Alternating ibuprofen and acetaminophen may be more effective in the treatment of fever in children

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• Sarrell EM, Wielunsky E, Cohen HA. Antipyretic treatment in young children with fever: Acetaminophen, ibuprofen, or both alternating in a randomized, double-blind study. Arch Pediatr Adolesc Med 2006;160:197-202
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EDITOR’S NOTE: Journals reviewed for this issue: Archives of Disease in Childhood, Archives of Pediatrics and Adolescent Medicine, British Medical Journal, Journal of the American Medical Association, Journal of Pediatrics, The Lancet, New England Journal of Medicine, Pediatric Infectious Diseases Journal, and Pediatrics; Gurpreet K. Rana, B.Sc., M.L.I.S, Taubman Medical Library, University of Michigan, contributed to the review and selection of this month’s abstracts.

—John G. Frohna, MD, MPH

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Sarrell EM, Wielunsky E, Cohen HA. Antipyretic treatment in young children with fever: Acetaminophen, ibuprofen, or both alternating in a randomized, double-blind study. Arch Pediatr Adolesc Med 2006;160:197-202 

Question Among young children aged 6 to 36 months with fever, does an alternating regimen of acetaminophen and ibuprofen have an improved antipyretic effect compared with either drug alone?

Design Randomized, double-blind, parallel-group trial.

Setting Three primary pediatric community ambulatory centers in Israel.

Participants 464 children, aged 6 to 36 months, with fever.

Intervention Infants were assigned to receive either acetaminophen (12.5 mg/kg per dose every 6 hours) (n = 154) or ibuprofen (5 mg/kg per dose every 8 hours) (n = 155) or to receive alternating acetaminophen and ibuprofen (every 4 hours) (n = 155) for 3 days after a loading dose.

Outcomes Temperature, stress score, amount of antipyretic received, total days that the infant or caregiver was absent from day care or work, respectively, at the 3-day time point, recurrence of fever, and number of emergency department visits.

Main results The group given the alternating regimen was characterized by a lower mean temperature, more rapid reduction of fever, receiving less antipyretic medication, less stress, and less absenteeism from day care as compared with the other groups; all of the differences were statistically significant (P < .001). None of the regimens was associated with a significantly higher number of emergency department visits (P = .65) or serious long-term complications (P = .66). The drug used for initial loading had no effect on outcome in any of the groups.

Conclusions An alternating treatment regimen of acetaminophen (12.5 mg/kg per dose) and ibuprofen (5 mg/kg per dose) every 4 hours for 3 days, regardless of the initial loading medication, is more effective than monotherapy in lowering fever in infants and children.

Commentary Sarrell et al should be applauded for tackling the issue of alternating antipyretics. “Should we alternate?” is one of the most common questions pediatricians are being asked by parents and almost a standard method of antipyresis in some community and academic emergency departments and clinics around the country. However, there are some issues that need a second thought before recommending alternating acetaminophen and ibuprofen. First, the dose used in the study from Israel is lower than the currently recommended dose in North America (they gave a dose of 12.5 mg/kg acetaminophen and 5 mg/kg ibuprofen). But more importantly, one should consider whether the comparison between a single regimen and an alternating one is completely “kosher,” because the alternating drug was given every 4 hours whereas the acetaminophen and ibuprofen were given every 6 and 8 hours, respectively. Obviously, there is a higher level of “serum antipyretics” with the alternating regimen, a fact that might explain the superiority of this method. Also, the safety of alternating antipyretics, compared with traditional monotherapy, will need an answer in the future. Whereas 90% of acetaminophen is metabolized in the liver by glucuronide and sulfate conjugates, a fraction is excreted unchanged by the kidney. Ibuprofen is metabolized by the kidney. While interaction in recommended dosages is unlikely, the question is still unanswered.

Finally, we need to ask ourselves whether alternating is so important that we need to continue to investigate it. “Fever phobia,” as described by Schmitt¹ more than a quarter century ago, is still fueling the discovery of ways to win the battle over fever in children. It is challenging to reassure parents that fever is a “physiological response” while nurses, nurse-practitioners, and pediatricians are constantly recommending antipyretics on the basis of the temperature alone. However, if the outcome measure is the child’s well-being and comfort, simultaneously with reduced utilization of crowded emergency departments, decrease in cost from a community perspective, and better decision-making processes by parents—some of which were addressed in this study—the quest for the ultimate antipyretic is far from over.

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Reference 

1. Schmitt BD . Fever phobia. Misconceptions of parents about fever . Am J Dis Child . 1980;134:176–181
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