices (2C); head-of-bed ele- the first 48 h after a diagnosis of support, evidence-based recommen- vation in mechanically ventilated severe sepsis/septic shock (2C); and dations regarding the acute patients unless contraindicated (1B); addressing goals of care, including management of sepsis and septic a conservative fluid strategy for treatment plans and end-of-life plan- shock are the foundation of improved patients with established ARDS who ning (as appropriate) (1B), as early as outcomes for this important group of do not have evidence of tissue hypo- feasible, but within 72 h of intensive critically ill patients. perfusion (1C); protocols for weaning care unit admission (2C). Recom- and sedation (1A); minimizing use of mendations specific to pediatric Keywords Sepsis Á Severe sepsis Á either intermittent bolus sedation or severe sepsis include: therapy with Septic shock Á Sepsis syndrome Á continuous infusion sedation target- face mask oxygen, high flow nasal Infection Á Grading of ing specific titration endpoints (1B); cannula oxygen, or nasopharyngeal Recommendations Assessment, avoidance of neuromuscular blockers continuous PEEP in the presence of Development and Evaluation criteria Á if possible in the septic patient with- respiratory distress and hypoxemia GRADE Á Guidelines Á out ARDS (1C); a short course of (2C), use of physical examination Evidence-based medicine Á neuromuscular blocker (no longer therapeutic endpoints such as capil- Surviving Sepsis Campaign Á than 48 h) for patients with early lary refill (2C); for septic shock Sepsis bundles ARDS and a PaO2/FIO2 \150 mm Hg associated with hypovolemia, the use (2C); a protocolized approach to of crystalloids or albumin to deliver a

Sepsis is a systemic, deleterious host response to infection making capability when he or she is presented with a leading to severe sepsis (acute organ dysfunction sec- patient’s unique set of clinical variables. Most of these ondary to documented or suspected infection) and septic recommendations are appropriate for the severe sepsis shock (severe sepsis plus hypotension not reversed with patient in the intensive care unit (ICU) and non-ICU fluid resuscitation). Severe sepsis and septic shock are settings. In fact, the committee believes that the greatest major healthcare problems, affecting millions of people outcome improvement can be made through education around the world each year, killing one in four (and often and process change for those caring for severe sepsis more), and increasing in incidence [1–5]. Similar to patients in the non-ICU setting and across the spectrum of polytrauma, acute myocardial infarction, or stroke, the acute care. Resource limitations in some institutions and speed and appropriateness of therapy administered in the countries may prevent physicians from accomplishing initial hours after severe sepsis develops are likely to particular recommendations. Thus, these recommenda- influence outcome. tions are intended to be best practice (the committee The recommendations in this document are intended to considers this a goal for clinical practice) and not created provide guidance for the clinician caring for a patient with to represent standard of care. The Surviving Sepsis severe sepsis or septic shock. Recommendations from Campaign (SSC) Guidelines Committee hopes that over these guidelines cannot replace the clinician’s decision- time, particularly through education programs and formal audit and feedback performance improvement initiatives, to address content needs for the development process. Four the guidelines will influence bedside healthcare practi- clinicians with experience in the GRADE process applica- tioner behavior that will reduce the burden of sepsis tion (referred to in this document as GRADE group or worldwide. Evidence-Based Medicine [EBM] group) took part in the guidelines development. The guidelines development process began with appointment of group heads and assignment of committee Methodology members to groups according to their specific expertise. Each group was responsible for drafting the initial update to Definitions the 2008 edition in their assigned area (with major additional elements of information incorporated into the evolving Sepsis is defined as the presence (probable or documented) manuscript through year-end 2011 and early 2012). of infection together with systemic manifestations of infec- With input from the EBM group, an initial group meet- tion. Severe sepsis is defined as sepsis plus sepsis-induced ing was held to establish procedures for literature review and organ dysfunction or tissue hypoperfusion (Tables 1, 2)[6]. development of tables for evidence analysis. Committees Throughout this manuscript and the performance improve- and their subgroups continued work via phone and the ment bundles, which are included, a distinction is made Internet. Several subsequent meetings of subgroups and key between definitions and therapeutic targets or thresholds. individuals occurred at major international meetings Sepsis-induced hypotension is defined as a systolic blood (nominal groups), with work continuing via teleconferences pressure (SBP)\90 mmHg or mean arterial pressure (MAP) and electronic-based discussions among subgroups and \70 mmHg or a SBP decrease[40 mmHg or less than two members of the entire committee. Ultimately, a meeting of standard deviations below normal for age in the absence of all group heads, executive committee members, and other other causes of hypotension. An example of a therapeutic key committee members was held to finalize the draft doc- target or typical threshold for the reversal of hypotension is ument for submission to reviewers. seen in the sepsis bundles for the use of vasopressors. In the bundles, the MAP threshold is C65 mmHg. The use of defi- nition versus threshold will be evident throughout this article. Search techniques Septic shock is defined as sepsis-induced hypotension per- sisting despite adequate fluid resuscitation. Sepsis-induced A separate literature search was performed for each clearly tissue hypoperfusion is defined as infection-induced hypo- defined question. The committee chairs worked with sub- tension, elevated lactate, or oliguria. group heads to identify pertinent search terms that were to include, at a minimum, sepsis, severe sepsis, septic shock, and sepsis syndrome crossed against the subgroup’s general History of the guidelines topic area, as well as appropriate key words of the specific question posed. All questions used in the previous guide- These clinical practice guidelines are a revision of the 2008 lines publications were searched, as were pertinent new SSC guidelines for the management of severe sepsis and questions generated by general topic-related searches or septic shock [7]. The initial SSC guidelines were published recent trials. The authors were specifically asked to look for in 2004 [8] and incorporated the evidence available through existing meta-analyses related to their question and search a the end of 2003. The 2008 publication analyzed evidence minimum of one general database (i.e., MEDLINE, EM- available through the end of 2007. The most current iteration BASE) and the Cochrane Library [both The Cochrane is based on updated literature search incorporated into the Database of Systematic Reviews (CDSR) and Database of evolving manuscript through fall 2012. Abstracts of Reviews of Effectiveness (DARE)]. Other databases were optional (ACP Journal Club, Evidence- Based Medicine Journal, Cochrane Registry of Controlled Selection and organization of committee members Clinical Trials, International Standard Randomised Con- trolled Trial Registry (http://www.controlled-trials.com/ The selection of committee members was based on interest isrctn/)ormetaRegister of Controlled Trials (http://www. and expertise in specific aspects of sepsis. Co-chairs and controlled-trials.com/mrct/). Where appropriate, available executive committee members were appointed by the evidence was summarized in the form of evidence tables. Society of Critical Care Medicine and European Society of Intensive Care Medicine governing bodies. Each sponsor- ing organization appointed a representative who had sepsis Grading of recommendations expertise. Additional committee members were appointed by the co-chairs and executive committee to create conti- We advised the authors to follow the principles of the nuity with the previous committees’ membership as well as GRADE system to guide assessment of quality of Table 1 Diagnostic criteria for sepsis

Infection, documented or suspected, and some of the following: General variables Fever ([38.3 °C) Hypothermia (core temperature \36 °C) Heart rate [90 min-1 or more than two SD above the normal value for age Tachypnea Altered mental status Significant edema or positive fluid balance ([ 20 mL/kg over 24 h) Hyperglycemia (plasma glucose [140 mg/dL or 7.7 mmol/L) in the absence of diabetes Inflammatory variables Leukocytosis (WBC count [12,000 lL-1) Leukopenia (WBC count \4,000 lL-1) Normal WBC count with greater than 10 % immature forms Plasma C-reactive protein more than two SD above the normal value Plasma procalcitonin more than two SD above the normal value Hemodynamic variables Arterial hypotension (SBP \90 mmHg, MAP \70 mmHg, or an SBP decrease [40 mmHg in adults or less than two SD below normal for age) Organ dysfunction variables Arterial hypoxemia (PaO2/FiO2 \300) Acute oliguria (urine output \0.5 mL kg-1 h-1 for at least 2 h despite adequate fluid resuscitation) Creatinine increase [0.5 mg/dL or 44.2 lmol/L Coagulation abnormalities (INR [1.5 or aPTT [60 s) Ileus (absent bowel sounds) Thrombocytopenia (platelet count \100,000 lL-1) Hyperbilirubinemia (plasma total bilirubin [4 mg/dL or 70 lmol/L) Tissue perfusion variables Hyperlactatemia ([1 mmol/L) Decreased capillary refill or mottling SD standard deviation, WBC white blood cell, SBP systolic blood hypothermia (rectal temperature [38.5 or \35 °C), tachycardia pressure, MAP mean arterial pressure, INR international normalized (may be absent in hypothermic patients), and at least one of the ratio, aPTT activated partial thromboplastin time following indications of altered organ function: altered mental sta- Diagnostic criteria for sepsis in the pediatric population are signs tus, hypoxemia, increased serum lactate level, or bounding pulses and symptoms of inflammation plus infection with hyper- or Adapted from [6]

Table 2 Severe sepsis The GRADE system is based on a sequential assess- Severe sepsis definition = sepsis-induced tissue hypoperfusion or ment of the quality of evidence, followed by assessment organ dysfunction (any of the following thought to be due to the of the balance between the benefits and risks, burden, and infection) cost, leading to development and grading of a manage- Sepsis-induced hypotension ment recommendation. Keeping the rating of quality of Lactate above upper limits laboratory normal Urine output \0.5 mL kg-1 h-1 for more than 2 h despite evidence and strength of recommendation explicitly sep- adequate fluid resuscitation arate constitutes a crucial and defining feature of the Acute lung injury with PaO2/FiO2 \250 in the absence of GRADE approach. This system classifies quality of evi- pneumonia as infection source dence as high (grade A), moderate (grade B), low (grade Acute lung injury with PaO2/FiO2 \200 in the presence of pneumonia as infection source C), or very low (grade D). Randomized trials begin as Creatinine [2.0 mg/dL (176.8 lmol/L) high-quality evidence but may be downgraded due to Bilirubin [2 mg/dL (34.2 lmol/L) limitations in implementation, inconsistency, or impreci- Platelet count \100,000 lL sion of the results, indirectness of the evidence, and Coagulopathy (international normalized ratio [1.5) possible reporting bias (Table 3). Examples of indirect- Adapted from [6] ness of the evidence include population studied, interventions used, outcomes measured, and how these evidence from high (A) to very low (D) and to determine the relate to the question of interest. Well-done observational strength of recommendations (Tables 3, 4)[9–11]. The SSC (nonrandomized) studies begin as low-quality evidence, Steering Committee and individual authors collaborated but the quality level may be upgraded on the basis of a with GRADE representatives to apply the system during the large magnitude of effect. An example of this is the SSC guidelines revision process. The members of the quality of evidence for early administration of antibiotics. GRADE group were directly involved, either in person or References to supplemental digital content appendices of via e-mail, in all discussions and deliberations among the GRADEpro Summary of Evidence Tables appear through- guidelines committee members as to grading decisions. out this document. Table 3 Determination of the quality of evidence Table 4 Factors determining strong versus weak recommendation

Underlying methodology What should be considered Recommended process A (high) RCTs B (moderate) downgraded RCTs or upgraded observational studies High or moderate evidence (is The higher the quality of C (low) well-done observational studies with control RCTs there high or moderate quality evidence, the more likely a D (very low) downgraded controlled studies or expert opinion evidence?) strong recommendation. based on other evidence Certainty about the balance of The larger the difference Factors that may decrease the strength of evidence benefits versus harms and between the desirable and 1. Poor quality of planning and implementation of available RCTs, burdens (is there certainty?) undesirable consequences and suggesting high likelihood of bias the certainty around that 2. Inconsistency of results, including problems with subgroup difference, the more likely a analyses strong recommendation. The 3. Indirectness of evidence (differing population, intervention, smaller the net benefit and the control, outcomes, comparison) lower the certainty for that 4. Imprecision of results benefit, the more likely a weak 5. High likelihood of reporting bias recommendation Main factors that may increase the strength of evidence Certainty in or similar values (is The more certainty or similarity 1. Large magnitude of effect (direct evidence, relative risk [ 2 there certainty or similarity?) in values and preferences, the with no plausible confounders) more likely a strong 2. Very large magnitude of effect with relative risk [ 5 and no recommendation threats to validity (by two levels) Resource implications (are The lower the cost of an 3. Dose–response gradient resources worth expected intervention compared to the benefits?) alternative and other costs RCT randomized controlled trial related to the decision–i.e., fewer resources consumed— the more likely a strong The GRADE system classifies recommendations as recommendation strong (grade 1) or weak (grade 2). The factors influencing this determination are presented in Table 4.Theassignment of strong or weak is considered of greater clinical impor- intervention and that most clinicians should use it in most tance than a difference in letter level of quality of evidence. situations. Circumstances may exist in which a strong The committee assessed whether the desirable effects of recommendation cannot or should not be followed for an adherence would outweigh the undesirable effects, and the individual because of that patient’s preferences or clinical strength of a recommendation reflects the group’s degree of characteristics that make the recommendation less appli- confidence in that assessment. Thus, a strong recommen- cable. A strong recommendation does not automatically dation in favor of an intervention reflects the panel’s opinion imply standard of care. For example, the strong recom- that the desirable effects of adherence to a recommendation mendation for administering antibiotics within 1 h of the (beneficial health outcomes; lesser burden on staff and diagnosis of severe sepsis, as well as the recommendation patients; and cost savings) will clearly outweigh the unde- for achieving a central venous pressure (CVP) of sirable effects (harm to health; more burden on staff and 8 mmHg and a central venous oxygen saturation (ScvO2) patients; and greater costs). The potential drawbacks of of 70 % in the first 6 h of resuscitation of sepsis-induced making strong recommendations in the presence of low- tissue hypoperfusion, although deemed desirable, are not quality evidence were taken into account. A weak recom- yet standards of care as verified by practice data. mendation in favor of an intervention indicates the judgment Significant education of committee members on the that the desirable effects of adherence to a recommendation GRADE approach built on the process conducted during probably will outweigh the undesirable effects, but the panel 2008 efforts. Several members of the committee were is not confident about these tradeoffs—either because some trained in the use of GRADEpro software, allowing more of the evidence is low quality (and thus uncertainty remains formal use of the GRADE system [12]. Rules were dis- regarding the benefits and risks) or the benefits and down- tributed concerning assessing the body of evidence, and sides are closely balanced. A strong recommendation is GRADE representatives were available for advice worded as ‘‘we recommend’’ and a weak recommendation throughout the process. Subgroups agreed electronically as ‘‘we suggest.’’ on draft proposals that were then presented for general Throughout the document are a number of statements discussion among subgroup heads, the SSC Steering that either follow graded recommendations or are listed as Committee (two co-chairs, two co-vice chairs, and an at- stand-alone numbered statements followed by ‘‘ungraded’’ large committee member), and several selected key in parentheses (UG). In the opinion of the committee, committee members who met in July 2011 in Chicago. these recommendations were not conducive for the The results of that discussion were incorporated into the GRADE process. next version of recommendations and again discussed The implications of calling a recommendation strong with the whole group using electronic mail. Draft rec- are that most well-informed patients would accept that ommendations were distributed to the entire committee and finalized during an additional nominal group meeting Management of severe sepsis in Berlin in October 2011. Deliberations and decisions were then recirculated to the entire committee for Initial resuscitation and infection issues (Table 5) approval. At the discretion of the chairs and following A. Initial resuscitation discussion, competing proposals for wording of recom- 1. We recommend the protocolized, quantitative resus- mendations or assigning strength of evidence were citation of patients with sepsis- induced tissue resolved by formal voting within subgroups and at nom- hypoperfusion (defined in this document as hypoten- inal group meetings. The manuscript was edited for style sion persisting after initial fluid challenge or blood and form by the writing committee with final approval by lactate concentration C4 mmol/L). This protocol subgroup heads and then by the entire committee. To should be initiated as soon as hypoperfusion is rec- satisfy peer review during the final stages of manuscript ognized and should not be delayed pending ICU approval for publication, several recommendations were admission. During the first 6 h of resuscitation, the edited with approval of the SSC executive committee goals of initial resuscitation of sepsis-induced hypo- group head for that recommendation and the EBM lead. perfusion should include all of the following as a part of a treatment protocol (grade 1C): Conflict of interest policy (a) CVP 8–12 mmHg (b) MAP C65 mmHg -1 Since the inception of the SSC guidelines in 2004, no (c) Urine output C0.5 mL kg h members of the committee represented industry; there (d) Superior vena cava oxygenation saturation (ScvO2) was no industry input into guidelines development; and or mixed venous oxygen saturation (SvO2)70or no industry representatives were present at any of the 65 %, respectively. meetings. Industry awareness or comment on the recom- 2. We suggest targeting resuscitation to normalize lactate mendations was not allowed. No member of the in patients with elevated lactate levels as a marker of guidelines committee received honoraria for any role in tissue hypoperfusion (grade 2C). the 2004, 2008, or 2012 guidelines process. A detailed description of the disclosure process and all Rationale. In a randomized, controlled, single-center author disclosures appear in Supplemental Digital Content 1 study, early quantitative resuscitation improved survival in the supplemental materials to this document. Appendix 2 for emergency department patients presenting with septic shows a flowchart of the COI disclosure process. Committee shock [13]. Resuscitation targeting the physiologic goals members who were judged to have either financial or non- expressed in recommendation 1 (above) for the initial 6-h financial/academic competing interests were recused during period was associated with a 15.9 % absolute reduction in the closed discussion session and voting session on that 28-day mortality rate. This strategy, termed early goal- topic. Full disclosure and transparency of all committee directed therapy, was evaluated in a multicenter trial of members’ potential conflicts were sought. 314 patients with severe sepsis in eight Chinese centers On initial review, 68 financial conflict of interest [14]. This trial reported a 17.7 % absolute reduction in (COI) disclosures and 54 non-financial disclosures were 28-day mortality (survival rates, 75.2 vs. 57.5 %, submitted by committee members. Declared COI disclo- P = 0.001). A large number of other observational stud- sures from 19 members were determined by the COI ies using similar forms of early quantitative resuscitation subcommittee to be not relevant to the guidelines content in comparable patient populations have shown significant process. Nine who were determined to have COI (finan- mortality reduction compared to the institutions’ histori- cial and non-financial) were adjudicated by group cal controls (Supplemental Digital Content 2). Phase III reassignment and requirement to adhere to SSC COI of the SSC activities, the international performance policy regarding discussion or voting at any committee improvement program, showed that the mortality of septic meetings where content germane to their COI was dis- patients presenting with both hypotension and lactate cussed. Nine were judged as having conflicts that could C4 mmol/L was 46.1 %, similar to the 46.6 % mortality not be resolved solely by reassignment. One of these found in the first trial cited above [15]. As part of per- individuals was asked to step down from the committee. formance improvement programs, some hospitals have The other eight were assigned to the groups in which they lowered the lactate threshold for triggering quantitative had the least COI. They were required to work within resuscitation in the patient with severe sepsis, but these their group with full disclosure when a topic for which thresholds have not been subjected to randomized trials. they had relevant COI was discussed, and they were not The consensus panel judged use of CVP and SvO2 targets allowed to serve as group head. At the time of final to be recommended physiologic targets for resuscitation. approval of the document, an update of the COI statement Although there are limitations to CVP as a marker of was required. No additional COI issues were reported that intravascular volume status and response to fluids, a low required further adjudication. CVP generally can be relied upon as supporting positive Table 5 Recommendations: initial resuscitation and infection issues

A. Initial resuscitation 1. Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (defined in this document as hypotension persisting after initial fluid challenge or blood lactate concentration C4 mmol/L). Goals during the first 6 h of resuscitation: (a) Central venous pressure 8–12 mmHg (b) Mean arterial pressure (MAP) C 65 mmHg (c) Urine output C 0.5 mL kg-1 h (d) Central venous (superior vena cava) or mixed venous oxygen saturation 70 or 65 %, respectively (grade 1C) 2. In patients with elevated lactate levels targeting resuscitation to normalize lactate as rapidly as possible (grade 2C) B. Screening for sepsis and performance improvement 1. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy (grade 1C) 2. Hospital-based performance improvement efforts in severe sepsis (UG) C. Diagnosis 1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay ([45 min) in the start of antimicrobial(s) (grade 1C). At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (\48 h) inserted (grade 1C) 2. Use of the 1,3 b-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C), if available and invasive candidiasis is in differential diagnosis of cause of infection. 3. Imaging studies performed promptly to confirm a potential source of infection (UG) D. Antimicrobial therapy 1. Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C) as the goal of therapy 2a. Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis (grade 1B) 2b. Antimicrobial regimen should be reassessed daily for potential deescalation (grade 1B) 3. Use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C) 4a. Combination empirical therapy for neutropenic patients with severe sepsis (grade 2B) and for patients with difficult to treat, multidrug-resistant bacterial pathogens such as Acinetobacter and Pseudomonas spp. (grade 2B). For patients with severe infections associated with respiratory failure and septic shock, combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia (grade 2B). A combination of beta-lactam and macrolide for patients with septic shock from bacteremic Streptococcus pneumoniae infections (grade 2B) 4b. Empiric combination therapy should not be administered for more than 3–5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known (grade 2B) 5. Duration of therapy typically 7–10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia (grade 2C) 6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin (grade 2C) 7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause (UG) E. Source control 1. A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 h after the diagnosis is made, if feasible (grade 1C) 2. When infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and nonviable tissues has occurred (grade 2B) 3. When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (e.g., percutaneous rather than surgical drainage of an abscess) (UG) 4. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established (UG) F. Infection prevention 1a. Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia; This infection control measure can then be instituted in health care settings and regions where this methodology is found to be effective (grade 2B) 1b. Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated pneumonia in ICU patients with severe sepsis (grade 2B) response to fluid loading. Either intermittent or continuous achieve the ScvO2 or SvO2 goal are options. The strong measurements of oxygen saturation were judged to be recommendation for achieving a CVP of 8 mmHg and an acceptable. During the first 6 h of resuscitation, if ScvO2 less ScvO2 of 70 % in the first 6 h of resuscitation of sepsis- than 70 % or SvO2 equivalent of less than 65 % persists with induced tissue hypoperfusion, although deemed desirable, what is judged to be adequate intravascular volume reple- are not yet the standard of care as verified by practice data. tion in the presence of persisting tissue hypoperfusion, then The publication of the initial results of the international SSC dobutamine infusion (to a maximum of 20 lgkg-1 min-1) performance improvement program demonstrated that or transfusion of packed red blood cells to achieve a adherence to CVP and ScvO2 targets for initial resuscitation hematocrit of greater than or equal to 30 % in attempts to was low [15]. In mechanically ventilated patients or those with known (n = 30). The second trial included 348 patients with lactate preexisting decreased ventricular compliance, a higher target levels C3 mmol/L [36]. The strategy in this trial was based CVP of 12–15 mmHg should be achieved to account for the on a greater than or equal to 20 % decrease in lactate levels impediment in filling [16]. Similar consideration may be per 2 h of the first 8 h in addition to ScvO2 target achieve- warranted in circumstances of increased abdominal pressure ment, and was associated with a 9.6 % absolute reduction in [17]. Elevated CVP may also be seen with preexisting clin- mortality (P = 0.067; adjusted hazard ratio, 0.61; 95 % CI, ically significant pulmonary artery hypertension, making use 0.43–0.87; P = 0.006). of this variable untenable for judging intravascular volume status. Although the cause of tachycardia in septic patients may be multifactorial, a decrease in elevated pulse rate with B. Screening for sepsis and performance improvement fluid resuscitation is often a useful marker of improving 1. We recommend routine screening of potentially intravascular filling. Published observational studies have infected seriously ill patients for severe sepsis to demonstrated an association between good clinical outcome increase the early identification of sepsis and allow in septic shock and MAP C65 mmHg as well as ScvO2 implementation of early sepsis therapy (grade 1C). C70 % (measured in the superior vena cava, either inter- mittently or continuously) [18]. Many studies support the Rationale. The early identification of sepsis and imple- value of early protocolized resuscitation in severe sepsis and mentation of early evidence-based therapies have been sepsis-induced tissue hypoperfusion [19–24]. Studies of documented to improve outcomes and decrease sepsis- patients with shock indicate that SvO2 runs 5–7 % lower than related mortality [15]. Reducing the time to diagnosis of ScvO2 [25]. While the committee recognized the controversy severe sepsis is thought to be a critical component of surrounding resuscitation targets, an early quantitative reducing mortality from sepsis-related multiple organ resuscitation protocol using CVP and venous blood gases dysfunction [35]. Lack of early recognition is a major can be readily established in both emergency department and obstacle to sepsis bundle initiation. Sepsis screening tools ICU settings [26]. Recognized limitations to static ventric- have been developed to monitor ICU patients [37–41], ular filling pressure estimates exist as surrogates for fluid and their implementation has been associated with resuscitation [27, 28], but measurement of CVP is currently decreased sepsis-related mortality [15]. the most readily obtainable target for fluid resuscitation. Targeting dynamic measures of fluid responsiveness during 2. Performance improvement efforts in severe sepsis resuscitation, including flow and possibly volumetric indices should be used to improve patient outcomes (UG). and microcirculatory changes, may have advantages [29– 32]. Available technologies allow measurement of flow at Rationale. Performance improvement efforts in sepsis the bedside [33, 34]; however, the efficacy of these moni- have been associated with improved patient outcomes [19, toring techniques to influence clinical outcomes from early 42–46]. Improvement in care through increasing compli- sepsis resuscitation remains incomplete and requires further ance with sepsis quality indicators is the goal of a severe study before endorsement. sepsis performance improvement program [47]. Sepsis The global prevalence of severe sepsis patients initially management requires a multidisciplinary team (physicians, presenting with either hypotension with lactate C4 mmol/L, nurses, pharmacy, respiratory, dieticians, and administra- hypotension alone, or lactate C4 mmol/L alone, is reported tion) and multispecialty collaboration (medicine, surgery, as 16.6, 49.5, and 5.4 %, respectively [15]. The mortality and emergency medicine) to maximize the chance for suc- rate is high in septic patients with both hypotension and cess. Evaluation of process change requires consistent lactate C4 mmol/L (46.1 %) [15], and is also increased in education, protocol development and implementation, data severely septic patients with hypotension alone (36.7 %) collection, measurement of indicators, and feedback to and lactate C4 mmol/L alone (30 %) [15]. If ScvO2 is not facilitate the continuous performance improvement. available, lactate normalization may be a feasible option in Ongoing educational sessions provide feedback on indi- the patient with severe sepsis-induced tissue hypoperfusion. cator compliance and can help identify areas for ScvO2 and lactate normalization may also be used as a additional improvement efforts. In addition to traditional combined endpoint when both are available. Two multi- continuing medical education efforts to introduce guide- center randomized trials evaluated a resuscitation strategy lines into clinical practice, knowledge translation efforts that included lactate reduction as a single target or a target have recently been introduced as a means to promote the combined with ScvO2 normalization [35, 36]. The first trial use of high-quality evidence in changing behavior [48]. reported that early quantitative resuscitation based on lactate Protocol implementation associated with education and clearance (decrease by at least 10 %) was noninferior to performance feedback has been shown to change clini- early quantitative resuscitation based on achieving ScvO2 of cian behavior and is associated with improved outcomes 70 % or more [35]. The intention-to-treat group contained and cost effectiveness in severe sepsis [19, 23, 24, 49]. In 300, but the number of patients actually requiring either partnership with the Institute for Healthcare Improve- ScvO2 normalization or lactate clearance was small ment, phase III of the SSC targeted the implementation of a core set (‘‘bundle’’) of recommendations in hospital devices with signs of inflammation, catheter dysfunction, or environments where change in behavior and clinical indicators of thrombus formation). Obtaining blood cultures impact were measured [50]. The SSC guidelines and peripherally and through a vascular access device is an bundles can be used as the basis of a sepsis performance important strategy. If the same organism is recovered from improvement program. both cultures, the likelihood that the organism is causing the Application of the SSC sepsis bundles led to sustained, severe sepsis is enhanced. continuous quality improvement in sepsis care and was In addition, if equivalent volumes of blood drawn for associated with reduced mortality [15]. Analysis of the data culture and the vascular access device is positive much from nearly 32,000 patient charts gathered from 239 hospi- earlier than the peripheral blood culture (i.e., more than 2 h tals in 17 countries through September 2011 as part of phase earlier), the data support the concept that the vascular access III of the campaign informed the revision of the bundles in device is the source of the infection [36, 51, 52]. Quantitative conjunction with the 2012 guidelines. As a result, for the cultures of catheter and peripheral blood may also be useful 2012 version, the management bundle was dropped and the for determining whether the catheter is the source of infec- resuscitation bundle was broken into two parts and modified tion. The volume of blood drawn with the culture tube should as shown in Fig. 1. For performance improvement quality be C10 mL [53]. Quantitative (or semiquantitative) cultures indicators, resuscitation target thresholds are not considered. of respiratory tract secretions are often recommended for the However, recommended targets from the guidelines are diagnosis of ventilator-associated pneumonia (VAP) [54], included with the bundles for reference purposes. but their diagnostic value remains unclear [55]. The Gram stain can be useful, in particular for respira- tory tract specimens, to determine if inflammatory cells are C. Diagnosis present (greater than five polymorphonuclear leukocytes/ 1. We recommend obtaining appropriate cultures before high-powered field and less than 10 squamous cells/low- antimicrobial therapy is initiated if such cultures do powered field) and if culture results will be informative of not cause significant delay ([45 min) in the start of lower respiratory pathogens. Rapid influenza antigen testing antimicrobial(s) administration (grade 1C). To opti- during periods of increased influenza activity in the com- mize identification of causative organisms, we munity is also recommended. A focused history can provide recommend obtaining at least two sets of blood cul- vital information about potential risk factors for infection tures (both aerobic and anaerobic bottles) before and likely pathogens at specific tissue sites. The potential antimicrobial therapy, with at least one drawn percu- role of biomarkers for diagnosis of infection in patients taneously and one drawn through each vascular access presenting with severe sepsis remains undefined. The utility device, unless the device was recently (\48 h) inser- of procalcitonin levels or other biomarkers (such as ted. These blood cultures can be drawn at the same C-reactive protein) to discriminate the acute inflammatory time if they are obtained from different sites. Cultures pattern of sepsis from other causes of generalized inflam- of other sites (preferably quantitative where appropri- mation (e.g., postoperative, other forms of shock) has not ate), such as urine, cerebrospinal fluid, wounds, been demonstrated. No recommendation can be given for respiratory secretions, or other body fluids that may be the use of these markers to distinguish between severe the source of infection, should also be obtained before infection and other acute inflammatory states [56–58]. antimicrobial therapy if doing so does not cause sig- In the near future, rapid, non-culture-based diagnostic nificant delay in antibiotic administration (grade 1C). methods (polymerase chain reaction, mass spectroscopy, microarrays) might be helpful for a quicker identification of Rationale. Although sampling should not delay timely pathogens and major antimicrobial resistance determinants administration of antimicrobial agents in patients with [59]. These methodologies could be particularly useful for severe sepsis (e.g., lumbar puncture in suspected meningi- difficult-to-culture pathogens or in clinical situations where tis), obtaining appropriate cultures before administration of empiric antimicrobial agents have been administered before antimicrobials is essential to confirm infection and the culture samples were been obtained. Clinical experience responsible pathogens, and to allow de-escalation of anti- remains limited, and more clinical studies are needed before microbial therapy after receipt of the susceptibility profile. recommending these non-culture molecular methods as a Samples can be refrigerated or frozen if processing cannot replacement for standard blood culture methods [60, 61]. be performed immediately. Because rapid sterilization of blood cultures can occur within a few hours after the first 2. We suggest the use of the 1,3 b-D-glucan assay (grade antimicrobial dose, obtaining those cultures before therapy 2B), mannan and anti-mannan antibody assays (grade is essential if the causative organism is to be identified. Two 2C), when invasive candidiasis is in the differential or more blood cultures are recommended [51]. In patients diagnosis of infection. with indwelling catheters (for more than 48 h), at least one blood culture should be drawn through each lumen of each Rationale. The diagnosis of systemic fungal infection vascular access device (if feasible, especially for vascular (usually candidiasis) in the critically ill patient can be Fig. 1 Surviving sepsis campaign care bundles SURVIVING SEPSIS CAMPAIGN CARE BUNDLES

TO BE COMPLETED WITHIN 3 HOURS: 1) Measure lactate level 2) Obtain blood cultures prior to administration of antibiotics 3) Administer broad spectrum antibiotics 4) Administer 30 mL/kg crystalloid for hypotension or lactate ≥ 4mmol/L

TO BE COMPLETED WITHIN 6 HOURS: 5) Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg 6) In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate ≥ 4 mmol/L (36 mg/dL): - Measure central venous pressure (CVP)* - Measure central venous oxygen saturation (ScvO2)* 7) Remeasure lactate if initial lactate was elevated*

*Targets for quantitative resuscitation included in the guidelines are CVP of ≥8 mm Hg, ScvO2 of ≥ 70%, and normalization of lactate.

challenging, and rapid diagnostic methodologies, such as shock (grade 1C) should be the goal of therapy. antigen and antibody detection assays, can be helpful in Remark: Although the weight of the evidence supports detecting candidiasis in the ICU patient. These suggested prompt administration of antibiotics following the tests have shown positive results significantly earlier than recognition of severe sepsis and septic shock, the standard culture methods [62–67], but false-positive feasibility with which clinicians may achieve this ideal reactions can occur with colonization alone, and their state has not been scientifically evaluated. diagnostic utility in managing fungal infection in the ICU needs additional study [65]. Rationale. Establishing vascular access and initiating aggressive fluid resuscitation are the first priorities when 3. We recommend that imaging studies be performed managing patients with severe sepsis or septic shock. promptly in attempts to confirm a potential source of Prompt infusion of antimicrobial agents should also be a infection. Potential sources of infection should be sam- priority and may require additional vascular access ports pled as they are identified and in consideration of patient [68, 69]. In the presence of septic shock, each hour delay risk for transport and invasive procedures (e.g., careful in achieving administration of effective antibiotics is coordination and aggressive monitoring if the decision is associated with a measurable increase in mortality in a made to transport for a computed tomography-guided number of studies [15, 68, 70–72]. Overall, the prepon- needle aspiration). Bedside studies, such as ultrasound, derance of data support giving antibiotics as soon as may avoid patient transport (UG). possible in patients with severe sepsis with or without septic shock [15, 68, 70–77]. The administration of anti- Rationale. Diagnostic studies may identify a source of microbial agents with a spectrum of activity likely to treat infection that requires removal of a foreign body or drainage the responsible pathogen(s) effectively within 1 h of the to maximize the likelihood of a satisfactory response to diagnosis of severe sepsis and septic shock. Practical therapy. Even in the most organized and well-staffed considerations, for example challenges with clinicians’ healthcare facilities, however, transport of patients can be early identification of patients or operational complexities dangerous, as can be placing patients in outside-unit imaging in the drug delivery chain, represent unstudied variables devices that are difficult to access and monitor. Balancing that may impact achieving this goal. Future trials should risk and benefit is therefore mandatory in those settings. endeavor to provide an evidence base in this regard. This should be the target goal when managing patients with D. Antimicrobial therapy septic shock, whether they are located within the hospital 1. The administration of effective intravenous antimi- ward, the emergency department, or the ICU. The strong crobials within the first hour of recognition of septic recommendation for administering antibiotics within 1 h shock (grade 1B) and severe sepsis without septic of the diagnosis of severe sepsis and septic shock, although judged to be desirable, is not yet the standard of agents, or if Candida glabrata infection is suspected from care as verified by published practice data [15]. earlier culture data. Knowledge of local resistance pat- If antimicrobial agents cannot be mixed and delivered terns to antifungal agents should guide drug selection promptly from the pharmacy, establishing a supply of until fungal susceptibility test results, if available, are premixed antibiotics for such urgent situations is an performed. Risk factors for candidemia, such as immu- appropriate strategy for ensuring prompt administration. nosuppressed or neutropenic state, prior intense antibiotic Many antibiotics will not remain stable if premixed in a therapy, or colonization in multiple sites, should also be solution. This risk must be taken into consideration in considered when choosing initial therapy. institutions that rely on premixed solutions for rapid Because patients with severe sepsis or septic shock have availability of antibiotics. In choosing the antimicrobial little margin for error in the choice of therapy, the initial regimen, clinicians should be aware that some antimi- selection of antimicrobial therapy should be broad enough crobial agents have the advantage of bolus administration, to cover all likely pathogens. Antibiotic choices should be while others require a lengthy infusion. Thus, if vascular guided by local prevalence patterns of bacterial pathogens access is limited and many different agents must be and susceptibility data. Ample evidence exists that failure to infused, bolus drugs may offer an advantage. initiate appropriate therapy (i.e., therapy with activity 2a. We recommend that initial empiric anti-infective ther- against the pathogen that is subsequently identified as the apy include one or more drugs that have activity against causative agent) correlates with increased morbidity and all likely pathogens (bacterial and/or fungal or viral) mortality in patients with severe sepsis or septic shock [68, and that penetrate in adequate concentrations into the 71, 79, 80]. Recent exposure to antimicrobials (within last tissues presumed to be the source of sepsis (grade 1B). 3 months) should be considered in the choice of an empiric antibacterial regimen. Patients with severe sepsis or septic Rationale. The choice of empirical antimicrobial therapy shock warrant broad-spectrum therapy until the causative depends on complex issues related to the patient’s history, organism and its antimicrobial susceptibilities are defined. including drug intolerances, recent receipt of antibiotics Although a global restriction of antibiotics is an important (previous 3 months), underlying disease, the clinical syn- strategy to reduce the development of antimicrobial resis- drome, and susceptibility patterns of pathogens in the tance and to reduce cost, it is not an appropriate strategy in community and hospital, and that previously have been the initial therapy for this patient population. However, as documented to colonize or infect the patient. The most soon as the causative pathogen has been identified, de- common pathogens that cause septic shock in hospitalized escalation should be performed by selecting the most patients are Gram-positive bacteria, followed by Gram- appropriate antimicrobial agent that covers the pathogen negative and mixed bacterial microorganisms. Candidiasis, and is safe and cost-effective. Collaboration with antimi- toxic shock syndromes, and an array of uncommon patho- crobial stewardship programs, where they exist, is gens should be considered in selected patients. An especially encouraged to ensure appropriate choices and rapid avail- wide range of potential pathogens exists for neutropenic ability of effective antimicrobials for treating septic patients. Recently used anti-infective agents should gener- patients. All patients should receive a full loading dose of ally be avoided. When choosing empirical therapy, each agent. Patients with sepsis often have abnormal and clinicians should be cognizant of the virulence and growing vacillating renal or hepatic function, or may have abnor- prevalence of oxacillin (methicillin)-resistant Staphylococ- mally high volumes of distribution due to aggressive fluid cus aureus, and resistance to broad-spectrum beta-lactams resuscitation, requiring dose adjustment. Drug serum con- and carbapenem among Gram-negative bacilli in some centration monitoring can be useful in an ICU setting for communities and healthcare settings. Within regions in those drugs that can be measured promptly. Significant which the prevalence of such drug-resistant organisms is expertise is required to ensure that serum concentrations significant, empiric therapy adequate to cover these patho- maximize efficacy and minimize toxicity [81, 82]. gens is warranted. Clinicians should also consider whether candidemia is 2b. The antimicrobial regimen should be reassessed daily a likely pathogen when choosing initial therapy. When for potential de-escalation to prevent the develop- deemed warranted, the selection of empirical antifungal ment of resistance, to reduce toxicity, and to reduce therapy (e.g., an echinocandin, triazoles such as fluco- costs (grade 1B). nazole, or a formulation of amphotericin B) should be tailored to the local pattern of the most prevalent Candida Rationale. Once the causative pathogen has been iden- species and any recent exposure to antifungal drugs [78]. tified, the most appropriate antimicrobial agent that Recent Infectious Diseases Society of America (IDSA) covers the pathogen and is safe and cost-effective should guidelines recommend either fluconazole or an echino- be selected. On occasion, continued use of specific candin. Empiric use of an echinocandin is preferred in combinations of antimicrobials might be indicated even most patients with severe illness, especially in those after susceptibility testing is available (e.g., Pseudomonas patients who have recently been treated with antifungal spp. only susceptible to aminoglycosides; enterococcal endocarditis; Acinetobacter spp. infections susceptible only 4b. We suggest that combination therapy, when used to polymyxins). Decisions on definitive antibiotic choices empirically in patients with severe sepsis, should not should be based on the type of pathogen, patient charac- be administered for longer than 3–5 days. De-esca- teristics, and favored hospital treatment regimens. lation to the most appropriate single-agent therapy Narrowing the spectrum of antimicrobial coverage and should be performed as soon as the susceptibility reducing the duration of antimicrobial therapy will reduce profile is known (grade 2B). Exceptions would the likelihood that the patient will develop superinfection include aminoglycoside monotherapy, which should with other pathogenic or resistant organisms, such as be generally avoided, particularly for P. aeruginosa Candida species, Clostridium difficile, or vancomycin- sepsis, and for selected forms of endocarditis, where resistant Enterococcus faecium. However, the desire to prolonged courses of combinations of antibiotics are minimize superinfections and other complications should warranted. not take precedence over giving an adequate course of therapy to cure the infection that caused the severe sepsis Rationale. A propensity-matched analysis, meta-analy- or septic shock. sis, and meta-regression analysis, along with additional observational studies, have demonstrated that combina- 3. We suggest the use of low procalcitonin levels or tion therapy produces a superior clinical outcome in similar biomarkers to assist the clinician in the dis- severely ill, septic patients with a high risk of death [86– continuation of empiric antibiotics in patients who 90]. In light of the increasing frequency of resistance to appeared septic, but have no subsequent evidence of antimicrobial agents in many parts of the world, broad- infection (grade 2C). spectrum coverage generally requires the initial use of Rationale. This suggestion is predicated on the prepon- combinations of antimicrobial agents. Combination ther- derance of the published literature relating to the use of apy used in this context connotes at least two different procalcitonin as a tool to discontinue unnecessary antimi- classes of antibiotics (usually a beta-lactam agent with a crobials [58, 83]. However, clinical experience with this macrolide, fluoroquinolone, or aminoglycoside for select strategy is limited and the potential for harm remains a patients). A controlled trial suggested, however, that concern [83]. No evidence demonstrates that this practice when using a carbapenem as empiric therapy in a popu- reduces the prevalence of antimicrobial resistance or the risk lation at low risk for infection with resistant of antibiotic-related diarrhea from C. difficile. One recent microorganisms, the addition of a fluoroquinolone does study failed to show any benefit of daily procalcitonin not improve outcomes of patients [85]. A number of other measurement in early antibiotic therapy or survival [84]. recent observational studies and some small, prospective trials support initial combination therapy for selected 4a. Empiric therapy should attempt to provide antimi- patients with specific pathogens (e.g., pneumococcal crobial activity against the most likely pathogens sepsis, multidrug-resistant Gram-negative pathogens) based upon each patient’s presenting illness and local [91–93], but evidence from adequately powered, ran- patterns of infection. We suggest combination empiric domized clinical trials is not available to support therapy for neutropenic patients with severe sepsis combination over monotherapy other than in septic (grade 2B) and for patients with difficult-to- treat, patients at high risk of death. In some clinical scenarios, multidrug-resistant bacterial pathogens such as Acine- combination therapies are biologically plausible and are tobacter and Pseudomonas spp. (grade 2B). For likely clinically useful even if evidence has not demon- selected patients with severe infections associated with strated improved clinical outcome [89, 90, 94, 95]. respiratory failure and septic shock, combination ther- Combination therapy for suspected or known Pseudo- apy with an extended spectrum beta-lactam and either monas aeruginosa or other multiresistant Gram-negative an aminoglycoside or a fluoroquinolone is suggested for pathogens, pending susceptibility results, increases the P. aeruginosa bacteremia (grade 2B). Similarly, a more likelihood that at least 1 drug is effective against that complex combination of beta-lactam and a macrolide is strain and positively affects outcome [88, 96]. suggested for patients with septic shock from bactere- mic Streptococcus pneumoniae infections (grade 2B). 5. We suggest that the duration of therapy typically be 7–10 days if clinically indicated; longer courses may Rationale. Complex combinations might be needed in be appropriate in patients who have a slow clinical settings where highly antibiotic-resistant pathogens are response, undrainable foci of infection, bacteremia with prevalent, with such regimens incorporating carbapen- S. aureus; some fungal and viral infections, or immu- ems, colistin, rifampin, or other agents. However, a recent nologic deficiencies, including neutropenia (grade 2C). controlled trial suggested that adding a fluoroquinolone to a carbapenem as empiric therapy did not improve out- Rationale. Although patient factors may influence the come in a population at low risk for infection with length of antibiotic therapy, in general, a duration of 7–10 resistant microorganisms [85]. days (in the absence of source control issues) is adequate. Thus, decisions to continue, narrow, or stop antimicrobial infected with an antimicrobial-resistant pathogen or will therapy must be made on the basis of clinician judgment develop a drug-related adverse effect. Although it is and clinical information. Clinicians should be cognizant important to stop unnecessary antibiotics early, clinicians of blood cultures being negative in a significant percent- should be cognizant that blood cultures will be negative in age of cases of severe sepsis or septic shock, despite the more than 50 % of cases of severe sepsis or septic shock fact that many of these cases are very likely caused by if the patients are receiving empiric antimicrobial therapy; bacteria or fungi. Clinicians should be cognizant that yet many of these cases are very likely caused by bacteria blood cultures will be negative in a significant percentage or fungi. Thus, the decisions to continue, narrow, or stop of cases of severe sepsis or septic shock, despite many of antimicrobial therapy must be made on the basis of cli- these cases are very likely caused by bacteria or fungi. nician judgment and clinical information. 6. We suggest that antiviral therapy be initiated as early as possible in patients with severe sepsis or septic E. Source control shock of viral origin (grade 2C). 1. We recommend that a specific anatomical diagnosis of Rationale. Recommendations for antiviral treatment infection requiring consideration for emergent source include the use of: a) early antiviral treatment of sus- control (e.g., necrotizing soft tissue infection, peritonitis, pected or confirmed influenza among persons with severe cholangitis, intestinal infarction) be sought and diagnosed influenza (e.g., those who have severe, complicated, or or excluded as rapidly as possible, and intervention be progressive illness or who require hospitalization); b) undertaken for source control within the first 12 h after early antiviral treatment of suspected or confirmed influ- the diagnosis is made, if feasible (grade 1C). enza among persons at higher risk for influenza 2. We suggest that when infected peripancreatic necrosis is complications; and c) therapy with a neuraminidase identified as a potential source of infection, definitive inhibitor (oseltamivir or zanamivir) for persons with intervention is best delayed until adequate demarcation influenza caused by 2009 H1N1 virus, influenza A of viable and nonviable tissues has occurred (grade 2B). (H3N2) virus, or influenza B virus, or when the influenza 3. When source control in a severely septic patient is virus type or influenza A virus subtype is unknown [97, required, the effective intervention associated with the 98]. Susceptibility to antivirals is highly variable in a least physiologic insult should be used (e.g., percutane- rapidly evolving virus such as influenza, and therapeutic ous rather than surgical drainage of an abscess) (UG). decisions must be guided by updated information 4. If intravascular access devices are a possible source of regarding the most active, strain-specific, antiviral agents severe sepsis or septic shock, they should be removed during influenza epidemics [99, 100]. promptly after other vascular access has been estab- The role of cytomegalovirus (CMV) and other her- lished (UG). pesviruses as significant pathogens in septic patients, especially those not known to be severely immunocom- Rationale. The principles of source control in the promised, remains unclear. Active CMV viremia is management of sepsis include a rapid diagnosis of the common (15–35 %) in critically ill patients; the presence specific site of infection and identification of a focus of of CMV in the bloodstream has been repeatedly found to infection amenable to source control measures (specifi- be a poor prognostic indicator [101, 102]. What is not cally the drainage of an abscess, debridement of infected known is whether CMV simply is a marker of disease necrotic tissue, removal of a potentially infected device, severity or if the virus actually contributes to organ injury and definitive control of a source of ongoing microbial and death in septic patients [103]. No treatment recom- contamination) [105]. Foci of infection readily amenable mendations can be given based on the current level of to source control measures include an intra-abdominal evidence. In those patients with severe primary or gen- abscess or gastrointestinal perforation, cholangitis or eralized varicella-zoster virus infections, and in rare pyelonephritis, intestinal ischemia or necrotizing soft patients with disseminated herpes simplex infections, tissue infection, and other deep space infection, such as an antiviral agents such as acyclovir can be highly effective empyema or septic arthritis. Such infectious foci should when initiated early in the course of infection [104]. be controlled as soon as possible following successful initial resuscitation [106–108], and intravascular access 7. We recommend that antimicrobial agents not be used devices that are potentially the source of severe sepsis or in patients with severe inflammatory states determined septic shock should be removed promptly after estab- to be of noninfectious cause (UG). lishing other sites for vascular access [109, 110]. An RCT comparing early to delayed surgical inter- Rationale. When infection is found not to be present, vention for peripancreatic necrosis showed better antimicrobial therapy should be stopped promptly to outcomes with a delayed approach [111]. Moreover, a minimize the likelihood that the patient will become randomized surgical study found that a minimally invasive, step-up approach was better tolerated by debate, despite the recent evidence that the incidence of patients and had a lower mortality than open necrosec- antimicrobial resistance does not change appreciably with tomy in necrotizing pancreatitis [112], although areas of current SDD regimens [119–121]. The grade 2B was uncertainty exist, such as definitive documentation of designated for both SOD and CHG as it was felt that risk infection and appropriate length of delay. The selection of was lower with CHG and the measure better accepted optimal source control methods must weigh the benefits despite less published literature than with SOD. and risks of the specific intervention as well as risks of Supplemental Digital Content 3 shows a GRADEpro transfer [113]. Source control interventions may cause Summary of Evidence Table for the use of topical further complications, such as bleeding, fistulas, or inad- digestive tract antibiotics and CHG for prophylaxis vertent organ injury. Surgical intervention should be against VAP. considered when other interventional approaches are inadequate or when diagnostic uncertainty persists despite radiologic evaluation. Specific clinical situations require Hemodynamic support and adjunctive therapy consideration of available choices, the patient’s prefer- (Table 6) ences, and the clinician’s expertise. G. Fluid therapy of severe sepsis 1. We recommend crystalloids be used as the initial fluid F. Infection prevention of choice in the resuscitation of severe sepsis and 1. We suggest that selective oral decontamination (SOD) septic shock (grade 1B). and selective digestive decontamination (SDD) should 2. We recommend against the use of hydroxyethyl be introduced and investigated as a method to reduce starches (HES) for fluid resuscitation of severe sepsis the incidence of VAP; this infection control measure and septic shock (grade 1B). (This recommendation is can then be instituted in healthcare settings and regions based on the results of the VISEP [128], CRYSTMAS where this methodology is found to be effective (grade [122], 6S [123], and CHEST [124] trials. The results of 2B). the recently completed CRYSTAL trial were not 2. We suggest oral chlorhexidine gluconate (CHG) be considered.) used as a form of oropharyngeal decontamination to 3. We suggest the use of albumin in the fluid resuscita- reduce the risk of VAP in ICU patients with severe tion of severe sepsis and septic shock when patients sepsis (grade 2B). require substantial amounts of crystalloids (grade 2C).

Rationale. Careful infection control practices (e.g., hand washing, expert nursing care, catheter care, barrier pre- cautions, airway management, elevation of the head of the Rationale. The absence of any clear benefit following bed, subglottic suctioning) should be instituted during the the administration of colloid solutions compared to care of septic patients as reviewed in the nursing con- crystalloid solutions, together with the expense associated siderations for the SSC [114]. The role of SDD with with colloid solutions, supports a high-grade recommen- systemic antimicrobial prophylaxis and its variants (e.g., dation for the use of crystalloid solutions in the initial SOD, CHG) has been a contentious issue ever since the resuscitation of patients with severe sepsis and septic concept was first developed more than 30 years ago. The shock. notion of limiting the acquisition of opportunistic, often Three recent multicenter RCTs evaluating 6 % HES multiresistant, healthcare-associated microorganisms has 130/0.4 solutions (tetra starches) have been published. its appeal by promoting ‘‘colonization resistance’’ from The CRYSTMAS study demonstrated no difference in the resident microbiome existing along mucosal surfaces mortality with HES versus 0.9 % normal saline (31 vs. of the alimentary tract. However, the efficacy of SDD, its 25.3 %, P = 0.37) in the resuscitation of septic shock safety, propensity to prevent or promote antibiotic resis- patients; however, the study was underpowered to detect tance, and cost-effectiveness remain debatable despite a the 6 % difference in absolute mortality observed [122]. number of favorable meta-analyses and controlled clinical In a sicker patient cohort, a Scandinavian multicenter trials [115]. The data indicate an overall reduction in VAP study in septic patients (6S Trial Group) showed but no consistent improvement in mortality, except in increased mortality rates with 6 % HES 130/0.42 fluid selected populations in some studies. Most studies do not resuscitation compared to Ringer’s acetate (51 vs. 43 %. specifically address the efficacy of SDD in patients who P = 0.03) [123]. The CHEST study, conducted in a het- present with sepsis, but some do [116–118]. erogenous population of patients admitted to intensive Oral CHG is relatively easy to administer, decreases care (HES vs. isotonic saline, n = 7000 critically ill risk of nosocomial infection, and reduces the potential patients), showed no difference in 90-day mortality concern over promotion of antimicrobial resistance by between resuscitation with 6 % HES with a molecular SDD regimens. This remains a subject of considerable weight of 130 kD/0.40 and isotonic saline (18 vs. 17 %, Table 6 Recommendations: hemodynamic support and adjunctive therapy

G. Fluid therapy of severe sepsis 1. Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock (grade 1B). 2. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock (grade 1B). 3. Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids (grade 2C). 4. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients (grade 1C). 5. Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (e.g., change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables (UG). H. Vasopressors 1. Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg (grade 1C). 2. Norepinephrine as the first choice vasopressor (grade 1B). 3. Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure (grade 2B). 4. Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage (UG). 5. Low dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension and vasopressin doses higher than 0.03-0.04 units/minute should be reserved for salvage therapy (failure to achieve adequate MAP with other vasopressor agents) (UG). 6. Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia) (grade 2C). 7. Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target (grade 1C). 8. Low-dose dopamine should not be used for renal protection (grade 1A). 9. All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available (UG). I. Inotropic therapy 1. A trial of dobutamine infusion up to 20 micrograms/kg/min be administered or added to vasopressor (if in use) in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP (grade 1C). 2. Not using a strategy to increase cardiac index to predetermined supranormal levels (grade 1B). J. Corticosteroids 1. Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200 mg per day (grade 2C). 2. Not using the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone (grade 2B). 3. In treated patients hydrocortisone tapered when vasopressors are no longer required (grade 2D). 4. Corticosteroids not be administered for the treatment of sepsis in the absence of shock (grade 1D). 5. When hydrocortisone is given, use continuous flow (grade 2D).

P = 0.26); the need for renal replacement therapy was clinical trial comparing crystalloids and colloids, was higher in the HES group [7.0 vs. 5.8 %; relative risk (RR), recently completed and will provide additional insight 1.21; 95 % confidence interval (CI), 1.00–1.45; into HES fluid resuscitation. P = 0.04] [124]. A meta-analysis of 56 randomized trials The SAFE study indicated that albumin administration found no overall difference in mortality between crys- was safe and equally as effective as 0.9 % saline [129]. A talloids and artificial colloids (modified gelatins, HES, meta-analysis aggregated data from 17 randomized trials dextran) when used for initial fluid resuscitation [125]. (n = 1977) of albumin versus other fluid solutions in Information from 3 randomized trials (n = 704 patients patients with severe sepsis/septic shock [130]; 279 deaths with severe sepsis/septic shock) did not show survival occurred among 961 albumin-treated patients versus 343 benefit with use of heta-, hexa-, or pentastarches com- deaths among 1,016 patients treated with other fluids, thus pared to other fluids (RR, 1.15; 95 % CI, 0.95–1.39; favoring albumin [odds ratio (OR), 0.82; 95 % CI, random effect; I2 = 0%)[126–128]. However, these 0.67–1.00; I2 = 0 %]. When albumin-treated patients solutions increased substantially the risk of acute kidney were compared with those receiving crystalloids (7 trials, injury (RR, 1.60; 95 % CI, 1.26–2.04; I2 = 0%)[126– n = 1441), the OR of dying was significantly reduced for 128]. The evidence of harm observed in the 6S and albumin-treated patients (OR, 0.78; 95 % CI, 0.62–0.99; CHEST studies and the meta-analysis supports a high- I2 = 0 %). A multicenter randomized trial (n = 794) in level recommendation advising against the use of HES patients with septic shock compared intravenous albumin solutions in patients with severe sepsis and septic shock, (20 g, 20 %) every 8 h for 3 days to intravenous saline particularly since other options for fluid resuscitation solution [130]; albumin therapy was associated with exist. The CRYSTAL trial, another large prospective 2.2 % absolute reduction in 28-day mortality (from 26.3 to 24.1 %), but did not achieve statistical significance. sepsis-induced hypotension for use of MAP in the diag- These data support a low-level recommendation regarding nosis of severe sepsis is different (MAP \70 mmHg) the use of albumin in patients with sepsis and septic shock from the evidence-based target of 65 mmHg used in this (personal communication from J.P. Mira and as presented recommendation. In any case, the optimal MAP should be at the 32nd International ISICEM Congress 2012, Brus- individualized as it may be higher in patients with ath- sels and the 25th ESICM Annual Congress 2012, Lisbon). erosclerosis and/or previous hypertension than in young patients without cardiovascular comorbidity. For exam- 4. We recommend an initial fluid challenge in patients ple, a MAP of 65 mmHg might be too low in a patient with sepsis-induced tissue hypoperfusion with suspi- with severe uncontrolled hypertension; in a young, pre- cion of hypovolemia to achieve a minimum of 30 mL/ viously normotensive patient, a lower MAP might be kg of crystalloids (a portion of this may be albumin adequate. Supplementing endpoints, such as blood pres- equivalent). More rapid administration and greater sure, with assessment of regional and global perfusion, amounts of fluid may be needed in some patients (see such as blood lactate concentrations, skin perfusion, Initial Resuscitation recommendations) (grade 1C). mental status, and urine output, is important. Adequate 5. We recommend that a fluid challenge technique be fluid resuscitation is a fundamental aspect of the hemo- applied wherein fluid administration is continued as long dynamic management of patients with septic shock and as there is hemodynamic improvement either based on should ideally be achieved before vasopressors and ino- dynamic (e.g., change in pulse pressure, stroke volume tropes are used; however, using vasopressors early as an variation) or static (e.g., arterial pressure, heart rate) emergency measure in patients with severe shock is fre- variables (UG). quently necessary, as when diastolic blood pressure is too low. When that occurs, great effort should be Rationale. Dynamic tests to assess patients’ responsive- directed to weaning vasopressors with continuing fluid ness to fluid replacement have become very popular in resuscitation. recent years in the ICU [131]. These tests are based on monitoring changes in stroke volume during mechanical 2. We recommend norepinephrine as the first-choice ventilation or after passive leg raising in spontaneously vasopressor (grade 1B). breathing patients. A systematic review (29 trials, n = 685 3. We suggest epinephrine (added to and potentially critically ill patients) looked at the association between substituted for norepinephrine) when an additional stroke volume variation, pulse pressure variation, and/or agent is needed to maintain adequate blood pressure stroke volume variation and the change in stroke volume/ (grade 2B). cardiac index after a fluid or positive end-expiratory pres- 4. Vasopressin (up to 0.03 U/min) can be added to sure (PEEP) challenge [132]. The diagnostic OR of fluid norepinephrine with the intent of raising MAP to target responsiveness was 59.86 (14 trials, 95 % CI, or decreasing norepinephrine dosage (UG). 23.88–150.05) and 27.34 (5 trials, 95 % CI, 3.46–55.53) for 5. Low-dose vasopressin is not recommended as the the pulse pressure variation and the stroke volume variation, single initial vasopressor for treatment of sepsis- respectively. Utility of pulse pressure variation and stroke induced hypotension, and vasopressin doses higher volume variation is limited in the presence of atrial fibril- than 0.03–0.04 U/min should be reserved for salvage lation, spontaneous breathing, and low pressure support therapy (failure to achieve an adequate MAP with breathing. These techniques generally require sedation. other vasopressor agents) (UG). 6. We suggest dopamine as an alternative vasopressor agent to norepinephrine only in highly selected H. Vasopressors patients (e.g., patients with low risk of tachyarrhyth- 1. We recommend that vasopressor therapy initially tar- mias and absolute or relative bradycardia) (grade 2C). get a MAP of 65 mmHg (grade 1C). 7. Phenylephrine is not recommended in the treatment of septic shock except in the following circumstances: Rationale. Vasopressor therapy is required to sustain (a) norepinephrine is associated with serious arrhyth- life and maintain perfusion in the face of life-threatening mias, (b) cardiac output is known to be high and blood hypotension, even when hypovolemia has not yet been pressure persistently low, or (c) as salvage therapy resolved. Below a threshold MAP, autoregulation in when combined inotrope/vasopressor drugs and low- critical vascular beds can be lost, and perfusion can dose vasopressin have failed to achieve the MAP become linearly dependent on pressure. Thus, some target (grade 1C). patients may require vasopressor therapy to achieve a minimal perfusion pressure and maintain adequate flow Rationale. The physiologic effects of vasopressor and [133, 134]. The titration of norepinephrine to a MAP as combined inotrope/vasopressors selection in septic shock low as 65 mmHg has been shown to preserve tissue are set out in an extensive number of literature entries perfusion [134]. Note that the consensus definition of [135–147]. Table 7 depicts a GRADEpro Summary of Table 7 Norepinephrine compared with dopamine in severe sepsis summary of evidence

Norepinephrine compared with dopamine in severe sepsis

Patient or population: patients with severe sepsis Settings: intensive care unit Intervention: norepinephrine Comparison: dopamine Sources: analysis performed by Djillali Annane for Surviving Sepsis Campaign using following publications: De Backer D. N Engl J Med 2010; 362:779–789; Marik PE. JAMA 1994; 272:1354–1357; Mathur RDAC. Indian J Crit Care Med 2007; 11:186–191; Martin C. Chest 1993; 103:1826–1831; Patel GP. Shock 2010; 33:375–380; Ruokonen E. Crit Care Med 1993; 21:1296–1303 Outcomes Illustrative comparative risksa (95 % CI) Relative effect No. of Quality of Comments (95 % CI) participants the evidence Assumed risk Corresponding risk (Studies) (GRADE) Dopamine Norepinephrine

Short-term Study population RR 0.91 (0.83–0.99) 2,043 (6 studies) ÈÈÈÉ mortality 530 per 1000 482 per 1,000 (440–524) moderateb,c Serious adverse Study population RR 0.47 (0.38–0.58) 1,931 (2 studies) ÈÈÈÉ events— 229 per 1,000 82 per 1,000 (34–195) moderateb,c supraventricular arrhythmias Serious adverse Study population RR 0.35 (0.19–0.66) 1,931 (2 studies) ÈÈÈÉ events— 39 per 1,000 15 per 1000 moderateb,c ventricular (8–27) arrhythmias

CI confidence interval, RR risk ratio b Strong heterogeneity in the results (I2 = 85 %), however, this reflects degree of a The assumed risk is the control group risk across studies. The corre- effect, not direction of effect. We have decided not to lower the evidence quality sponding risk (and its 95 % CI) is based on the assumed risk in the c Effect results in part from hypovolemic and cardiogenic shock patients in comparison group and the relative effect of the intervention (and its 95 % [152] CI)

Evidence Table comparing dopamine and norepinephrine and produces hyperlactatemia, no clinical evidence shows in the treatment of septic shock. Dopamine increases that epinephrine results in worse outcomes, and it should be MAP and cardiac output, primarily due to an increase in the first alternative to norepinephrine. Indeed, information stroke volume and heart rate. Norepinephrine increases from 4 randomized trials (n = 540) comparing norepi- MAP due to its vasoconstrictive effects, with little change nephrine to epinephrine found no evidence for differences in in heart rate and less increase in stroke volume compared the risk of dying (RR, 0.96; CI, 0.77–1.21; fixed effect; with dopamine. Norepinephrine is more potent than I2 = 0%)[142, 147, 154, 155]. Epinephrine may increase dopamine and may be more effective at reversing hypo- aerobic lactate production via stimulation of skeletal mus- tension in patients with septic shock. Dopamine may be cles’ b2-adrenergic receptors and thus may prevent the use particularly useful in patients with compromised systolic of lactate clearance to guide resuscitation. With its almost function but causes more tachycardia and may be more pure a-adrenergic effects, phenylephrine is the adrenergic arrhythmogenic than norepinephrine [148]. It may also agent least likely to produce tachycardia, but it may influence the endocrine response via the hypothalamic decrease stroke volume and is therefore not recommended pituitary axis and have immunosuppressive effects. for use in the treatment of septic shock except in circum- However, information from five randomized trials stances where norepinephrine is: (a) associated with serious (n = 1,993 patients with septic shock) comparing nor- arrhythmias, or (b) cardiac output is known to be high, or epinephrine to dopamine does not support the routine use (c) as salvage therapy when other vasopressor agents have of dopamine in the management of septic shock [136, 149– failed to achieve target MAP [156]. Vasopressin levels in 152]. Indeed, the relative risk of short-term mortality was septic shock have been reported to be lower than anticipated 0.91 (95 % CI, 0.84–1.00; fixed effect; I2 = 0 %) in favor of for a shock state [157]. Low doses of vasopressin may be norepinephrine. A recent meta-analysis showed dopamine effective in raising blood pressure in patients, refractory to was associated with an increased risk [RR, 1.10 (1.01–1.20); other vasopressors and may have other potential physiologic P = 0.035]; in the two trials that reported arrhythmias, these benefits [158–163]. Terlipressin has similar effects but is were more frequent with dopamine than with norepinephrine long acting [164]. Studies show that vasopressin concen- [RR, 2.34 (1.46–3.77); P = 0.001] [153]. trations are elevated in early septic shock, but decrease to Although some human and animal studies suggest epi- normal range in the majority of patients between 24 and nephrine has deleterious effects on splanchnic circulation 48 h as shock continues [165]. This has been called relative vasopressin deficiency because in the presence of hypo- vasopressor (if in use) in the presence of: (a) myocardial tension, vasopressin would be expected to be elevated. The dysfunction, as suggested by elevated cardiac filling significance of this finding is unknown. The VASST trial, a pressures and low cardiac output, or (b) ongoing signs of randomized, controlled trial comparing norepinephrine hypoperfusion, despite achieving adequate intravascular alone to norepinephrine plus vasopressin at 0.03 U/min, volume and adequate MAP (grade 1C). showed no difference in outcome in the intent-to-treat 2. We recommend against the use of a strategy to population [166]. An a priori defined subgroup analysis increase cardiac index to predetermined supranormal demonstrated that survival among patients receiving levels (grade 1B). \15 lg/min norepinephrine at the time of randomization was better with the addition of vasopressin; however, the Rationale. Dobutamine is the first choice inotrope for pretrial rationale for this stratification was based on patients with measured or suspected low cardiac output in exploring potential benefit in the population requiring the presence of adequate left ventricular filling pressure C15 lg/min norepinephrine. Higher doses of vasopressin (or clinical assessment of adequate fluid resuscitation) and have been associated with cardiac, digital, and splanchnic adequate MAP. Septic patients who remain hypotensive ischemia and should be reserved for situations where after fluid resuscitation may have low, normal, or alternative vasopressors have failed [167]. Information increased cardiac outputs. Therefore, treatment with a from 7 trials (n = 963 patients with septic shock) compar- combined inotrope/vasopressor, such as norepinephrine or ing norepinephrine with vasopressin (or terlipressin) does epinephrine, is recommended if cardiac output is not not support the routine use of vasopressin or its analog ter- measured. When the capability exists for monitoring lipressin [93, 95, 97, 99, 159, 161, 164, 166, 168–170]. cardiac output in addition to blood pressure, a vasopres- Indeed, the relative risk of dying was 1.12 (95 % CI, sor, such as norepinephrine, may be used separately to 0.96–1.30; fixed effects; I2 = 0 %). However, the risk of target specific levels of MAP and cardiac output. Large supraventricular arrhythmias was increased with norepi- prospective clinical trials, which included critically ill nephrine (RR, 7.25; 95 % CI, 2.30–22.90; fixed effect; ICU patients who had severe sepsis, failed to demonstrate I2 = 0 %). Cardiac output measurement targeting mainte- benefit from increasing oxygen delivery to supranormal nance of a normal or elevated flow is desirable when these targets by use of dobutamine [173, 174]. These studies did pure vasopressors are instituted. not specifically target patients with severe sepsis and did not target the first 6 h of resuscitation. If evidence of 8. We recommend that low-dose dopamine not be used tissue hypoperfusion persists despite adequate intravas- for renal protection (grade 1A). cular volume and adequate MAP, a viable alternative (other than reversing underlying insult) is to add inotropic Rationale. A large randomized trial and meta-analysis therapy. comparing low-dose dopamine to placebo found no dif- ference in either primary outcomes (peak serum creatinine, need for renal replacement, urine output, time J. Corticosteroids to recovery of normal renal function) or secondary out- comes (survival to either ICU or hospital discharge, ICU 1. We suggest not using intravenous hydrocortisone as a stay, hospital stay, arrhythmias) [171, 172]. Thus, the treatment of adult septic shock patients if adequate available data do not support administration of low doses fluid resuscitation and vasopressor therapy are able to of dopamine solely to maintain renal function. restore hemodynamic stability (see goals for Initial Resuscitation). If this is not achievable, we suggest 9. We recommend that all patients requiring vasopressors intravenous hydrocortisone alone at a dose of 200 mg have an arterial catheter placed as soon as practical if per day (grade 2C). resources are available (UG). Rationale. The response of septic shock patients to fluid Rationale. In shock states, estimation of blood pressure and vasopressor therapy seems to be an important factor using a cuff is commonly inaccurate; use of an arterial cannula in selection of patients for optional hydrocortisone ther- provides a more appropriate and reproducible measurement apy. One French multicenter RCT of patients in of arterial pressure. These catheters also allow continuous vasopressor-unresponsive septic shock (hypotension analysis so that decisions regarding therapy can be based on despite fluid resuscitation and vasopressors for more than immediate and reproducible blood pressure information. 60 min) showed significant shock reversal and reduction of mortality rate in patients with relative adrenal insuffi- ciency [defined as postadrenocorticotropic hormone I. Inotropic therapy (ACTH) cortisol increase B9 lg/dL] [175]. Two smaller 1. We recommend that a trial of dobutamine infusion up RCTs also showed significant effects on shock reversal to 20 lgkg-1 min-1 be administered or added to with steroid therapy [176, 177]. In contrast, a large, European multicenter trial (CORTICUS) that enrolled [184]. Although the clinical significance is not clear, it is patients without sustained shock and had a lower risk of now recognized that etomidate, when used for induction death than the French trial failed to show a mortality for intubation, will suppress the hypothalamic–pituitary– benefit with steroid therapy [178]. Unlike the French trial adrenal axis [185, 186]. Moreover, a subanalysis of the that only enrolled shock patients with blood pressure CORTICUS trial [178] revealed that the use of etomidate unresponsive to vasopressor therapy, the CORTICUS before application of low-dose steroids was associated study included patients with septic shock regardless of with an increased 28-day mortality rate [187]. An inap- how the blood pressure responded to vasopressors; the propriately low random cortisol level (\18 lg/dL) in a study baseline (placebo) 28-day mortality rate was 61 and patient with shock would be considered an indication for 31 %, respectively. The use of the ACTH test (responders steroid therapy along traditional adrenal insufficiency and nonresponders) did not predict the faster resolution of guidelines. shock. In recent years, several systematic reviews have examined the use of low-dose hydrocortisone in septic 3. We suggest that clinicians taper the treated patient shock with contradictory results: Annane et al. [179] from steroid therapy when vasopressors are no longer analyzed the results of 12 studies and calculated a sig- required (grade 2D). nificant reduction in 28-day mortality with prolonged Rationale. low-dose steroid treatment in adult septic shock patients There has been no comparative study (RR, 0.84; 95 % CI, 0.72–0.97; P = 0.02). In parallel, between a fixed-duration and clinically guided regimen or Sligl and colleagues [180] used a similar technique, but between tapering and abrupt cessation of steroids. Three only identified eight studies for their meta-analysis, six of RCTs used a fixed-duration protocol for treatment [175, which had a high-level RCT design with low risk of bias 177, 178], and therapy was decreased after shock reso- [181]. In contrast to the aforementioned review, this lution in two RCTs [176, 182]. In four studies, steroids analysis revealed no statistically significant difference in were tapered over several days [176–178, 182], and ste- mortality (RR, 1.00; 95 % CI, 0.84–1.18). Both reviews, roids were withdrawn abruptly in two RCTs [175, 183]. however, confirmed the improved shock reversal by using One crossover study showed hemodynamic and immu- low-dose hydrocortisone [180, 181]. A recent review on nologic rebound effects after abrupt cessation of the use of steroids in adult septic shock underlined the corticosteroids [188]. Furthermore, a study revealed that importance of selection of studies for systematic analysis there is no difference in outcome of septic shock patients [181] and identified only 6 high-level RCTs as adequate if low-dose hydrocortisone is used for 3 or 7 days; hence, for systematic review [175–178, 182, 183]. When only no recommendation can be given with regard to the these six studies are analyzed, we found that in ‘‘low risk’’ optimal duration of hydrocortisone therapy [189]. patients from three studies (i.e., those with a placebo 4. We recommend that corticosteroids not be adminis- mortality rate of less than 50 %, which represents the tered for the treatment of sepsis in the absence of majority of all patients), hydrocortisone failed to show shock (grade 1D). any benefit on outcome (RR 1.06). The minority of patients from the remaining three studies, who had a placebo mor- Rationale. Steroids may be indicated in the presence of tality of greater than 60 %, showed a nonsignificant trend to a history of steroid therapy or adrenal dysfunction, but lower mortality by using hydrocortisone. See Supplemental whether low-dose steroids have a preventive potency in Digital Content 4, Summary of Evidence Table. reducing the incidence of severe sepsis and septic shock 2. We suggest not using the ACTH stimulation test to in critically ill patients cannot be answered. A preliminary identify the subset of adults with septic shock who study of stress-dose level steroids in community-acquired should receive hydrocortisone (grade 2B). pneumonia showed improved outcome measures in a small population [190], and a recent confirmatory RCT Rationale. In one study, the observation of a potential revealed reduced hospital length of stay without affecting interaction between steroid use and ACTH test was not mortality [191]. statistically significant [175]. Furthermore, no evidence of 5. When low-dose hydrocortisone is given, we suggest this distinction was observed between responders and using continuous infusion rather than repetitive bolus nonresponders in a recent multicenter trial [178]. Random injections (grade 2D). cortisol levels may still be useful for absolute adrenal insufficiency; however, for septic shock patients who Rationale. Several randomized trials on the use of low- suffer from relative adrenal insufficiency (no adequate dose hydrocortisone in septic shock patients revealed a stress response), random cortisol levels have not been significant increase of hyperglycemia and hypernatremia demonstrated to be useful. Cortisol immunoassays may [175] as side effects. A small prospective study demon- over- or underestimate the actual cortisol level, affecting strated that repetitive bolus application of hydrocortisone the assignment of patients to responders or nonresponders leads to a significant increase in blood glucose; this peak effect was not detectable during continuous infusion. of erythropoietin in severe sepsis and septic shock would Furthermore, considerable inter-individual variability was not be expected to be more beneficial than in other critical seen in this blood glucose peak after the hydrocortisone conditions. Patients with severe sepsis and septic shock bolus [192]. Although an association of hyperglycemia may have coexisting conditions that meet indications for and hypernatremia with patient outcome measures could the use of erythropoietin. not be shown, good practice includes strategies for avoidance and/or detection of these side effects. 3. We suggest that fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures (grade 2D). Supportive therapy of severe sepsis (Table 8) Rationale. Although clinical studies have not assessed K. Blood product administration the impact of transfusion of fresh frozen plasma on out- 1. Once tissue hypoperfusion has resolved and in the comes in critically ill patients, professional organizations absence of extenuating circumstances, such as myocar- have recommended it for coagulopathy when there is a dial ischemia, severe hypoxemia, acute hemorrhage, or documented deficiency of coagulation factors (increased ischemic coronary artery disease, we recommend that prothrombin time, international normalized ratio, or par- red blood cell transfusion occur when the hemoglobin tial thromboplastin time) and the presence of active concentration decreases to\7.0 g/dL to target a hemo- bleeding or before surgical or invasive procedures [200– globin concentration of 7.0–9.0 g/dL in adults (grade 203]. In addition, transfusion of fresh frozen plasma 1B). usually fails to correct the prothrombin time in nonblee- ding patients with mild abnormalities [204, 205]. No studies suggest that correction of more severe coagulation abnormalities benefits patients who are not bleeding. Rationale. Although the optimum hemoglobin concen- 4. We recommend against antithrombin administration tration for patients with severe sepsis has not been for the treatment of severe sepsis and septic shock specifically investigated, the Transfusion Requirements in (grade 1B). Critical Care trial suggested that a hemoglobin level of 7–9 g/dL, compared with 10–12 g/dL, was not associated Rationale. A phase III clinical trial of high-dose anti- with increased mortality in critically ill adults [193]. No thrombin did not demonstrate any beneficial effect on significant differences in 30-day mortality rates were 28-day all-cause mortality in adults with severe sepsis and observed between treatment groups in the subgroup of septic shock. High-dose antithrombin was associated with patients with severe infections and septic shock (22.8 and an increased risk of bleeding when administered with 29.7 %, respectively; P = 0.36), heparin [206]. Although a post hoc subgroup analysis of Although less applicable to septic patients, results of a patients with severe sepsis and high risk of death showed randomized trial in patients undergoing cardiac surgery better survival in patients receiving antithrombin, this with cardiopulmonary bypass support a restrictive trans- agent cannot be recommended until further clinical trials fusion strategy using a threshold hematocrit of \24 % are performed [207]. (hemoglobin & 8 g/dL) as equivalent to a transfusion threshold of hematocrit of \30 % (hemoglobin & 10 g/ 5. In patients with severe sepsis, we suggest that platelets dL) [194]. Red blood cell transfusion in septic patients be administered prophylactically when counts are B10,000/mm3 (10 9 109/L) in the absence of apparent increases oxygen delivery but does not usually increase 3 oxygen consumption [195–197]. The transfusion thresh- bleeding, as well when counts are B20,000/mm (20 9 109/L) if the patient has a significant risk of old of 7 g/dL contrasts with early goal-directed 3 resuscitation protocols that use a target hematocrit of bleeding. Higher platelet counts [C50,000/mm (50 9 109/L)] are advised for active bleeding, surgery, 30 % in patients with low ScvO2 during the first 6 h of resuscitation of septic shock [13]. or invasive procedures (grade 2D). 2. We recommend not using erythropoietin as a specific Rationale. Guidelines for transfusion of platelets are treatment of anemia associated with severe sepsis derived from consensus opinion and experience in (grade 1B). patients with chemotherapy-induced thrombocytopenia. Patients with severe sepsis are likely to have some limi- Rationale. No specific information regarding erythro- tation of platelet production similar to that in poietin use in septic patients is available, but clinical trials chemotherapy-treated patients, but they also are likely to of erythropoietin administration in critically ill patients have increased platelet consumption. Recommendations show some decrease in red cell transfusion requirement take into account the etiology of thrombocytopenia, with no effect on clinical outcome [198, 199]. The effect platelet dysfunction, risk of bleeding, and presence of Table 8 Recommendations: other supportive therapy of severe sepsis

K. Blood product administration 1. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, or ischemic heart disease, we recommend that red blood cell transfusion occur only when hemoglobin concentration decreases to \7.0 g/dL to target a hemoglobin concentration of 7.0–9.0 g/dL in adults (grade 1B). 2. Not using erythropoietin as a specific treatment of anemia associated with severe sepsis (grade 1B). 3. Fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures (grade 2D). 4. Not using antithrombin for the treatment of severe sepsis and septic shock (grade 1B). 5. In patients with severe sepsis, administer platelets prophylactically when counts are B10,000/mm3 (10 9 109/L) in the absence of apparent bleeding. We suggest prophylactic platelet transfusion when counts are B20,000/mm3 (20 9 109/L) if the patient has a significant risk of bleeding. Higher platelet counts (C50,000/mm3 [50 9 109/L]) are advised for active bleeding, surgery, or invasive procedures (grade 2D). L. Immunoglobulins 1. Not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock (grade 2B). M. Selenium 1. Not using intravenous selenium for the treatment of severe sepsis (grade 2C). N. History of Recommendations Regarding Use of Recombinant Activated Protein C (rhAPC) A history of the evolution of SSC recommendations as to rhAPC (no longer available) is provided. O. Mechanical ventilation of sepsis-induced acute respiratory distress syndrome (ARDS) 1. Target a tidal volume of 6 mL/kg predicted body weight in patients with sepsis-induced ARDS (grade 1A vs. 12 mL/kg). 2. Plateau pressures be measured in patients with ARDS and initial upper limit goal for plateau pressures in a passively inflated lung be B30 cm H2O (grade 1B). 3. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at end expiration (atelectotrauma) (grade 1B). 4. Strategies based on higher rather than lower levels of PEEP be used for patients with sepsis- induced moderate or severe ARDS (grade 2C). 5. Recruitment maneuvers be used in sepsis patients with severe refractory hypoxemia (grade 2C). 6. Prone positioning be used in sepsis-induced ARDS patients with a PaO2/FIO2 ratio B100 mm Hg in facilities that have experience with such practices (grade 2B). 7. That mechanically ventilated sepsis patients be maintained with the head of the bed elevated to 30–45 degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia (grade 1B). 8. That noninvasive mask ventilation (NIV) be used in that minority of sepsis-induced ARDS patients in whom the benefits of NIV have been carefully considered and are thought to outweigh the risks (grade 2B). 9. That a weaning protocol be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria: a) arousable; b) hemodynamically stable (without vasopressor agents); c) no new potentially serious conditions; d) low ventilatory and end-expiratory pressure requirements; and e) low FIo2 requirements which can be met safely delivered with a face mask or nasal cannula. If the spontaneous breathing trial is successful, consideration should be given for extubation (grade 1A). 10. Against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS (grade 1A). 11. A conservative rather than liberal fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion (grade 1C). 12. In the absence of specific indications such as bronchospasm, not using beta 2-agonists for treatment of sepsis- induced ARDS. (Grade 1B). P. Sedation, analgesia, and neuromuscular blockade in sepsis 1. Continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration endpoints (grade 1B). 2. Neuromuscular blocking agents (NMBAs) be avoided if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs must be maintained, either intermittent bolus as required or continuous infusion with train-of-four monitoring of the depth of blockade should be used (grade 1C). 3. A short course of NMBA of not greater than 48 hours for patients with early sepsis-induced ARDS and a PaO2/FIO2 \150 mm Hg (grade 2C). Q. Glucose control 1. A protocolized approach to blood glucose management in ICU patients with severe sepsis commencing insulin dosing when 2 consecutive blood glucose levels are [180 mg/dL. This protocolized approach should target an upper blood glucose B180 mg/dL rather than an upper target blood glucose B110 mg/dL (grade 1A). 2. blood glucose values be monitored every 1–2 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs thereafter (grade 1C). 3. glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may not accurately estimate arterial blood or plasma glucose values (UG). R. Renal replacement therapy 1. Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure (grade 2B). 2. Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (grade 2D). Table 8 continued

S. Bicarbonate therapy 1. Not using sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH C7.15 (grade 2B). T. Deep vein thrombosis prophylaxis 1. Patients with severe sepsis receive daily pharmacoprophylaxis against venous thromboembolism (VTE) (grade 1B). This should be accomplished with daily subcutaneous low-molecular weight heparin (LMWH) (grade 1B versus twice daily UFH, grade 2C versus three times daily UFH). If creatinine clearance is \30 mL/min, use dalteparin (grade 1A) or another form of LMWH that has a low degree of renal metabolism (grade 2C) or UFH (grade 1A). 2. Patients with severe sepsis be treated with a combination of pharmacologic therapy and intermittent pneumatic compression devices whenever possible (grade 2C). 3. Septic patients who have a contraindication for heparin use (eg, thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage) not receive pharmacoprophylaxis (grade 1B), but receive mechanical prophylactic treatment, such as graduated compression stockings or intermittent compression devices (grade 2C), unless contraindicated. When the risk decreases start pharmacoprophylaxis (grade 2C). U. Stress ulcer prophylaxis 1. Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor be given to patients with severe sepsis/septic shock who have bleeding risk factors (grade 1B). 2. When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA (grade 2D) 3. Patients without risk factors do not receive prophylaxis (grade 2B). V. Nutrition 1. Administer oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock (grade 2C). 2. Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (e.g., up to 500 calories per day), advancing only as tolerated (grade 2B). 3. Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock (grade 2B). 4. Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating supplementation in patients with severe sepsis (grade 2C). W. Setting goals of care 1. Discuss goals of care and prognosis with patients and families (grade 1B). 2. Incorporate goals of care into treatment and end-of-life care planning, utilizing palliative care principles where appropriate (grade 1B). 3. Address goals of care as early as feasible, but no later than within 72 hours of ICU admission (grade 2C). concomitant disorders [200, 202, 203, 208, 209]. Factors immunoglobulin (Ig) M-enriched polyclonal IVIG that may increase the bleeding risk and indicate the need (n = 528) [212]. Compared with placebo, IVIG resulted for a higher platelet count are frequently present in in a significant reduction in mortality (RR, 0.81 and 95 % patients with severe sepsis. Sepsis itself is considered to CI, 0.70–0.93; and RR, 0.66 and 95 % CI, 0.51–0.85, be a risk factor for bleeding in patients with chemother- respectively). Also the subgroup of IgM-enriched IVIGs apy-induced thrombocytopenia. Other factors considered (n = 7 trials) showed a significant reduction in mortality to increase the risk of bleeding in patients with severe rates compared with placebo (RR, 0.66; 95 % CI, sepsis include temperature higher than 38 °C, recent 0.51–0.85). Trials with low risk of bias showed no minor hemorrhage, rapid decrease in platelet count, and reduction in mortality with polyclonal IVIG (RR, 0.97; other coagulation abnormalities [203, 208, 209]. 95 % CI, 0.81–1.15; five trials, n = 945). Three of these trials [210, 213, 214] used standard polyclonal IVIG and two IgM-enriched IVIG [215, 216]. L. Immunoglobulins These findings are in accordance with those of 2 older 1. We suggest not using intravenous immunoglobulins meta-analyses [217, 218] from other Cochrane authors. in adult patients with severe sepsis or septic shock One systematic review [217] included a total of 21 trials (grade 2B). and showed a relative risk of death of 0.77 with immu- noglobulin treatment (95 % CI, 0.68–0.88); however, the Rationale. One larger multicenter RCT (n = 624) [210] results of only high-quality trials (total of 763 patients) in adult patients and one large multinational RCT in showed a relative risk of 1.02 (95 % CI, 0.84–1.24). infants with neonatal sepsis (n = 3,493) [211] found no Similarly, Laupland et al. [218] found a significant benefit for intravenous immunoglobulin (IVIG). (For reduction in mortality with the use of IVIG treatment more on this trial, see ‘‘Pediatric considerations in severe (OR, 0.66; 95 % CI, 0.53–0.83; P \ 0.005). When only sepsis’’.). A meta-analysis by the Cochrane collaboration, high-quality studies were pooled, the OR for mortality which did not include this most recent RCT, identified 10 was 0.96 (95 % CI, 0.71–1.3; P = 0.78). Two meta- polyclonal IVIG trials (n = 1,430) and seven trials on analyses, which used less strict criteria to identify sources of bias or did not state their criteria for the assessment of (glutamine was also tested in a two-factorial design) to study quality, found significant improvement in patient parenteral nutrition in critically ill patients reduces mortality with IVIG treatment [219, 220]. In contrast to infections and improves outcome [226]. Selenium supple- the most recent Cochrane review, Kreymann et al. [219] mentation did not significantly affect the development of a classified five studies that investigated IgM-enriched new infection (OR, 0.81; 95 % CI, 0.57–1.15), and the preparation as high-quality studies, combining studies in 6-month mortality rate was not unaffected (OR, 0.89; 95 % adults and neonates, and found an OR for mortality of 0.5 CI, 0.62–1.29). In addition, length of stay, days of antibiotic (95 % CI, 0.34–0.73). use, and modified Sequential Organ Failure Assessment Most IVIG studies are small, some have methodo- score were not significantly affected by selenium [227]. logical flaws; the only large study (n = 624) showed no In addition to the lack of evidence, the questions of effect [210]. Subgroup effects between IgM-enriched and optimal dosing and application mode remain unanswered. nonenriched formulations reveal substantial heterogene- Reported high-dose regimens have involved a loading dose ity. In addition, indirectness and publication bias were followed by an infusion, while animal trials suggest that considered in grading this recommendation. The low- bolus dosing could be more effective [227]; this, however, quality evidence led to the grading as a weak recom- has not been tested in humans. These unsolved problems mendation. The statistical information that comes from require additional trials, and we encourage conducting large the high-quality trials does not support a beneficial effect multicenter studies to further evaluate the effectiveness of of polyclonal IVIG. We encourage conducting large intravenous selenium in patients with severe sepsis. This multicenter studies to further evaluate the effectiveness of recommendation does not exclude the use of low-dose other polyclonal immunoglobulin preparations given selenium as part of the standard minerals and oligo-ele- intravenously in patients with severe sepsis. ments used during total parenteral nutrition (TPN).

M. Selenium N. History of recommendations regarding use 1. We suggest not using intravenous selenium to treat of recombinant activated protein C severe sepsis (grade 2C). Recombinant human activated protein C (rhAPC) was Rationale. Selenium was administered in the hope that it approved for use in adult patients in a number of countries could correct the known reduction of selenium concentra- in 2001 following the Recombinant Human Activated tion in sepsis patients and provide a pharmacologic effect Protein C Worldwide Evaluation in Severe Sepsis through an antioxidant defense. Although some randomized (PROWESS) trial, which enrolled 1,690 severe sepsis controlled trials are available, the evidence on the use of patients and showed a significant reduction in mortality intravenous selenium is still very weak. Only one large (24.7 %) with rhAPC compared with placebo (30.8 %, clinical trial has examined the effect on mortality rates, and P = 0.005) [228]. The 2004 SSC guidelines recom- no significant impact was reported on the intent-to-treat mended use of rhAPC in line with the product labeling population with severe systemic inflammatory response instructions required by the US and European regulatory syndrome, sepsis, or septic shock (OR, 0.66; 95 % CI, authorities with a grade B quality of evidence [7, 8]. 0.39–1.10; P = 0.109) [221]. Overall, there was a trend By the time of publication of the 2008 SSC guidelines, toward a concentration-dependent reduction in mortality; no additional studies of rhAPC in severe sepsis (as required differences in secondary outcomes or adverse events were by regulatory agencies) had shown it ineffective in less detected. Finally, no comment on standardization of sepsis severely ill patients with severe sepsis as well as in management was included in this study, which recruited 249 children [229, 230]. The 2008 SSC recommendations patients over a period of 6 years (1999–2004) [221]. reflected these findings, and the strength of the rhAPC A French RCT in a small population revealed no effect recommendation was downgraded to a suggestion for use on primary (shock reversal) or secondary (days on in adult patients with a clinical assessment of high risk of mechanical ventilation, ICU mortality) endpoints [222]. death, most of whom will have Acute Physiology and Another small RCT revealed less early VAP in the selenium Chronic Health Evaluation (APACHE) II scores C25 or group (P = 0.04), but no difference in late VAP or sec- multiple organ failure (grade 2C; quality of evidence was ondary outcomes such as ICU or hospital mortality [223]. also downgraded from 2004, from B to C) [7]. The 2008 This is in accordance with 2 RCTs that resulted in reduced guidelines also recommended against use of rhAPC in number of infectious episodes [224] or increase in gluta- low-risk adult patients, most of whom will have APACHE thione peroxidase concentrations [225]; neither study, II scores B20 or single organ failures (grade 1A), and however, showed a beneficial effect on secondary outcome against use in all pediatric patients (grade 1B). measures (renal replacement, ICU mortality) [224, 225]. The results of the PROWESS SHOCK trial (1,696 A more recent large RCT tried to determine if the patients) were released in late 2011, showing no benefit of addition of relatively low doses of supplemental selenium rhAPC in patients with septic shock (mortality 26.4 % for rhAPC, 24.2 % placebo) with a relative risk of 1.09 and a patients who are passively inflated. Conversely, patients P value of 0.31 [231]. The drug was withdrawn from the with very stiff chest walls may require plateau pressures market and is no longer available, negating any need for [30 cmH2O to meet vital clinical objectives. A retro- an SSC recommendation regarding its use. spective study suggested that tidal volumes should be lowered even with plateau pressures B30 cmH2O[244]as lower plateau pressures were associated with decreased O. Mechanical ventilation of sepsis-induced acute in-hospital mortality [245]. respiratory distress syndrome High tidal volumes that are coupled with high plateau 1. We recommend that clinicians target a tidal volume of pressures should be avoided in ARDS. Clinicians should 6 mL/kg predicted body weight in patients with sepsis- use as a starting point the objective of reducing tidal induced acute respiratory distress syndrome (ARDS) volume over 1–2 h from its initial value toward the goal (grade 1A vs. 12 mL/kg). of a ‘‘low’’ tidal volume (&6 mL/kg PBW) achieved in 2. We recommend that plateau pressures be measured in conjunction with an end-inspiratory plateau pressure patients with ARDS and that the initial upper limit B30 cmH2O. If the plateau pressure remains[30 cmH2O goal for plateau pressures in a passively inflated lung after reduction of tidal volume to 6 mL/kg PBW, tidal be B 30 cmH O (grade 1B). volume may be reduced further to as low as 4 mL/kg 2 PBW per protocol. (Appendix 3 provides ARDSNet Rationale. Of note, studies used to determine recom- ventilator management and formulas to calculate PBW.) mendations in this section enrolled patients using criteria Using volume- and pressure-limited ventilation may lead from the American-European Consensus Criteria Defini- to hypercapnia with maximum tolerated set respiratory tion for Acute Lung Injury (ALI) and ARDS [232]. For this rates. In such cases, hypercapnia that is otherwise not document, we have used the updated Berlin definition and contraindicated (e.g., high intracranial pressure) and used the terms mild, moderate, and severe ARDS (PaO / appears to be tolerated should be allowed. Sodium 2 bicarbonate or tromethamine (THAM) infusion may be FIO2 B300, B200, and B100 mm Hg, respectively) for the syndromes previously known as ALI and ARDS [233]. considered in selected patients to facilitate use of limited Several multicenter randomized trials have been per- ventilator conditions that result in permissive hypercapnia formed in patients with established ARDS to evaluate the [246, 247]. effects of limiting inspiratory pressure through moderation A number of observational trials in mechanically of tidal volume [234–238]. These studies showed differing ventilated patients have demonstrated a decreased risk of results that may have been caused by differences in airway developing ARDS when smaller trial volumes are used pressures in the treatment and control groups [233, 234, [248–251]. Accordingly, high tidal volumes and plateau 239]. Several meta-analyses suggest decreased mortality in pressures should be avoided in mechanically ventilated patients with a pressure- and volume-limited strategy for patients at risk for developing ARDS, including those established ARDS [240, 241]. with sepsis. The largest trial of a volume- and pressure-limited No single mode of ventilation (pressure control, vol- strategy showed an absolute 9 % decrease in all-cause ume control) has consistently been shown to be mortality in patients with ARDS ventilated with tidal advantageous when compared with any other that respects volumes of 6 mL/kg compared with 12 mL/kg of pre- the same principles of lung protection. dicted body weight (PBW), and aiming for a plateau 3. We recommend that PEEP be applied to avoid alveolar pressure B30 cm H2O[233]. The use of lung-protective collapse at end expiration (atelectotrauma) (grade 1B). strategies for patients with ARDS is supported by clinical 4. We suggest strategies based on higher rather than trials and has been widely accepted, but the precise choice lower levels of PEEP for patients with sepsis-induced of tidal volume for an individual patient with ARDS may moderate to severe ARDS (grade 2C). require adjustment for such factors as the plateau pressure achieved, the level of PEEP chosen, the compliance of the Rationale. Raising PEEP in ARDS keeps lung units thoracoabdominal compartment, and the vigor of the open to participate in gas exchange. This will increase patient’s breathing effort. Patients with profound meta- PaO2 when PEEP is applied through either an endotra- bolic acidosis, high obligate minute ventilations, or short cheal tube or a face mask [252–254]. In animal stature may require additional manipulation of tidal vol- experiments, avoidance of end-expiratory alveolar col- umes. Some clinicians believe it may be safe to ventilate lapse helps minimize ventilator-induced lung injury when with tidal volumes[6 mL/kg PBW as long as the plateau relatively high plateau pressures are in use. Three large pressure can be maintained B30 cm H2O[242, 243]. The multicenter trials using higher versus lower levels of validity of this ceiling value will depend on the patient’s PEEP in conjunction with low tidal volumes did not effort, as those who are actively breathing generate higher uncover benefit or harm [255–257]. A meta-analysis using transalveolar pressures for a given plateau pressure than individual patient data showed no benefit in all patients with ARDS; however, patients with moderate or severe release ventilation, and extracorporeal membrane oxygen- ARDS (Pao2/FIo2 ratio B200 mm Hg) had decreased ation [271], may be considered as rescue therapies in centers mortality with the use of higher PEEP, whereas those with with expertise and experience with their use [261, 271–274]. mild ARDS did not [258]. Two options are recommended Inhaled nitric oxide does not improve mortality rates in for PEEP titration. One option is to titrate PEEP (and tidal patients with ARDS and should not be routinely used [275]. volume) according to bedside measurements of thoraco- pulmonary compliance with the objective of obtaining the 7. We recommend that mechanically ventilated sepsis best compliance, reflecting a favorable balance of lung patients be maintained with the head of the bed ele- recruitment and overdistension [259]. The second option vated between 30 and 45 degrees to limit aspiration is to titrate PEEP based on severity of oxygenation deficit risk and to prevent the development of VAP (grade 1B). and guided by the FIo2 required to maintain adequate oxygenation [234, 255, 256]. A PEEP[5cmH0 is usually 2 Rationale. required to avoid lung collapse [260]. The ARDSNet The semi-recumbent position has been standard PEEP strategy is shown in Appendix 3. The higher demonstrated to decrease the incidence of VAP [276]. PEEP strategy recommended for ARDS is shown in Enteral feeding increased the risk of developing VAP; 50 % Appendix 4 and comes from the ALVEOLI trial [257]. of the patients who were fed enterally in the supine position developed VAP compared with 9 % of those fed in the semi- 5. We suggest recruitment maneuvers in sepsis patients recumbent position [276]. However, the bed position was with severe refractory hypoxemia due to ARDS (grade monitored only once a day, and patients who did not achieve 2C). the desired bed elevation were not included in the analysis 6. We suggest prone positioning in sepsis-induced ARDS [276]. One study did not show a difference in incidence of patients with a PaO2/FiO2 ratio B100 mmHg in facilities VAP between patients maintained in supine and semi- that have experience with such practices (grade 2B). recumbent positions [277]; patients assigned to the semi- recumbent group did not consistently achieve the desired Rationale. Many strategies exist for treating refractory head of the bed elevation, and the head of bed elevation in hypoxemia in patients with severe ARDS [261]. Tempo- the supine group approached that of the semi-recumbent rarily raising transpulmonary pressure may facilitate group by day 7 [277]. When necessary, patients may be laid opening atelectatic alveoli to permit gas exchange [260], flat for procedures, hemodynamic measurements, and dur- but could also overdistend aerated lung units leading to ing episodes of hypotension. Patients should not be fed ventilator-induced lung injury and temporary hypoten- enterally while supine. sion. The application of transient sustained use of continuous positive airway pressure (CPAP) appears to 8. We suggest that noninvasive mask ventilation (NIV) be improve oxygenation in patients initially, but these effects used in that minority of sepsis-induced ARDS patients in can be transient [262]. Although selected patients with whom the benefits of NIV have been carefully consid- severe hypoxemia may benefit from recruitment maneu- ered and are thought to outweigh the risks (grade 2B). vers in conjunction with higher levels of PEEP, little Rationale. evidence supports the routine use in all ARDS patients Obviating the need for airway intubation [262]. Blood pressure and oxygenation should be moni- confers multiple advantages: better communication, lower tored and recruitment maneuvers discontinued if incidence of infection, and reduced requirements for deterioration in these variables is observed. sedation. Two RCTs in patients with acute respiratory Several small studies and one large study in patients failure demonstrated improved outcome with the use of with hypoxemic respiratory failure or ARDS have shown NIV when it can be used successfully [278, 279]. that most patients respond to the prone position with Unfortunately, only a small percentage of sepsis patients improved oxygenation [263–266]. None of the individual with life-threatening hypoxemia can be managed in this trials of prone positioning in patients with ARDS or way [280, 281]. hypoxemic respiratory failure demonstrated a mortality ben- NIV should be considered in patients with sepsis- efit [267–270]. One meta-analysis suggested potential induced ARDS if they are responsive to relatively low levels benefits for prone positioning in patients with profound hyp- of pressure support and PEEP with stable hemodynamics, can be made comfortable, and are easily arousable; if they oxemia and PaO2/FiO2 ratio B100 mmHg, but not in those with less severe hypoxemia [270]. Prone positioning may be are able to protect the airway and spontaneously clear the associated with potentially life-threatening complications, airway of secretions; and if they are anticipated to recover including accidental dislodging of the endotracheal and chest rapidly from the precipitating insult [280, 281]. A low tubes; these complications occur more frequently in patients threshold for airway intubation should be maintained. in the prone compared with supine position [270]. 9. We recommend that a weaning protocol be in place Other methods to treat refractory hypoxemia, including and that mechanically ventilated patients with severe high-frequency oscillatory ventilation, airway pressure sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ven- ventilation [297, 298]. A fluid-conservative strategy to tilation when they satisfy the following criteria: minimize fluid infusion and weight gain in patients with (a) arousable; (b) hemodynamically stable (without ARDS, based on either a central venous catheter (CVP vasopressor agents); (c) no new potentially serious \4 mmHg) or a PA catheter (pulmonary artery wedge conditions; (d) low ventilatory and end-expiratory pressure\8 mmHg), along with clinical variables to guide pressure requirements; and (e) low FiO2 requirements treatment, led to fewer days of mechanical ventilation and which can be safely delivered with a face mask or nasal reduced length of ICU stay without altering the incidence of cannula. If the spontaneous breathing trial is successful, renal failure or mortality rates [299]. This strategy was only extubation should be considered (grade 1A). used in patients with established ARDS, some of whom had shock present during the ICU stay, and active attempts to Rationale. Spontaneous breathing trial options include a reduce fluid volume were conducted only outside periods of low level of pressure support, CPAP (&5 cmH2O), or a shock. use of a T-piece. Studies demonstrated that daily spon- taneous breathing trials in appropriately selected patients 12. In the absence of specific indications such as bron- reduce the duration of mechanical ventilation [282, 283]. chospasm, we recommend against the use of These breathing trials should be conducted in conjunction b2-agonists for treatment of patients with sepsis- with a spontaneous awakening trial [284]. Successful induced ARDS (grade 1B). completion of spontaneous breathing trials leads to a high likelihood of successful early discontinuation of Rationale. Patients with sepsis-induced ARDS often mechanical ventilation. develop increased vascular permeability. Preclinical and early clinical data suggest that b-adrenergic agonists may 10. We recommend against the routine use of the pul- speed resorption of alveolar edema [300]. Two random- monary artery catheter for patients with sepsis- ized clinical trials studied the effect of b-agonists in induced ARDS (grade 1A). patients with ARDS [301, 302]. In one, a comparison of aerosolized albuterol and placebo in 282 patients with Rationale. Although insertion of a pulmonary artery ARDS, the trial was stopped for futility [301]. Patients (PA) catheter may provide useful information on a receiving albuterol had higher heart rates on day 2, and a patient’s volume status and cardiac function, these bene- trend was detected toward decreased ventilator-free days fits may be confounded by differences in the (days alive and off the ventilator). The rates of death interpretation of results [285–287], lack of correlation of before discharge were 23.0 % in the albuterol group PA occlusion pressures with clinical response [288], and versus 17.7 % in placebo-treated patients. More than half an absence of a proven strategy to use catheter results to of the patients enrolled in this trial had pulmonary or improve patient outcomes [173]. Two multicenter ran- nonpulmonary sepsis as the cause of the ARDS [301]. domized trials, one in patients with shock or ARDS [289] The use of intravenous salbutamol was tested in the and the other in those with only ARDS [290], failed to BALTI-2 trial [302]. Three hundred twenty-six patients show benefit with the routine use of PA catheters in with ARDS, 251 of whom had pulmonary or nonpulmo- ARDS. In addition, other studies in different types of nary sepsis as cause, were randomized to intravenous critically ill patients have failed to show definitive benefit salbutatmol, 15 lg/kg of ideal body weight, or placebo with routine use of the PA catheter [291–293]. Well- for up to 7 days. Patients treated with salbutamol had selected patients remain appropriate candidates for PA increased 28-day mortality rates (34 vs. 23 %; RR, 1.4; catheter insertion only when the answers to important 95 % CI, 1.03–2.08) leading to early termination of the management decisions depend on information solely trial [302]. obtainable from direct measurements made within the PA b2-agonists may have specific indications, such as [292, 294]. treatment of bronchospasm and hyperkalemia. In the absence of these conditions, we recommend against the 11. We recommend a conservative fluid strategy for routine use of b-agonists, either in intravenous or aero- patients with established sepsis-induced ARDS who do solized form, for the treatment of patients with sepsis- not have evidence of tissue hypoperfusion (grade 1C). induced ARDS. Rationale. Mechanisms for the development of pul- monary edema in patients with ARDS include increased P. Sedation, analgesia, and neuromuscular blockade capillary permeability, increased hydrostatic pressure, and in sepsis decreased oncotic pressure [295]. Small prospective studies in patients with critical illness and ARDS 1. We recommend that either continuous or intermittent have suggested that low weight gain is associated with sedation be minimized in mechanically ventilated sepsis improved oxygenation [296] and fewer days of mechanical patients, targeting specific titration endpoints (grade 1B). Rationale. A growing body of evidence indicates that mechanical ventilation or lengths of stay between the limiting the use of sedation in critically ill ventilated groups; and daily interruption was associated with higher patients can reduce the duration of mechanical ventilation daily opioid and benzodiazepines doses, as well as higher and ICU and hospital lengths of stay [303–305]. While nurse workload. Additionally, a randomized prospective studies limiting sedation have been performed in a wide blinded observational study demonstrated that although range of critically ill patients, there is little reason to myocardial ischemia is common in critically ill ventilated assume that septic patients will not derive benefit from patients, daily sedative interruption is not associated with this approach [305]. The use of protocols for sedation is an increased occurrence of myocardial ischemia [312]. one method to limit sedation use, and a randomized, Regardless of sedation approach, early physical rehabili- controlled clinical trial found that protocolized sedation tation should be a goal [313]. compared with usual care reduced duration of mechanical ventilation, lengths of stay, and tracheostomy rates [305]. 2. We recommend that NMBAs be avoided if possible in Avoidance of sedation is another strategy. A recent the septic patient without ARDS due to the risk of observational study of 250 critically ill patients suggests prolonged neuromuscular blockade following discon- that deep sedation is common in mechanically ventilated tinuation. If NMBAs must be maintained, either patients [306]. A randomized, controlled clinical trial intermittent bolus as required or continuous infusion found that patients treated with intravenous morphine with train-of-four monitoring of the depth of blockade boluses preferentially, had significantly more days with- should be used (grade 1C). out ventilation, shorter stay in ICU and hospital, than 3. We suggest a short course of an NMBA (B48 h) for patients who received sedation (propofol and midazolam) patients with early, sepsis-induced ARDS and PaO2/ in addition to morphine [307]. However, agitated delirium FIO2 \150 mm Hg (grade 2C). was more frequently detected in the intervention group. Although not specifically studied in patients with sepsis, Rationale. Although NMBAs are often administered to the administration of intermittent sedation, daily sedative critically ill patients, their role in the ICU is not well defined. interruption, and systematic titration to a predefined No evidence exists that neuromuscular blockade in this endpoint have been demonstrated to decrease the duration patient population reduces mortality or major morbidity. In of mechanical ventilation [284, 305, 308, 309]. Patients addition, no studies have been published that specifically receiving neuromuscular blocking agents (NMBAs) must address the use of NMBAs in septic patients. be individually assessed regarding discontinuation of The most common indication for NMBA use in the sedative drugs because the neuromuscular blockade must ICU is to facilitate mechanical ventilation [314]. When first be reversed. The use of intermittent vs. continuous appropriately used, these agents may improve chest wall methods for the delivery of sedation in critically ill compliance, prevent respiratory dyssynchrony, and patients has been examined in an observational study of reduce peak airway pressures [315]. Muscle paralysis may mechanically ventilated patients that showed that patients also reduce oxygen consumption by decreasing the work receiving continuous sedation had significantly longer of breathing and respiratory muscle blood flow [316]. durations of mechanical ventilation and ICU and hospital However, a randomized, placebo-controlled clinical trial lengths of stay [310]. in patients with severe sepsis demonstrated that oxygen Clinical trials have evaluated daily interruption of delivery, oxygen consumption, and gastric intramucosal continuous sedative infusions. A prospective, randomized pH were not improved during deep neuromuscular controlled trial in 128 mechanically ventilated adults blockade [317]. receiving continuous intravenous sedation demonstrated A recent randomized clinical trial of continuous that a daily interruption in the continuous sedative infu- infusions of cisatracurium in patients with early ARDS sion until the patient was awake decreased the duration of and a PaO2/FIO2 \150 mm Hg showed improved adjus- mechanical ventilation and ICU length of stay [310]. ted survival rates and more organ failure-free days Although the patients did receive continuous sedative without an increased risk in ICU-acquired weakness infusions in this study, the daily interruption and awak- compared with placebo-treated patients [318]. The ening allowed for titration of sedation, in effect making investigators used a high fixed dose of cisatracurium the dosing intermittent. In addition, a paired spontaneous without train-of-four monitoring, and half of the patients awakening trial combined with a spontaneous breathing in the placebo group received at least a single dose of trial decreased the duration of mechanical ventilation, NMBA. Whether another NMBA would have similar length of ICU and hospital stay, and 1-year mortality effects is unknown. Although many of the patients [284]. More recently, a multicenter randomized trial enrolled into this trial appeared to meet sepsis criteria, it compared protocolized sedation with protocolized seda- is not clear whether similar results would occur in sepsis tion plus daily sedation interruption in 423 critically ill patients. A GRADEpro Summary of Evidence Table mechanically ventilated medical and surgical patients regarding use of NMBA in ARDS appears in Supple- [311]. There were no differences in duration of mental Digital Content 5. An association between NMBA use and myopathies length of stay of more than 3 days in three medical ICUs and neuropathies has been suggested by case studies and and overall mortality was not reduced [327]. prospective observational studies in the critical care Since these studies [326, 327] and the previous Sur- population [315, 319–322], but the mechanisms by which viving Sepsis Guidelines [7] appeared, several RCTs NMBAs produce or contribute to myopathies and neur- [128, 328–332] and meta-analyses [333– 337] of intensive opathies in these patients are unknown. Although no insulin therapy have been performed. The RCTs studied studies are specific to the septic patient population, it mixed populations of surgical and medical ICU patients seems clinically prudent, based on existing knowledge, [128, 328–332] and found that intensive insulin therapy that NMBAs not be administered unless there is a clear did not significantly decrease mortality [128, 328–332], indication for neuromuscular blockade that cannot be whereas the NICE-SUGAR trial demonstrated an safely achieved with appropriate sedation and analgesia increased mortality [331]. All studies [128, 326–332] [315]. reported a much higher incidence of severe hypoglycemia Only one prospective RCT has compared peripheral (glucose B40 mg/dL) (6–29 %) with intensive insulin nerve stimulation and standard clinical assessment in ICU therapy. Several meta-analyses confirmed that intensive patients [323]. Rudis et al. randomized 77 critically ill insulin therapy was not associated with a mortality benefit ICU patients requiring neuromuscular blockade to receive in surgical, medical, or mixed ICU patients [333, 335, dosing of vecuronium based on train-of-four stimulation 337]. The meta-analysis by Griesdale and colleagues or on clinical assessment (control group). The peripheral [334], using between-trial comparisons driven mainly by nerve stimulation group received less drug and recovered the 2001 study by van den Berghe et al. [326], found that neuromuscular function and spontaneous ventilation fas- intensive insulin therapy was beneficial in surgical ICU ter than the control group. Nonrandomized observational patients [risk ratio 0.63 (0.44–0.9)], whereas the meta- studies have suggested that peripheral nerve monitoring analysis by Friedrich et al. [336], using within-trial reduces or has no effect on clinical recovery from comparisons, showed no benefit for surgical patients in NMBAs in the ICU [324, 325]. mixed medical-surgical ICUs [risk ratio 0.99 (0.82–1.11)] Benefits to neuromuscular monitoring, including faster and no subgroup of surgical patients who benefited from recovery of neuromuscular function and shorter intuba- intensive insulin therapy. Interestingly, the RCTs that tion times, appear to exist. A potential for cost savings reported [326, 337] compared intensive insulin therapy to (reduced total dose of NMBAs and shorter intubation high controls (180–200 mg/dL) [OR 0.89 (0.73–1.09)], times) also may exist, although this has not been studied whereas those that did not demonstrate benefit [330–332] formally. compared intensive therapy to moderate controls (108–180 mg/dL) [OR 1.14 (1.02 to -1.26)]. See Sup- plemental Digital Content 6 for details. Q. Glucose control The trigger to start an insulin protocol for blood glu- 1. We recommend a protocolized approach to blood cose levels [180 mg/dL with an upper target blood glucose management in ICU patients with severe glucose level \180 mg/dL derives from the NICE- sepsis, commencing insulin dosing when two consec- SUGAR study [331], which used these values for initi- utive blood glucose levels are [180 mg/dL. This ating and stopping therapy. The NICE-SUGAR trial is the approach should target an upper blood glucose level largest, most compelling study to date on glucose control B180 mg/dL rather than an upper target blood glucose in ICU patients given its inclusion of multiple ICUs and B110 mg/dL (grade 1A). hospitals and a general patient population. Several med- 2. We recommend blood glucose values be monitored ical organizations, including the American Association of every 1–2 h until glucose values and insulin infusion Clinical Endocrinologists, American Diabetes Associa- rates are stable, then every 4 h thereafter (grade 1C). tion, American Heart Association, American College of 3. We recommend that glucose levels obtained with Physicians, and Society of Critical Care Medicine, have point-of-care testing of capillary blood be interpreted published consensus statements for glycemic control of with caution, as such measurements may not accu- hospitalized patients [338–341]. These statements usually rately estimate arterial blood or plasma glucose values targeted glucose levels between 140 and 180 mg/dL. As (UG). there is no evidence that targets between 140 and 180 mg/ dL are different from targets of 110–140 mg/dL, the Rationale. One large RCT single center trial in a pre- recommendations use an upper target blood glucose dominantly cardiac surgical ICU demonstrated a B180 mg/dL without a lower target other than hypogly- reduction in ICU mortality with intensive intravenous cemia. Treatment should avoid hyperglycemia ([180 mg/ insulin (Leuven protocol) targeting blood glucose to dL), hypoglycemia, and wide swings in glucose levels. 80–110 mg/dL [326]. A second randomized trial of The continuation of insulin infusions, especially with the intensive insulin therapy using the Leuven protocol cessation of nutrition, has been identified as a risk factor enrolled medical ICU patients with an anticipated ICU for hypoglycemia [332]. Balanced nutrition may be associated with a reduced risk of hypoglycemia [342]. analyses [365, 366] reported the absence of significant Several studies have suggested that the variability in difference in hospital mortality between patients who glucose levels over time is an important determinant of receive continuous and intermittent renal replacement mortality [343–345]. Hyperglycemia and glucose vari- therapies. This absence of apparent benefit of one ability seem to be unassociated with increased mortality modality over the other persists even when the analysis rates in diabetic patients compared to nondiabetic patients is restricted to RCT studies [366]. To date, five pro- [346, 347]. spective RCTs have been published [367–371]; four Several factors may affect the accuracy and repro- found no significant difference in mortality [367–371], ducibility of point-of-care testing of blood capillary blood whereas one found significantly higher mortality in the glucose, including the type and model of the device used, continuous treatment group [367], but imbalanced ran- user expertise, and patient factors, including hematocrit domization had led to a higher baseline severity of (false elevation with anemia), PaO2, and drugs [348]. illness in this group. When a multivariable model was Plasma glucose values by capillary point-of-care testing used to adjust for severity of illness, no difference in have been found to be inaccurate with frequent false mortality was apparent between the groups [367]. Most elevations [349] over the range of glucose levels [350], studies comparing modes of renal replacement in the but especially in the hypoglycemic [349, 351] and critically ill have included a small number of patients hyperglycemic ranges [351] and in hypotensive patients and some major weaknesses (i.e., randomization failure, [352] or patients receiving catecholamines [353]. A modifications of therapeutic protocol during the study review of 12 published insulin infusion protocols for period, combination of different types of continuous critically ill patients showed wide variability in dose renal replacement therapies, small number of heteroge- recommendations and variable glucose control [354]. This neous groups of enrollees). The most recent and largest lack of consensus about optimal dosing of intravenous RCT [371] enrolled 360 patients and found no significant insulin may reflect variability in patient factors (severity difference in survival between the continuous and of illness, surgical vs medical settings), or practice pat- intermittent groups. Moreover, no evidence supports the terns (e.g., approaches to feeding, intravenous dextrose) use of continuous therapies in sepsis independent of in the environments in which these protocols were renal replacement needs. developed and tested. Alternatively, some protocols may No evidence supports a better tolerance with contin- be more effective than others, conclusion supported by uous treatments regarding the hemodynamic tolerance of the wide variability in hypoglycemia rates reported with each method. Two prospective studies [369, 372] have protocols [128, 326–333]. Thus, the use of established reported a better hemodynamic tolerance with continuous insulin protocols is important not only for clinical care but treatment, with no improvement in regional perfusion also for the conduct of clinical trials to avoid hypogly- [372] and no survival benefit [369]. Four other prospec- cemia, adverse events, and premature termination of trials tive studies did not find any significant difference in MAP before the efficacy signal, if any, can be determined. or drop in systolic pressure between the two methods Several studies have suggested that computer-based [368, 370, 371, 373]. Two studies reported a significant algorithms result in tighter glycemic control with a improvement in goal achievement with continuous reduced risk of hypoglycemia [355, 356]. Further study of methods [367, 369] regarding fluid balance management. validated, safe, and effective protocols for controlling In summary, the evidence is insufficient to draw strong blood glucose concentrations and variability in the severe conclusions regarding the mode of replacement therapy sepsis population is needed. for acute renal failure in septic patients. The effect of dose of continuous renal replacement on outcomes in patients with acute renal failure has shown R. Renal replacement therapy mixed results [374, 375]. None of these trials was con- 1. We suggest that continuous renal replacement thera- ducted specifically in patients with sepsis. Although the pies and intermittent hemodialysis are equivalent in weight of evidence suggests that higher doses of renal patients with severe sepsis and acute renal failure replacement may be associated with improved outcomes, because they achieve similar short-term survival rates these results may not be generalizable. Two large multi- (grade 2B). center randomized trials comparing the dose of renal 2. We suggest the use of continuous therapies to facilitate replacement (Acute Renal Failure Trial Network in the management of fluid balance in hemodynamically United States and RENAL Renal Replacement Therapy unstable septic patients (grade 2D). Study in Australia and New Zealand) failed to show benefit of more aggressive renal replacement dosing [376, 377]. A typical dose for continuous renal replacement Rationale. Although numerous nonrandomized studies -1 -1 have reported a nonsignificant trend toward improved therapy would be 20–25 mL kg h of effluent survival using continuous methods [357–364], two meta- generation. S. Bicarbonate therapy Rationale. ICU patients are at risk for deep vein 1. We recommend against the use of sodium bicarbonate thrombosis (DVT) [380]. It is logical that patients with therapy for the purpose of improving hemodynamics severe sepsis would be at a similar or higher risk than the or reducing vasopressor requirements in patients with general ICU population. The consequences of VTE in the hypoperfusion-induced lactic acidemia with pH C7.15 setting of sepsis (increased risk of potentially fatal pul- (grade 2B). monary emboli in an already hemodynamically compromised patient) are dire. Therefore, prevention of Rationale. Although bicarbonate therapy may be useful VTE is highly desirable, especially if it can be done safely in limiting tidal volume in ARDS in some situations of and effectively. permissive hypercapnia (see ‘‘Mechanical ventilation’’ Prophylaxis is generally effective. In particular, nine of ARDS), no evidence supports the use of bicarbonate placebo-controlled RCTs of VTE prophylaxis have been therapy in the treatment of hypoperfusion-induced lactic conducted in general populations of acutely ill patients acidemia associated with sepsis. Two blinded, crossover [381–389]. All trials showed reduction in DVT or pul- RCTs that compared equimolar saline and bicarbonate monary embolism, a benefit that is also supported by in patients with lactic acidosis failed to reveal any dif- meta-analyses [390, 391]. Thus, the evidence strongly ference in hemodynamic variables or vasopressor supports the value of VTE prophylaxis (grade 1A). The requirements [378, 379]. The number of patients with prevalence of infection/sepsis was 17 % in those studies \7.15 pH in these studies was small. Bicarbonate in which this could be ascertained. One study investigated administration has been associated with sodium and only ICU patients only, and 52 % of those enrolled had infection/sepsis. The need to extrapolate from general, fluid overload, an increase in lactate and PCO2,anda decrease in serum ionized calcium, but the relevance of acutely ill patients to critically ill patients to septic these variables to outcome is uncertain. The effect of patients downgrades the evidence. That the effect is bicarbonate administration on hemodynamics and pronounced and the data are robust somewhat mitigate vasopressor requirements at lower pH, as well as the against the extrapolation, leading to a grade B determi- effect on clinical outcomes at any pH, is unknown. No nation. Because the patient’s risk of administration is studies have examined the effect of bicarbonate small, the gravity of not administering may be great, and administration on outcomes. the cost is low, the strength of the recommendation is strong [1]. Deciding how to provide prophylaxis is decidedly T. Deep vein thrombosis prophylaxis more difficult. The Canadian Critical Care Trials Group compared UFH (5000 IU twice daily) to LMWH (dal- 1. We recommend that patients with severe sepsis receive teparin, 5000 IU once per day and a second placebo daily pharmacoprophylaxis against venous thrombo- injection to ensure parallel-group equivalence) [392]. No embolism (VTE) (grade 1B). We recommend that this statistically significant difference in asymptomatic DVTs be accomplished with daily subcutaneous low-molec- was found between the two groups (hazard ratio, 0.92; ular weight heparin (LMWH) (grade 1B versus 95 % CI, 0.68–1.23; P = 0.57), but the proportion of unfractionated heparin [UFH] twice daily and grade patients diagnosed with pulmonary embolism on CT scan, 2C versus UFH given thrice daily). If creatinine high-probability ventilation perfusion scan, or autopsy clearance is \30 mL/min we recommend use of dal- was significantly lower in the LMWH group (hazard ratio, teparin (grade 1A) or another form of LMWH that has 0.51; 95 % CI, 0.30–0.88; P = 0.01).The study did not a low degree of renal metabolism (grade 2C) or UFH account for the use of other forms of LMWH. These data (grade 1A). suggest that LMWH (dalteparin) is the treatment of 2. We suggest that patients with severe sepsis be treated choice over UFH administered twice daily in critically ill with a combination of pharmacologic therapy and patients. Also, because the study included septic patients, intermittent pneumatic compression devices whenever the evidence supporting the use of dalteparin over twice possible (grade 2C). daily UFH in critically ill, and perhaps septic, patients is 3. We recommend that septic patients who have a strong. Similarly, a meta-analysis of acutely ill, general contraindication to heparin use (e.g., thrombocytope- medical patients comparing UFH twice and thrice daily nia, severe coagulopathy, active bleeding, recent demonstrated that the latter regimen was more effective at intracerebral hemorrhage) not receive pharmacopro- preventing VTE, but twice daily dosing produced less phylaxis (grade 1B). Rather we suggest they receive bleeding [393]. Both critically ill and septic patients were mechanical prophylactic treatment, such as graduated included in these analyses, but their numbers are unclear. compression stockings or intermittent compression Nonetheless, the quality of evidence supporting the use of devices (grade 2C), unless contraindicated. When the three times daily, as opposed to twice daily, UFH dosing risk decreases, we suggest starting pharmacoprophy- in preventing VTE in acutely ill medical patients is high laxis (grade 2C). (A). However, comparing LMWH to twice daily UFH, or twice daily UFH to three times daily UFH, in sepsis 2. When stress ulcer prophylaxis is used, we suggest the requires extrapolation, downgrading the data. No data use of proton pump inhibitors rather than H2 receptor exist on direct comparison of LMWH to UFH adminis- antagonists (H2RA) (grade 2C). tered three times daily, nor are there any studies directly 3. We suggest that patients without risk factors should comparing twice daily and thrice daily UFH dosing in not receive prophylaxis (grade 2B). septic or critically ill patients. Therefore, it is not possible to state that LMWH is superior to three times daily UFH Rationale. Although no study has been performed spe- or that three times daily dosing is superior to twice daily cifically in patients with severe sepsis, trials confirming administration in sepsis. This downgrades the quality of the benefit of stress ulcer prophylaxis in reducing upper the evidence and therefore the recommendation. gastrointestinal (GI) bleeding in general ICU populations Douketis et al. [394] conducted a study of 120 criti- included 20–25 % of patients with sepsis [403–406]. This cally ill patients with acute kidney injury (creatinine benefit should be applicable to patients with severe sepsis clearance \30 mL/min) who received VTE prophylaxis and septic shock. In addition, the risk factors for GI with dalteparin 5,000 IU daily for between 4 and 14 days bleeding (e.g., coagulopathy, mechanical ventilation for at and had at least one trough anti-factor Xa level measured. least 48 h, possibly hypotension) are frequently present in None of the patients had bio-accumulation (trough anti- patients with severe sepsis and septic shock [407, 408]. factor Xa level lower than 0.06 IU/mL). The incidence of Patients without these risk factors are unlikely (0.2 %; major bleeding was somewhat higher than in trials of 95 % CI, 0.02–0.5) to have clinically important bleeding other agents, but most other studies did not involve crit- [407]. ically ill patients, in whom the bleeding risk is higher. Both old and new meta-analyses show prophylaxis- Further, bleeding did not correlate with detectable trough induced reduction in clinically significant upper GI levels [394]. Therefore, we recommend that dalteparin bleeding, which we consider significant even in the can be administered to critically ill patients with acute absence of proven mortality benefit [409–411]. The ben- renal failure (A). Data on other LMWHs are lacking. efit of prevention of upper GI bleeding must be weighed Consequently, these forms should probably be avoided or, against the potential (unproven) effect of increased if used, anti-factor Xa levels should be monitored (grade stomach pH on a greater incidence of VAP and C. difficile 2C). UFH is not renally cleared and is safe (grade 1A). infection [409, 412, 413]. (See Supplemental Digital Mechanical methods (intermittent compression Content 6, 7 and 8, Summary of Evidence Tables for devices and graduated compression stockings) are rec- effects of treatments on specific outcomes.) In an ommended when anticoagulation is contraindicated [395– exploratory hypothesis, we considered (as did the authors 397]. A meta-analysis of 11 studies, including six RCTs, of the meta-analysis) [411] the possibility of less benefit published in the Cochrane Library concluded that the and more harm in prophylaxis among patients receiving combination of pharmacologic and mechanical prophy- enteral nutrition but decided to provide one recommen- laxis was superior to either modality alone in preventing dation while lowering the quality of evidence. The DVT and was better than compression alone in preventing balance of benefits and risks may thus depend on the pulmonary embolism [398]. This analysis did not focus on individual patient’s characteristics as well as on the local sepsis or critically ill patients but included studies of epidemiology of VAP and C. difficile infections. The prophylaxis after orthopedic, pelvic, and cardiac surgery. rationale for considering only suppression of acid pro- In addition, the type of pharmacologic prophylaxis varied, duction (and not sucralfate) is based on the study of 1,200 including UFH, LMWH, aspirin, and warfarin. Nonethe- patients by Cook et al. [414] comparing H2 blockers and less, the minimal risk associated with compression sucralfate. More recent meta-analyses provide low-quality devices lead us to recommend combination therapy in evidence suggesting more effective GI bleeding protec- most cases. In very-high-risk patients, LMWH is pre- tion with the use of proton pump inhibitors than with ferred over UFH [392, 399–401]. Patients receiving H2RA [415–417]. Patients should be periodically evalu- heparin should be monitored for development of heparin- ated for the continued need for prophylaxis. induced thrombocytopenia. These recommendations are consistent with those developed by the American College of Chest Physicians [402]. V. Nutrition 1. We suggest administering oral or enteral (if necessary) feedings, as tolerated, rather than either complete U. Stress ulcer prophylaxis fasting or provision of only intravenous glucose within 1. We recommend that stress ulcer prophylaxis using H2 the first 48 h after a diagnosis of severe sepsis/septic blocker or proton pump inhibitor be given to patients shock (grade 2C). with severe sepsis/septic shock who have bleeding risk 2. We suggest avoiding mandatory full caloric feeding in factors (grade 1B). the first week, but rather suggest low dose feeding (e.g., up to 500 kcal per day), advancing only as Underfeeding/trophic feeding strategies did not exclude tolerated (grade 2B). advancing diet as tolerated in those who improved 3. We suggest using intravenous glucose and enteral quickly. nutrition rather than TPN alone or parenteral nutrition Some form of parenteral nutrition has been compared in conjunction with enteral feeding in the first 7 days to alternative feeding strategies (e.g., fasting or enteral after a diagnosis of severe sepsis/septic shock (grade nutrition) in well over 50 studies, although only one 2B). exclusively studied sepsis [436], and eight meta-analyses 4. We suggest using nutrition with no specific immuno- have been published [429, 437–443]. Two of the meta- modulating supplementation in patients with severe analyses summarize comparisons of parenteral nutrition sepsis (grade 2C). versus fasting or intravenous glucose [437, 438], and 6 look at parenteral versus enteral nutrition [429, 439–443], Rationale. Early enteral nutrition has theoretical two of which attempted to explore the effect of early advantages in the integrity of gut mucosa and prevention enteral nutrition [441, 442]. Recently, a study much larger of bacterial translocation and organ dysfunction, but also than most earlier nutrition trials compared ICU patients concerning is the risk of ischemia, mainly in hemody- randomized to early use of parenteral nutrition to augment namically unstable patients. enteral feeding versus enteral feeding with only late ini- Unfortunately, no clinical trial has specifically tiation of parenteral nutrition if necessary [444]. addressed early feeding in septic patients. Studies on No direct evidence supports the benefits or harm of different subpopulations of critically ill patients, mostly parenteral nutrition in the first 48 h in sepsis. Rather, the surgical patients, are not consistent, with great variability evidence is generated predominantly from surgical, burn, in the intervention and control groups; all are of low and trauma patients. None of the meta-analyses reports a methodological quality [418–427] and none was indi- mortality benefit with parenteral nutrition, except one vidually powered for mortality, with very low mortality suggesting parenteral nutrition may be better than late rates [418–420, 423, 426]. Authors of previously pub- introduction of enteral nutrition [442]. Several suggested lished meta-analyses of optimal nutrition strategies for the that parenteral nutrition had higher infectious complica- critically ill all reported that the studies they included had tions compared both to fasting or intravenous glucose and high heterogeneity and low quality [418–430]. Although to enteral nutrition [429, 431, 438, 439, 442]. Enteral no consistent effect on mortality was observed, there was feeding was associated with a higher rate of enteral evidence of benefit from some early enteral feeding on complications (e.g., diarrhea) than parenteral nutrition secondary outcomes, such as reduced incidence of [438]. The use of parenteral nutrition to supplement ent- infectious complications [418, 422, 426, 427–430], eral feeding was also analyzed by Dhaliwal et al. [440], reduced length of mechanical ventilation [421, 427], and who also reported no benefit. The trial by Casaer et al. reduced ICU [421, 427] and hospital stays [428]. No [444] reported that early initiation of parenteral nutrition evidence of harm was demonstrated in any of those led to longer hospital and ICU stays, longer duration of studies. Therefore, there is insufficient evidence to issue a organ support, and higher incidence of ICU-acquired strong recommendation, but the suggestion of benefit and infection. One-fifth of patients had sepsis and there was absence of harm supports a suggestion that some enteral no evidence of heterogeneity in treatment effects across feeding is warranted. subgroups, including the sepsis subjects. Therefore, no Studies comparing full caloric early enteral feeding to studies suggest the superiority of TPN over enteral alone lower targets in the critically ill have produced incon- in the first 24 h. In fact, there is a suggestion that enteral clusive results. In four studies, no effect on mortality was nutrition may in fact be superior to TPN vis a vis infec- seen [431–434]; one reported fewer infectious complica- tious complications and possibly requirement for tions [431], and the others reported increased diarrhea and intensive care and organ support. gastric residuals [433, 434] and increased incidence of Immune system function can be modified through infectious complications with full caloric feeding [432]. alterations in the supply of certain nutrients, such as In another study, mortality was greater with higher arginine, glutamine, or omega-3 fatty acids. Numerous feeding, but differences in feeding strategies were modest studies have assessed whether use of these agents as and the sample size was small [435]. Therefore, evidence nutritional supplements can affect the course of critical is insufficient to support an early target of full caloric illness, but few specifically addressed their early use in intake and, indeed, some possibility of harm exists. sepsis. Four meta-analyses evaluated immune-enhancing Underfeeding (60–70 % of target) or trophic feeding nutrition and found no difference in mortality, neither in (upper limit of 500 kcal) is probably a better nutritional surgical nor medical patients [445–448]. However, they strategy in the first week of severe sepsis/septic shock. analyzed all studies together, regardless of the immuno- This upper limit for trophic feeding is a somewhat arbi- component used, which could have compromised their trary number, but based in part on the fact that the two conclusions. Other individual studies analyzed diets with recent studies used a range of 240–480 kcal [433, 434]. a mix of arginine, glutamine, antioxidants, and/or omega- 3 with negative results [449, 450] including a small study arachidonic acid-derived equivalents, reducing the pro- in septic patients showing a non-significant increase in inflammatory impact on the immune response [452, 453]. ICU mortality [451, 452]. Three early studies were summarized in a meta-analysis Arginine. Arginine availability is reduced in sepsis, that reported a significant mortality reduction, increased which can lead to reduced nitric oxide synthesis, loss of ventilator-free days, and reduced risk of new organ dys- microcirculatory regulation, and enhanced production of function [470]. However, only one study was in septic superoxide and peroxynitrite. However, arginine supple- patients [471], none was individually powered for mor- mentation could lead to unwanted vasodilation and tality [472, 473], and all three used a diet with high hypotension [452, 453]. Human trials of L-arginine sup- omega-6 lipid content in the control group, which is not plementation have generally been small and reported the usual standard of care in the critically ill. The authors variable effects on mortality [454–457]. The only study in who first reported reduced mortality in sepsis [471] con- septic patients showed improved survival, but had limi- ducted a follow-up multicenter study and again found tations in study design [455]. Other studies suggested no improvement in nonmortality outcomes, though notably benefit [449, 454, 455] or possible harm [455] in the with no demonstrable effect on mortality [474]. Other subgroup of septic patients. Some authors found studies using enteral [475–477] or parenteral [478–480] improvement in secondary outcomes in septic patients, fish oil failed to confirm these findings in general critical such as reduced infectious complications [454, 455] and illness or acute lung injury. Thus, no large, reproducible length of hospital stay [454], but the relevance of these findings suggest a clear benefit in the use of immuno- findings in the face of potential harm is unclear. modulating nutritional supplements in sepsis, though Glutamine. Glutamine levels are also reduced during larger trials are ongoing. critical illness. Exogenous supplementation can improve gut mucosal atrophy and permeability, possibly leading to reduced bacterial translocation. Other potential benefits W. Setting goals of care are enhanced immune cell function, decreased pro- inflammatory cytokine production, and higher levels of 1. We recommend that goals of care and prognosis be glutathione and antioxidative capacity [452, 453]. How- discussed with patients and families (grade 1B). ever, the clinical significance of these findings is not 2. We recommend that the goals of care be incorporated clearly established. into treatment and end-of-life care planning, utilizing Although a previous meta-analysis showed mortality palliative care principles where appropriate (grade 1B). reduction [428], four other meta-analyses did not [458– 3. We suggest that goals of care be addressed as early as 462]. Other small studies not included in those meta- feasible, but no later than within 72 h of ICU admission analyses had similar results [463, 464]. Three recent well- (grade 2C). designed studies also failed to show a mortality benefit in the primary analyses [227, 465, 466], but again, none Rationale. The majority of ICU patients receive full focused specifically on septic patients. Two small studies support with aggressive, life-sustaining treatments. Many on septic patients showed no benefit in mortality rates patients with multiple organ system failure or severe neu- [467, 468] but a significant reduction in infectious com- rologic injuries will not survive or will have a poor quality of plications [467] and a faster recovery of organ life. Decisions to provide less-aggressive life-sustaining dysfunction [468]. Some previous individual studies and treatments or to withdraw life-sustaining treatments in these meta-analyses showed positive secondary outcomes, such patients may be in the patient’s best interest and may be what as reduction in infectious morbidity [461, 462, 465] and patients and their families desire [481]. Physicians have organ dysfunction [462]. Beneficial effects were found different end-of-life practices based on their region of mostly in trials using parenteral rather than enteral glu- practice, culture, and religion [482]. Although the outcome tamine. However, recent and well-sized studies could not of intensive care treatment in critically ill patients may be demonstrate a reduction of infectious complications [227] difficult to prognosticate accurately, establishing realistic or organ dysfunction [465, 466], even with parenteral treatment goals is important in promoting patient-centered glutamine. An ongoing trial (REDOXS) of 1,200 patients care in the ICU [483]. Models for structuring initiatives to will test both enteral and parenteral glutamine and anti- enhance care in the ICU highlight the importance of incor- oxidant supplementation in critically ill, mechanically porating goals of care along with the prognosis into ventilated patients [469]. Although no clear benefit could treatment plans [484]. Additionally, discussing the prog- be demonstrated in clinical trials with supplemental glu- nosis for achieving the goals of care and level of certainty of tamine, there is no sign of harm. prognosis has been identified as an important component of The omega-3 fatty acids eicosapentaenoic acid (EPA) surrogate decision-making in the ICU [485, 486]. However, and gamma-linolenic acid (GLA) are eicosanoid precur- variations exist in the use of advanced care planning and sors. The prostaglandins, leukotrienes, and thromboxanes integration of palliative and end-of-life care in the ICU, produced from EPA/GLA are less potent than their which can lead to conflicts that may threaten overall quality of care [487, 488]. The use of proactive family care con- require early intubation; however, during intubation and ferences to identify advanced directives and treatment mechanical ventilation, increased intrathoracic pressure goals within 72 h of ICU admission promotes communi- can reduce venous return and lead to worsening shock if cation and understanding between the patient’s family and the patient is not volume loaded. In those who desaturate the care team; improves family satisfaction; decreases despite administration of face mask oxygen, high-flow stress, anxiety, and depression in surviving relatives; nasal cannula oxygen or nasopharyngeal CPAP can be facilitates end-of-life decision making; and shortens used to increase functional residual capacity and reduce length of stay for patients who die in the ICU [489–494]. the work of breathing, allowing for establishment of Clinical practice guidelines for support of the ICU patient intravenous or intraosseous access for fluid resuscitation and family promote: early and repeated care conferencing and peripheral inotrope delivery [502, 503]. Drugs used to reduce family stress and improve consistency in com- for sedation have important side effects in these patients. munication; open flexible visitation; family presence For example, etomidate is associated with increased during clinical rounds and resuscitation; and attention to mortality in children with meningococcal sepsis because cultural and spiritual support [495]. Additionally, the of adrenal suppression effect [504, 505]. Because integration of advanced care planning and palliative care attainment of central access is more difficult in children focused on pain management, symptom control, and than adults, reliance on peripheral or intraosseous access family support has been shown to improve symptom can be substituted until and unless central access is management and patient comfort, and to improve family available. communication [484, 490, 496].

2. We suggest that the initial therapeutic endpoints of Pediatric considerations in severe sepsis (Table 9) resuscitation of septic shock be capillary refill of B2s, normal blood pressure for age, normal pulses with no While sepsis in children is a major cause of death in differential between peripheral and central pulses, industrialized countries with state-of-the-art ICUs, the warm extremities, urine output [1mLkg-1 h-1, and overall mortality from severe sepsis is much lower than normal mental status. Thereafter, ScvO2 saturation that in adults, estimated at about 2–10 % [497–499]. The greater than or equal to 70 % and cardiac index hospital mortality rate for severe sepsis is 2 % in previ- between 3.3 and 6.0 L min-1 m-2 should be targeted ously healthy children and 8 % in chronically ill children (grade 2C). in the US [497]. Definitions of sepsis, severe sepsis, septic shock, and multiple organ dysfunction/failure syndromes Rationale. Adult guidelines recommend lactate clear- are similar to adult definitions but depend on age-specific ance as well, but children commonly have normal lactate heart rate, respiratory rate, and white blood cell count levels with septic shock. Because of the many modalities cutoff values [500, 501]. This document provides rec- used to measure ScvO and cardiac index, the specific ommendations only for term newborns and children in the 2 choice is left to the practitioner’s discretion [506–512]. industrialized resource-rich setting with full access to mechanical ventilation ICUs. 3. We recommend following the American College of Critical Care Medicine-Pediatric Advanced Life Sup- A. Initial resuscitation port guidelines for the management of septic shock 1. We suggest starting with oxygen administered by face (grade 1C). mask or, if needed and available, high-flow nasal cannula oxygen or nasopharyngeal CPAP for respira- Rationale. The recommended guidelines are summa- tory distress and hypoxemia. Peripheral intravenous rized in Fig. 2 [510–512]. access or intraosseous access can be used for fluid resuscitation and inotrope infusion when a central line is not available. If mechanical ventilation is required, 4. We recommend evaluating for and reversing pneumo- then cardiovascular instability during intubation is less thorax, pericardial tamponade, or endocrine emergencies likely after appropriate cardiovascular resuscitation in patients with refractory shock (grade 1C). (grade 2C). Rationale. Endocrine emergencies include hypoadre- nalism and hypothyroidism. In select patients, intra- Rationale. Due to low functional residual capacity, abdominal hypertension may also need to be considered young infants and neonates with severe sepsis may [513–515]. Table 9 Recommendations: special considerations in pediatrics

A. Initial resuscitation 1. For respiratory distress and hypoxemia start with face mask oxygen or if needed and available, high flow nasal cannula oxygen or nasopharyngeal CPAP (NP CPAP). For improved circulation, peripheral intravenous access or intraosseus access can be used for fluid resuscitation and inotrope infusion when a central line is not available. If mechanical ventilation is required then cardiovascular instability during intubation is less likely after appropriate cardiovascular resuscitation (grade 2C). 2. Initial therapeutic end points of resuscitation of septic shock: capillary refill of B2 s, normal blood pressure for age, normal pulses with no differential -1 -1 between peripheral and central pulses, warm extremities, urine output [1mLkg h , and normal mental status. ScvO2 saturation C70% and cardiac index between 3.3 and 6.0 L/min/m2 should be targeted thereafter (grade 2C). 3. Follow American College of Critical Care Medicine-Pediatric Life Support ( ACCM-PALS) guidelines for the management of septic shock (grade 1C). 4. Evaluate for and reverse pneumothorax, pericardial tamponade, or endocrine emergencies in patients with refractory shock (grade 1C). B. Antibiotics and source control 1. Empiric antibiotics be administered within 1 hr of the identification of severe sepsis. Blood cultures should be obtained before administering antibiotics when possible but this should not delay administration of antibiotics. The empiric drug choice should be changed as epidemic and endemic ecologies dictate (eg H1N1, MRSA, chloroquine resistant malaria, penicillin-resistant pneumococci,recent ICU stay, neutropenia) (grade 1D). 2. Clindamycin and anti-toxin therapies for toxic shock syndromes with refractory hypotension (grade 2D). 3. Early and aggressive source control (grade 1D). 4. Clostridium difficile colitis should be treated with enteral antibiotics if tolerated. Oral vancomycin is preferred for severe disease (grade 1A). C. Fluid resuscitation 1. In the industrialized world with access to inotropes and mechanical ventilation, initial resuscitation of hypovolemic shock begins with infusionof isotonic crystalloids or albumin with boluses of up to 20 mL/kg crystalloids (or albumin equivalent ) over 5–10 minutes, titrated to reversing hypotension, increasing urine output, and attaining normal capillary refill, peripheral pulses, and level of consciousness without inducing hepatomegaly or rales. If hepatomegaly or rales exist then inotropic support should be implemented, not fluid resuscitation. In non-hypotensive children with severe hemolytic anemia (severe malaria or sickle cell crises) blood transfusion is considered superior to crystalloid or albumin bolusing (grade 2C). D. Inotropes/vasopressors/vasodilators 1. Begin peripheral inotropic support until central venous access can be attained in children who are not responsive to fluid resuscitation (grade 2C). 2. Patients with low cardiac output and elevated systemic vascular resistance states with normal blood pressure be given vasodilator therapies in addition to inotropes (grade 2C). E. Extracorporeal membrane oxygenation (ECMO) 1. Consider ECMO for refractory pediatric septic shock and respiratory failure (grade 2C). F. Corticosteroids 1. Timely hydrocortisone therapy in children with fluid refractory, catecholamine resistant shock and suspected or proven absolute (classic) adrenal insufficiency (grade 1 A) . G. Protein C and activated protein concentrate No recommendation as no longer available H. Blood products and plasma therapies 1. Similar hemoglobin targets in children as in adults. During resuscitation of low superior vena cava oxygen saturation shock (\70 %), hemoglobin levels of 10 g/dL are targeted. After stabilization and recovery from shock and hypoxemia then a lower target [7.0 g/dL can be considered reasonable (grade 1B). 2. Similar platelet transfusion targets in children as in adults (grade 2C). 3. Use plasma therapies in children to correct sepsis-induced thrombotic purpura disorders, including progressive disseminated intravascular coagulation, secondary thrombotic microangiopathy, and thrombotic thrombocytopenic purpura (grade 2C). I. Mechanical ventilation 1. Lung-protective strategies during mechanical ventilation (grade 2C). J. Sedation/analgesia/drug toxicities 1. We recommend use of sedation with a sedation goal in critically ill mechanically ventilated patients with sepsis (grade 1D). 2. Monitor drug toxicity labs because drug metabolism is reduced during severe sepsis, putting children at greater risk of adverse drug-related events (grade 1C). K. Glycemic control 1. Control hyperglycemia using a similar target as in adults B180 mg/dL. Glucose infusion should accompany insulin therapy in newborns and children because some hyperglycemic children make no insulin whereas others are insulin resistant (grade 2C). L. Diuretics and renal replacement therapy 1. Use diuretics to reverse fluid overload when shock has resolved, and if unsuccessful then continuous venovenous hemofiltration (CVVH) or intermittent dialysis to prevent [10 % total body weight fluid overload (grade 2C). M. Deep vein thrombosis (DVT) prophylaxis No recommendation on the use of DVT prophylaxis in prepubertal children with severe sepsis. N. Stress ulcer (SU) prophylaxis No recommendation on the use of SU prophylaxis in prepubertal children with severe sepsis O. Nutrition 1. Enteral nutrition given to children who can be fed enterally, and parenteral feeding in those who cannot (grade 2C). Fig. 2 Algorithm for time sensitive, goal-directed stepwise management of hemodynamic support in infants and children. Reproduced from [510]

B. Antibiotics and source control resistant malaria, penicillin-resistant pneumococci, 1. We recommend that empiric antimicrobials be admin- recent ICU stay, neutropenia) (grade 1D). istered within 1 h of the identification of severe sepsis. Blood cultures should be obtained before administering Rationale. Vascular access and blood drawing is antibiotics when possible, but this should not delay ini- more difficult in newborns and children. Antimicro- tiation of antibiotics. The empiric drug choice should be bials can be given intramuscularly or orally (if changed as epidemic and endemic ecologies dictate (e.g., tolerated) until intravenous line access is available H1N1, methicillin-resistant S. aureus, chloroquine- [516–519]. 2. We suggest the use of clindamycin and antitoxin transfusion is considered superior to crystalloid or therapies for toxic shock syndromes with refractory albumin bolusing (grade 2C). hypotension (grade 2D). Rationale. Three RCTs compared the use of colloid to Rationale. Children are more prone to toxic shock than crystalloid resuscitation in children with hypovolemic adults because of their lack of circulating antibodies to dengue shock with near 100 % survival in all treatment toxins. Children with severe sepsis and erythroderma and arms [542–544]. In the industrialized world, two before- suspected toxic shock should be treated with clindamycin and-after studies observed tenfold reductions in mortality to reduce toxin production. The role of IVIG in toxic when children with purpura/meningococcal septic shock shock syndrome is unclear, but it may be considered in were treated with fluid boluses, inotropes, and mechanical refractory toxic shock syndrome [520–527]. ventilation in the community emergency department [545, 546]. In one randomized trial, septic shock mortality was reduced (40–12 %) when increased fluid boluses, blood, and inotropes were given to attain a ScvO monitoring 3. We recommend early and aggressive infection source 2 goal of greater than 70 % [511]. A quality improvement control (grade 1D). study achieved a reduction in severe sepsis mortality (from 4.0 to 2.4 %) with the delivery of fluid boluses and Rationale. De´bridement and source control is para- antibiotics in the first hour in a pediatric emergency mount in severe sepsis and septic shock. Conditions department to reverse clinical signs of shock [547]. requiring de´bridement or drainage include necrotizing Children normally have a lower blood pressure than pneumonia, necrotizing fasciitis, gangrenous myonecro- adults, and a fall in blood pressure can be prevented by sis, empyema, and abscesses. Perforated viscus requires vasoconstriction and increasing heart rate. Therefore, repair and peritoneal washout. Delay in use of an appro- blood pressure alone is not a reliable endpoint for priate antibiotic, inadequate source control, and failure to assessing the adequacy of resuscitation. However, once remove infected devices are associated with increased hypotension occurs, cardiovascular collapse may soon mortality in a synergistic manner [528–538]. follow. Thus, fluid resuscitation is recommended for both normotensive and hypotensive children in hypovolemic shock [542–554]. Because hepatomegaly and/or rales 4. C. difficile colitis should be treated with enteral occur in children who are fluid overloaded, these findings antibiotics if tolerated. Oral vancomycin is preferred can be helpful signs of hypervolemia. In the absence of for severe disease (grade 1A). these signs, large fluid deficits can exist, and initial volume resuscitation can require 40–60 mL/kg or more; Rationale. In adults, metronidazole is a first choice; however, if these signs are present, then fluid adminis- however, response to treatment with C. difficile can be tration should be ceased and diuretics should be given. best with enteral vancomycin. In very severe cases where Inotrope infusions and mechanical ventilation are com- diverting ileostomy or colectomy is performed, parenteral monly required for children with fluid refractory shock. treatment should be considered until clinical improvement is ascertained [539–541]. D. Inotropes/vasopressors/vasodilators 1. We suggest beginning peripheral inotropic support C. Fluid resuscitation until central venous access can be attained in children 1. In the industrialized world with access to inotropes and who are not responsive to fluid resuscitation (grade mechanical ventilation, we suggest that initial resus- 2C). citation of hypovolemic shock begin with infusion of isotonic crystalloids or albumin, with boluses of up to Rationale. Cohort studies show that delay in the use of 20 mL/kg for crystalloids (or albumin equivalent) over inotropic therapies is associated with major increases in 5–10 min. These should be titrated to reversing mortality risk [553, 554]. This delay is often related to hypotension, increasing urine output, and attaining difficulty in attaining central access. In the initial resus- normal capillary refill, peripheral pulses and level of citation phase, inotrope/vasopressor therapy may be consciousness without inducing hepatomegaly or rales. required to sustain perfusion pressure, even when hypo- If hepatomegaly or rales develop, inotropic support volemia has not yet been resolved. Children with severe should be implemented, not fluid resuscitation. In sepsis can present with low cardiac output and high sys- children with severe hemolytic anemia (severe malaria temic vascular resistance, high cardiac output and low or sickle cell crises) who are not hypotensive, blood systemic vascular resistance, or low cardiac output and low systemic vascular resistance shock [555]. A child [574], with one center reporting 74 % survival to hospital may move from one hemodynamic state to another. discharge using central cannulation via sternotomy [575]. Vasopressor or inotrope therapy should be used according ECMO has been used successfully in critically ill H1N1 to the hemodynamic state [555]. Dopamine-refractory pediatric patients with refractory respiratory failure [576, shock may reverse with epinephrine or norepinephrine 577]. infusion. In the case of extremely low systemic vascular resistance despite the use of norepinephrine, the use of vasopressin and terlipressin has been described in a F. Corticosteroids number of case reports, yet evidence to support this in 1. We suggest timely hydrocortisone therapy in children pediatric sepsis, as well as safety data, are still lacking. with fluid-refractory, catecholamine-resistant shock Indeed, two RCTs showed no benefit in outcome with use and suspected or proven absolute (classic) adrenal of vasopressin or terlipressin in children [556–559]. insufficiency (grade 1A). Interestingly, while vasopressin levels are reduced in adults with septic shock, such levels seem to vary extensively in children. When vasopressors are used for Rationale. Approximately 25 % of children with septic refractory hypotension, the addition of inotropes is com- shock have absolute adrenal insufficiency. Patients at risk monly needed to maintain adequate cardiac output [510, for absolute adrenal insufficiency include children with 511, 555]. severe septic shock and purpura, those who have previ- ously received steroid therapies for chronic illness, and children with pituitary or adrenal abnormalities. Initial 2. We suggest that patients with low cardiac output and treatment is hydrocortisone infusion given at stress doses (50 mg/m2/24 h); however, infusions up to 50 mg kg-1 elevated systemic vascular resistance states with -1 normal blood pressure be given vasodilator therapies day may be required to reverse shock in the short term. in addition to inotropes (grade 2C). Death from absolute adrenal insufficiency and septic shock occurs within 8 h of presentation. Obtaining a serum cortisol level at the time empiric hydrocortisone is Rationale. The choice of vasoactive agent is initially administered may be helpful [578–583]. determined by the clinical examination; however, for the child with invasive monitoring in place and demonstration of a persistent low cardiac output state with high systemic G. Protein C and activated protein concentrate vascular resistance and normal blood pressure despite fluid resuscitation and inotropic support, vasodilator See ‘‘History of recommendations regarding use of therapy can reverse shock. Type III phosphodiesterase recombinant activated protein C’’. inhibitors (amrinone, milrinone, enoximone) and the calcium sensitizer levosimendan can be helpful because they overcome receptor desensitization. Other important H. Blood products and plasma therapies vasodilators include nitrosovasodilators, prostacyclin, and fenoldopam. In two RCTs, pentoxifylline reduced mor- 1. We suggest similar hemoglobin targets in children as tality from severe sepsis in newborns [510, 560–569]. in adults. During resuscitation of low superior vena cava oxygen saturation shock (\70 %), hemoglobin levels of 10 g/dL are targeted. After stabilization and recovery from shock and hypoxemia, then a lower target E. Extracorporeal Membrane Oxygenation [7.0 g/dL can be considered reasonable (grade 1B). 1. We suggest ECMO in children with refractory septic shock or with refractory respiratory failure associated Rationale. The optimal hemoglobin for a critically ill with sepsis (grade 2C). child with severe sepsis is not known. A recent multi- center trial reported no difference in mortality in Rationale. ECMO may be used to support children and hemodynamically stable critically ill children managed neonates with septic shock or sepsis-associated respira- with a transfusion threshold of 7 g/dL compared with tory failure [570, 571]. The survival of septic patients those managed with a transfusion threshold of 9.5 g/dL; supported with ECMO is 73 % for newborns and 39 % however, the severe sepsis subgroup had an increase in for older children, and is highest in those receiving nosocomial sepsis and lacked clear evidence of equiva- venovenous ECMO [572]. Forty-one percent of children lence in outcomes with the restrictive strategy [584, 585]. with a diagnosis of sepsis requiring ECMO for respiratory Blood transfusion is recommended by the World Health failure survive to hospital discharge [573]. Venoarterial Organization for severe anemia, hemoglobin value \5g/ ECMO is useful in children with refractory septic shock dL, and acidosis. A RCT of early goal-directed therapy for pediatric septic shock using the threshold hemoglobin of Rationale. Although there are no data supporting any 10 g/dL for patients with a SvcO2 saturation less than 70 % in particular drugs or regimens, propofol should not be used the first 72 h of pediatric ICU admission showed improved for long-term sedation in children younger than 3 years survival in the multimodal intervention arm [511]. because of the reported association with fatal metabolic acidosis. The use of etomidate and/or dexmedetomidine during septic shock should be discouraged, or at least 2. We suggest similar platelet transfusion targets in considered carefully, because these drugs inhibit the children as in adults (grade 2C). adrenal axis and the sympathetic nervous system, 3. We suggest the use of plasma therapies in children to respectively, both of which are needed for hemodynamic correct sepsis-induced thrombotic purpura disorders, stability [617–620]. including progressive disseminated intravascular coag- ulation, secondary thrombotic microangiopathy, and thrombotic thrombocytopenic purpura (grade 2C). 2. We recommend monitoring drug toxicity labs because drug metabolism is reduced during severe sepsis, Rationale. We give plasma to reverse thrombotic micro- putting children at greater risk of adverse drug-related angiopathies in children with thrombocytopenia-associated events (grade 1C). multiple organ failure and progressive purpura because fresh frozen plasma contains protein C, antithrombin III, Rationale. Children with severe sepsis have reduced and other anticoagulant proteins. Rapid resuscitation of drug metabolism [621]. shock reverses most disseminated intravascular coagula- tion; however, purpura progresses in some children in part due to critical consumption of antithrombotic proteins (e.g., K. Glycemic control protein C, antithrombin III, ADAMTS 13). Plasma is 1. We suggest controlling hyperglycemia using a similar infused with the goal of correcting prolonged prothrombin/ target as in adults (B180 mg/dL). Glucose infusion partial thromboplastin times and halting purpura. Large should accompany insulin therapy in newborns and volumes of plasma require concomitant use of diuretics, children (grade 2C). continuous renal replacement therapy, or plasma exchange to prevent greater than 10 % fluid overload [586–611]. Rationale. In general, infants are at risk for developing hypoglycemia when they depend on intravenous fluids. -1 -1 I. Mechanical ventilation This means that a glucose intake of 4–6 mg kg min or maintenance fluid intake with dextrose 10 % normal 1. We suggest providing lung-protective strategies during saline containing solution is advised (6–8 mg kg-1 min-1 mechanical ventilation (grade 2C). in newborns). Associations have been reported between hyperglycemia and an increased risk of death and longer Rationale. Some patients with ARDS will require length of stay. A retrospective pediatric ICU study increased PEEP to attain functional residual capacity and reported associations of hyperglycemia, hypoglycemia, maintain oxygenation, and peak pressures above and glucose variability with increased length of stay and 30–35 cmH2O to attain effective tidal volumes of 6–8 mL/kg mortality rates. An RCT of strict glycemic control com- with adequate CO2 removal. In these patients, physicians pared to moderate control using insulin in a pediatric ICU generally transition from conventional pressure control ven- population found a reduction in mortality with an increase tilation to pressure release ventilation (airway pressure release in hypoglycemia. Insulin therapy should only be con- ventilation) or to high-frequency oscillatory ventilation. ducted with frequent glucose monitoring in view of the These modes maintain oxygenation with higher mean airway risks for hypoglycemia which can be greater in newborns pressures using an ‘‘open’’ lung ventilation strategy. To be and children due to a) relative lack of glycogen stores and effective, these modes can require a mean airway pressure muscle mass for gluconeogenesis, and b) the heteroge- 5cmH2O higher than that used with conventional ventilation. neity of the population with some excreting no This can reduce venous return leading to greater need for fluid endogenous insulin and others demonstrating high insulin resuscitation and vasopressor requirements [612–616]. levels and insulin resistance [622–628].

J. Sedation/analgesia/drug toxicities L. Diuretics and renal replacement therapy 1. We recommend use of sedation with a sedation goal in 1. We suggest the use of diuretics to reverse fluid over- critically ill mechanically ventilated patients with sepsis load when shock has resolved and if unsuccessful, then (grade 1D). continuous venovenous hemofiltration or intermittent dialysis to prevent greater than 10 % total body weight Summary and future directions fluid overload (grade 2C). Although this document is static, the optimum treatment Rationale. A retrospective study of children with of severe sepsis and septic shock is a dynamic and meningococcemia showed an associated mortality risk evolving process. Additional evidence that has appeared when children received too little or too much fluid since the publication of the 2008 guidelines allows more resuscitation [549, 553]. A retrospective study of 113 certainty with which we make severe sepsis recommen- critically ill children with multiple-organ dysfunction dations; however, further programmatic clinical research syndrome reported that patients with less fluid overload in sepsis is essential to optimize these evidence-based before continuous venovenous hemofiltration had better medicine recommendations. survival [629–631], New interventions will be proven and established interventions may need modification. This publication represents an ongoing process. The SSC and the con- sensus committee members are committed to updating the M. DVT prophylaxis guidelines regularly as new interventions are tested and 1. We make no graded recommendations on the use of results published. DVT prophylaxis in prepubertal children with severe sepsis. Acknowledgments The revision process was funded through a grant from the Gordon and Betty Irene Moore Foundation. We would also like to acknowledge the dedication and untold hours of Rationale. Most DVTs in young children are associated donated time of committee members over the last 2 years; the with central venous catheters. Heparin-bonded catheters sponsoring organizations that worked with us toward the reality of a consensus document across so many disciplines, specialties, and may decrease the risk of catheter-associated DVT. No continents; and those that contribute in so many ways to create the data exist on the efficacy of UFH or LMWH prophylaxis new science to move us forward in treating this potentially dev- to prevent catheter-related DVT in children in the ICU astating disease: the funders of research, the investigators, the [632, 633]. subjects, and those associated with the evidence publishing bodies. Finally, we thank Deborah McBride for the incredible editorial support provided persistently over months that brought the manu- script to life and finalization.

N. Stress ulcer prophylaxis Conflicts of interest Dr. Dellinger consulted for Biotest (immu- 1. We make no graded recommendations on stress ulcer noglobulin concentrate available in Europe for potential use in sepsis) and AstraZeneca (anti-TNF compound unsuccessful in prophylaxis. recently completed sepsis clinical trial); his institution received consulting income from IKARIA for new product development Rationale. Studies have shown that clinically important (IKARIA has inhaled nitric oxide available for off-label use in ARDS) and grant support from Spectral Diagnostics Inc (current GI bleeding in children occurs at rates similar to those of endotoxin removal clinical trial), Ferring (vasopressin analog adults. Stress ulcer prophylaxis is commonly used in clinical trial-ongoing), as well as serving on speakers bureau for children who are mechanically ventilated, usually with H2 Eisai (anti-endotoxin compound that failed to show benefit in blockers or proton pump inhibitors, although Its effect is clinical trial). Dr. Levy received grant support from Eisai (Ocean State Clinical Coordinating Center to fund clinical trial [$500 K]), not known [634, 635]. he received honoraria from Eli Lilly (lectures in India $8,000), and he has been involved with the Surviving Sepsis Campaign guideline from its beginning. Dr. Rhodes consulted for Eli Lilly with mon- O. Nutrition etary compensation paid to himself as well as his institution (Steering Committee for the PROWESS Shock trial) and LiDCO; 1. Enteral nutrition should be used in children who can travel/accommodation reimbursement was received from Eli Lilly tolerate it, parenteral feeding in those who cannot and LiDCO; he received income for participation in review activ- ities such as data monitoring boards, statistical analysis from Orion, (grade 2C). and for Eli Lilly; he is an author on manuscripts describing early goal-directed therapy, and believes in the concept of minimally Rationale. Dextrose 10 % (always with sodium-con- invasive hemodynamic monitoring. Dr. Annane participated on the Fresenius Kabi International Advisory Board (honorarium 2000€). taining solution in children) at maintenance rate provides His nonfinancial disclosures include being the principal investigator the glucose delivery requirements for newborns and of a completed investigator-led multicenter randomized controlled children [636]. Patients with sepsis have increased glu- trial assessing the early guided benefit to risk of NIRS tissue cose delivery needs which can be met by this regimen. oxygen saturation; he was the principal investigator of an investi- Specific measurement of caloric requirements are thought gator-led randomized controlled trial of epinephrine versus norepinephrine (CATS study)–Lancet 2007; he also is the principle to be best attained using a metabolic cart as they are investigator of an ongoing investigator-led multinational random- generally less in the critically ill child than in the healthy ized controlled trial of crystalloids versus colloids (Crystal Study). child. Dr. Gerlach disclosed that he has no potential conflicts of interest; he is an author of a review on the use of activated protein C in government funded (nonindustry) grant. Grant awarded to chief surgical patients (published in the New England Journal of Medi- investigator from ICNARC. She is a trial clinician for ProMISe. Dr. cine, 2009). Dr. Opal consulted for Genzyme Transgenics Nunnally received a stipend for a chapter on diabetes mellitus; he is (consultant on transgenic antithrombin $1,000), Pfizer (consultant an author of editorials contesting classic tight glucose control. Dr. on TLR4 inhibitor project $3,000), British Therapeutics (consultant Townsend is an advocate for healthcare quality improvement. Dr. on polyclonal antibody project $1,000), and Biotest A (consultant Reinhart consulted for EISAI (Steering Committee member—less on immunoglobin project $2,000). His institution received grant then US $10,000); BRAHMS Diagnostics (less than US $10,000); support from Novartis (Clinical Coordinating Center to assist in and SIRS-Lab Jena (founding member, less than US $10,000). He patient enrollment in a phase III trial with the use of Tissue Factor received honararia for lectures including service on the speakers’ Pathway Inhibitor (TFPI) in severe community acquired pneumonia bureau from Biosyn Germany (less than €10,000) and Braun (SCAP) $30,000 for 2 years), Eisai ($30,000 for 3 years), Astra Melsungen (less than €10,000). He received royalties from Edwards Zeneca ($30,000 for 1 year), Aggenix ($30,000 for 1 year), Inimex Life Sciences for sales of central venous oxygen catheters ($10,000), Eisai ($10,000), Atoxbio ($10,000), Wyeth ($20,000), (*$100,000). Dr. Kleinpell received monetary compensation for Sirtris (preclinical research $50,000), and Cellular Bioengineering providing expert testimony (four depositions and one trial in the Inc. ($500). He received honoraria from Novartis (clinical evalua- past year). Her institution receives grants from the Agency for tion committee TFPI study for SCAP $20,000) and Eisai ($25,000). Healthcare Research and Quality and the Prince Foundation (4-year He received travel/accommodations reimbursed from Sangart (data R01 grant, PI and 3-year foundation grant, Co-l). She received and safety monitoring $2,000), Spectral Diagnostics (data and honoraria from the Cleveland Clinic and the American Association safety monitoring $2,000), Takeda (data and safety monitoring of Critical Care Nurses for keynote speeches at conferences; she $2,000) and Canadian trials group ROS II oseltamivir study (data received royalties from McGraw Hill (co-editor of critical care and safety monitoring board (no money). He is also on the Data review book); travel/accommodations reimbursed from the Amer- Safety Monitoring Board for Tetraphase (received US $600 in ican Academy of Nurse Practitioners, Society of Critical Care 2012). Dr. Sevransky received grant support to his institution from Medicine, and American Association of Critical Care Nurses (one Sirius Genomics Inc; he consulted for Idaho Technology ($1,500); night hotel coverage at national conference). Dr. Angus consulted he is the co-principal investigator of a multicenter study evaluating for Eli Lilly (member of the Data Safety Monitoring Board, Mul- the association between ICU organizational and structural factors, ticenter trial of a PC for septic shock), Eisai Inc (Anti-TLR4 including protocols and in-patient mortality. He maintains that therapy for severe sepsis), and Idaho Technology (sepsis bio- protocols serve as useful reminders to busy clinicians to consider markers); he received grant support (investigator, long-term follow- certain therapies in patients with sepsis or other life threatening up of phase III trial of an anti-TLR4 agent in severe sepsis), a illness. Dr. Sprung received grants paid to his institution from consulting income (anti-TRL4 therapy for severe sepsis), and tra- Artisan Pharma ($25,000–$50,000), Eisai, Corp ($1,000-$5,000 vel/accommodation expense reimbursement from Eisai, Inc; he is ACCESS), Ferring Pharmaceuticals A/S ($5,000–$10,000), the primary investigator for an ongoing National Institutes of Hutchinson Technology Incorporated ($1,000-$5,000), Novartis Health-funded study comparing early resuscitation strategies for Corp (less than $1,000). His institution receives grant support for sepsis induced tissue hypoperfusion. Dr. Deutschman has nonfi- patients enrolled in clinical studies from Eisai Corporation (PI. nancial involvement as a coauthor of the Society of Critical Care Patients enrolled in the ACCESS study $50,000–$100,000), Takeda Medicine’s Glycemic Control guidelines. Dr. Machado reports (PI. Study terminated before patients enrolled). He received grants unrestricted grant support paid to her institution for Surviving paid to his institution and consulting income from Artisan Pharma/ Sepsis Campaign implementation in Brazil (Eli Lilly do Brasil); she Asahi Kasei Pharma America Corp ($25,000–$50,000). He con- is the primary investigator for an ongoing study involving vaso- sulted for Eli Lilly (Sabbatical Consulting fee $10,000–$25,000) pressin. Dr. Rubenfeld received grant support from nonprofit and received honoraria from Eli Lilly (lecture $1,000–$5,000). He agencies or foundations including National Institutes of Health ($10 is a member of the Australia and New Zealand Intensive Care million), Robert Wood Johnson Foundation ($500,000), and CIHR Society Clinical Trials Group for the NICE SUGAR Study (no ($200,000). His institution received grants from for-profit compa- money received); he is a council member of the International Sepsis nies including Advanced Lifeline System ($150,000), Siemens Forum (as of Oct. 2010); he has held long time research interests in ($50,000), Bayer ($10,000), Byk Gulden ($15,000), AstraZeneca steroids in sepsis, PI of Corticus study, end-of-life decision making ($10,000), Faron Pharmaceuticals ($5,000), and Cerus Corporation and PI of Ethicus, Ethicatt, and Welpicus studies. Dr. Douglas ($11,000). He received honoraria, consulting fees, editorship, roy- received grants paid to his institution from Eli Lilly (PROWESS alties, and Data and Safety Monitoring Board membership fees paid Shock site), Eisai (study site), National Institutes of Health (ARDS to him from Bayer ($500), DHD ($1,000), Eli Lilly ($5,000), Network), Accelr8 (VAP diagnostics), CCCTG (Oscillate Study), Oxford University Press ($10,000), Hospira ($15,000), Cerner and Hospira (Dexmedetomidine in Alcohol Withdrawal RCT). His ($5,000), Pfizer ($1,000), KCI ($7,500), American Association for institution received an honorarium from the Society of Critical Care Respiratory Care ($10,000), American Thoracic Society ($7,500), Medicine (Paragon ICU Improvement); he consulted for Eli Lilly BioMed Central ($1,000), National Institutes of Health ($1,500), (PROWESS Shock SC and Sepsis Genomics Study) in accordance and the Alberta Heritage Foundation for Medical Research ($250). with institutional policy; he received payment for providing expert He has database access or other intellectual (non-financial) support testimony (Smith Moore Leatherwood LLP); travel/accommoda- from Cerner. Dr. Webb consulted for AstraZeneca (anti-infectives tions reimbursed by Eli Lilly and Company (PROWESS Shock $1,000–$5,000) and Jansen-Cilag (ani-infectives $1,000-$5,000). Steering Committee) and the Society of Critical Care Medicine He received grant support from a NHMRC project grant (ARISE (Hospital Quality Alliance, Washington DC, four times per year RECT of EGDT); NHMRC project grant and Fresinius-unrestricted 2009–2011); he received honoraria from Covidien (non-CME lec- grant (CHEST RCT of voluven vs saline); RCT of steroid versus ture 2010, US$500) and the University of Minnesota Center for placebo for septic shock); NHMRC project grant (BLISS study of Excellence in Critical Care CME program (2009, 2010); he has a bacteria detection by PRC in septic shock) Intensive Care Foun- pending patent for a bed backrest elevation monitor. Dr. Jaeschke dation-ANZ (BLING pilot RCT of betalactam administration by disclosed that he has no potential conflicts of interest. Dr. Osborn infusion); Hospira (SPICE programme of sedation delirium consulted for Sui Generis Health ($200). Her institution receives research); NHMRC Centres for Research Excellent Grant (critical grant support from the National Institutes of Health Research, illness microbiology observational studies); Hospira-unrestricted Health Technology Assessment Programme-United Kingdom (trial grant (DAHlia RCT of dexmedetomidine for agitated delirium). doctor for sepsis related RCT). Salary paid through the NIHR Travel/accommodations reimbursed by Jansen-Cilag ($5,000– $10,000) and AstraZeneca ($1,000–$5,000); he has a patent for a Paolo Biban,3 Julian F. Bion, Thierry Calandra, Joseph A. meningococcal vaccine. He is chair of the ANZICS Clinical Trials Carcillo, Terry P. Clemmer, Clifford S. Deutschman, J.V. Group and is an investigator in trials of EGDT, PCR for deter- Divatia,4 Ivor S. Douglas, Bin Du,5 Seitaro Fujishima, mining bacterial load and a steroid in the septic shock trial. Dr. 6 Beale received compensation for his participation as board member Satoshi Gando, Herwig Gerlach, Caryl Goodyear- for Eisai, Inc, Applied Physiology, bioMe´rieux, Covidien, SIRS- Bruch,7 Gordon Guyatt, Jan A. Hazelzet, Hiroyuki Lab, and Novartis; consulting income was paid to his institution Hirasawa,8 Steven M. Hollenberg, Judith Jacobi, Roman from PriceSpective Ltd, Easton Associates (soluble guanylate Jaeschke, Ian Jenkins,9 Edgar Jimenez,10 Alan E. Jones,11 cyclase activator in acute respiratory distress syndrome/acute lung 12 injury adjunct therapy to supportive care and ventilation strategies), Robert M. Kacmarek, Winfried Kern, Ruth M. Eisai (eritoran), and Phillips (Respironics); he provided expert Kleinpell,1 Shin Ok Koh,13 Joji Kotani, Mitchell Levy,14 testimony for Eli Lilly and Company (paid to his institution); Flavia Machado,15 John Marini, John C. Marshall, Henry honoraria received (paid to his institution) from Applied Physiol- Masur, Sangeeta Mehta, John Muscedere,16 Lena M. ogy (Applied Physiology PL SAB, Applied Physiology SAB, 17 18 Brussels, Satellite Symposium at the ISICEM, Brussels), bio- Napolitano, Mark E. Nunnally, Steven M. Opal, Tif- 19 Me´rieux (GeneXpert Focus Group, France), SIRS-Lab (SIRS-LAB fany M. Osborn, Margaret M. Parker, Joseph E. SAB Forum, Brussels and SIRS-LAB SAB, Lisbon), Eli Lilly Parrrillo, Haibo Qiu,20 Adrienne G. Randolph, Konrad (CHMP Hearing), Eisai (eritoran through leader touch plan in Reinhart,21 Jordi Rello, Ederlon Resende,22 Andrew Brussels), Eli Lilly (Lunchtime Symposium, Vienna), Covidien 23 24 (adult monitoring advisory board meeting, Frankfurt), Covidien Rhodes, Emanuel P. Rivers, Gordon D. Rubenfeld, (Global Advisory Board CNIBP Boulder USA), Eli Lilly and Christa A. Schorr, Jonathan E. Sevransky, Khalid Shu- Company (development of educational presentations including kri,25 Eliezer Silva, Mark D. Soth, Charles L. Sprung, service on speaker’ bureaus (intensive care school hosted in Ann E. Thompson,26 Sean R. Townsend, Jeffery S. department); travel/accommodations were reimbursed from bio- Vender,27 Jean-Louis Vincent, Steve A. Webb,28 Tobias Merieux (GeneXpert Focus Group, France) and LiDCO (Winter 29 Anaesthetic and Critical Care Review Conference), Surviving Welte, Janice L. Zimmerman. Sepsis Campaign (Publications Meeting, New York; Care Bundles 1World Federation of Critical Care Nurses; 2Emirates Conference, Manchester), SSC Publication Committee Meeting and Intensive Care Society; 3European Society of Pediatric SSC Executive Committee Meeting, Nashville; SSC Meeting, and Neonatal Intensive Care; 4Indian Society of Critical Manchester), Novartis (Advisory Board Meeting, Zurich), Institute 5 of Biomedical Engineering (Hospital of the Future Grand Chal- Care Medicine; Chinese Society of Critical Care Medi- 6 lenge Kick-Off Meeting, Hospital of the Future Grand Challenge cine; Japanese Association for Acute Medicine; Interviews EPSRC Headquarters, Swindon, Philips (Kick-Off 7American Association of Critical-Care Nurses, 8Japanese Meeting, Boeblingen, Germany; MET Conference, Cohenhagen), Society of Intensive Care Medicine; 9Society of Hospital Covidien (Adult Monitoring Advisory Board Meeting, Frankfurt), Medicine; 10World Federation of Societies of Intensive Eisai (ACCESS Investigators Meeting, Barcelona). His non-finan- 11 cial disclosures include authorship of the position statement on fluid and Critical Care Medicine; Society of Academic resuscitation from the ESICM task force on colloids (yet to be Emergency Medicine; 12European Society of Clinical finalized). Dr. Vincent reports consulting income paid to his insti- Microbiology and Infectious Diseases; 13Asia Pacific tution from Astellas, AstraZeneca, Curacyte, Eli Lilly, Eisai, Association of Critical Care Medicine; 14Society of Ferring, GlaxoSmithKline, Merck, and Pfizer. His institution 15 received honoraria on his behalf from Astellas, AstraZeneca, Cu- Critical Care Medicine; Latin American Sepsis Insti- racyte, Eli Lilly, Eisai, Ferring, Merck, and Pfizer. His institution tute; 16Canadian Critical Care Society; 17Surgical received grant support from Astellas, Curacyte, Eli Lilly, Eisai, Infection Society; 18Infectious Diseases Society of Ferring, and Pfizer. His institution received payment for educa- America; 19American College of Emergency Physicians; tional presentations from Astellas, AstraZeneca, Curacyte, Eli 20 Lilly, Eisai, Ferring, Merck, and Pfizer. Dr. Moreno consulted for Chinese Society of Critical Care-China Medical Asso- 21 22 bioMerieux (expert meeting). He is a coauthor of a paper on cor- ciation; German Sepsis Society; Brazilian Society of ticosteroids in patients with septic shock. He is the author of several Critical Care (AMIB); 23European Society of Intensive manuscripts defining sepsis and stratification of the patient with Care Medicine; 24American Thoracic Society; 25Interna- sepsis. He is also the author of several manuscripts contesting the tional Pan Arab Critical Care Medicine Society; utility of sepsis bundles. Complete author and committee disclo- 26 sures are listed in Supplemental Digital Content 1. Pediatric Acute Lung Injury and Sepsis Investigators; 27American College of Chest Physicians; 28Australian and New Zealand Intensive Care Society; 29European Respi- ratory Society; World Federation of Pediatric Intensive and Critical Care Societies. Appendix 1 2012 Surviving Sepsis Campaign Guidelines Pediatric Subgroup Committee Jan A. Hazelzet, Adrienne G. Randolph, Margaret M. R. Phillip Dellinger, (Co-Chair); Rui Moreno (Co-Chair); Parker, Ann E. Thompson, Paolo Biban, Alan Duncan, Leanne Aitken,1 Hussain Al Rahma,2 Derek C. Angus, Cristina Mangia, Niranjan Kissoon, and Joseph A. Car- Dijillali Annane, Richard J. Beale, Gordon R. Bernard, cillo (Head). Appendix 2 Conflict of interest process Appendix 3

ARDSnet ventilator management

Assist control mode—volume ventilation Reduce tidal volume to 6 mL/kg lean body weight Keep plateau pressure \30 cmH2O Reduce tidal volume as low as 4 mL/kg predicted body weight to limit plateau pressure Maintain SaO2/SpO2 between 88 and 95 % Anticipated PEEP settings at various Fio2 requirements FIo2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0 PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 20–24 Predicted body weight calculation Male—50 ? 2.3 [height (in.) - 60] or 50 ? 0.91 [height (cm) - 152.4] Female—45.5 ? 2.3 [height (in.) - 60] or 45.5 ? 0.91 [height (cm) - 152.4] Adapted from [234] Sao2 arterial oxygen saturation, PEEP positive end-expiratory pressure, Spo2 oxygen saturation on pulse oximetry

Appendix 4

Summary of ventilator procedures in the higher-PEEP groups of the ALVEOLI Trial

Procedure Value

Ventilator mode Volume assist/control Tidal-volume goal 6 mL/kg of predicted body weight Plateau-pressure goal B30 cmH2O Ventilator rate and pH 6–35, adjusted to achieve arterial pH C7.30 if possible goal Inspiration:expiration 1:1–1:3 time Oxygenation goal PaO2 55–80 mmHg SpO2 88–95 % Weaning Weaning attempted by means of pressure support when level of arterial oxygenation acceptable with PEEP \8 cmH2O and FiO2 \0.40 a Allowable combinations of PEEP and FiO2 Higher-PEEP group (after protocol changed to use higher levels of PEEP) FiO2 0.3 0.3 0.4 0.4 0.5 0.5 0.5–0.8 0.8 0.9 1 PEEP 12 14 14 16 16 18 20 22 22 22–24

Complete ventilator procedures and eligibility criteria can be found a In both study groups (lower and higher PEEP), additional at ‘‘http://www.ardsnet.org’’ increases in PEEP to 34 cm H2O were allowed but not required O Sp 2 oxyhemoglobin saturation as measured by pulse oximetry, after Fio2 had been increased to 1.0, according to the protocol FIO2 fraction of inspired oxygen, PEEP positive end-expiratory Adapted from [257] pressure References

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