Systematic Review/Meta-analysis
Otolaryngology–
Postoperative Bleeding Associated with
Ibuprofen Use after Tonsillectomy:
A Meta-analysis
William Stokes, MD1, Robert T. Swanson2, Jane Schubart, MBA, PhD3,4,
and Michele M. Carr, DDS, MD, PhD1
No sponsorships or competing interests have been disclosed for this article.
Abstract
Objective. To better quantify the risk of ibuprofen-associated
posttonsillectomy hemorrhage (PTH).
Data Sources. PUBMED/MEDLINE, Web of Science, and
Cochrane Clinical Trials Database.
Review Method. Literature searches were performed for
English-language publications containing the terms tonsillect-
omy, ibuprofen, and tonsillectomy from database inception to
May 2017. Human clinical trials, prospective cohort studies,
and retrospective cohort studies related to tonsillectomy,
ibuprofen use, and posttonsillectomy hemorrhage among
pediatric patients were selected. Electronic searches
revealed 151 studies, of which 12 were deemed eligible for
analysis. Studies were weighted according to level of evi-
dence and risk of bias.
Results. Pooling of results across all studies showed a statisti-
cally significant increase in PTH among the patients taking
ibuprofen (odds ratio, 1.38; 95% confidence interval, 1.11-
1.72). The I2 statistic of 20.8% demonstrates overall low
study heterogeneity and good comparability of the results.
Conclusion. Our meta-analysis of available cohort studies and
randomized controlled trials (RCTs) shows possible
increased tendency to PTH with the use of ibuprofen. This
has not been demonstrated in other studies and systematic
reviews because their analyses were limited by use of multi-
ple nonsteroidal anti-inflammatory drugs and inclusion of
studies limited to the perioperative period and low sample
size. However, the current analysis is limited due to inclu-
sion of many retrospective cohort studies with unclear
follow-up and no blinding. Further RCTs will be required to
investigate this trend toward increased PTH.
Keywords
tonsillectomy, hemorrhage, posttonsillectomy hemorrhage,
ibuprofen, tonsil, pediatric
Received January 27, 2019; revised April 1, 2019; accepted May 2,
2019.
Head and Neck Surgery
1–8
Ó American Academy of
Otolaryngology–Head and Neck
Surgery Foundation 2019
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/0194599819852328
http://otojournal.org
T
onsillectomy is a common procedure in the pediatric
population, with indications for surgery, including
obstructive sleep apnea, sleep-disordered breathing,
and chronic tonsillitis.1,2 Postoperative tonsillectomy
analgesia is typically obtained with a combination of aceta-
minophen, ibuprofen, and opioids.2 Deaths have been
reported related to respiratory depression after use of
codeine in children.3 In particular, young and obese children
with a history of sleep apnea are at higher risk of develop-
ing serious opioid-related respiratory depression.3 Other
children may possess forms of the liver microenzyme
CYP2D6, which make them extensive or ultrarapid metabo-
lizers of codeine.3,4 In 2013, the US Food and Drug
Administration (FDA) issued a Boxed Warning against
using codeine in children after tonsillectomy. This warning
resulted in many surgeons turning to the use of ibuprofen
after tonsillectomy. As a nonsteroidal anti-inflammatory
drug (NSAID), ibuprofen use remains an area of debate in
postoperative pain management. Ibuprofen is a nonselective
inhibitor of cyclooxygenase (COX) and works by limiting
the production of proinflammatory cytokines.5,6 Its nonse-
lective inhibition of COX also leads to blocking of the for-
mation of thromboxane A2, a component in the platelet
aggregation cascade.5,6 This inhibition may cause a systemic
bleeding tendency in patients taking these medications.5,6
One of the most concerning complications after tonsil-
lectomy is posttonsillectomy hemorrhage (PTH). This can
cause significant morbidity and even mortality in this vul-
nerable population. Typical rates of PTH range from 0.1 to
5.0%.1,7-10 The low rate of this potentially catastrophic
1
Department of Otolaryngology–Head and Neck Surgery, West Virginia
University, Morgantown, West Virginia, USA
2
College of Medicine, Pennsylvania State University, Hershey, Pennsylvania,
USA
3
Department of Surgery, College of Medicine, Pennsylvania State University,
Hershey, Pennsylvania, USA
4
Department of Public Health Sciences, College of Medicine, Hershey,
Pennsylvania State University, Pennsylvania, USA
Corresponding Author:
William Stokes, MD, Department of Otolaryngology–Head and Neck
Surgery, West Virginia University School of Medicine, PO Box 9200,
Morgantown, WV 26501, USA.
Email: wastokes@hsc.wvu.edu
2 Otolaryngology–Head and Neck Surgery
Table 1. PICO Statement.
Variable
Population Children \18 years old who underwent tonsillectomy and were followed past the immediate postoperative period
Intervention Ibuprofen used for posttonsillectomy analgesia
Control No use of NSAID for posttonsillectomy analgesia
Outcome Posttonsillectomy hemorrhage
Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.
complication makes it difficult to obtain sufficient power in
a single study to identify a significant difference in bleed
rates between patients taking ibuprofen and controls. A pre-
vious systematic review and meta-analysis in 2013 looking
at all NSAIDs, including ketorolac, showed an increased
risk of bleeding requiring surgical intervention among the
NSAID population, but this was not statistically significant;
there was a wide range in the confidence interval, a small
sample size, and high study heterogeneity.11 We performed
an up-to-date, focused systematic review of all previous
randomized controlled trials (RCTs) and cohort studies
that looked at PTH after tonsillectomy with and without
the use of ibuprofen to better clarify the risk of PTH in
this population.
Method
A systematic review of articles related to PTH, ibuprofen, and
tonsillectomy was conducted. The study methodology was
based upon the Cochrane Handbook for Systematic Reviews of
Interventions.12 A review protocol was written in accordance
with the Preferred Reporting Items for Systematic Reviews
and Meta-Analysis Protocols (PRISMA-P), and PUBMED/
MEDLINE, Web of Science, and Cochrane Clinical Trials
Database were searched from inception to September 2018 for
English-language articles using the terms tonsillectomy, ibu-
profen, and tonsillectomy and ibuprofen (see Appendix 1,
available in the online version of the article).
Human RCTs, prospective cohort studies, and retrospec-
tive cohort studies related to tonsillectomy, ibuprofen use,
and PTH were reviewed. Inclusion criteria were studies
involving pediatric patients, \18 years old, that compared
bleeding rates in patients treated with and without post-
operative ibuprofen and followed patients past the initial
postoperative period to assess for delayed bleeding. Factors
such as age, tonsillectomy technique, use of postoperative
antibiotics, indication for surgery, and postoperative steroids
were considered possible confounding variables when asses-
sing study bias. The primary outcome was PTH. See Table 1
for full PICO statement.
Two authors (W.S. and R.T.S.) independently screened
titles and abstracts identified from the electronic search and
then independently assessed full-text papers for eligibility.
Electronic search revealed 151 studies, of which 117 were
excluded based on screening of the title and abstract. An
additional 19 articles were identified as duplicates. Three
studies were excluded because of the use of a control group
Description
151 records identified through database
searching.
MEDLINE 49; Web of Science 67; Cochrane
Clinical Trial Database: 35.
117 results were excluded
based on title and abstract
34 articles identified
19 duplicates excluded
15 full-text articles assess for eligibility
3 articles excluded due to inappropriate control
group (prednisolone and Cox-2 inhibitors)
1 article excluded due to focus on non-pediatric
patients
12 articles included
in final review and data extraction
Figure 1. Preferred Reporting Items for Systematic Reviews and
Meta-Analysis (PRISMA) diagram.
that could theoretically increase the rate of PTH (2 studies
used COX-2 inhibitors for the control group13,14 and 1
group used prednisolone15). Finally, 1 study16 was excluded
because it included both adult and pediatric patients. This
identified 12 studies eligible for analysis (Figure 1).
The appropriate level of evidence for each study was
determined with guidelines established by the Center for
Evidence-Based Medicine (http://www.cebm.net/index). A
study bias assessment was performed with the 12 eligible
studies by 2 separate authors (W.S. and R.T.S.) according to
the Newcastle-Ottawa Quality Assessment Scale for cohort
studies (NOS)17 and the Cochrane Collaboration’s tool for
assessing risk of bias for RCTs.18 The NOS involves a star
system in which a study is judged based on 3 broad perspec-
tives: the selection of the study group, comparability of the
groups, and ascertainment of the outcome of interest.
Higher quality studies can be awarded up to 9 stars in the
NOS. The risk of bias in RCTs was assessed with the
Cochrane Collaboration’s tool for assessing risk of bias.18
Seven quality items were scored as low, high, or unclear
risk of bias. Disagreements were resolved by reviewing the
studies in consensus.
All outcome variables were dichotomous, and the total
number of patients and the number of events for all cases of
PTH were obtained. One study19 had 3 separate study
groups (ibuprofen, metamizole sodium, and acetaminophen).
For the purposes of comparing rates of PTH, the metamizole
Stokes et al
sodium and acetaminophen groups were combined into a
control group given there is no reported increased rates of
PTH with either of these types of drugs. Studies were
weighted according to the sample size and estimate of
treatment effect. Pooled odds ratios (ORs) of PTH were
assessed with the ‘‘metan’’ procedure in Stata/IC 12.1
(StataCorp LLC, College Station, Texas). A random-effects
model was constructed using the DerSimonian and Laird
method, with the estimate of heterogeneity being taken from
the Mantel-Haenszel model. Assessment of heterogeneity
between studies was performed using the I2 statistic.20,21 A
funnel plot was performed to assess for general publication
bias.
Results
Table 2 shows the general demographics for the 12 studies
selected for inclusion in the systematic review. Seven of the
studies included were retrospective cohort studies,7,19,22-27 1
was a prospective cohort study,19 1 was a retrospective data-
base study,28 and 3 were RCTs.19,29-31 All studies included
pediatric patients who underwent tonsillectomy for OSA or
chronic tonsillitis. Techniques for tonsillectomy included
intra- and extracapsular tonsillectomy performed with cold
steel, monopolar cautery, coblator, and bipolar cautery.
Although tonsillectomy technique varied widely across all
the studies, in each individual study, technique used was
consistent and well represented except for 4 stud-
ies.22,23,28,29 Ibuprofen doses varied across the studies and
ranged from 5 to 10 mg/kg. Other possible confounding fac-
tors such as indication for surgery were controlled in 3 of
12 studies.22,26,27 Age at time of surgery, a well-documented
bleeding risk factor,8 was controlled for in only 7 of 12
studies.7,19,27-31
Assessment of bias in observational studies and RCTs
can be found in Table 3 and Table 4, respectively. Overall,
we found a low risk of selection and outcome bias across all
observational studies. Comparability of control groups was
fair, with 4 of 9 studies7,19,27,28 adequately controlling for
age and 6 of 9 studies7,19,24-27 controlling for surgical tech-
nique. Among the RCTs, Kelly et al29 and Harley and
Dattolo31 showed overall low risk of bias, but no studies
reported adequate blinding of participants and patients
during the studies’ duration. Kelly et al29 was stopped early
because of concerns about oxygen desaturations in the
opioid group and therefore suffers from early conclusion
bias. St Charles et al30 was subject to possible high selection
bias with poor randomization and unclear blinding of patient
allocation.
All studies recorded PTH with various reporting mechan-
isms. Retrospective cohort studies identified PTH by look-
ing at Current Procedural Terminology (CPT) codes for
admission and procedures performed7,28 or by retrospective
chart review of patients returning to the emergency depart-
ment (ED) after surgery.7,19,22-27 RCTs used parental report-
ing and ED readmissions to identify PTH, and all
incidences of bleeding, including blood-tinged saliva, were
reported in these studies.19,29-31
3
The overall study heterogeneity was low at 20.8% as
assessed by I2 statistic, which resulted in all studies being
included in the final analysis (Figure 2). Pooling of results
across all studies showed a statistically increased tendency
for PTH among the patients taking ibuprofen (OR = 1.38;
confidence interval [CI], 1.11-1.72) (Figure 2). Studies
were weighted according to sample size and treatment
effect. In addition, we performed a funnel plot to assess for
publication bias (Figure 3). We found no evidence of pub-
lication bias, with most studies lying within the 95% CI of
the funnel plot. Secondary analysis was performed, limiting
the studies to those that controlled for age.
Discussion
Our systematic review shows an increased tendency for
PTH with the use of ibuprofen (OR = 1.38; CI, 1.11-1.72).
This tendency has been demonstrated in a previous systema-
tic review by Cochrane in 2013 that showed a PTH requir-
ing surgical intervention (OR = 1.6 for patients taking
NSAIDs).11 However, their analysis was limited due to its
heterogeneity with the use of multiple NSAIDs, such as
ketorolac, and inclusion of studies that looked only at bleed-
ing rates in the immediate postoperative period. Overall,
their results were not statistically significant but showed a
trend toward increased bleeding.
Ibuprofen’s impact on PTH is difficult to demonstrate in
a single institutional study because of the overall low likeli-
hood of PTH (0.1%-5%).7-10 Assuming a PTH rate of 5%, it
would take ~17,000 patients to detect even a 20% increase
in PTH rate with ibuprofen. Therefore, our systematic
review and analysis allowed us to see a statistically signifi-
cant 35% increase in PTH with ibuprofen due to a sample
size of 319,305 patients. By including only studies that used
ibuprofen and looked at the bleeding rates for the entire
postoperative period, we get a better assessment of the typi-
cal bleeding rates seen in a clinical setting.
Our study was limited due to the lack of available data
on the rate of PTH requiring return to the operating room
(OR) and the general severity of PTH. This lack of data
makes it difficult to assess the severity and therefore clinical
significance of the PTH. This study shows a greater odds of
PTH associated with ibuprofen use but does not assess the
severity of those bleeds.
A possible limitation of the meta-analysis is the lack of
control of age in 5 of 12 studies. This is a well-documented
risk factor for bleeding, as noted in previous studies.8,32,33
However, it appears that age did not play a significant
factor in skewing our data. Restricting the meta-analysis to
the 7 studies that controlled for age resulted in similar
results (OR = 1.26; CI, 1.04-1.51; I2 = 0.0%). The meta-
analysis results were similar (OR = 1.42; CI, 1.12-1.81) and
heterogeneity remained of low importance (I2 = 32.1%).
Surgical technique also varied across the different stud-
ies. The techniques ranged from extracapsular tonsillectomy
performed with harmonic scalpel, monopolar cautery, cobla-
tor, or cold knife to intracapsular tonsillectomy performed
with coblator. However, the individual surgical technique
4
Table 2. Study Demographics.
Ibuprofen Group Control Group Possible Confounders Bleed Identification
Article Study Type No. (No. with PTH) (No. with PTH) Control Used Addressed Ibuprofen Dose Technique Notes

Pfaff et al7 Retrospective cohort 6014 2697 (98) 3317 (113) Acetaminophen with Age, surgical technique 10 mg/kg Retrospective analysis Extracapsular tonsillectomy with
codeine of CPT for tonsillar harmonic scalpel performed in all
hemorrhage cases. Follow-up in clinic, time not
reported
D’Souza et al26 Retrospective cohort 2180 449 (17) 1731 (19) Acetaminophen with Surgical technique, Not stated Retrospective analysis of ED Intracapsular tonsillectomy performed in
codeine indication for surgery admission for tonsillar all cases. Cases from 2002 to 2005
hemorrhage received control medication and cases
from 2011 to 2013 received ibuprofen.
The control group was significantly
younger (age = 6) than the ibuprofen
group (9.5 years) at the time of
surgery. Follow-up in clinic, time not
reported
Bedwell et al25 Retrospective cohort 666 177 (3) 489 (17) Acetaminophen with Surgical technique 5 mg/kg Retrospective analysis of ED Extracapsular tonsillectomy with
codeine admission for tonsillar monopolar cautery performed in all
hemorrhage case. Codeine group was significantly
older (8.1 years) than the ibuprofen
group (6.2). Follow-up in clinic, time
not reported
Mattos et al22 Retrospective cohort 1065 783 (66) 282 (23) Acetaminophen 6 Indication for surgery 10 mg/kg q6hp Retrospective analysis of ED Extracapsular tonsillectomy with
opioid admission for tonsillar monopolar cautery or coblator.
hemorrhage Ibuprofen used as rescue medication in
ibuprofen group. Part of the ibuprofen
group received codeine, and the other
part did not. It was not clear how
often ibuprofen was dosed. Four- to 6-
week follow-up
Yaman et al24 Retrospective cohort 171 62 (3) 109 (4) Acetaminophen Surgical technique Not stated Retrospective analysis of ED Extracapsular tonsillectomy with cold
admission for tonsillar technique. Only 1 week of follow-up
hemorrhage
Jeyakumar et al23 Retrospective cohort 1148 480 (5) 668 (5) Acetaminophen with None 5 mg/kg Retrospective analysis of ED Surgical technique not noted. Study
codeine admission for tonsillar performed at 2 separate institutions
hemorrhage with the ibuprofen group coming from
institution B and the control group
coming from both institutions A and B.
One month of follow-up
O’Connell Retrospective 306,536 1206 (46) 305,330 (8224) Not ibuprofen Age Unknown Retrospective analysis Database study, tracked medications by
Ferster et al28 database cohort of ED admission for dates filled at pharmacy. Technique for
tonsillar hemorrhage tonsillectomy not noted; medications
for control group were not tracked
Swanson et al27 Retrospective cohort 773 504 (44) 269 (16) Acetaminophen 6 Age, surgical technique, Unknown Retrospective analysis of ED Extracapsular tonsillectomy with
opioid indication for surgery admission for tonsillar monopolar cautery performed in all
hemorrhage case. Two-week follow-up
Harley and Dattolo31 Randomized 27 16 (2) 11 (0) Acetaminophen with Age, surgical technique, 5 mg/kg q6h Parental report, readmission Extracapsular tonsillectomy with
controlled trial codeine antibiotic, steroids to the ED monopolar cautery or cold technique.
(none given) Two-week follow-up
St Charles et al30 Randomized 110 55 (4) 55 (5) Acetaminophen with Age, surgical technique, 10 mg/kg Parental report, readmission Extracapsular tonsillectomy with
controlled trial codeine antibiotic, steroids to the ED monopolar cautery performed in all
(none given) cases. Follow-up in clinic, time not
reported

(continued)
 Table 2. (continued)

Ibuprofen Group Control Group Possible Confounders Bleed Identification

Article Study Type No. (No. with PTH) (No. with PTH) Control Used Addressed Ibuprofen Dose Technique Notes

Kelly et al29 Randomized 86 41 (3) 45 (2) Acetaminophen with Age, antibiotics (none 10 mg/kg Parental report, readmission Surgical technique was not noted. Study
controlled trial morphine given), steroids (none to the ED was stopped early due to increased
given) rate of early postoperative
desaturations in the morphine group
(however, there was no change in mean
desaturation rate and lowest saturation
level in the study). Follow-up at least 5
days
Ozkiris et al19 Prospective cohort 340 115 (6) 225 (8) Metamizole sodium/ Age, surgical technique, 5 mg/kg q4h Parental report, readmission Extracapsular tonsillectomy with bipolar
acetaminophen antibiotic, steroids to the ED cautery, RCT with 3 arms (ibuprofen,
(none given) metamizole sodium, and
acetaminophen). Metamizole sodium
and acetaminophen groups were
combined for analysis. One-week
follow-up

Abbreviations: CPT, Current Procedural Terminology; ED, emergency department; PTH, posttonsillectomy hemorrhage; RCT, randomized controlled trial.

Table 3. Newcastle-Ottawa Quality Assessment Scale for Cohort Studies.a

Outcome of
Selection of Ascertainment of Interest Not Comparability of Assessment of Follow-up Adequacy of
Article Representativeness Control Exposure Present at Start Controls Outcome Long Enough Follow-up Overall Bias

Pfaff et al7 * * * * ** * * ******** (8)

D’Souza et al26 * * * * * * * ******* (7)
Bedwell et al25 * * * * * * * ******* (7)
Mattos et al22 * * * * * ***** (5)
Yaman et al24 * * * * * * * ******* (7)
Jeyakumar et al23 * * * * * ***** (5)
O’Connell Ferster et al28 * * * * * * * ******* (7)
Swanson et al27 * * * * ** * * ******** (8)
Ozkiris et al19 * * * * * * ****** (6)
a
Studies with 7 asterisks were considered high quality. Studies with 4 asterisks were considered low quality.

5
6 Otolaryngology–Head and Neck Surgery

Table 4. Assessing Risk of Bias for Randomized Controlled Trials.

Blinding of Incomplete Selective Free of
Sequence Allocation Participants Blinding of Outcome Reporting Other Sources
Article Generation Concealment and Personnel Outcome Data Bias of Bias

Harley and Dattolo31 Low Low High Low High Low Low
St Charles et al30 Unclear Unclear High High Low Low Low
Kelly et al29 Low Low High Low Low Low High

A further limitation is that no studies can state that the

Figure 2. Forest plot of comparison: ibuprofen vs control (acetami-
nophen 6 codeine). Outcome: posttonsillectomy hemorrhage. 1 =
Swanson et al27; 2 = Mattos et al22; 3 = Bedwell et al25; 4 = Ozkiris
et al19; 5 = Kelly et al29; 6 = Yaman et al24; 7 = Harley and
Dattolo31; 8 = Pfaff et al7; 9 = St Charles et al30; 10 = D’Souza
et al26; 11 = Ferster et al28; 12 = Jeyakumar et al.23
patients received the prescribed ibuprofen, as there are no
third-party medication diaries or drug blood levels available.
The dosing regimen in these studies varies; giving ibuprofen
as a multidrug pain control regimen may result in fewer
doses being taken as patients have other options. Also,
many studies used a lower dose of ibuprofen, 5 mg/kg, than
is typically prescribed in clinical practice. Both these factors
could further reduce the rates of PTH associated with ibu-
profen that we have seen in our study.
Two previous meta-analyses11,34 did not prove an
increased rate of PTH with NSAID use. Their findings were
not significant due to low power and study heterogeneity,11
but by including cohort and RCT studies that used ibuprofen
and looked for delayed bleeding throughout the posttonsil-
lectomy period, we were able to improve on previous meta-
analysis heterogeneity and show an increase in PTH in
patients prescribed ibuprofen. Yet, a major limitation of our
analysis is the lack of large RCTs assessing PTH. We await
the RCTs adequately powered to detect an increased rate of
PTH with ibuprofen use and that compares PTH to opioid-
based therapy and its inherit risk of respiratory depression.

Figure 3. Funnel plot assessing publication bias.
was controlled for in 8 of 12 studies. The wide variation in
techniques makes it hard to relate one study to another;
however, our results are strengthened once again due to the
low heterogeneity between the groups.
Conclusion
Interest in using ibuprofen after tonsillectomy is high cur-
rently. This study suggests that caution may be indicated
when doing so. Under the Clinical Practice Guideline for
Tonsillectomy in Children, ibuprofen is recommended for
postoperative analgesia after tonsillectomy. This meta-
analysis demonstrates an increased rate of delayed hemor-
rhage after tonsillectomy. However, this study cannot assess
the severity and clinical relevance of increased PTH due to
limitations in the available data. We need an adequately
powered, likely multi-institutional, RCT that adequately
assesses the risk of ibuprofen-associated PTH vs the risk of
opioid-related respiratory depression after tonsillectomy.
Data in the literature suggest an increased rate of PTH in
older children with chronic tonsillitis7 and increased rate of
respiratory depression in younger children who typically
have OSA.3 This does open the possibility of using different
medications for different age groups/indications, but addi-
tional studies will be required to further assess these risks.
Author Contributions
William Stokes, obtained data, drafted the work, approved final
work, accountable for all aspects; Robert T. Swanson, obtained
Stokes et al
data, revised the work for important intellectual content, approved
final work, accountable for all aspects; Jane Schubart, data analy-
sis, revised the work for important intellectual content, approved
final work, accountable for all aspects; Michele M. Carr, per-
formed study design and oversaw execution, revised the work for
important intellectual content, approved final work, accountable
for all aspects.
Disclosures
Competing interests: None.
Sponsorships: None.
Funding source: None.
Supplemental Material
Additional supporting information is available in the online version
of the article.
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