Postoperative Ibuprofen and the Risk of Bleeding After Tonsillectomy With or Without Adenoidectomy

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2012 by Massachusetts Eye and Ear Infirmary
Sponsor:
Information provided by (Responsible Party):
Massachusetts Eye and Ear Infirmary
ClinicalTrials.gov Identifier:
NCT01605903
First received: May 23, 2012
Last updated: November 19, 2013
Last verified: May 2012
  Purpose

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.


Condition Intervention Phase
Tonsillectomy
Adenoidectomy
Drug: Ibuprofen
Drug: Acetaminophen
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Postoperative Ibuprofen and the Risk of Bleeding After Tonsillectomy With or Without Adenoidectomy

Resource links provided by NLM:


Further study details as provided by Massachusetts Eye and Ear Infirmary:

Primary Outcome Measures:
  • Level 3 postoperative hemorrhage [ Time Frame: Data about post-tonsillectomy bleeding will be obtained after the end of a 14-day postoperative period. ] [ Designated as safety issue: Yes ]
    Postoperative hemorrhage is defined as any history of bleeding occurring within the 14 day postoperative period. Hemorrhage will be stratified into 3 levels of severity. Level 1: includes children with a history of postoperative bleeding evaluated and/or treated by a physician in the emergency room, inpatient unit or operating room; Level 2: children requiring inpatient admission for postoperative bleeding regardless of the need for operative intervention; Level 3: children requiring inpatient admission and return to the operating room for control of post-tonsillectomy hemorrhage.


Estimated Enrollment: 722
Study Start Date: September 2011
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: January 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment with Ibuprofen
Children will be randomly assigned to receive either ibuprofen or acetaminophen prior to surgery. 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.
Drug: Ibuprofen
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.
Active Comparator: Treatment with Acetaminophen
Children will be randomly assigned to either the treatment arm or active comparator prior to surgery. Children in the active comparator group (Acetaminophen) will receive grape flavored 160 mg/5 ml acetaminophen. Acetaminophen will be dispensed at 15 mg/kg (max dose 650/mg) Q6.
Drug: Acetaminophen
During the postoperative period, ibuprofen 10mg/kg (max dose 600 mg) will be dispensed Q6.

  Hide Detailed Description

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 bleeding rate in patients treated with postoperative ibuprofen after tonsillectomy will be increased compared to the rate in patients given acetaminophen.

  Eligibility

Ages Eligible for Study:   2 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients ages 2-18 undergoing tonsillectomy with or without adenoidectomy by electrocautery alone for sleep disordered breathing or infectious tonsillitis will be included.
  • Patients with complex medical conditions and craniofacial abnormalities will be included.
  • Informed consent and child assent will be required for enrollment

Exclusion Criteria:

  • Patients with a known personal or family history of a bleeding disorder will be excluded.
  • Patients with a history of asthma, kidney or liver problems will also be excluded.
  • Patients with tonsillectomy or adenoidectomy performed using a cold knife technique, microdebrider, coblation or plasma knife.
  • Patients on NSAIDs for other medical conditions, or those who have taken NSAIDs within 1 week of surgery will be excluded.
  • Patients with allergy to aspirin or other NSAIDs, acetaminophen, Red Dye #40 or Red Dye #33 will also be excluded.
  • Pregnancy testing using urine beta-HCG will be performed on all children > 13 years of age, or those younger than 13 who are menstruating; this is the testing protocol used at the Children's Hospital of Boston. Patients found to be pregnant will be excluded from participation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01605903

Contacts
Contact: Christopner J Hartnick, MD 617-572-4206 christopher_hartnick@meei.harvard.edu
Contact: Gillian Diercks, MD gillian_diercks@meei.harvard.edu

Locations
United States, Massachusetts
Massachusetts Eye and Ear Infirmary Recruiting
Boston, Massachusetts, United States, 02114
Contact: Christopher M Hartnick, MD    617-573-4206    christopher_hartnick@meei.harvard.edu   
Contact: Gillian Diercks, MD       gillian_diercks@meei.harvard.edu   
Principal Investigator: Christopher Hartnick, MD         
Sponsors and Collaborators
Massachusetts Eye and Ear Infirmary
Investigators
Principal Investigator: Christopher J Hartnick, MD Massachusetts Eye and Ear Infirmary
  More Information

Publications:

Responsible Party: Massachusetts Eye and Ear Infirmary
ClinicalTrials.gov Identifier: NCT01605903     History of Changes
Other Study ID Numbers: 11-054H
Study First Received: May 23, 2012
Last Updated: November 19, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Massachusetts Eye and Ear Infirmary:
Tonsillectomy
adenoidectomy
bleeding
bleeding rates
Tonsillectomy with and without adenoidectomy

Additional relevant MeSH terms:
Hemorrhage
Pathologic Processes
Acetaminophen
Ibuprofen
Antipyretics
Physiological Effects of Drugs
Pharmacologic Actions
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Central Nervous System Agents
Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal
Anti-Inflammatory Agents
Antirheumatic Agents
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 22, 2014