The Laryngoscope

C 2014 The American Laryngological,

V
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 cri-
teria 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]: 2.08–15.27; P <.001). In contrast, children under 18 are not at statistically significantly increased
risk (RR: 1.39; 95% CI: 0.84–2.30; 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, 124:1789–1793, 2014

INTRODUCTION bleeding with ketorolac, the findings were not statisti-

Ketorolac is a nonsteroidal anti-inflammatory
drug (NSAID) administered intravenously for analge-
sia. It is an alternative or adjunct to narcotics, acet-
aminophen, 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
hemorrhage in some settings.1 A recent 2010 Cochrane
review2 of NSAID use in children undergoing tonsillec-
tomy specifically examined six randomized controlled
studies and concluded that there is no statistically
significantly increased risk of reoperation for post-
tonsillectomy hemorrhage in patients who receive
ketorolac compared to controls. However, the reported
summary odds ratio (3.12, 95% confidence interval
[CI]: 0.53-18.38; 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, 2013.
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 94115. E-mail: dylan.chan@ucsf.edu
DOI: 10.1002/lary.24555
cally significant. Furthermore, recent 2011 American
Academy of Otolaryngology–Head and Neck Surgery
(AAO-HNS) guidelines for pediatric tonsillectomy3
stated that “post-tonsillectomy hemorrhage rates with
ketorolac range from 4.4% to 18%, and therefore ketor-
olac 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 recom-
mendation. 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 predomi-
nantly reported results on adults, not children.
Given the lack of clarity on this issue in the litera-
ture, 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 hemor-
rhage with and without ketorolac use in adults and
children.

Laryngoscope 124: August 2014 Chan and Parikh: Ketorolac and Tonsillectomy
1789

Fig. 1. Flowchart of study inclusion. [Color figure can be viewed in
the online issue, which is available at www.laryngoscope.com.]
MATERIALS AND METHODS
Systematic Review
PubMed search from 1970 to 2013 with the terms “[ketoro-
lac OR toradol] AND tonsillectomy” was performed by two inde-
pendent authors (D.K.C., S.R.P.). Inclusion criteria were as
follows: 1) original study reporting unique individual patient-
level data; 2) patients underwent tonsillectomy by any tech-
nique; 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 mini-
mum or maximum length of follow-up required after interven-
tion. 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 ketor-
olac 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 refer-
ence 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 appropri-
ate 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 vari-
ation in treatment; high: significant variation in treatment.
5. Standardization (outcome). Low: outcome measures deter-
mined identically for all subjects; mid: some variation in
Laryngoscope 124: August 2014
1790
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.
Data were compiled from included studies by direct extrac-
tion of individual patient-level data and subjected to meta-
analysis. 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 postoper-
ative hemorrhage rates. Of the remaining 10 studies1,4,8–15
(Fig. 1), seven exclusively included children under the age
of 18, though the exact age range varied from one study to
another. Two studies4,8 included both adults and children;
data specific to children, as defined by the study, were
extracted from each study and included for further analy-
sis. One study1 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 pro-
spective and retrospective studies.
Meta-analysis
When all 10 studies are considered together, a sum-
mary RR of 2.04 (95% CI: 1.32–3.15; 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
Chan and Parikh: Ketorolac and Tonsillectomy
 TABLE I.
Risk of Bias of Included Studies.
Treatment Standardization Standardization Selective Complete
Study Year Design Randomization Allocation Blinding (Treatment) (Outcome) Reporting Data

Agrawal10 1999 R High High High Low Mid Low Low

Bailey1 1997 P Mid High Low Low Mid Low Low
Gallagher8 1995 R High High High Mid Mid Mid Low
Gunter11 1995 P Low High Low Low Low Low Low
Judkins4 1996 R High High High Mid Mid Mid Low
Keidan12 2004 P Mid High High Low Low Low Low
Romsing13 1998 P Low Mid Low Low Low Low Low
Rusy14 1995 P Mid High High Low Low Low Low
9
Splinter 1996 P Low High High Mid Low Low Low
Sutter15 1995 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: 2.08–15.27; P <.001) com-
pared to children (RR: 1.39; 95% CI: 0.84–2.30; P 5.20).
However, adults receiving ketorolac had over five times the
increased risk of bleeding, which was statistically signifi-
cantly elevated compared to control, but there was no sig-
nificantly increased risk of bleeding in children. The adult
data included three studies, two retrospective and one pro-
spective 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 con-
sistent; six prospective studies gave a summary RR of
1.49 (95% CI: 0.71–3.13; P 5.30), whereas three retro-
spective studies yielded a summary RR of 1.31 (95% CI:
0.66–2.59; P 5.45). Timing of ketorolac administration
also did not affect the RR: preoperative (RR: 1.43; 95%
CI: 0.60–3.42; P 5.43) and intra- or postoperative (RR:
1.37; 95% CI: 0.74–2.54; P 5.32) ketorolac administra-
tion 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 associ-
ated with an increased risk of post-tonsillectomy hemor-
rhage in adults but not in children. Results of seven
prospective, randomized controlled studies, as well as out-
comes 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 post-
tonsillectomy 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 tonsillec-
tomy 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
risk16; 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 follow-
up. 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 2.02. One of these studies9 was an outlier,
with an RR of 9.17 (95% CI: 0.53–159.14; P 5.13). This
prospective, randomized, single-blinded, placebo-con-
trolled 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 demon-
strate a difference in RR with preoperative and postop-
erative ketorolac administration.
It remains a possibility that an increased risk of
bleeding exists in children, and that the existing studies

Laryngoscope 124: August 2014 Chan and Parikh: Ketorolac and Tonsillectomy
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 TABLE II.
Post-Tonsillectomy Hemorrhage Rates in Subjects Receiving Perioperative Ketorolac and Unexposed Controls.
Study Year Population Design Timing Toradol Toradol (%) Control Control (%)

Agrawal10 1999 Pediatric R Intra 5/213 2.3 3/97 3.1

Bailey1 1997 Adult P Post 7/37 18.9 3/43 7.0
Gallagher8 1995 Pediatric R Intra 7/107 6.5 2/60 3.3
Gallagher8 1995 Adult R Intra 10/62 16.1 0/29 0.0
Gunter11 1995 Pediatric P Post 6/41 14.6 5/39 12.8
Judkins4 1996 Pediatric R Intra 4/36 11.1 11/200 5.5
Judkins4 1996 Adult R Intra 6/22 27.3 1/53 1.9
Keidan12 2004 Pediatric P Pre 0/25 0.0 0/32 0.0
Romsing13 1998 Pediatric P Pre/post 8/40 20.0 5/20 25.0
Rusy14 1995 Pediatric P Pre 0/25 0.0 0/25 0.0
Splinter 9 1996 Pediatric P Pre 5/35 14.3 0/29 0.0
Sutter15 1995 Pediatric P Post 0/45 0.0 0/42 0.0
All children 35/567 6.2 26/544 4.8
All adults 23/121 19.0 4/125 3.2
Pediatric prospective 19/211 9.0 10/187 5.3
Pediatric retrospective 16/356 4.5 16/357 4.5
All studies 58/688 8.4 30/669 4.5

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 1.39. If this is accu-
rate, 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 approxi-
mately 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 meta-
analysis 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 www.laryngoscope.com.]

Laryngoscope 124: August 2014 Chan and Parikh: Ketorolac and Tonsillectomy
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 Despite being relatively underpowered compared to
the pediatric data, the adult data show statistically sig-
nificantly increased risk of post-tonsillectomy hemor-
rhage 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 pro-
cedure 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 gen-
eral 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.
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