Postoperative Ibuprofen and the Risk of Bleeding After Tonsillectomy With or Without Adenoidectomy
Condition: Tonsillectomy; Adenoidectomy
MeSH terms: Hemorrhage
Study type: Interventional
Phase: Phase 2

Summary: 
      Tonsillectomy (the surgical removal of the tonsils) is a commonly performed surgery in
      children. One risk of tonsillectomy is postoperative bleeding, and this can be more dangerous
      in children because their blood volume is lower than adults. Ibuprofen, a nonsteroidal
      anti-inflammatory medication (NSAID), is an effective pain medication. Recent guidelines,
      published by the American Academy of Otolaryngology, advocated use of ibuprofen after
      tonsillectomy. However, NSAIDs are associated with altered platelet function and a
      theoretical increased risk of bleeding after surgery. The investigators would like to explore
      the effect that ibuprofen has on postoperative bleeding, as well as validate previous studies
      demonstrating it is an effective pain medication after tonsillectomy.
    

Detailed description: 
      Tonsillectomy with and without adenoidectomy is one of the most commonly performed surgical
      procedures in the pediatric population. The incidence of adenotonsillectomy has increased
      over the past four decades (1). This is mainly due to increased awareness of the potential
      adverse consequences that pediatric sleep disordered breathing (SDB) may have on development
      and long-term pulmonary and cardiovascular health. SDB has surpassed recurrent tonsillitis as
      the most common indication for adenotonsillectomy in children (2-5). Over the past decade,
      according to the CDC's National Health Statistic Report on ambulatory surgery performed in
      the US, annual rates of tonsillectomy performed with and without adenoidectomy in children
      aged 15 and younger increased from 287,000 to 530,000 (6, 7). Adenotonsillectomy is the
      second most common procedure performed on children under the age of 15. Although generally
      considered a safe procedure, adenotonsillectomy has significant morbidity and potential for
      complications, particularly in the pediatric population. Complications include postoperative
      hemorrhage, dehydration, pain, anesthetic complications and airway risks, aspiration, and
      post-obstructive pulmonary edema (8). In young children, the risk of adenotonsillectomy is
      more critical due to smaller airways and respiratory reserve, as well as smaller blood volume
      (5).

      Postoperative bleeding can be categorized as a primary event, occurring < 24 hours after
      surgery, or a secondary event, occurring >24 hours after tonsillectomy. Additionally, events
      can be further described by the interventions taken, such as emergency room visits, admission
      for observation, or return to the operating room to achieve hemostasis. Postoperative
      bleeding rates, including both primary and secondary events, range from 3.3-20%, with a mean
      of 4.5% (9). Thus, annually, tens of thousands of children experience exposure to potentially
      life-threatening postoperative hemorrhage, often requiring readmission, anesthetic exposure,
      and operative control of hemorrhage.

      Postoperative pain contributes significantly to post-tonsillectomy morbidity. While narcotics
      are effective in controlling postoperative pain, they are often contraindicated, particularly
      in children with sleep disordered breathing, because of their potentially adverse side
      effects on respiration and the central nervous system (10). Nonsteroidal anti-inflammatories
      (NSAIDS), which block prostaglandin-induced inflammation and edema, are an attractive
      therapeutic option because they do not result in respiratory and central nervous system
      depression, and therefore may reduce the risk of postoperative respiratory depression, nausea
      and vomiting, excessive sedation and urinary retention. NSAIDS have been shown to be
      effective analgesics after tonsillectomy (11,12). However, because their mechanism of action
      may also interfere with platelet aggregation and increase bleeding time, their use is
      balanced with concern about an increased risk of postoperative hemorrhage. Aspirin, which
      irreversibly inhibits cyclooxygenase, affects coagulation and bleeding for up to 10 days, has
      been associated with an increased bleed rate after tonsillectomy (13). However, non-aspirin
      NSAIDs demonstrate a reversible inhibition of COX-1 and COX-2, and therefore do not have the
      same severe, prolonged effects on bleeding (14). Ibuprofen, a derivative of propionic acid,
      is widely used for musculoskeletal pain, but the study of its use for post-tonsillectomy
      analgesia is limited.

      In 2011, The American Academy of Otolaryngology published Clinical Practice Guidelines
      outlining evidence-based selection and perioperative management strategies for tonsillectomy
      in children. As part of a recommendation that clinicians educate caregivers about the
      importance of postoperative pain management, Baugh et al advocated the use of ibuprofen
      postoperatively, stating, "ibuprofen can be used safely for pain control after surgery" (15),
      citing a 2005 Cochrane Review of NSAIDs and post-tonsillectomy bleeding in support of this
      guideline (16). The Cochrane Review recently added additional studies to their analysis and
      results remained similar. The most recent Cochrane Review, published in 2010, evaluated 15
      randomized trials comparing NSAIDs with other analgesics or placebo, and determined that
      NSAID use did not significantly alter the number of perioperative bleeding episodes, both
      requiring and not requiring surgical intervention; this review did not distinguish between
      primary and secondary bleeding events (17). Because post-tonsillectomy hemorrhage is an
      uncommon event, a large number of participants is required to provide an adequate number of
      events to give a significant result, therefore the large sample size of >1000 children in the
      Cochrane Review is admirable. However, sample sizes were not adequate to compare the risk of
      bleeding with each individual NSAID. Additionally, NSAIDs were given in both oral and
      parenteral forms, as well as preoperatively, intraoperatively and postoperatively, and the
      duration of postoperative analgesic use differed between studies. The surgical technique used
      was not uniform between studies as well. It is our feeling that because of these limitations,
      the data is not sufficient to broadly implement the Academy's recommendation that ibuprofen
      can be safely used for post-tonsillectomy analgesia without more carefully controlled,
      prospective study.

      Although there are many studies in the literature evaluating NSAID use after tonsillectomy,
      there are few randomized-prospective trials evaluating the use of ibuprofen, and few trials
      are powered to adequately assess the risk of postoperative hemorrhage. Designing and
      executing a study to specifically evaluate ibuprofen after pediatric tonsillectomy and rates
      of post-operative hemorrhage requiring return to the operating room for control is important
      to the pediatric otolaryngology community, particularly given the American Academy of
      Otolaryngology's recent clinical guidelines. The results of such a definitive study would
      possibly affect the tens of thousands of children at risk for post-tonsillectomy hemorrhage
      every year. It would affect our own standards of care as well as national and international
      norms.

      Preliminary Studies:

      At the Massachusetts Eye and Ear Infirmary there is no precedent for administering ibuprofen
      to children after tonsillectomy with or without adenoidectomy. Despite American Academy of
      Otolaryngology support for the use of ibuprofen in the postoperative setting, pediatric
      otolaryngologists at our institution are still hesitant to administer ibuprofen
      postoperatively without additional study of its use.

      Within the Department of Pediatric Otolaryngology at the Massachusetts Eye and Ear Infirmary
      there is a precedent for successful completion of randomized, controlled trials involving
      adenotonsillectomy (19, 20). With principal investigators dedicated to clinical research, as
      well as research nurses and coordinators at our disposal, a prospective, controlled clinical
      trial of ibuprofen use after tonsillectomy can be implemented. Additionally, the
      Massachusetts Eye and Ear Infirmary calculates annual post-tonsillectomy hemorrhage rates,
      including percentage of patients returning to the emergency room for evaluation for possible
      post-operative bleeding, as well as the percentage of patients returning to the operating
      room for control of bleeding. Thus, there is a precedent for collecting data on postoperative
      bleeding events, as well as a controlled bleed rate to which prospective study hemorrhage
      rates can be compared.

      The goal of our study is to determine if postoperative ibuprofen affects the rate of
      post-tonsillectomy hemorrhage using a non-inferiority trial design, which is intended to show
      that the effect of ibuprofen is no worse than acetaminophen, which will serve as our control.
      This differs from an equivalence trial, which aims to demonstrate that the experimental and
      control group do not differ more than a specified amount. The equivalence margin set for
      non-inferiority trials is often smaller than the treatment difference for which a
      placebo-controlled trial is powered, requiring a larger sample size. This will address two
      issues we have with the current literature evaluating NSAID use after tonsillectomy:
      inadequate sample size, and unrealistic treatment differences, including up to a 20%
      difference in bleed rates, required to detect a significant difference between NSAID and
      control groups. Because our trial will be designed to test non-inferiority, the null
      hypothesis will assume inferiority: the rate of hemorrhage requiring operative intervention
      in patients treated with postoperative ibuprofen after tonsillectomy will be increased
      compared to the rate in patients given acetaminophen.
    

Intervention name(s): Ibuprofen; Acetaminophen
Intervention type(s): Drug; Drug
Intervention description(s): Children in the ibuprofen group will be receive grape-flavored ibuprofen 100mg/5 mL. During the postoperative period, ibuprofen 10mg/kg (max dose 600 mg) will be dispensed Q6.; During the postoperative period, ibuprofen 10mg/kg (max dose 600 mg) will be dispensed Q6.
Other intervention name(s): Advil, Motrin; Tylenol
Intervention MeSH terms: Acetaminophen; Ibuprofen
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Tonsillectomy; adenoidectomy; bleeding; bleeding rates; Tonsillectomy with and without adenoidectomy