Perioperative Ketorolac Increases Post-Tonsillectomy Hemorrhage in Adults But Not Children

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1 The Laryngoscope VC 2014 The American Laryngological, Rhinological and Otological Society, Inc. Perioperative Ketorolac Increases Post-Tonsillectomy Hemorrhage in Adults But Not Children Dylan K. Chan, MD, PhD; Sanjay R. Parikh, MD Objectives/Hypothesis: To evaluate the risk of post-tonsillectomy hemorrhage associated with perioperative ketorolac use. Study Design: Systematic review and meta-analysis of primary articles reporting individual-level post-tonsillectomy hemorrhage rates in subjects receiving perioperative ketorolac and matched controls. Retrospective and prospective studies were both included. Methods: PubMed search was performed for [ketorolac OR toradol] AND tonsillectomy. Articles fulfilling inclusion criteria were subjected to meta-analysis to determine summary relative risk (RR). Results: Adults are at five times increased risk for post-tonsillectomy hemorrhage with ketorolac use (RR: 5.64; 95% confidence interval [CI]: ; P <.001). In contrast, children under 18 are not at statistically significantly increased risk (RR: 1.39; 95% CI: ; P 5.20). Both retrospective and prospective studies yield consistent findings. There is no association of RR with pre- or postoperative administration of ketorolac. Conclusions: Ketorolac can be used safely in children, but is associated with a five-fold increased bleeding risk in adults. Key Words: Tonsillectomy, hemorrhage, ketorolac, obstructive sleep apnea. Level of Evidence: NA Laryngoscope, 124: , 2014 INTRODUCTION Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) administered intravenously for analgesia. It is an alternative or adjunct to narcotics, acetaminophen, and ibuprofen in the management of perioperative pain, and is of particular interest for use around the time of tonsillectomy. However, ketorolac use is associated with increased risk of postoperative hemorrhageinsomesettings. 1 A recent 2010 Cochrane review 2 of NSAID use in children undergoing tonsillectomy specifically examined six randomized controlled studies and concluded that there is no statistically significantly increased risk of reoperation for posttonsillectomy hemorrhage in patients who receive ketorolac compared to controls. However, the reported summary odds ratio (3.12, 95% confidence interval [CI]: ; P 5.21) was high, and the CI was wide. Though this may suggest an increased risk of From the Division of Pediatric Otolaryngology, Department of Otolaryngology Head and Neck Surgery (D.K.C.), University of California, San Francisco, California; and the Division of Pediatric Otolaryngology (S.R.P.), University of Washington School of Medicine, Seattle Children s Hospital, Seattle, Washington, U.S.A. Editor s Note: This Manuscript was accepted for publication December 9, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Dylan K. Chan, MD, 2233 Post Street, 3rd Floor, Box 1225, San Francisco, CA dylan.chan@ucsf.edu DOI: /lary bleeding with ketorolac, the findings were not statistically significant. Furthermore, recent 2011 American Academy of Otolaryngology Head and Neck Surgery (AAO-HNS) guidelines for pediatric tonsillectomy 3 stated that post-tonsillectomy hemorrhage rates with ketorolac range from 4.4% to 18%, and therefore ketorolac use should be avoided. The choice of the Cochrane collaboration to narrowly analyze reoperation, rather than any hemorrhage, lowered the incidence of the analyzed outcome, and subsequently widened the reported CI. In practice, decision making for reoperation may vary between surgeons, and likely did between studies. As the Cochrane protocol limits analysis to prospective, randomized, controlled studies, sample size was limited; retrospective case-control studies, which had larger numbers, were not considered in the final recommendation. The AAO-HNS guidelines, although citing the Cochrane review, referred specifically to two studies that found increased rates of post-tonsillectomy hemorrhage associated with ketorolac use, 1,4 both of which predominantly reported results on adults, not children. Given the lack of clarity on this issue in the literature, and the increasing focus on non-narcotic analgesics given the recent US Food and Drug Administration black-box warnings regarding codeine use in children, 5 we have performed an updated systematic review and meta-analysis of retrospective and prospective studies examining the incidence of post-tonsillectomy hemorrhage with and without ketorolac use in adults and children. 1789

2 outcome measurement; high: significant variation in outcome measurement. 6. Selective reporting. Low: well-described inclusion/exclusion criteria; mid: unclear inclusion/exclusion criteria; high: no inclusion/exclusion criteria. 7. Complete data. Low: all data present for all subjects; mid: 0% to 10% data missing; high: >10% data missing. Fig. 1. Flowchart of study inclusion. [Color figure can be viewed in the online issue, which is available at MATERIALS AND METHODS Systematic Review PubMed search from 1970 to 2013 with the terms [ketorolac OR toradol] AND tonsillectomy was performed by two independent authors (D.K.C., S.R.P.). Inclusion criteria were as follows: 1) original study reporting unique individual patientlevel data; 2) patients underwent tonsillectomy by any technique; 3) two groups assessed, those who received ketorolac in the perioperative period and those who did not. Studies in any language were considered. All patients, including children and adults, were included. There was no minimum or maximum length of follow-up required after intervention. Abstracts were reviewed. Studies that obviously did not fulfill inclusion criteria, including review articles, basic-science studies, case reports, as well as reports either not involving ketorolac or tonsillectomy were excluded. Conflicts between the two reviewers would be resolved after discussion; however, this did not apply for any of the studies considered. The remaining articles were submitted to full-length review and individual-level data extracted for meta-analysis (Fig. 1). In addition, the reference lists for each included article were reviewed, and no other articles fulfilling inclusion criteria were identified. Each study was assessed for risk of bias according to guidelines put forth by the Cochrane Collaboration. 6 This was evaluated on seven domains as follows: 1. Randomization. Low risk: adequate description of appropriate randomization technique; mid: randomization performed, but no technique specified; high: no randomization. 2. Treatment allocation. Low: allocation procedure unbiased and described fully; mid: allocation procedure described, but unclear bias; high: no allocation procedure described 3. Blinding. Low: all parties blinded; mid: some parties blinded; high: no parties blinded. 4. Standardization (treatment). Low: all subjects undergoing consistent and well-defined treatment plans; mid: some variation in treatment; high: significant variation in treatment. 5. Standardization (outcome). Low: outcome measures determined identically for all subjects; mid: some variation in 1790 Data were compiled from included studies by direct extraction of individual patient-level data and subjected to metaanalysis. Data collected were as follows: patient age (or age range), study design, perioperative ketorolac administration (yes/no), and postoperative hemorrhage (yes/no). The summary relative risk (RR) of post-tonsillectomy hemorrhage for ketorolac compared to control was calculated using a random effects model (metan function, Stata 12.1; StataCorp, College Station, TX). All RR values are presented with 95% confidence intervals (CIs) and P values assessing statistical significance relative to the null hypothesis of no difference in risk. Subgroup analyses were performed on specific subsets of studies based on their design and patient population. Performance, reporting, and analysis of this systematic review and meta-analysis has been done in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. 7 RESULTS Systematic Review Of the 21 abstracts reviewed, 12 studies fulfilled the inclusion criteria of being primary studies describing the use of ketorolac in association with tonsillectomy. Nine studies were excluded on title/abstract review for the following reasons: six were review articles, two did not involve ketorolac, and one did not involve tonsillectomy. Two of the remaining 12 studies were subsequently excluded after full-length review for not reporting postoperative hemorrhage rates. Of the remaining 10 studies 1,4,8 15 (Fig. 1), seven exclusively included children under the age of 18, though the exact age range varied from one study to another. Two studies 4,8 included both adults and children; data specific to children, as defined by the study, were extracted from each study and included for further analysis. One study 1 exclusively included adults over the age of 18 years. Except for one study, 8 all patients >18 years old were considered adults, and all patients 18 years old were considered children. In one study, 8 the reporting cutoff was at age 13 years, therefore some patients from age 13 to 18 years would have been reported together with the over- 18 adults. Definition of postoperative bleeding varied between studies, ranging from any bleeding noticed by the patient to a return to operating room for control. Analysis of risk of bias (Table I) revealed significant risk of bias across many domains for all reports, including both prospective and retrospective studies. Meta-analysis When all 10 studies are considered together, a summary RR of 2.04 (95% CI: ; P <.002; Fig. 2) was calculated. This implies a significantly increased risk of post-tonsillectomy hemorrhage associated with ketorolac use (P <.001). However, when pediatric and adult patients were assessed independently, there was a greatly increased

3 TABLE I. Risk of Bias of Included Studies. Study Year Design Randomization Treatment Allocation Blinding Standardization (Treatment) Standardization (Outcome) Selective Reporting Complete Data Agrawal R High High High Low Mid Low Low Bailey P Mid High Low Low Mid Low Low Gallagher R High High High Mid Mid Mid Low Gunter P Low High Low Low Low Low Low Judkins R High High High Mid Mid Mid Low Keidan P Mid High High Low Low Low Low Romsing P Low Mid Low Low Low Low Low Rusy P Mid High High Low Low Low Low Splinter P Low High High Mid Low Low Low Sutter P High High Mid Mid Low Low Low Each of the 10 included studies was assessed for risk of bias in seven domains according to Cochrane Collaboration guidelines. 6 P 5 prospective, randomized, controlled study; R 5 retrospective case-control study. risk in adults (RR: 5.64; 95% CI: ; P <.001) compared to children (RR: 1.39; 95% CI: ; P 5.20). However, adults receiving ketorolac had over five times the increased risk of bleeding, which was statistically significantly elevated compared to control, but there was no significantly increased risk of bleeding in children. The adult data included three studies, two retrospective and one prospective randomized, blinded, controlled; all three studies were consistent in reporting increased risk with ketorolac. Nine pediatric studies were included. The results from the retrospective and prospective studies were consistent; six prospective studies gave a summary RR of 1.49 (95% CI: ; P 5.30), whereas three retrospective studies yielded a summary RR of 1.31 (95% CI: ; P 5.45). Timing of ketorolac administration also did not affect the RR: preoperative (RR: 1.43; 95% CI: ; P 5.43) and intra- or postoperative (RR: 1.37; 95% CI: ; P 5.32) ketorolac administration had equivalent risk of post-tonsillectomy bleeding. Overall postoperative hemorrhage rates from individual studies and pooled subgroups are shown in Table II. DISCUSSION Perioperative administration of ketorolac is associated with an increased risk of post-tonsillectomy hemorrhage in adults but not in children. Results of seven prospective, randomized controlled studies, as well as outcomes reported in three larger retrospective case-control studies, support these findings. Analysis of validity and bias of these studies demonstrated some limitations. Among the prospective studies, there was inconsistent, and usually sparse, detail regarding the exact method of randomization and treatment allocation. Furthermore, blinding was not always sufficient to completely remove risk of bias. Though outcome assessment and reporting were consistent within each study, the definition of posttonsillectomy hemorrhage varied from one study to another. In particular, many studies (Fig. 2) had only 24- or 48-hour follow-up, and thus would have missed all secondary hemorrhage events. Tonsillectomy technique and indication for tonsillectomy are theoretical confounders for this analysis. We did not include tonsillectomy technique in the analysis because of variability in reporting; most prospective studies specified and controlled for technique in their two comparison groups, which is reflected in the low risk of bias with treatment standardization (Table I), whereas retrospective studies had incomplete reporting on technique with respect to assignment of outcomes. Tonsillectomy technique has not, however, been shown definitively to be related to differential hemorrhage risk 16 ; therefore, it likely has a limited confounding role. Indication for tonsillectomy (tonsillitis or sleep apnea) was not reported in any of the included studies at the individual patient level, so it could not be assessed as a confounder. Length of follow-up is a severe limitation in the interpretation of these studies. Most prospective studies only report 1 to 2 days of study-mandated followup. It is not clear from these studies what the timing of the post-tonsillectomy hemorrhage was in the individual cases. The retrospective studies relied on chart review for ascertainment of post-tonsillectomy hemorrhage, and none of them specified follow-up time in their methods. These studies are subject to significant reporting bias. In adults, two retrospective and one prospective study are highly consistent in reporting an increased risk of bleeding with ketorolac use. In children, 9 studies were analyzed; eight of these (three retrospective, five prospective) were highly consistent, with RRs ranging from 0.76 to One of these studies 9 was an outlier, with an RR of 9.17 (95% CI: ; P 5.13). This prospective, randomized, single-blinded, placebo-controlled study examined preoperative ketorolac, and was halted after five post-tonsillectomy hemorrhages were noted in the ketorolac group. There were no notable study design features that would explain these aberrant results; in general, our meta-analysis did not demonstrate a difference in RR with preoperative and postoperative ketorolac administration. It remains a possibility that an increased risk of bleeding exists in children, and that the existing studies 1791

4 TABLE II. Post-Tonsillectomy Hemorrhage Rates in Subjects Receiving Perioperative Ketorolac and Unexposed Controls. Study Year Population Design Timing Toradol Toradol (%) Control Control (%) Agrawal Pediatric R Intra 5/ / Bailey Adult P Post 7/ / Gallagher Pediatric R Intra 7/ / Gallagher Adult R Intra 10/ / Gunter Pediatric P Post 6/ / Judkins Pediatric R Intra 4/ / Judkins Adult R Intra 6/ / Keidan Pediatric P Pre 0/ / Romsing Pediatric P Pre/post 8/ / Rusy Pediatric P Pre 0/ / Splinter Pediatric P Pre 5/ / Sutter Pediatric P Post 0/ / All children 35/ / All adults 23/ / Pediatric prospective 19/ / Pediatric retrospective 16/ / All studies 58/ / Data for 12 groups from 10 studies are reported. Individual-level data from each study were pooled for analysis in the specified subgroups. P 5 prospective, randomized, controlled study; Pre/Intra/Post 5 ketorolac given before/during/after surgery; R 5 retrospective case-control study. are insufficiently powered to detect this difference. The summary RR for the 10 studies is If this is accurate, then ketorolac may have a 39% increased risk of post-tonsillectomy hemorrhage. To detect this difference with 95% confidence given a control hemorrhage rate of 5%, which is supported in the pooled data, would require a prospective, randomized, controlled study of approximately 1,500 patients in each arm. Future studies need to be carefully designed, controlled, and reported to avoid the risks of bias identified in prior efforts. Fig. 2. Relative risk (RR) of post-tonsillectomy hemorrhage in subjects receiving perioperative ketorolac compared to unexposed controls. Twelve groups from 10 studies are included for meta-analysis. RR values are depicted with black closed diamonds (RR), black lines (95% CI), and grey boxes (weighting for the overall meta-analysis. Black open diamonds indicate summary RR and 95% CIs for subgroup metaanalysis of the pediatric and adult studies, and for all studies pooled together. Higher RR indicates increased risk of post-tonsillectomy hemorrhage with ketorolac use. Follow-up indicates the number of days reported. C 5 cold; CI 5 confidence interval; E 5 electrocautery; L 5 laser; NR 5 not reported; P 5 prospective, randomized, controlled study; pre/intra/post 5 ketorolac given before/during/after surgery; R 5 retrospective case-control study. [Color figure can be viewed in the online issue, which is available at

5 Despite being relatively underpowered compared to the pediatric data, the adult data show statistically significantly increased risk of post-tonsillectomy hemorrhage with ketorolac use. This may reflect differences in indications for tonsillectomy in children compared to adults; tonsillectomy done for obstructive sleep apnea in children may carry less risk compared to the same procedure done for tonsillitis in adults. Prior studies have suggested overall increased rate of post-tonsillectomy hemorrhage in adults and older children compared to young children. 17 It is possible that the same risk factors that predispose to post-tonsillectomy hemorrhage in general in older patients also predispose to additional risk associated with ketorolac use. CONCLUSION Ketorolac is associated with an increased risk of post-tonsillectomy hemorrhage in adults but not children. BIBLIOGRAPHY 1. Bailey R, Sinha C, Burgess LP. Ketorolac tromethamine and hemorrhage in tonsillectomy: a prospective, randomized, double-blind study. Laryngoscope 1997;107: Cardwell ME, Siviter G, Smith AF. Nonsteroidal anti-inflammatory drugs and perioperative bleeding in paediatric tonsillectomy. Cochrane Database of Syst Rev 2010;7:CD Baugh RF, Archer SM, Mitchell RB, et al.; American Academy of Otolaryngology-Head and Neck Surgery Foundation. Clinical practice guideline: tonsillectomy in children. Otolaryngol Head Neck Surg 2011; 144:S1 S Judkins JH, Dray TG, Hubbell RN. Intraoperative ketorolac and posttonsillectomy bleeding. Arch Otolaryngol Head Neck Surg 1996;122: Kuehn BM. FDA: no codeine after tonsillectomy for children. JAMA 2013; 309: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version (updated March 2011). The Cochrane Collaboration, Available at: Accessed September 1, Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e Gallagher JE, Blauth J, Fornadley JA. Perioperative ketorolac tromethamine and postoperative hemorrhage in cases of tonsillectomy and adenoidectomy. Laryngoscope 1995;105: Splinter WM, Rhine EJ, Roberts DW, Reid CW, Macneill HB. Preoperative ketorolac increases bleeding after tonsillectomy in children. Can J Anaesth 1996;43: Agrawal A, Gerson CR, Seligman I, Dsida RM. Postoperative hemorrhage after tonsillectomy: use of ketorolac tromethamine. Otolaryngol Head Neck Surg 1999;120: Gunter JB, Varughese AM, Harrington JF, et al. Recovery and complications after tonsillectomy in children: a comparison of ketorolac and morphine. Anesth Analg 1996;81: Keidan I, Zaslansky R, Eviatar E, Segal S, Sarfaty SM. Intraoperative ketorolac is an effective substitute for fentanyl in children undergoing outpatient adenotonsillectomy. Paediatr Anaesth 2004;14: Romsing J, Ostergard D, Walther-Larsen S, Valentin N. Analgesic efficacy and safety of preoperative versus postoperative ketorolac in pediatric tonsillectomy. Acta Anaesthesiol Scand 1998;42: Rusy LM, Houck CS, Sullivan LJ, et al. A double-blind evaluation of ketorolac tromethamine versus acetaminophen in pediatric tonsillectomy: analgesia and bleeding. Anesth Analg 1995;80: Sutter KA, Levine JD, Dibble S, Savedra M, Miaskowski C. Analgesic efficacy and safety of single-dose intramuscular ketorolac for postoperative pain management in children following tonsillectomy. Pain 1995;61: Pinder DK, Wilson H, Hilton MP. Dissection versus diathermy for tonsillectomy. Cochrane Database Syst Rev 2011;3:CD Sarny S, Ossimitz G, Habemann W, Stammberger H. Hemorrhage following tonsil surgery: a multicenter prospective study. Laryngoscope 2011; 121: