Combined and alternating acetaminophen and ibuprofen therapy for febrile children.

Abstract

For the current issue of the Journal, we asked Drs Niraj Mistry and Alan Hudak to comment on and put into context the Cochrane Review on combining and alternating acetaminophen and ibuprofen for treating fever in children (1). Background Health care professionals frequently recommend fever treatment regimens for children that either combine acetaminophen and ibuprofen or alternate them. However, there is uncertainty about whether these regimens are better than the use of single agents, and about the adverse-effect profile of combination regimens. Methods Search strategy: In September 2013, the Cochrane Infectious Diseases Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS and International Pharmaceutical Abstracts (2009–2011) were searched. Selection criteria: Randomized controlled trials comparing alternating or combined acetaminophen and ibuprofen regimens with monotherapy in children with fever were included. Data analysis: One review author and two assistants independently screened the searches and applied inclusion criteria. Two authors assessed risk of bias and graded the evidence independently. Separate analyses were conducted for different comparison groups (combined therapy versus monotherapy, alternating therapy versus monotherapy and combined therapy versus alternating therapy). Results Six studies, enrolling 915 participants, were included. Compared with giving a single antipyretic alone, giving combined acetaminophen and ibuprofen to febrile children resulted in a lower mean temperature at 1 h after treatment (mean difference [MD] −0.27°C [95% CI −0.45 to −0.08]; two trials, 163 participants, moderate-quality evidence). If no additional antipyretics are given, combined treatment likely also results in a lower mean temperature at 4 h (MD −0.70°C [95% CI −1.05 to −0.35]; two trials, 196 participants, moderate-quality evidence), and in fewer children remaining or becoming febrile for at least 4 h after treatment (RR 0.08 [95% CI 0.02 to 0.42]; two trials, 196 participants, moderate-quality evidence). Only one trial assessed a measure of child discomfort (fever-associated symptoms at 24 h and 48 h), but did not find a significant difference in this measure between the treatment regimens (one trial, 156 participants, evidence quality not graded). In practice, caregivers are often advised to initially give a single agent (acetaminophen or ibuprofen), and then give a further dose of the alternative if the child’s fever fails to resolve or recurs. Giving alternating treatment in this way may result in a lower mean temperature 1 h after the second dose (MD −0.60°C [95% CI −0.94 to −0.26]; two trials, 78 participants, low-quality evidence) and may also result in fewer children remaining or becoming febrile for up to 3 h after it is given (RR 0.25 [95% CI 0.11 to 0.55]; two trials, 109 participants, low-quality evidence). One trial assessed child discomfort (mean pain scores at 24 h, 48 h and 72 h) and found that mean scores were lower with alternating therapy, despite fewer doses of antipyretic being given overall (one trial, 480 participants, low-quality evidence). Only one small trial compared alternating therapy with combined therapy. No statistically significant differences were observed in mean temperature or the number of febrile children at 1 h, 4 h or 6 h (one trial, 40 participants, very low-quality evidence). There were no serious adverse events in the trials that were directly attributed to the medications used. Conclusions There is some evidence that both alternating and combined antipyretic therapy may be more effective at reducing temperatures than monotherapy alone. However, the evidence for improvements in measures of child discomfort remains inconclusive. There is insufficient evidence to determine whether combined or alternating therapy may be more beneficial. Future research needs to measure child discomfort using standardized tools, and assess the safety of combined and alternating antipyretic therapy. The full text of the Cochrane Review is available in The Cochrane Library (1).