Comparison of Ibuprofen vs Acetaminophen and Severe Bleeding Risk After Pediatric Tonsillectomy: A Noninferiority Randomized Clinical Trial

Abstract

Importance: Ibuprofen is an effective analgesic after tonsillectomy alone or tonsillectomy with adenoidectomy, but concerns remain about whether it increases postoperative hemorrhage.

Objective: To investigate the effect of ibuprofen compared with acetaminophen on posttonsillectomy bleeding (PTB) requiring surgical intervention in children.

Design, setting, and participants: A multicenter, randomized, double-blind noninferiority trial was conducted at 4 tertiary medical centers (Massachusetts Eye and Ear Infirmary, Boston; Naval Medical Center, San Diego, California; Naval Medical Center, Portsmouth, Virginia; Madigan Army Medical Center, Tacoma, Washington). A total of 1832 children were assessed for eligibility (presence of sleep-disordered breathing or obstructive sleep apnea, adenotonsillar hypertrophy, or infectious tonsillitis undergoing extracapsular tonsillectomy by electrocautery). Of these, 1091 were excluded because they did not meet eligibility criteria (n = 681) or refused to participate (n = 410); thus, 741 children aged 2 to 18 years undergoing tonsillectomy alone or tonsillectomy with adenoidectomy were enrolled between May 3, 2012, and January 20, 2017.

Interventions: Participants were randomized to receive ibuprofen, 10 mg/kg (n = 372), or acetaminophen, 15 mg/kg (n = 369), every 6 hours for the first 9 postoperative days.

Main outcomes and measures: Rate and severity of posttonsillectomy bleeding were recorded using a postoperative bleeding severity scale: type 1 (bleeds that were observed at home or evaluated in the emergency department without further intervention), type 2 (bleeds that required readmission for observation), and type 3 (bleeds that required a return to the operating room for control of hemorrhage). Type 3 bleeding was the main outcome measure. The noninferiority margin was set at 3%, and modified intention-to-treat analysis was used.

Results: Of the 741 children enrolled, 688 children (92.8%) (median [interquartile range] age, 5 [4] years; 366 boys [53.2%]) received the study medication and were included in a modified intention-to-treat analysis. The rate of bleeding requiring operative intervention was 1.2% in the acetaminophen group and 2.9% in the ibuprofen group (difference, 1.7%; 97.5% CI upper limit, 3.8%; P = .12 for noninferiority). There were no significant adverse events or deaths.

Conclusions and relevance: This study could not exclude a higher rate of severe bleeding in children receiving ibuprofen after tonsillectomy alone or tonsillectomy with adenoidectomy. This finding should be considered when selecting a postoperative analgesic regimen. Further studies are needed to understand if bleeding risk is affected when ibuprofen is used for a shorter duration or in combination with acetaminophen for postoperative analgesia.

Trial registration: ClinicalTrials.gov identifier: NCT01605903.

Conflict of interest statement

Conflict of Interest Disclosures: Ms Bennett reported other from Massachusetts Eye and Ear Infirmary, Department of Otolaryngology during the conduct of the study; other from Harvard T. H. Chan School of Public Health, other from Simon Fraser University, other from Hawaii Center for AIDS, other from Massachusetts General Hospital, Center for Global Health, other from Brigham and Women's Hospital Inc, and other from Prolong Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Participant Flow

Patients were enrolled between May 3, 2012, and January 20, 2017.

Figure 2.. Type 3 Bleeding Event Rate by Noninferiority Modified Intention-to-Treat Analysis

Treatment difference determined as ibuprofen treatment minus acetaminophen treatment.