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Alternating Acetaminophen and Ibuprofen versus Monotherapies in Improvements of Distress and Reducing Refractory Fever in Febrile Children: A Randomized Controlled Trial

Abstract

Background

No evidence can be found in the medical literature about the efficacy of alternating acetaminophen and ibuprofen treatment in children with refractory fever.

Objective

Our objective was to assess the effect of alternating acetaminophen and ibuprofen therapy on distress and refractory fever compared with acetaminophen or ibuprofen as monotherapy in febrile children.

Methods

A total of 474 febrile children with axillary temperature ≥38.5 °C and fever history ≤3 days in a tertiary hospital were randomly assigned to receive either (1) alternating acetaminophen and ibuprofen (acetaminophen 10 mg/kg per dose with shortest interval of 4 h and ibuprofen 10 mg/kg per dose with shortest interval of 6 h and the shortest interval between acetaminophen and ibuprofen ≥2 h; n = 158), (2) acetaminophen monotherapy (10 mg/kg per dose with shortest interval of 4 h; n = 158), or (3) ibuprofen monotherapy (10 mg/kg per dose with shortest interval of 6 h; n = 158). The mean Non-Communicating Children’s Pain Checklist (NCCPC) score was measured every 4 h, and axillary temperatures were measured every 2 h.

Results

In total, 471 children were included in an intention-to-treat analysis. No significant clinical or statistical difference was found in mean NCCPC score or temperature during the 24-h treatment period in all febrile children across the three groups. Although the proportion of children with refractory fever for 4 h and 6 h was significantly lower in the alternating group than in the monotherapy groups (4 h: 11.54% vs. 26.58% vs. 21.66%, respectively [p = 0.003]; 6 h: 3.85% vs. 10.13% vs. 17.83%, respectively [p < 0.001]), the mean NCCPC score of children with refractory fever for 4 or 6 h was not lower than those in either of the monotherapy groups. The number of patients who developed persistent high body temperature was consistent across all study groups.

Conclusions

Alternating acetaminophen and ibuprofen can reduce the proportion of children with refractory fever, but if one cycle of alternating therapy cannot reduce febrile distress as defined by NCCPC score, two or more cycles of alternating therapy may have minimal to no clinical efficacy in some cases.

The trial was registered with the Chinese Clinical Trial Registry as ChiCTR-TRC-13003440 and the WHO Registry Network as U1111-1146-6714.

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Acknowledgements

The authors thank all the children and parents who agreed to participate in our study.

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Authors

Corresponding author

Correspondence to Chaomin Wan.

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Conflict of interest

Luo SH, Ran MD, Luo QH, Shu M, Guo Q, Zhu Y, Xie XP, Zhang CF, and Wan CM have no conflicts of interest.

Ethics approval and informed consent

This trial was approved by the Ethics Committee of West China Second University Hospital of Sichuan University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent to participate in the study was obtained from participants’ parents.

Funding

The study was supported by the Program for Changjiang Scholars and the Innovative Research Team at the University Ministry of Education of China (IRT0935) and the Applied Basic Research Project of Sichuan Province (No. 2012JY0008).

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Luo, S., Ran, M., Luo, Q. et al. Alternating Acetaminophen and Ibuprofen versus Monotherapies in Improvements of Distress and Reducing Refractory Fever in Febrile Children: A Randomized Controlled Trial. Pediatr Drugs 19, 479–486 (2017). https://doi.org/10.1007/s40272-017-0237-1

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Keywords

  • Ibuprofen
  • Acetaminophen
  • Febrile Seizure
  • Monotherapy Group
  • Axillary Temperature