CADTH RAPID RESPONSE REPORT: SUMMARY OF ABSTRACTS Perioperative Use of NSAIDs: Safety and Guidelines

Service Line: Rapid Response Service Version: 1.0 Publication Date: April 5, 2018 Report Length: 19 Pages

Authors: Casey Gray, Charlene Argaez

Cite As: Perioperativ e use of NSAIDs: saf ety and guidelines. Ottawa: CADTH; 2018 Apr. (CADTH rapid response report: summary of abstracts).

Acknowledgments:

Disclaimer: The inf ormation in this document is intended to help Canadian health care decision-makers, health care prof essionals, health sy stems leaders, and policy -makers make well-inf ormed decisions and thereby improv e the quality of health care serv ices. While patients and others may access this document, the document is made av ailable f or inf ormational purposes only and no representations or warranties are made with respect to its f itness f or any particular purpose. The inf ormation in this document should not be used as a substitute f or prof essional medical adv ice or as a substitute f or the application of clinical judgment in respect of the care of a particular patient or other prof essional judgment in any decision-making process. The Canadian Agency f or Drugs and Technologies in Health (CADTH) does not endorse any inf ormation, drugs, therapies, treatments, products, processes, or serv ic es.

While care has been taken to ensure that the inf ormation prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was f irst published by CADTH, CADTH does not make any guarantees to that ef f ect. CADTH does not guarantee and is not responsible f or the quality , currency , propriety , accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. The v iews and opinions of third parties published in this document do not necessarily state or ref lect those of CADTH.

CADTH is not responsible f or any errors, omissions, injury , loss, or damage arising f rom or relating to the use (or misuse) of any inf ormation, statements, or conclusions contained in or implied by the contents of this document or any of the source materials.

This document may contain links to third-party websites. CADTH does not hav e control ov er the content of such sites. Use of third-party sites is gov erned by the third-party website owners’ own terms and conditions set out f or such sites. CADTH does not make any guarantee with respect to any inf ormation contained on such third-party sites and CADTH is not responsible f or any injury , loss, or damage suf f ered as a result of using such third-party sites. CADTH has no responsibility f or the collection, use, and disclosure of personal inf ormation by third-party sites.

Subject to the af orementioned limitations, the v iews expressed herein are those of CADTH and do not necessarily represent the v iews of Canada’s f ederal, prov incial, or territorial gov ernments or any third party supplier of inf ormation.

This document is prepared and intended f or use in the context of the Canadian health care sy stem. The use of this document outside of Canada is done so at the user’s own risk.

This disclaimer and any questions or matters of any nature arising f rom or relating to the content or use (or misuse) of this document will be gov erned by and interpreted in accordance with the laws of the Prov ince of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusiv e jurisdiction of the courts of the Prov ince of Ontario, Canada.

The copy right and other intellectual property rights in this document are owned by CADTH and its licensors. These rights are protected by the Canadian Copyright Act and other national and international laws and agreements. Users are permitted to make copies of this document f or non-commercial purposes only , prov ided it is not modif ied when reproduced and appropriate credit is giv en to CADTH and its licensors.

About CADTH: CADTH is an independent, not-f or-prof it organization responsible f or prov iding Canada’s health care decision-makers with objectiv e ev idence to help make inf ormed decisions about the optimal use of drugs, medical dev ices, diagnostics, and procedures in our health care sy stem.

Funding: CADTH receiv es f unding f rom Canada’s f ederal, prov incial, and territorial gov ernments, with the exception of Quebec.

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 2

Research Questions

1. What is the clinical evidence regarding the safety and harms of the perioperative use of nonsteroidal anti-inflammatory drugs (NSAIDs)?

2. What are the evidence-based guidelines regarding the perioperative use of NSAIDs?

Key Findings

Eight systematic reviews (six with meta-analyses), six randomized controlled trials, 21 non- randomized studies, and three evidence-based guidelines were identified regarding the perioperative use of NSAIDs.

Methods

A limited literature search was conducted on key resources including PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination (CRD) databases and a focused Internet search. No methodological filters were applied to limit the retrieval by study type. The search was limited to English language documents published between January 1, 2013 and March 21, 2018. Internet links were provided, where available.

Selection Criteria

One reviewer screened citations and selected studies based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria

Population Patients (all ages) undergoing surgery

Intervention Nonsteroidal anti-inflammatory drugs (NSAIDs)

Comparator Q1: No treatment with NSAIDs, standard therapy. Q2: No comparator

Outcomes Q1: Safety and harms (e.g., adverse events, anastomotic leak rate, post-operative bleeding) Q2: Evidence-based guidelines

Study Designs Health technology assessments, systematic reviews, meta-analysis, randomized controlled trials, non- randomized studies, evidence-based guidelines

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 3

Results

Rapid Response reports are organized so that the higher quality evidence is presented first. Therefore, health technology assessment reports, systematic reviews, and meta-analyses are presented first. These are followed by randomized controlled trials, non-randomized studies, and evidence-based guidelines.

Eight systematic reviews (six with meta-analyses), six randomized controlled trials, 21 non- randomized studies, and three evidence-based guidelines were identified regarding the perioperative use of NSAIDs. No relevant health technology assessments were identified.

Additional references of potential interest are provided in the appendix.

Overall Summary of Findings

Eight systematic reviews 1-8 (six with meta-analyses),2-6,8 six randomized controlled trials,9-13 and 21 non-randomized studies14-34 were identified regarding the perioperative use of NSAIDs. Detailed study characteristics are provided in Table 2.

Five studies were identified regarding perioperative NSAID use and anastomotic leaks. One systematic review showed an increased risk with non-selective NSAIDs and no increased risk with selective NSAIDs,4 and one systematic review was inconclusive.1 Three non- randomized studies reported no difference in anastomotic leaks between NSAID administration and their comparison groups.14-16

Eight studies with divergent results were identified regarding perioperative NSAID use and bleeding. Four systematic reviews,2-3,7-8 one randomized controlled trial,13 and three non- randomized studies18,21-22 showed no relationship between NSAID administration and postoperative bleeding. The authors of two systematic reviews5-6 and one non-randomized study17 observed that NSAID use was associated with postoperative bleeding.

One systematic review6 and five randomized controlled trials 9-13 showed that perioperative NSAID use was not associated with a higher incidence of adverse events compared with controls. Non-randomized studies reported divergent findings; seven studies20,22-23,25-26,30,32 showed NSAIDs were well tolerated, did not result in adverse events, or resulted in fewer adverse events when compared to the comparison group, while seven studies21,24,27-29,31,33 showed that NSAIDs were associated with serious or non-serious adverse events.

Three evidence-based guidelines35-37 were identified regarding the perioperative use of NSAIDs. In the clinical practice guidelines for enhanced recovery after colon and rectal surgery, the American Society of Colon and Rectal Surgeons and Society of American Gastrointestinal and Endoscopic Surgeons indicates that there is increased risk of anastomotic leakage associated with NSAID use after surgery.35 The Institute for Clinical Systems Improvement (ICSI) included a recommendation to discontinue the use of NSAIDs preoperatively in their Perioperative protocol and Health care protocol.36 The National Institute for Health and Care Excellence (NICE) guideline on prevention, detection, and management of acute kidney injury indicated that there is increased risk of acute kidney injury in adults with use of NSAIDs after surgery.37

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 4

Table 2: Summary of Included Studies on the Perioperative use of Nonsteroidal Anti- Inflammatory Drugs (NSAIDs)

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions Systematic Reviews and Meta-Analyses Cata, 20171  NR  GI cancer  Anastomotic NR The literature is not Leaks conclusive on whether the use of NSAIDs is associated with anastomotic leaks after gastrointestinal cancer surgery

Teerawattananon,  COX-2  NR  Postoperative No increased risk of Perioperative, single 20172 inhibitors bleeding postoperative dose, or short course of (celecoxib,  Intraoperative bleeding events, COX-2 inhibitors can be parecoxib, or blood loss intraoperative blood safely used in etoricoxib)  Postoperative loss, or individuals who are blood loss postoperative blood undergoing surgery loss

Kelley, 20163  Ibuprofen  Soft tissue  Postoperative No differences in Ibuprofen is a safe plastics bleeding bleeding events postoperative analgesic between ibuprofen in patients undergoing and comparator common plastic surgery soft-tissue procedures

Peng, 20164  Selective and  GI  Anastomotic  Overall, NSAIDs The meta-analysis non-selective leak increased suggested that NSAIDs incidence of postoperative NSAIDs, anastomotic leak especially nonselective  Non-selective NSAIDs, could increase NSAIDs (but not the incidence of selective NSAIDs) anastomotic leaks increased the incidence of anastomotic leak compared with other analgesic control

Chan, 20145  Ketorolac  Tonsillectomy  Hemorrhage Adults, but not Ketorolac can be used children, have an safely in children, but is increased risk of associated with a five- post-surgical fold increased risk of hemorrhage with bleeding in adults perioperative ketorolac use

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 5

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions

Gobble, 20146  Ketorolac  NR  Postoperative  The odds of Postoperative bleeding bleeding postoperative was not significantly  AEs bleeding were increased with ketorolac higher in the when compared with ketorolac group controls, and AEs were compared with the not statistically different control group between the groups  AEs did not differ between groups  There was a lower incidence of AEs with low-dose ketorolac

Lewis, 20137  NR  Tonsillectomy  Bleeding The use of NSAIDs There is insufficient  Adenotonsillec- in children was not evidence to exclude an tomy associated with increased risk of bleeding requiring bleeding when NSAIDs surgical intervention are used in pediatric or bleeding not tonsillectomy requiring surgical intervention when compared with other analgesics or placebo

Riggin, 20138  NR  Tonsillectomy  Bleeding rates  The use of These results suggest  Bleeding NSAIDs after that NSAIDs can be severity tonsillectomy was considered as a safe not associated method of analgesia with bleeding among children  Use of NSAIDs in undergoing general or in tonsillectomy children was not associated with bleeding in general, most severe bleeding, secondary hemorrhage, readmission, or need of reoperation due to bleeding  There was no increased odds of bleeding for

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 6

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions specific NSAIDs in adults or children

Randomized Controlled Trials Gago, 20169  IV ibuprofen  Abdominal  AEs There was no  IV-Ibuprofen was safe surgery difference in AEs and well tolerated  Orthopedic between ibuprofen  The authors surgery and placebo groups concluded that 800 mg of IV-Ibuprofen administered every 6 hours can help manage postoperative pain while reducing the potential risks associated with morphine consumption

Beckmann, 201510  Naproxen  Arthroscopic  AEs Minor adverse Not relevant surgery for reactions did not femoroaceta- differ between bular naproxen and impingement placebo

Hovanesian,  Ketorolac  Cataract  AEs Clinically significant The authors determined 201511 surgery AEs did not differ that phenylephrine between ketorolac 1.0%-ketorolac 0.3% and placebo administered intracamerally with irrigation solution during cataract surgery was safe and effective for maintaining mydriasis during the procedure and reducing postoperative ocular pain

Shi, 201512  Etoricoxib  Lumbar fusion  AEs No serious AEs Suggest that etoricoxib surgery was effective in safely managing the pain during the lumbar fusion surgery and recovery

Moss, 201413  IV-Ibuprofen  Tonsillectomy  AEs No significant Not relevant  Surgical blood differences in the loss incidence of SAEs,  Postoperative surgical blood loss,

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 7

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions bleeding incidence of  Need for postoperative surgical re- bleeding, or a need exploration for surgical re- exploration between Ibuprofen and placebo groups

Non-Randomized Studies Haddad, 201714  NR  Emergency  GI AF (AF; GI AF rate did not  Perioperative NSAID general surgery dehiscence/ differ between utilization appears to leak, fistula, or NSAID and no be safe in patients abscess) NSAID undergoing small- bowel resection and anastomosis  NSAID administration should be used cautiously in patients with colon or rectal anastomoses

Rushfeldt, 201615  Ketorolac  Surgery  Anastomotic Compared with no Other factors than  Diclofenac involving an leak medication perioperative drugs are intestinal receivers, adjusted crucial for risk of AL anastomosis (age, sex, and propensity score) odds of anastomotic leak did not differ for ketorolac

Saleh, 201416  Ketorolac  Colorectal  Anastomotic There was no There does not appear resection with leak difference between to be a significant primary ketorolac and no association between anastomosis ketorolac after perioperative ketorolac adjusting for use and anastomotic smoking, steroid leakage after colorectal use, and age surgery

Gao, 201817  Ketorolac  Circumcision  Postoperative  Patients receiving Although a promising bleeding ketorolac were analgesic, ketorolac  Postoperative more likely to requires additional admission return to the investigation for safe  Further emergency usage in circumcisions medical department or due to possible intervention clinic for bleeding increased risk of Patients receiving bleeding ketorolac were more likely to have

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 8

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions postoperative sanguineous drainage  There was no significant difference in the number of patients requiring postoperative admission or further medical intervention

Richardson,  Ketorolac  Neuro-surgery  Radiographic  There was no Short-term ketorolac 201618 hemorrhage association therapy does not appear  Clinically between clinically to be associated with an significant significant increased risk of bleeding bleeding events or bleeding documented events radiographic on postoperative hemorrhage and imaging in pediatric the perioperative neurosurgical patients administration of ketorolac

Abdelmageed,  Ketorolac  Tonsillec-tomy  Bleeding time  Estimated Pre-emptive ketorolac 19 2015 with or without  Intraoperative intraoperative infusion during pediatric adenoidec-tomy blood loss blood loss did not tonsillectomy provides  Postoperative differ between superior postoperative bleeding ketorolac and analgesia with no effect incidence and paracetamol on intraoperative or severity  Bleeding time postoperative clinical increased bleeding between preoperative and postoperative assessments in both groups, with significant postoperative elevation in the ketorolac group  Overall incidence of post- tonsillectomy bleeding did not differ between ketorolac and

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 9

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions paracetamol groups

Oliveri, 201420  Ketorolac  Cardiac surgery  GI bleeding  Ketorolac did not Ketorolac appears to be  AEs differ or had well-tolerated for use better when administered postoperative selectively after cardiac outcomes than surgery comparators, including: GI bleeding, renal failure requiring dialysis, perioperative, stroke or transient ischemic attack, and death  Treatment with ketorolac was not a predictor for adverse outcome in this cohort

Ying, 201821  NR  Orthopedic  AKI The authors The authors concluded surgery observed a linear that perioperative relationship NSAID drugs was frequency of NSAID significantly associated administration and with postoperative AKI postoperative AKI risk

Modjahedi, 201722  Topical  Cataract  Postoperative  NSAID use was  Topical NSAIDs were surgery macular associated with a associated with a edema lower incidence of modest reduction of postoperative postoperative macular macular edema in edema incidence in patients without patients undergoing diabetes and cataract surgery; diabetics without however, this retinopathy relationship was not  NSAID use was seen among those not associated with diabetic with a change in retinopathy the incidence of  The risk for postoperative postoperative macular macular edema edema is low and the among patients number of patients with diabetic benefiting from

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 10

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions retinopathy treatment is small

Naseem, 201723  Ketorolac  Pediatric  LOS  Ketorolac was  Ketorolac was not appendectomy  Readmission associated with a associated with an with diagnosis decrease in same- increase in visit surgical postoperative LOS, of peritoneal postoperative abscess or complications and infection, or any- other not associated cause 30-day postoperative with readmission, readmission infection postoperative  Ketorolac was  Transabdomin LOS, or independently al drainage postoperative associated with a infection lower overall rate of performed postoperative  Ketorolac was complications associated with a decrease in any complication and not associated with readmission, postoperative LOS, or postoperative infection

Takahashi, 201724  Ketorolac  Laparoscopic GFR  GFR at 1 year was Ketorolac appears to be live-donor significantly lower a risk factor for renal nephrectomy in patients who dysfunction in the long received ketorolac term after live-donor than in those who nephrectomy did not  The differences in GFR and GFR percentage between 2 weeks and 1 year after surgery was lower with ketorolac  Urinary albumin/creatinine ratio 1 year after surgery was significantly higher in the ketorolac group compared to the non-ketorolac group  Ketorolac use was

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 11

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions an independent risk factor for low GFR percentage 1 year after surgery

Donohue, 201625  Ketorolac  Femoral and  Time to union  Average time to Ketorolac administered tibial shaft union of the femur in the first 24 hours after repair with was 147 days for fracture repair for acute intramedullary those pain management does rod fixation administered not seem to have a ketorolac and 159 negative impact on time days for group not to healing or incidence administered of nonunion for femoral ketorolac or tibial shaft fractures  Average time to union of the tibia was 175 days for ketorolac and 175 days for no- ketorolac group

Lohisinwat, 201626  COX-2  Colorectal  Postoperative  There was no Perioperative inhibitors surgery complications difference in administration of oral  Median overall selective COX-2 postoperative postoperative inhibitors significantly stay complications decreased intravenous between COX-2 opioid consumption, administration and shortened time to GI no COX-2 recovery and reduced administration hospital stay after open  Median colorectal surgery postoperative stay was 1 day shorter with COX-2 prescription

Warth, 201627  Celecoxib  Primary and  AKI NSAIDs use was Not relevant  Ketorolac revision total hip associated with a (when arthroplasty and 4.8% rate of AKI, necessary) total knee which is 2.7 times arthroplasty higher than the reported literature

Behman, 201528  COX-2 and  Pancreatic  PF  NSAID use was  COX-2 inhibitors are non-selective duodenectomy not associated associated with PF in inhibitors with PF, or the early difference in major postoperative period morbidity or  While non-selective

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 12

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions mortality inhibitors appear safe  Use of non- in this setting, caution selective inhibitors is warranted with the was not use of COX-2 associated with an inhibitors increase in PF  COX-2 inhibitors were associated with increased PF but no difference in major morbidity or mortality  Use of COX-2 inhibitors was independently associated with PF

Gan, 201529  IV-ibuprofen  Not specified  SAEs and non-  ~22% of patients Our study found that IV SAEs reported AEs, ibuprofen infused over 5 including: to 10 minutes at infusion site pain induction of anesthesia Nine SAEs were is a safe administration reported and were option for surgical judged unrelated patients to ibuprofen

Lizardo, 201530  Ketorolac  Video-assisted  LOS There were no Despite the intrinsic thorascopic  Radiographic differences in anti-inflammatory surgery with pneumothorax average LOS, properties of ketorolac, pleurodesis for resolution prior incidence of residual our data suggests that pneumothorax to discharge pneumothorax at its use for patients  Ipsilateral discharge, or undergoing pleurodesis recurrence ipsilateral recurrence for spontaneous rates between ketorolac pneumothorax does not use and no ketorolac detrimentally influence use the outcomes of surgery

Jian, 201431  Flurbiprofen,  Craniotomy  Post- Hematoma requiring  Intraoperative and hypertension, craniotomy surgery was postoperative or HES intracranial associated with hypertension and the hematoma flurbiprofen use use of flurbiprofen requiring during but not after during surgery are risk surgery the surgery. The factors for post- intraoperative craniotomy infusion of HES intracranial hematoma showed no requiring surgery difference between  The intraoperative patients who had a infusion of HES was

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 13

First Author, NSIAD(s) Type of Outcome(s) of Results Authors’ Year Surgery Interest Conclusions hematoma and not associated with a those who did not higher incidence of hematoma

STARSurg  NR  GGI surgery  Major  NSAID use was Early use of NSAIDs is Collaborative, complications associated with a associated with a 201432 reduction in overall reduction in complications postoperative adverse  This effect events following major predominantly GI surgery comprised a reduction in minor complications with high-dose NSAIDs

Beckmann, 201433  Naproxen  Hip arthroscopy  AEs Complications of Side effects from the NSAID use included investigated NSAID acute renal failure, regimen can be serious hematochezia from and should be weighed acute colitis, and against the potential gastritis benefits in preventing the formation of Heterotopic Ossification

AE = adv erse ev ent; AF = anastomotic f ailure; AKI = acute kidney injury ; COX = cy clooxy genase; GFR = glomerular f iltration rate; GI = gastrointestinal; HES = hy droxy ethyl starch; IV = intrav enous; LOS = length of stay ; NR = not reported; NSAID = non-steroidal anti-inf lammatory ; PF = pancreatic f istula; SAEs = serious adv erse ev ent.

References Summarized

Health Technology Assessments

No literature identified.

Systematic Reviews and Meta-analyses

1. Cata JP, Guerra CE, Chang GJ, Gottumukkala V, Joshi GP. Non-steroidal anti- inflammatory drugs in the oncological surgical population: beneficial or harmful? A systematic review of the literature. Br J Anaesth. 2017 Oct 1;119(4):750-64. PubMed: PM29121285

2. Teerawattananon C, Tantayakom P, Suwanawiboon B, Katchamart W. Risk of perioperative bleeding related to highly selective cyclooxygenase-2 inhibitors: a systematic review and meta-analysis. Semin Arthritis Rheum. 2017 Feb;46(4):520-8. PubMed: PM27569276

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 14

3. Kelley BP, Bennett KG, Chung KC, Kozlow JH. Ibuprofen may not increase bleeding risk in plastic surgery: a systematic review and meta-analysis. Plast Reconstr Surg. 2016 Apr;137(4):1309-16. PubMed: PM27018685

4. Peng F, Liu S, Hu Y, Yu M, Chen J, Liu C. Influence of perioperative nonsteroidal anti - inflammatory drugs on complications after gastrointestinal surgery: a meta-analysis. Acta Anaesthesiol Taiwan. 2016 Dec;54(4):121-8. PubMed: PM28089636

5. Chan DK, Parikh SR. Perioperative ketorolac increases post-tonsillectomy hemorrhage in adults but not children. Laryngoscope. 2014 Aug;124(8):1789-93. PubMed: PM24338331

6. Gobble RM, Hoang HL, Kachniarz B, Orgill DP. Ketorolac does not increase perioperative bleeding: a meta-analysis of randomized controlled trials. Plast Reconstr Surg. 2014 Mar;133(3):741-55. PubMed: PM24572864

7. Lewis SR, Nicholson A, Cardwell ME, Siviter G, Smith AF. Nonsteroidal anti- inflammatory drugs and perioperative bleeding in paediatric tonsillectomy. Cochrane Database Syst Rev. 2013 Jul 18;(7):CD003591. PubMed: PM23881651

8. Riggin L, Ramakrishna J, Sommer DD, Koren G. A 2013 updated systematic review & meta-analysis of 36 randomized controlled trials; no apparent effects of non steroidal anti-inflammatory agents on the risk of bleeding after tonsillectomy. Clin Otolaryngol. 2013 Apr;38(2):115-29. PubMed: PM23448586

Randomized Controlled Trials

9. Gago MA, Escontrela RB, Planas RA, Martinez RA. Intravenous ibuprofen for treatment of post-operative pain: a multicenter, double blind, placebo-controlled, randomized clinical trial. PLoS ONE [Internet]. 2016 [cited 2018 Apr 5];11(5):e0154004. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4859493 PubMed: PM27152748

10. Beckmann JT, Wylie JD, Potter MQ, Maak TG, Greene TH, Aoki SK. Effect of naproxen prophylaxis on heterotopic ossification following hip arthroscopy: a double-blind randomized placebo-controlled trial. J Bone Joint Surg Am [Internet]. 2015 Dec 16 [cited 2018 Apr 5];97(24):2032-7. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673445 PubMed: PM26677237

11. Hovanesian JA, Sheppard JD, Trattler WB, Gayton JL, Malhotra RP, Schaaf DT, et al. Intracameral phenylephrine and ketorolac during cataract surgery to maintain intraoperative mydriasis and reduce postoperative ocular pain: Integrated results from 2 pivotal phase 3 studies. J Cataract Refract Surg. 2015 Oct;41(10):2060-8. PubMed: PM26703280

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 15

12. Shi Y, Wang P, Hu X, Ye Z. Evaluation of the etoricoxib-mediated pain-relieving effect in patients undergoing lumbar fusion procedures for degenerative lumbar scoliosis: a prospective randomized, double-blind controlled study. Cell Biochem Biophys. 2015 Apr;71(3):1313-8. PubMed: PM25391889

13. Moss JR, Watcha MF, Bendel LP, McCarthy DL, Witham SL, Glover CD. A multicenter, randomized, double-blind placebo-controlled, single dose trial of the safety and efficacy of intravenous ibuprofen for treatment of pain in pediatric patients undergoing tonsillectomy. Paediatr Anaesth. 2014 May;24(5):483-9. PubMed: PM24646068

Non-Randomized Studies

Anastomotic Leaks

14. Haddad NN, Bruns BR, Enniss TM, Turay D, Sakran JV, Fathalizadeh A, et al. Perioperative use of nonsteroidal anti-inflammatory drugs and the risk of anastomotic failure in emergency general surgery. J Trauma Acute Care Surg. 2017 Oct;83(4):657- 61. PubMed: PM28930958

15. Rushfeldt CF, Agledahl UC, Sveinbjornsson B, Soreide K, Wilsgaard T. Effect of perioperative dexamethasone and different NSAIDs on anastomotic leak risk: a propensity score analysis. World J Surg [Internet]. 2016 Nov [cited 2018 Apr 5];40(11):2782-9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073113 PubMed: PM27386865

16. Saleh F, Jackson TD, Ambrosini L, Gnanasegaram JJ, Kwong J, Quereshy F, et al. Perioperative nonselective non-steroidal anti-inflammatory drugs are not associated with anastomotic leakage after colorectal surgery. J Gastrointest Surg. 2014 Aug;18(8):1398-404. PubMed: PM24912914

Post-Operative Bleeding

17. Gao B, Remondini T, Dhaliwal N, Frusescu A, Patel P, Cook A, et al. Incidence of bleeding in children undergoing circumcision with ketorolac administration. Can Urol Assoc J [Internet]. 2018 Jan [cited 2018 Apr 5];12(1):E6-E9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783710 PubMed: PM29173273

18. Richardson MD, Palmeri NO, Williams SA, Torok MR, O'Neill BR, Handler MH, et al. Routine perioperative ketorolac administration is not associated with hemorrhage in pediatric neurosurgery patients. J Neurosurg Pediatr. 2016 Jan;17(1):107-15. PubMed: PM26451718

19. Abdelmageed WM, Soliman HF, Fatthallah MA. Pre-emptive intravenous ketorolac analgesia does not alter the risk of bleeding after tonsillectomy in children. Ain-Shams J Anaesthesiol [Internet] 2015 [cited 2018 Apr 5];8:43-9. Available from: http://www.asja.eg.net/article.asp?issn=1687- 7934;year=2015;volume=8;issue=1;spage=43;epage=49;aulast=Abdelmageed

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 16

20. Oliveri L, Jerzewski K, Kulik A. Black box warning: is ketorolac safe for use after cardiac surgery? J Cardiothorac Vasc Anesth. 2014 Apr;28(2):274-9. PubMed: PM24231193

Safety and Other Complications

21. Ying T, Chan S, Lane S, Somerville C. Acute kidney injury post-major orthopaedic surgery: a single-centre case-control study. Nephrology (Carlton). 2018 Feb;23(2):126- 32. PubMed: PM27706879

22. Modjtahedi BS, Paschal JF, Batech M, Luong TQ, Fong DS. Perioperative topical nonsteroidal anti-inflammatory drugs for macular edema prophylaxis following cataract surgery. Am J Ophthalmol. 2017 Apr;176:174-82. PubMed: PM28104155|

23. Naseem HU, Dorman RM, Ventro G, Rothstein DH, Vali K. Safety of perioperative ketorolac administration in pediatric appendectomy. J Surg Res. 2017 Oct;218:232-6. PubMed: PM28985855

24. Takahashi K, Patel AK, Nagai S, Safwan M, Putchakayala KG, Kane WJ, et al. Perioperative ketorolac use: a potential risk factor for renal dysfunction after live-donor nephrectomy. Ann Transplant. 2017 Sep 19;22:563-9. PubMed: PM28924138

25. Donohue D, Sanders D, Serrano-Riera R, Jordan C, Gaskins R, Sanders R, et al. Ketorolac administered in the recovery room for acute pain management does not affect healing rates of femoral and tibial fractures. J Orthop Trauma. 2016 Sep;30(9):479-82. PubMed: PM27124828

26. Lohsiriwat V. Opioid-sparing effect of selective cyclooxygenase-2 inhibitors on surgical outcomes after open colorectal surgery within an enhanced recovery after surgery protocol. World J Gastrointest Oncol [Internet]. 2016 Jul 15 [cited 2018 Apr 5];8(7):543- 9. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942742 PubMed: PM27559433

27. Warth LC, Noiseux NO, Hogue MH, Klaassen AL, Liu SS, Callaghan JJ. Risk of acute kidney injury after primary and revision total hip arthroplasty and total knee arthroplasty using a multimodal approach to perioperative pain control including ketorolac and celecoxib. J Arthroplasty. 2016 Jan;31(1):253-5. PubMed: PM26377377

28. Behman R, Karanicolas PJ, Lemke M, Hanna SS, Coburn NG, Law CH, et al. The effect of early postoperative non-steroidal anti-inflammatory drugs on pancreatic fistula following pancreaticoduodenectomy. J Gastrointest Surg. 2015 Sep;19(9):1632-9. PubMed: PM26123102

29. Gan TJ, Candiotti K, Turan A, Buvanendran A, Philip BK, Viscusi ER, et al. The shortened infusion time of intravenous ibuprofen, part 2: a multicenter, open-label, surgical surveillance trial to evaluate safety. Clin Ther. 2015 Feb 1;37(2):368-75. PubMed: PM25592331

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 17

30. Lizardo RE, Langness S, Davenport KP, Kling K, Fairbanks T, Bickler SW, et al. Ketorolac does not reduce effectiveness of pleurodesis in pediatric patients with spontaneous pneumothorax. J Pediatr Surg. 2015 Dec;50(12):2035-7. PubMed: PM26385568

31. Jian M, Li X, Wang A, Zhang L, Han R, Gelb AW. Flurbiprofen and hypertension but not hydroxyethyl starch are associated with post-craniotomy intracranial haematoma requiring surgery. Br J Anaesth. 2014 Nov;113(5):832-9. PubMed: PM24966149

32. STARSurg Collaborative. Impact of postoperative non-steroidal anti-inflammatory drugs on adverse events after gastrointestinal surgery. Br J Surg. 2014 Oct;101(11):1413-23. PubMed: PM25091299

33. Beckmann JT, Wylie JD, Kapron AL, Hanson JA, Maak TG, Aoki SK. The effect of NSAID prophylaxis and operative variables on heterotopic ossification after hip arthroscopy. Am J Sports Med. 2014 Jun;42(6):1359-64. PubMed: PM24664136

Guidelines and Recommendations

34.National Guideline Clearinghouse. Guideline summary: clinical practice guidelines for enhanced recovery after colon and rectal surgery from the American Society of Colon and Rectal Surgeons and Society of American Gastrointestinal and Endoscopic Surgeons. In : National Guideline Clearinghouse [Internet]. Rockville (MD): Agency for Healthcare Research and Quality; 2017 Aug [cited 2018 Apr 5]. Available from: https://www.guideline.gov/summaries/summary/51065/clinical-practice-guidelines-for- enhanced-recovery-after-colon-and-rectal-surgery-from-the-american-society-of-colon- and-rectal-surgeons-and-society-of-american-gastrointestinal-and-endoscopic- surgeons?q=nsaid+AND+Perioperat See section: Potential Harms

35.National Guideline Clearinghouse. Guideline summary: perioperative protocol: health care protocol. In: National Guideline Clearinghouse [Internet]. Rockville (MD): Agency for Healthcare Research and Quality; 2014 Mar [cited 2018 Apr 5]. Available from: https://www.guideline.gov/summaries/summary/48408/perioperative-protocol-health- care-protocol?q=nsaid+AND+Perioperat See section: 2.4.2 Drugs to Stop

36.Acute kidney injury: prevention, detection and management [Internet]. London: National Institute for Health and Care Excellence; 2013 Aug [cited 2018 Apr 5]. (NICE guideline; no. 169). Available from: https://www.nice.org.uk/guidance/cg169/resources/acute- kidney-injury-prevention-detection-and-management-pdf-35109700165573 See: Assessing risk factors in adults having surgery, page 11

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 18

Appendix — Further Information

Previous CADTH Reports

37. Ketorolac versus non-steroidal anti-inflammatory drugs for the management of acute pain: comparative clinical effectiveness [Internet]. Ottawa: CADTH; 2017 Jan [cited 2018 Apr 5]. (CADTH Rapid response report: summary of abstracts). Available from: https://www.cadth.ca/sites/default/files/pdf/htis/2017/RB1055%20Toradol%20vs%20NS AIDS%20Final.pdf

38. Non-steroidal anti-inflammatory drugs in patients with hypertension, chronic kidney disease, or heart failure: benefits, harms, and guidelines [Internet]. Ottawa: CADTH; 2015 Mar [cited 2018 Apr 5]. (CADTH Rapid response report: summary of abstracts). Available from: https://www.cadth.ca/sites/default/files/pdf/htis/mar- 2015/RB0809%20NSAIDs%20for%20HT%20CKD%20and%20HF%20Final.pdf

39. Ketorolac for pain management: a review of the clinical evidence [Internet]. Ottawa: CADTH; 2014 Jun [cited 2018 Apr 5]. (CADTH Rapid response report: summary of abstracts). Available from: https://www.cadth.ca/sites/default/files/pdf/htis/nov- 2014/RC0565%20Toradol%20Final.pdf

40. Non-steroidal anti-inflammatory drugs for pain: a review of safety [Internet]. Ottawa: CADTH; 2013 Aug [cited 2018 Apr 5]. (CADTH Rapid response report: summary with critical appraisal). Available from:https://www.cadth.ca/sites/default/files/pdf/htis/aug- 2013/RC0471%20NSAID%20safety%20final.pdf

Review Articles

41. Wick EC, Grant MC, Wu CL. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques: a review. JAMA Surg. 2017 Jul 1;152(7):691- 7. PubMed: PM28564673

Additional References

42. Scott WW, Levy M, Rickert KL, Madden CJ, Beshay JE, Sarode R. Assessment of common nonsteroidal anti-inflammatory medications by whole blood aggregometry: a clinical evaluation for the perioperative setting. World Neurosurg. 2014 Nov;82(5):e633- e638. PubMed: PM24698769

SUMMARY OF ABSTRACTS Perioperativ e use of NSAIDs 19