Tonsillectomy With or Without Adenoidectomy Clinical Trial
Official title:
Postoperative Ibuprofen Use and Risk of Bleeding in Pediatric Tonsillectomy
Pediatric tonsillectomy is one of the most common surgical procedures annually in the United States; risks include postoperative hemorrhage and poor pain control. Controversy exists regarding optimal pharmacologic pain management following surgery, as each drug's efficacy is balanced by its specific side effects. Ibuprofen is effective in controlling postoperative pain following tonsillectomy, but its mechanism of action results in decreased platelet function, which may increase postoperative bleeding events. This is a multicenter, randomized control non-inferiority trial designed to assess the relationship between short-course ibuprofen use and post-tonsillectomy bleeding when compared to acetaminophen.
Pediatric tonsillectomy is one of the most common surgical procedures in the United States,
with over 500,000 procedures performed annually.1,2 The most common indications for
tonsillectomy with and without adenoidectomy are sleep-disordered breathing and recurrent
tonsillitis, though significant demographic and regional variation exist.2 In recent years,
particular attention has been paid to the deleterious sequelae of pediatric obstructive sleep
apnea on children's behavior, cognition, and growth as well as its negative effects on
long-term pulmonary and cardiovascular health.3-5 Tonsillectomy is generally considered a
safe procedure, though potential exists for significant procedural morbidity. Potential risks
associated with tonsillectomy include postoperative hemorrhage, airway risk, aspiration, burn
injury, post-operative nausea and vomiting, and poor pain control.6,7 Postoperative
hemorrhage is the most serious post-tonsillectomy complication and can be divided according
to timing (primary occurring <24 hours from surgery, or secondary occurring >24 hours after
surgery) and severity (level 1: any history of bleeding, level 2: bleeding requiring
inpatient admission, level 3: bleeding requiring operative intervention). Following
discharge, inadequate analgesia can result in secondary complications such as dehydration,
nausea, bleeding, hospital readmission, and increased healthcare expenditures.8,9
Significant controversy exists as to the optimal pain management protocol following pediatric
tonsillectomy.8,9 Many studies have examined both pharmacologic and non-pharmacologic
modalities to improve pain control in this population. The most common medications prescribed
after tonsillectomy include acetaminophen (paracetamol), non-steroidal anti-inflammatory
drugs (NSAIDs) (e.g. ibuprofen), and narcotic pain medications, each with a unique mode of
action and risk profile.8,10-12 Acetaminophen, which has both peripheral and central
anti-nociceptive properties, is generally well-tolerated with low incidence of serious side
effects, but may not provide adequate pain control when used at recommended pediatric
dosages.13 Narcotic (opioid) pain medications act on the mu opioid receptor and effectively
decrease sensory and affective components of pain.14 Unfortunately, opioid pain medications
also result in dose-dependent respiratory depression; a significant contraindication in
patients with sleep-disordered breathing.15,16 The FDA has released a warning cautioning
against the use of codeine, an opioid, for postoperative analgesia following tonsillectomy.7
Furthermore, emerging data suggests that adolescent patients receiving prescription for
narcotic pain medication may be at risk for long-term opioid dependence and addiction.17
NSAIDs provide analgesia through reversible COX-1 and COX-2 pathway inhibition which results
in decreased prostaglandin-induced inflammation and edema.18 This mechanism of action also
interferes with platelet aggregation, potentially impacting bleeding in the postoperative
period. Ibuprofen, a derivative of propionic acid, is one of the most commonly prescribed
NSAID medications, with a half-life of less than 12 hours.19,20 Pain control in patients
receiving NSAIDs is equivalent, or superior to, those receiving acetaminophen alone or in
combination with narcotic medication.21-23 In 2011, the American Academy of Pediatrics
released its Clinical Practice Guidelines, which stated that ibuprofen can safely be used for
postoperative analgesia following tonsillectomy24, a recommendation based on a 2005 Cochrane
Review of NSAIDs and post-tonsillectomy bleeding. The most recent Cochrane review on this
topic, published in 2012 and based on 15 randomized control trials (RCTs), concludes that
there is insufficient evidence available to exclude an increased risk of bleeding with NSAID
use following pediatric tonsillectomy.25 This is supported by data from a prospective,
randomized control non-inferiority trial conducted at our own institution, in which
participants received either ibuprofen or acetaminophen for 9 days following surgery. In this
study, an increased rate of post-tonsillectomy bleeding requiring operative intervention
could not be excluded because the non-inferiority threshold was crossed. The duration of safe
NSAID use, if any, after tonsillectomy is unknown. A study definitively documenting safety
and efficacy of short-course NSAID administration following tonsillectomy in children would
affect our own standard of care as well as overall clinical practice guidelines.
This study serves as a follow-up clinical trial to a double-blind randomized control
non-inferiority trial titled "Postoperative Ibuprofen and the Risk of Bleeding After
Tonsillectomy with or without Adenoidectomy" conducted from 2012 to 2016 at Massachusetts Eye
and Ear and collaborating institutions. In this study, participants were randomized to
receive either ibuprofen (10 mg/kg every 6 hours) or acetaminophen (15 mg/kg every 6 hours)
for 9 days following surgery. The non-inferiority margin was set at 3%. Increased type 3
bleeding (bleeding requiring operative intervention) could not be excluded because the
non-inferiority threshold was crossed.
In this study, type 3 bleeding occurred in the ibuprofen group on an average postoperative
day of 5.95. Additional analyses were conducted on study subjects who discontinued the study
drugs prior to postoperative day 9 (the scheduled end point). A total of 50 patients
discontinued study medication on or before postoperative day 3. Of these, 21 were randomized
to the ibuprofen arm and 0/21 experienced postoperative bleeding events.
A recent systematic review by Tan et al examined commonly used medications following
tonsillectomy and efficacy and risks associated with each drug.8 Acetaminophen is commonly
used following tonsillectomy given its low side effect profile; however, analgesia is often
inadequate at recommended dosages.26 Despite a 2013 FDA warning cautioning against opioid use
following pediatric tonsillectomy due to increased risk of respiratory depression, these
medications continue to be prescribed following surgery. The majority of tonsillectomies are
now performed for sleep apnea and sleep disordered breathing; therefore, a large proportion
of patients have increased risk of respiratory compromise and desaturations following surgery
when opioid medications are administered.22 Furthermore, emerging data suggests that a
significant fraction of adolescent patients receiving opioid pain medications postoperatively
may subsequently develop addiction to these medications.17 NSAIDs are effective for
post-tonsillectomy analgesia, but concerns remain regarding increased risk of postoperative
hemorrhage with use of these medications despite current American Academy of Pediatrics
recommendations advocate that ibuprofen may be safely utilized following tonsillectomy in
children. Studies to date demonstrate conflicting or equivocal results with regard to
increased bleeding risk following NSAID administration. Given previous data from this
institution which cannot exclude increased incidence of type 3 bleeding following 9 days of
ibuprofen exposure, MEE standard of practice is to recommend against extended duration of
ibuprofen use in the postoplerative period. However, given concerns of inadequate analgesia
with acetaminophen and respiratory depression and addictive potential with opioid medication,
we feel that it is important to assess for postoperative time interval where NSAID
medications may be safely administered without increasing incidence of postoperative bleeding
events.
We propose a study comparing impact of maximally-dosed ibuprofen (10 mg/kg every 6 hours)
versus maximally-dosed acetaminophen (15 mg/kg every 6 hours) on postoperative pain and
bleeding when administered for four days (short-course) to children age 2-18 undergoing
tonsillectomy with or without adenoidectomy. We believe that a four-day course of medication
is appropriate given that the majority of post-tonsillectomy bleeding events occurred on day
6 and the half-life of ibuprofen is such that platelet function returns to baseline within 24
hours of drug discontinuation20. We hypothesize that children aged 2-18 receiving
short-course ibuprofen following tonsillectomy will not have increased incidence of bleeding
when compared to patients receiving acetaminophen postoperatively. A study definitively
documenting safety and efficacy of short-course NSAID administration following tonsillectomy
in children would affect our own standard of care as well as overall clinical practice
guidelines surrounding this procedure.
;