Background

Adenotonsillectomy and tonsillectomy (referred to as tonsillectomy hereafter) are common pediatric surgeries. Postoperative complications include hemorrhage requiring surgery (2 to 3% of cases) and pain. Although nonsteroidal anti-inflammatory drugs are commonly administered for postsurgical pain, controversy exists regarding bleeding risk with cyclooxygenase-1 inhibition and associated platelet dysfunction. Preliminary evidence suggests selective cyclooxygenase-2 inhibitors, for example celecoxib, effectively manage pain without adverse events including bleeding. Given the paucity of data for routine celecoxib use after tonsillectomy, this study was designed to investigate the association between postoperative celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery using chart-review data from the Children’s Hospital of Eastern Ontario.

Methods

After ethics approval, a retrospective single-center observational cohort study was performed in children less than 18 yr of age undergoing tonsillectomy from January 2007 to December 2017. Cases of adenoidectomy alone were excluded due to low bleed rates. The primary outcome was the proportion of patients with post-tonsillectomy hemorrhage requiring surgery. The association between a celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery was estimated using inverse probability of treatment weighting based on propensity scores and using generalized estimating equations to accommodate clustering by surgeon.

Results

An initial patient cohort of 6,468 was identified, and 5,846 children with complete data were included in analyses. Median (interquartile range) age was 6.10 (4.40, 9.00) yr, and 46% were female. In the cohort, 28.1% (n = 1,644) were prescribed celecoxib. Among the 4,996 tonsillectomy patients, 1.7% (n = 86) experienced post-tonsillectomy hemorrhage requiring surgery. The proportion with post-tonsillectomy hemorrhage requiring surgery among patients who had a tonsillectomy and were or were not prescribed celecoxib was 1.94% (30 of 1,548; 95% CI, 1.36 to 2.75) and 1.62% (56 of 3,448; 95% CI, 1.25 to 2.10), respectively. Modeling did not identify an association between celecoxib prescription and increased odds of post-tonsillectomy hemorrhage requiring surgery (odds ratio = 1.4; 95% CI, 0.85 to 2.31; P = 0.20).

Conclusions

Celecoxib does not significantly increase the odds of post-tonsillectomy hemorrhage requiring surgery, after adjusting for covariates. This large pediatric cohort study of celecoxib administered after tonsillectomy provides compelling evidence for safety but requires confirmation with a multisite randomized controlled trial.

Editor’s Perspective
What We Already Know about This Topic
  • Tonsillectomy and adenotonsillectomy are common pediatric surgeries

  • There is variation in practice in the use of nonsteroidal anti-inflammatory drugs for analgesia, including use of the COX-2 selective agents such as celecoxib

  • The reluctance to use celecoxib is partly driven by concerns around increased bleeding risk

What This Article Tells Us That Is New
  • In a large, single-center, retrospective cohort, the use of celecoxib did not increase the odds of postoperative hemorrhage requiring surgery

Adenotonsillectomy or tonsillectomy (which will hereafter be referred to as tonsillectomy) is a common pediatric surgery and is considered a high-value target for quality improvement. Despite this, substantial practice variation exists with inconsistent perioperative practices (e.g., use of antibiotics, systemic steroids, and analgesia) and variable rates of hospital revisits and bleeding.1,2  In North America, tonsillectomy is primarily an ambulatory procedure with two-thirds of cases performed for obstructive sleep disordered breathing or obstructive sleep apnea (OSA), and the remaining performed for recurrent infection.2  Postoperative complications include poorly controlled pain and post-tonsillectomy hemorrhage,3  which in 2 to 5% of tonsillectomies requires surgery.4–6  These potentially preventable complications increase healthcare utilization, making it resource intensive.5 

In the context of the opioid epidemic and risk of opioid misuse, abuse, and diversion7,8  and the increased risk of opioid-induced respiratory depression in children with severe OSA undergoing tonsillectomy,9,10  opioid-sparing nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are increasingly used to manage postoperative pain. The main mechanism of action of NSAIDs is the inhibition of cyclooxygenase enzymes including COX-1 and COX-2, which can affect bleeding risk through COX-1–mediated effects on hemostasis and platelet function.11,12  Although small cohort studies support the use of nonselective NSAIDs, reporting no changes in frequency of bleeding,13  evidence suggests they may increase post-tonsillectomy hemorrhage severity.14  Additionally, systematic reviews cite insufficient evidence to discount bleeding risks in children15,16  due to inadequate sample sizes to assess rare (less than 5%) bleeding events15–17  or inclusion of both children and adults in larger cohort studies.18  Given that nonselective NSAID safety is unclear, there is interest in studying other agents, including COX-2 selective inhibitors (e.g., celecoxib), devoid of the same associated platelet dysfunction.19–21 

A few small randomized controlled trials, including our own study in 2015,4  have shown that oral celecoxib adequately manages pain after adenotonsillectomy or tonsillectomy and is not associated with increased post-tonsillectomy hemorrhage22,23  and has been since adopted as the preferred postoperative analgesic at our center. Given limited real-world evidence for routine celecoxib use after tonsillectomy or adenoidectomy, our goal was to investigate the association of postoperative oral celecoxib with post-tonsillectomy hemorrhage requiring surgery, because this outcome can have lethal consequences from both exsanguination and anesthetic complications.24  Our primary objective was to compare the proportion of post-tonsillectomy hemorrhage requiring surgery in children who were and were not prescribed celecoxib postoperatively for pain management, using a retrospective design. The null hypothesis was that celecoxib would not increase the odds of post-tonsillectomy hemorrhage requiring surgery.

Study Design and Setting

After ethics board approval (research ethics board No. 18/19PE), we conducted a retrospective observational cohort study to address the primary objective by analyzing surgeries undergoing tonsillectomy or adenoidectomy from January 1, 2007, to December 31, 2017, at the Children’s Hospital of Eastern Ontario, a tertiary care free-standing pediatric hospital in Ottawa, Ontario, Canada. In Canada, healthcare is provided through a universal-access and publicly funded system in which each territory or provincial government is the primary payer. Children’s Hospital of Eastern Ontario provides tonsillectomy or adenoidectomy services to the surrounding region, including elective cases performed by community surgeons and medically complex patients referred from community hospitals to a tertiary-care specialist. The study period covered the earliest searchable timepoint of the Children’s Hospital of Eastern Ontario surgical information system database to 2 yr after celecoxib postoperative prescription became a standard of care after tonsillectomy. During this time, tonsillectomy surgeries at Children’s Hospital of Eastern Ontario were performed by 23 ear, nose, and throat surgeons (otolaryngologists) whose primary practice was in a tertiary adult center (43.4%), in a community practice (34.8%), or at Children’s Hospital of Eastern Ontario (21.7%). Our study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines including the REporting of studies Conducted using Observational Routinely collected health Data (RECORD) statement extension.

Data Sources

The primary and secondary study objectives required extraction of health administrative data from both Children’s Hospital of Eastern Ontario’s online computerized charting and scheduling system, the hospital’s gold-standard source of perioperative data, and patient charts. Patient charts were paper (2007 to 2016), a hybrid of electronic and/or paper (2017), and exclusively electronic as of 2018 using EPIC, the electronic medical record system software.

Two data sets were created by a trained data analyst independent from the study team. Each data set consisted of a denominator data set (index procedure of interest – tonsillectomy ± ear tube placement ± an additional procedure) and a numerator data set (primary outcome procedure of interest – post-tonsillectomy hemorrhage requiring surgery). The surgical information system contains several variables recorded for each patient encounter including unique identifiers, patient demographics, type of surgeon (e.g., otolaryngologist), encounter type, surgical pre- or postoperative indication or diagnosis as per the Pediatric Canadian Access Targets for Surgery, and surgeries performed (Supplemental Digital Content, supplemental table 1, https://links.lww.com/ALN/D549). The surgical information system has several checklists in place to ensure that the correct surgery for the correct indication is recorded; the data are confirmed after surgery by the surgeons. In this study, the surgical indication was based on the patient’s surgical note, as opposed to the Pediatric Canadian Access Targets for Surgery preoperative diagnosis, thought to be the most accurate. Additional index procedures beyond tonsillectomy or adenoidectomy (e.g., bronchoscopy) were further collapsed into categories by coauthors J.M. and K.M. as described in supplemental table 1 (https://links.lww.com/ALN/D549). Coauthors V.S. and K.M. independently reviewed 1,142 combinations of surgical indication, which were collapsed into one of four surgical categories: (1) obstructive sleep-disordered breathing or OSA, (2) recurrent infection, (3) obstructive sleep-disordered breathing or OSA and recurrent infection, and (4) other. Any discrepancies were resolved by our surgeon co-author (J.M.). Case-related data in supplemental table 1 (https://links.lww.com/ALN/D549) were uploaded to a REDCap database for the index procedure and the primary outcome of interest, respectively. Data extraction of additional variables is outlined in supplemental tables 2 and 3 (https://links.lww.com/ALN/D549). Ethnicity and race-related information was not collected based on current Canadian standards.

Data quality assurance was ascertained by the senior author (K.M.), who reviewed initial data extraction (n = 30 charts/assistant) to ensure that data entry error rates were less than 1%. Subsequent data quality assurance was performed before analysis on a randomly selected subset of medical records (n = 100, 1.5% of cohort; 4 contained sleep studies) with a data-entry error rate of 15 in 2,868 (0.52%) data fields assessed for each index surgery. In addition, a randomly selected subset of medical records (n = 7, 7% of cohort; 1 contained polysomnography) was found to have a data-entry error rate of 6 in 2,274 (0.3%). The analysis followed a prespecified plan and was performed by independent analysts (A.T. and G.Z.).

Cohort

Our cohort included children from 1 month to 17 yr old undergoing tonsillectomy or adenoidectomy at Children’s Hospital of Eastern Ontario to treat recurrent infection, obstructive sleep-disordered breathing or OSA, obstructive sleep-disordered breathing or OSA and recurrent infection, or other infrequent diagnosis that were included with cases of obstructive sleep-disordered breathing or OSA (e.g., cancer). Only the initial surgery (index surgery) was included for those children who underwent tonsillectomy or adenoidectomy more than once. Similarly, only the first post-tonsillectomy hemorrhage requiring surgery associated with the index surgery was included if there was more than one post-tonsillectomy hemorrhage requiring surgery. Cases who presented with post-tonsillectomy hemorrhage requiring surgery but who did not have their index surgery at Children’s Hospital of Eastern Ontario were excluded.

Exposure

Our primary exposure was a postoperative oral celecoxib prescription for any twice daily dose and duration, because these were at the discretion of the attending otolaryngologist. The celecoxib was prepared as a 10 mg/ml oral suspension in our hospital pharmacy using our validated formulation and was made available to surrounding pharmacies.25  Typically, children that received oral celecoxib were prescribed 3 mg/kg twice daily for 7 days after surgery and were also routinely administered a preoperative oral 6-mg/kg celecoxib loading dose. Exposure was determined through individual chart review by identifying a copy of the prescription in the paper chart or documented in the electronic medical record. Although our original randomized controlled trial patients received a preoperative oral 6-mg/kg celecoxib loading dose (maximum 550 mg) and a 3-mg/kg twice daily dosing for 3 days, celecoxib prescription now extends up to 10 days. Participants of our randomized controlled trial were eligible for inclusion in the current cohort and were deidentified to establish celecoxib prescription or placebo allocation. For our main outcome, patients prescribed postoperative celecoxib were compared to patients without prescribed celecoxib for pain management after surgery.

Outcomes

Our primary outcome was post-tonsillectomy hemorrhage requiring surgery after tonsillectomy. Bleeding after isolated adenoidectomy (less than 1%) was excluded from our primary analysis due to its rare occurrence (as per reviewer request).26  We included primary and secondary postoperative hemorrhage within 15 days of surgery, defined as occurring 24 h or less after surgery or more than 24 after surgery, respectively. Primary hemorrhage was included in the definition because patients prescribed postoperative celecoxib commonly received a preoperative 6-mg/kg oral loading dose. Further, a time-dependent hemorrhage definition would allow for a sensitivity analysis around the timing of post-tonsillectomy hemorrhage requiring surgery.

Covariates

Because patient,27,28  surgeon,29,30  and anesthetic factors15,31  can confound the association between celecoxib prescription and the primary outcome (post-tonsillectomy hemorrhage requiring surgery), we collected detailed baseline and perioperative data on all participants including age (in years), sex (binary), weight (calculated Z score),32  diagnostic indication for surgery (obstructive sleep-disordered breathing or OSA, recurrent infection, obstructive sleep-disordered breathing or OSA + recurrent infection, sleep-disordered breathing or OSA + other, other), sleep physician OSA diagnosis (none, mild, moderate, severe), surgeon experience (years since graduation), surgeon primary practice setting (community, tertiary care adults or pediatrics), surgical approach (tonsillectomy with or without adenoidectomy), duration of surgery (min), surgical classification (elective, emergent or urgent), and surgical designation (inpatient, ambulatory daycare).

During the study period, the surgical technique was complete excision of the tonsillar tissue including the capsule. Most surgeons (20 of 23) utilized mono- or uni-polar cautery, whereas a minority utilized a cold-steel or snare (2 of 23) or a combined cautery or snare technique (1 of 23) and operated on less than 2.1% (n = 48) of the study cohort. In our study, the American Society of Anesthesiologists (ASA) physical status score was not included because it was missing in 10 to 20% of our cohort and because of potential reporting variability of this parameter.33  Inpatient surgery status, a preoperative polysomnography and associated diagnosis of OSA severity interpreted by a pediatric sleep medicine specialist, surgical indication, classification, and cases performed by tertiary care specialists were captured as surrogate measures of medical complexity.3,34,35  Postoperative admission or an urgent or emergent surgery were indicative of increased medical complexity or severity of disease, and patients undergoing a polysomnography34  were considered higher risk for perioperative morbidity, as were patients with obstructive sleep-disordered breathing,35  possibly affecting the risk for hemorrhage after tonsillectomy.36,37  ASA physical status classification was available for patients with post-tonsillectomy hemorrhage requiring surgery who were or were not prescribed celecoxib.

The administration of intraoperative IV dexamethasone (150 μg/kg) for antiemetic prophylaxis was a standard of care during the study period, whereas administration of antibiotics was uncommon. Before and after the introduction of celecoxib, the hospital standard of care for postoperative analgesia specifically guided parents to avoid any other NSAID, including ibuprofen. To manage pain, children were routinely prescribed oral acetaminophen suspension (10 to 15 mg/kg every 6 h) and codeine (0.5 to 1 mg/kg every 4 to 6 h as needed), which transitioned to an oral morphine suspension (50 to 200 μg/kg every 4 to 6 h as needed) after 2009.

Statistical Analysis

All statistical analyses were performed using R statistical programming (version 4.2.1).38  Cohort and surgical characteristics are reported as frequencies for categorical variables and as medians with interquartile ranges or means and SD for variables with skewed or normal distribution, respectively. Missing data were low: 6.7% (417 of 6,263), among participants and was not imputed (supplemental table 4, https://links.lww.com/ALN/D549). Unadjusted differences in proportion of post-tonsillectomy hemorrhage requiring surgery between groups were calculated with Wilson score 95% CI. Propensity scores were derived to determine the probability of a participant receiving a prescription of celecoxib based on certain baseline characteristics. Differences in baseline characteristics between those who did and did not get a prescription for celecoxib was rebalanced using an inverse probability of treatment weighting. The following clinically relevant covariates were used to calculate this propensity score (using a multivariable logistic regression model): age, sex, weight Z-score, type of surgery (tonsillectomy with or without adenoidectomy), surgical indication, surgeon years of experience, surgical classification (elective vs. urgent or emergent) and surgeon practice setting. Individual weights were calculated as follows: 1/propensity score for those who received a celecoxib prescription and 1/(1 − propensity score) for those who did not. Standardized mean differences were used to compare the distribution of covariates between those who received a prescription of celecoxib versus those who did not, before and after weighting. Standardized mean differences of less than 0.1 were considered to indicate acceptable balance. In the primary analysis, the association of post-tonsillectomy hemorrhage requiring surgery with having received a celecoxib prescription was determined using logistic regression with inverse probability of treatment weighting and was performed using the R package Geepack for generalized estimating equation to account for clustering by surgeon.

Sensitivity Analysis and Exploratory Subanalysis

A sensitivity analysis was performed using the same modeling strategy with the following conditions: (1) assessing only secondary bleeds (a priori), (2) including adenoidectomy in the primary analysis (a priori), and (3) excluding those who had a surgery in 2007 given the high percentage of missing data in that year (per peer reviewer request).

For the participants who received a celecoxib prescription, an exploratory subanalysis of the association between celecoxib daily dose and post-tonsillectomy hemorrhage requiring surgery was performed using generalized estimating equations as above but without weighting, because only patients who received a celecoxib prescription were included. A second analysis was performed on the same cohort using both daily dose (mg) and prescription duration (days; post hoc exploratory).

Sample Size

This was a convenience sample to both maximize the number of patients undergoing the index surgery of interest and the number of patients receiving celecoxib, which became the standard of care in 2015. With approximately 100 post-tonsillectomy hemorrhages requiring surgery, we expected to conservatively have 10 degrees of freedom; however, not all index surgery cases were performed at Children’s Hospital of Eastern Ontario.

Study Cohort and Characteristics

Of 83,293 surgical cases at Children’s Hospital of Eastern Ontario from January 2007 to December 2017, we identified 6,468 (7.8%) procedures of interest. Initial surgical information system index case identification accuracy was confirmed with 6,468 of 6,471 charts (99.95%) and 113 of 114 charts (99.12%) correctly identifying the index procedure and the outcome of interest (post-tonsillectomy hemorrhage requiring surgery), respectively. After accounting for exclusions, 5,846 children with complete data were identified (fig. 1), including 850 children who underwent isolated adenoidectomy. Of note, the numerator data set for post-tonsillectomy hemorrhage requiring surgery identified 30 patients who were not included in the denominator data set (N = 6,468) due to index surgery occurring outside of Children’s Hospital of Eastern Ontario (n = 20), excessive intraoperative bleeding (n = 6), repeat cases of post-tonsillectomy hemorrhage requiring surgery (n = 2), and incomplete or missing data (n = 2). Overall, celecoxib was prescribed to 1,644 of 5,846 children (28.1%). Between 2007 and 2010, 32 of 1610 (less than 2.0%) children were prescribed celecoxib, but by 2016, this rose to more than 75% (fig. 2). The percentage of surgeons who prescribed celecoxib to more than 50% of their patients increased from 25% in 2013 to 83% between 2014 and 2015 and to 100% by 2017 (data not shown). Detailed participant and surgical characteristics stratified by celecoxib prescription are summarized in table 1. Children prescribed celecoxib were generally younger, underwent tonsillectomy, and were managed by a more experienced specialist pediatric surgeon. In addition, celecoxib was more likely prescribed for children undergoing inpatient or emergent or urgent surgery and those with more severe polysomnography-diagnosed OSA. Celecoxib twice-daily median mg/kg prescription dosage (interquartile range) was 2.93 (2.73, 3.02) for 7 (7.0, 10.0) days as described in supplemental tables 5 and 6 (https://links.lww.com/ALN/D549). The cohort was further modified to exclude adenoidectomy cases due to low bleed rates for the purposes of the primary outcome analysis, with a final cohort of 4,996 children undergoing tonsillectomy (fig. 1; table 2).

Table 1.

Participant Characteristics at the Time of Index Surgery

Participant Characteristics at the Time of Index Surgery
Participant Characteristics at the Time of Index Surgery
Table 2.

Characteristics of Patients Who Had Post-tonsillectomy Hemorrhage Requiring Surgery Excluding Adenoidectomies

Characteristics of Patients Who Had Post-tonsillectomy Hemorrhage Requiring Surgery Excluding Adenoidectomies
Characteristics of Patients Who Had Post-tonsillectomy Hemorrhage Requiring Surgery Excluding Adenoidectomies
Fig. 1.

Study flow chart.

Fig. 1.

Study flow chart.

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Fig. 2.

Proportion of annual post-tonsillectomy hemorrhages requiring surgery excluding adenoidectomy, with or without a celecoxib prescription. The figure illustrates unadjusted annual proportions of post-tonsillectomy hemorrhage requiring surgery with 95% CI overall and by presence or absence of celecoxib prescription. (Top) The gray line represents a 3.0% threshold rate of surgery for post-tonsillectomy hemorrhage, for reference. (Middle) The shaded band represents the 95% CI of the overall post-tonsillectomy hemorrhage requiring surgery proportion in the noncelecoxib group. The numbers above each graph indicate the number of bleeds per surgery volume in that group. The arrows represent when the upper limit of the CI extends beyond 20, defined as the upper limit of the graph.

Fig. 2.

Proportion of annual post-tonsillectomy hemorrhages requiring surgery excluding adenoidectomy, with or without a celecoxib prescription. The figure illustrates unadjusted annual proportions of post-tonsillectomy hemorrhage requiring surgery with 95% CI overall and by presence or absence of celecoxib prescription. (Top) The gray line represents a 3.0% threshold rate of surgery for post-tonsillectomy hemorrhage, for reference. (Middle) The shaded band represents the 95% CI of the overall post-tonsillectomy hemorrhage requiring surgery proportion in the noncelecoxib group. The numbers above each graph indicate the number of bleeds per surgery volume in that group. The arrows represent when the upper limit of the CI extends beyond 20, defined as the upper limit of the graph.

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Primary Outcome

In the study cohort, 86 of 4,996 undergoing tonsillectomy (1.7%) experienced the primary outcome of post-tonsillectomy hemorrhage requiring surgery. The difference in the proportion with post-tonsillectomy hemorrhage requiring surgery after tonsillectomy who were (30 of 1,548; 1.94%; 95% CI, 1.36 to 2.75) and were not prescribed celecoxib (56 of 3448; 1.62%; 95% CI, 1.25 to 2.10) was small, the absolute difference being 0.31% (95% CI, −0.44 to 1.21%), and the 95% CI included a zero difference. Propensity scores were derived, and standardized mean differences in the inverse probability of treatment-reweighted sample indicated balance (supplemental tables 7 and 8, https://links.lww.com/ALN/D549). In logistic regression with inverse probability of treatment weighting, accounting for clustering by surgeon, celecoxib prescription did not significantly increase the odds of post-tonsillectomy hemorrhage requiring surgery (odds ratio, 1.4; 95% CI, 0.85 to 2.31; P = 0.2).

The overall (unadjusted) proportion of surgeries with post-tonsillectomy hemorrhage requiring surgery was less than 2.5% at all time points, including after the introduction of celecoxib prescription into routine practice beginning in 2015 (fig. 2). Detailed characteristics of patients (undergoing tonsillectomy, excluding adenoidectomy) experiencing a post-tonsillectomy hemorrhage requiring surgery are summarized in table 2. Specifically, the median (interquartile range) age was 6.35 (4.93, 10.20) yr, ASA physical status did not differ between groups, and post-tonsillectomy hemorrhage requiring surgery was most common after adenotonsillectomy to treat obstructive sleep-disordered breathing or OSA in an elective ambulatory setting. Of all bleeds requiring surgery, most (79%) were secondary and occurred a median (interquartile range) of 5.00 (2.00, 8.00) days after surgery. Three patients received a blood transfusion, none of whom were prescribed celecoxib. Among patients with post-tonsillectomy hemorrhage requiring surgery, a median (interquartile range) intraoperative IV dexamethasone dose of 0.14 (0.11, 0.16) mg/kg was administered, and 14 (16%) patients were administered a celecoxib prescription after both their index surgery and post-tonsillectomy hemorrhage requiring surgery.

Sensitivity Analyses

When the outcome was limited to secondary post-tonsillectomy hemorrhage requiring surgery, there was no association with celecoxib prescription (odds ratio, 1.34; 95% CI, 0.75 to 2.38; P = 0.3). Furthermore, the results remained consistent when adenoidectomy cases were combined with tonsillectomy (odds ratio = 1.31; 95% CI, 0.80 to 2.15; P = 0.3; N = 5,846). The results for both post-tonsillectomy hemorrhage requiring surgery and secondary-only post-tonsillectomy hemorrhage requiring surgery remained consistent after excluding those patients who had a surgery in 2007 given the high percentage of missing data in that year.

Exploratory Analyses

In our exploratory analyses when clustering on surgeon identification, the total dose of celecoxib (daily dosage × number of days prescribed) was not associated with increased post-tonsillectomy hemorrhage requiring surgery risk (odds ratio, 1.00; 95% CI, 1.00 to 1.00; P > 0.9) nor when the model accounted for the patient’s weight in kg (odds ratio, 1.01; 95% CI, 0.99 to 1.03; P = 0.3) or surgery time in min (odds ratio, 1.02; 95% CI, 1.00 to 1.03; P = 0.054). Exploratory analyses looking at risk of post-tonsillectomy hemorrhage requiring surgery when accounting for daily celecoxib dose, weight, and surgical time yielded similar results. Supplemental figure S1 (https://links.lww.com/ALN/D549) illustrates the lack of association between the probability for post-tonsillectomy hemorrhage requiring surgery and celecoxib twice daily dosing (mg/kg).

A celecoxib prescription after tonsillectomy does not significantly increase the odds of post-tonsillectomy hemorrhage requiring surgery in children after accounting for demographic and surgical characteristics. We did not find a significant difference in the proportion of post-tonsillectomy hemorrhage requiring surgery in children prescribed celecoxib versus those not prescribed celecoxib. The results were consistent in sensitivity analyses when considering only secondary post-tonsillectomy hemorrhage requiring surgery and including adenoidectomy patients. Most post-tonsillectomy hemorrhage requiring surgery occurred at a time that coincides with fibrin clot separation and rapid capillary development in the vascular stoma being vulnerable to bleeding.39 

There is confusion in the literature around the definition and acceptable rates of post-tonsillectomy hemorrhage. Postoperative hemorrhage can be classified by three levels of severity: a type-1 hemorrhage is observed at home or assessed in the emergency department without further intervention, type 2 requires readmission for observation, and type 3 requires a return to the operating room for control of hemorrhage.27  We chose a type-3 post-tonsillectomy hemorrhage as our primary outcome because it is both a patient- and provider-centered outcome that involves anesthesiologists in a high-stakes and potentially lethal clinical setting. Although minor post-tonsillectomy hemorrhage rates may exceed 15%,39,40  the generally accepted post-tonsillectomy hemorrhage rate is less than 6%.40  Because bleeding requiring surgery can have lethal consequences,24  a lower post-tonsillectomy hemorrhage requiring surgery noninferiority rate of 3% has been used in drug comparison trials27  and for national benchmarking (range, 1.25 to 3.25%). In our study, the low rates of post-tonsillectomy hemorrhage requiring surgery in patients that were or were not prescribed celecoxib are consistent with both a meta-analysis of 59 studies reporting a post-tonsillectomy hemorrhage requiring surgery rate of 1.2% (range, 0.5 to 1.9%)41  and the 2019 American Academy of Otolaryngology–Head and Neck Surgery (Alexandria, Virginia) tonsillectomy guideline.34  Although the post-tonsillectomy hemorrhage requiring surgery rates were slightly higher in patients who were prescribed celecoxib, the clinical significance of this difference (0.31%) is questionable, and the rate of post-tonsillectomy hemorrhage requiring surgery in patients prescribed celecoxib (1.94%) is well within expected limits.40 

There is a bleeding controversy regarding the use of nonselective COX inhibitor NSAIDs (e.g., ibuprofen) that inhibit COX-1 for post-tonsillectomy analgesia.14,27  Although large retrospective observational studies suggest that ibuprofen does not increase bleeding risk,14,42–44  these studies rarely assessed drug compliance. A large randomized controlled trial was unable to exclude an increased risk of severe bleeding with ibuprofen compared with acetaminophen after tonsillectomy,27  and recently a prospective study demonstrated a reduction in post-tonsillectomy hemorrhage rates from 5% to less than 1% by increasing the dosing interval of oral ibuprofen (10 mg/kg) from 6 to 8 h.45  Systematic reviews are equivocal regarding NSAIDs after tonsillectomy and are limited by a number of factors including: insufficient pediatric subjects, heterogeneity in diagnostic indication for adenotonsillectomy, surgical approach and technique, and variable NSAID type, dose, and perioperative timing studied, among others.16,18,46–48  Finally, a recent meta-analysis of ibuprofen concluded an increased post-tonsillectomy hemorrhage odds ratio of 1.38 (95% CI, 1.11 to 1.72).49  Given the uncertain risk of bleeding with nonselective NSAIDs, the benefits of COX-2–specific inhibitors in terms of analgesic efficacy and platelet sparing effects, even at supra-therapeutic plasma levels,19  are noteworthy and have been the focus of a recent meta-analysis21  and demonstrated in five randomized controlled trials.4,22,23,50,51  Celecoxib is an ideal analgesic for tonsillectomy because its oral suspension formulation can be administered both preoperatively and postoperatively in a twice-daily dosing schedule with a low parental burden for analgesia administration52  and as part of a multimodal analgesic regimen after discharge. In adults, selective COX-2 inhibition is a recognized way to reliably reduce antiplatelet effects and bleeding risk.53 

Our exploratory analyses in children found no association between post-tonsillectomy hemorrhage requiring surgery rate and celecoxib total or daily dosing, suggesting a wide pediatric therapeutic index. A dose–response relationship with celecoxib in the acute pain literature exists54,55  and is linear between celecoxib maximum concentration (Cmax) and doses ranging from 200 to 800 mg in adults,54  in whom a 400-mg loading dose followed by 200 mg every 12 h is recommended. Higher doses of celecoxib are likely required in children because pediatric studies in nonoperative settings report a 40% larger volume of distribution (7.9 ± 7.8 l/kg) with two times faster clearance (CL/F 1.4 ± 0.9 l · h−1 · kg−1), resulting in a 50% shorter elimination half-life (4.0 ± 1.5 h).56,57  Although a bodyweight drug-dosing method underestimates dose in children,58  the bodyweight0.75 model, referred to as “allometric scaling,” is useful for scaling plasma clearance.59  When applied to celecoxib dosing in children, allometric scaling of the recommended adult maintenance dose for acute pain (detailed above) translates to 4 mg/kg in children, a 33% increase in the maintenance dose compared to a mg/kg adult dose.59  Given the higher volume of distribution and the need for rapid attainment of analgesic levels immediately after tonsillectomy, an even higher preoperative allometric scaled bodyweight1.0 loading dose (i.e., a minimum of 6 mg/kg) is likely needed in children. Given its shorter half-life, either a mid-day 3 mg/kg dose or a higher twice-daily maintenance dose (6 to 7 mg/kg) is required to safely sustain analgesic levels in children, as reported in a recent publication.23 

Although our study results suggest that celecoxib prescription does not increase the odds of post-tonsillectomy hemorrhage requiring surgery and supports its safe use, selective COX-2 specific analgesics are considered off-label in North American children younger than 18 yr old. Adult studies report that NSAIDs reduce dynamic pain with movement,60  and celecoxib, beyond its effectiveness as a pre-emptive analgesic, can decrease dynamic pain with swallowing4,61  and allows for a faster return to normal diet and activity after tonsillectomy compared with placebo23  or acetaminophen.22  This facilitates oral fluid and analgesic intake and may reduce the risk of postoperative hospital visits for dehydration and pain crises.4,62  Although evidence for respiratory depression was not measured, our results support celecoxib as part of a multimodal opioid-sparing analgesic approach7,23  to lower the risk of perioperative respiratory adverse events after tonsillectomy,4  with opioid-induced respiratory depression being a particular concern in patients with OSA.3  When NSAIDs are contraindicated, selective COX-2 inhibitors may be a safe alternative.63 

Our study has several strengths and limitations. We reported on a large retrospective but homogeneously managed cohort to evaluate the rare complication of post-tonsillectomy hemorrhage requiring surgery. Exposure misclassification risk was low, because we do not routinely prescribe nonselective NSAIDs postoperatively. Our study is also unique because it included surgical indication as a covariate and used propensity scoring to account for variables associated with post-tonsillectomy hemorrhage requiring surgery. Study limitations include the potential for unidentified confounding variables, incomplete data, and celecoxib prescription as a proxy for medication ingestion compliance. However, several factors support the administration of the prescribed celecoxib, including the inpatient status of medically complex patients (who received celecoxib while admitted), the increasing rate of surgeon celecoxib prescription over time, and the fact that 28% of patients were prescribed celecoxib after post-tonsillectomy hemorrhage requiring surgery, suggesting surgeon satisfaction and confidence in this analgesic. In addition, for outpatients, we have previously reported 96% drug compliance in our randomized controlled trial.4  Enhanced drug compliance is also afforded by our unique suspension formulation (industry suspension is unavailable), which makes celecoxib easy to ingest57  and palatable.64  As a single-center study, our findings may have limited generalizability. However, Children’s Hospital of Eastern Ontario provides operating room time to community surgeons, with approximately one third of the surgeons having a community-based practice. It is also possible a trainee instead of a staff surgeon performed the procedure, affecting our primary outcome.30  Another limitation is the possibility of missed post-tonsillectomy hemorrhage requiring surgery cases; however, this is unlikely because regionally most tonsillectomies are managed at Children’s Hospital of Eastern Ontario. Finally, although we are unable to comment on analgesic efficacy, our previous randomized controlled trial4  and one performed at the Children’s Hospital of Philadelphia23  have established celecoxib as a local standard of care.

In our study, we used several proxy measures of medical complexity and disease severity. In the future, our data set will be linked to provincial health administrative data to objectively derive validated measures of comorbidity including ASA physical status to further evaluate the impact of disease severity on post-tonsillectomy hemorrhage requiring surgery and to explore the association of celecoxib prescription on emergency visits, hospital admissions, and other healthcare utilization and patient-reported (and family-reported) experience measures and outcome measures. Finally, celecoxib pharmacokinetics or dynamics and genetics in children require investigation.

In conclusion, our study results suggest that celecoxib is safe for postoperative analgesia. However, adequately powered randomized controlled trials are needed to validate this practice. When designing a prospective trial to evaluate risk for post-tonsillectomy hemorrhage requiring surgery in children, patient factors (age or weight), surgical characteristics (indication and approach or technique), and operative duration should be considered.

Acknowledgments

The authors thank Johanna Spaans, M.Sc. Epi, Ottawa Hospital Research Institute (Ottawa, Canada), for her feedback and editing the article. They also thank Nick Barrowman, Ph.D., senior statistician at Children’s Hospital of Eastern Ontario Research Institute (Ottawa, Canada), for his advice and statistical support and Linda Huynh, as the Children’s Hospital of Eastern Ontario (Ottawa, Canada) Medical Records Research Coordinator clerk, for locating and providing the numerous patient paper charts.

Research Support

Supported by grant No. CHA-20-006 from the Children’s Hospital Academic Medical Organization Innovation Fund, a joint initiative of the Ministry of Health and the Ontario Medical Association (Ontario, Canada) that is managed by the Innovation Fund Provincial Oversight Committee.

Competing Interests

The authors declare no competing interests.

Supplemental tables, https://links.lww.com/ALN/D549

Supplemental Figure S1. Probability of post-tonsillectomy hemorrhage requiring surgery, by celecoxib dosage, https://links.lww.com/ALN/D549.

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