Evidence not persuasive for recommending a combination of ibuprofen and acetaminophen for feverish children

Article Outline

• Hay AD, Costelloe C, Redmond NM, Montgomery AA, Fletcher M, Hollinghurst S, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ 2008;337:1490-7
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Hay AD, Costelloe C, Redmond NM, Montgomery AA, Fletcher M, Hollinghurst S, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): randomised controlled trial. BMJ 2008;337:1490-7 

Question Among febrile children managed at home, is acetaminophen plus ibuprofen superior to either drug alone for increasing time without fever and the relief of fever-associated discomfort?

Design Randomized, blinded, 3-arm trial.

Setting Primary care settings in Bristol, England.

Participants A total of 156 children, ages 6 months to 6 years with axillary temperatures of at least 37.8° C and up to 41.0° C.

Intervention Advice on physical measures to reduce temperature and the provision of, and advice to give, acetaminophen plus ibuprofen, acetaminophen alone, or ibuprofen alone.

Outcomes Primary outcomes were the time without fever (<37.2° C) in the first 4 hours after the first dose was given and the proportion of children reported as being normal on the discomfort scale at 48 hours. Secondary outcomes were time to first occurrence of normal temperature (fever clearance), time without fever over 24 hours, fever-associated symptoms, and adverse effects.

Main Results On an intention to treat basis, acetaminophen plus ibuprofen were superior to acetaminophen for less time with fever in the first four hours (adjusted difference 55 minutes, 95% confidence interval 33 to 77; P < .001) and may have been as good as ibuprofen (16 minutes, −7 to 39; P = 0.2). For less time with fever over 24 hours, acetaminophen plus ibuprofen were superior to acetaminophen (4.4 hours, 2.4 to 6.3; P < .001) and to ibuprofen (2.5 hours, 0.6 to 4.4; P = .008). Combined therapy cleared fever 23 minutes (2 to 45; P = .025) faster than acetaminophen alone but no faster than ibuprofen alone (−3 minutes, 18 to −24; P = .8). No benefit was found for discomfort or other symptoms, although power was low for these outcomes. Adverse effects did not differ between groups.

Conclusions Parents, nurses, pharmacists, and doctors wanting to use medicines to supplement physical measures to maximize the time that children spend without fever should use ibuprofen first and consider the relative benefits and risks of using acetaminophen plus ibuprofen over 24 hours.

Commentary Fever is common in children and causes parents to worry. Most febrile children have self-limiting infections and will get better without treatment. But young children who are febrile are usually uncomfortable and miserable. It is standard practice for doctors to recommend, and parents to administer, antipyretic treatment. The 2 most widely used drugs are acetaminophen and ibuprofen. Recently it has become increasingly common for doctors to recommend a combination of both drugs, so this primary care study randomizing feverish young children to either drug alone or a combination of the 2 drugs is timely. The authors report 2 primary outcomes: time without fever in first 4 hours and fever-associated discomfort after 48 hours. The first could be argued to represent a proxy of parental concern, but it is fever-associated discomfort that is the key outcome. And for this outcome, the study is underpowered. One hundred fifty-six children were recruited and randomized from 1038 potentially eligible participants. Despite this, their results suggest no additional improvement in fever-associated discomfort or activity levels in the combined medication group at 24 hours, 48 hours, and 5 days. Their data confirm that ibuprofen is faster acting and has a longer duration than acetaminophen but that a combination of drugs has little advantage. Of some concern is their report of 31 children in the combined group receiving an overdose of medication even in clinical trial conditions. A larger trial is required to confirm their findings, but for now, I am not persuaded that prescribing a combination of acetaminophen and ibuprofen for the treatment of feverish young children has any advantage over use of either drug alone.