Pediatric Pyrexia management and Clinical Practice: Review

Though considered to be a physiologic host defense mechanism that is self–limiting by nature, fever can cause distress and discomfort in children, often leading to high parental concern. This may further trigger a sense of "fever phobia," over-treatment, and incorrect management of the febrile child (3,4,5).

Pediatric Pyrexia – Challenges and Dilemmas

Owing to certain distinctive physiological features like their small body size, high ratio of body surface area to weight, and low amount of subcutaneous fat, coupled with an immature immune system, infants and young children are particularly susceptible to fever(8). The fact that fever can be a strong predictor of underlying CNS infections, meningitis, and life-threatening febrile convulsions(8), further complicates matters and warrants for time management.

In the absence of a globally accepted consensus guideline on treating pediatric pyrexia, physicians face a major dilemma in advocating the appropriate drug therapy for children. Considering such scenarios, opting for drugs with a well-established safety profile, rare adverse effects and high potency remains a priority.

The combination of Paracetamol and ibuprofen exert their effects by blocking different points in the chemical pathway that leads to fever. (9) Paracetamol, (acetaminophen) reduces fever by inhibiting prostaglandin synthesis (PGE2) centrally within the anterior hypothalamus through the direct inhibition of cyclo-oxygenase11 as well as peripherally by suppressing inflammation and pyrogenic cytokine production. this explains the major antipyretic action of paracetamol. on the contrary, ibuprofen is a non-selective peripheral inhibitor of COX, resulting in reduced prostaglandin synthesis. This ensures a good analgesic and anti-inflammatory action. Such additive and synergistic effects make the combination therapy more potent in managing fever along with its associated symptoms, than when given individually. (9)

Ibuprofen Paracetamol Combination in Pediatric Pyrexia – Benefits of Starting Early

It has been scientifically affirmed that fever is the essential precursor to febrile convulsion, with the risk being highest when the temperature rises fastest. (14) This rationalizes the fact that diagnosis and initiating rapid treatment for fever should be the foremost concern for an attending physician.

Further, research has highlighted that a statistically and clinically significant improvement in distress levels was evident in the combined versus monotherapy groups. (14) Such results put forth the fact that timely intervention in managing fever, with the appropriate drug combination, can go a long way in relieving the child not only of the disease-associated symptoms and complications, rather waive away the caregiver's anxiety and fear as well.

Practice Pointers

1. Parents and clinicians should be aware that although a relatively short-lived symptom, childhood fever may have underlying serious prognostic implications. Treatment should be initiated at the earliest with analgesic –antipyretic combination to combat not only the symptom, rather the disease process as a whole.

2. Dual therapy with paracetamol –ibuprofen is the most studied, accepted, and recommended over-the-counter pharmacotherapy for pediatric pyrexia.

3. A massive body of research now highlights that combination therapy is more effective in the quick resolution of fever and associated inflammatory processes in children when compared with monotherapy or alternating therapy.

4. Despite the widespread use of ibuprofen and paracetamol, the rate of severe toxicity in children remains rare, thus alleviating safety concerns.

Standing the test of time, this combination has established its superiority in research and studies over and again. Some of the notable ones have been summarised below.

1. In an Indian study (10),89 children hospitalized in India with axillary temperatures >38.5°C.48 received ibuprofen 10mg/kg singly or in combination with paracetamol 10mg/kg, every three times daily. The paper revealed that the paracetamol–ibuprofen combination was more effective than paracetamol alone.
2. Another study with 70 children aged between 6 months and 12 years who had rectal temperatures ≥38.8°C, aimed to assess the benefits of adding paracetamol (15mg/kg) or placebo 4 hours after a baseline dose of ibuprofen (10mg/kg). the team concluded that more children in the active group than in the placebo group (83% versus 58% respectively) were afebrile at 6 hours and that these effects persisted for up to 8 hours. (11)
3. Another study (12) consisting of 28 febrile (>38.3°C) children aged 3–10 years aimed to compare the combined paracetamol (15mg/kg) and ibuprofen (10mg/kg) with ibuprofen monotherapy. Oral temperatures were measured by the parents at home at 2, 4, and 6 hours and the results were reported by telephone or post. Differences were observed in favor of combined treatment at 4 hours (0.7°C,p=0.05) and 6 hours (3.5°C, p=0.02).
4. In yet another study,38 febrile children presenting to secondary care, aged between 6 months and 6 years, were exposed to either paracetamol (15mg/kg) at time zero and 4 hours or paracetamol at time zero plus ibuprofen (10mg/kg) at 3 hours. Clinically significant temperature differences were found at 4 and 5 hours post-randomization with greater temperature reduction in the combined group. (8)
5. Meta-analysis (13) has confirmed that ibuprofen and paracetamol have similar safety and tolerability profiles in pediatric fever, busting the dogma that paracetamol was safer as compared to ibuprofen. It has further been elaborated that both drugs are associated with specific and very rare adverse events.

Conclusion

Backed up by ample evidence, paracetamol –ibuprofen dual drug therapy has a proven legacy of superiority, both in terms of efficacy and safety, in managing pediatric fever. This drug combination, working complimentarily has cemented its position as the 'go-to 'OTC drug for childhood fever and associated inflammatory processes.

References

1. Barbi, E., Marzuillo, P., Neri, E., Naviglio, S., & Krauss, B. S. (2017). Fever in Children: Pearls and Pitfalls. Children (Basel, Switzerland), 4(9), 81. 
2. El-Radhi A. S. (2019). Fever in Common Infectious Diseases. Clinical Manual of Fever in Children, 85–140. 
3. Crocetti M, Moghbeli N, Serwint J. Fever phobia revisited: have parental misconceptions about fever changed in 20 years? Pediatrics. (2001) 107:1241. doi: 10.1542/peds.107.6.1241
4. Karwowska A, Nijssen-Jordan C, Johnson D, Davies HD. Parental and health care provider understanding of childhood fever: a Canadian perspective.CJEM. (2002) 4:394–400. doi: 10.1017/S1481803500007892
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6. Tan E, Braithwaite I, McKinlay CJD, Dalziel SR. Comparison of Acetaminophen (Paracetamol) With Ibuprofen for Treatment of Fever or Pain in Children Younger Than 2 Years: A Systematic Review and Meta-analysis. JAMA Netw Open. 2020;3(10):e2022398. doi:10.1001/jamanetworkopen.2020.22398
7. Lundgren, M., Steed, L.J., Tamura, R. et al. Analgesic antipyretic use among young children in the TEDDY study: no association with islet autoimmunity. BMC Pediatr 17, 127 (2017). 
8. HayAD, Redmond NM, Costelloe C, Montgomery AA, Fletcher M, Hollinghurst S et al.Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomized controlled trial. Health Technol Assess 2009; 13(27).
9. Trippella G, Ciarcià M, de Martino M and Chiappini E (2019) Prescribing Controversies: An Updated Review and Meta-Analysis on Combined/Alternating Use of Ibuprofen and Paracetamol in Febrile Children. Front. Pediatr. 7:217.doi: 10.3389/fped.2019.00217
10. Lal A, Gomber S, Talukdar B. Antipyretic effects of nimesulide, paracetamol and ibuprofen paracetamol. Indian J Pediatr 2000;67:865–70.
11. Nabulsi MM, Tamim H, Mahfoud Z, Itani M, Sabra R, Chamseddine F, et al. Alternating ibuprofen and acetaminophen in the treatment of febrile children: a pilot study. BMC Med 2006;4:4.
12. Tenison M, Eberhardt M, Pellett N, Heller M. Is the combination of ibuprofen and acetaminophen a better pediatric antipyretic than ibuprofen alone? Ann Emerg Med 2005;46:S54.
13. Kanabar D. J. (2017). A clinical and safety review of paracetamol and ibuprofen in children. Inflammopharmacology, 25(1), 1–9. 
14. Leung, A. K., Hon, K. L., & Leung, T. N. (2018). Febrile seizures: an overview. Drugs in Context, 7, 212536. https://doi.org/10.7573/dic.212536