Understanding Role of Acetaminophen ibuprofen in febrile children: Review of global guidelines vs Studies

Fever in children is usually regarded to be a biologically controlled rise in temperature. Research has suggested that it seldom hits 41 degrees Celsius and does not spin out of control, despite constant worries by parents and health experts. Though research has consistently highlighted that fever is an evolutionary mechanism that assists in conquering acute illnesses, many healthcare practitioners and parents regard childhood fever as a nuisance. (1)

Managing childhood fevers-Where do we stand?

Different perspectives on pediatric fever have resulted in a great deal of variance in how it is treated. In an attempt to provide universal guidance in antipyretic treatment, while responding to discrepancies between evidence and clinical practice, and reducing irrational fear of fever and overzealous attempts to suppress it, Clinical practice guidelines (CPGs) for the symptomatic management of fever in children have been laid down by different healthcare organizations. (1)

Despite such efforts, the fact remains that even "high quality" guidelines are neither extensive in substance nor consistent in their suggestions. (2)

Under such controversial scenarios, physicians must look up to recent studies and case reports to arrive at a rational conclusion on the use of antipyretic therapy in febrile children.

Acetaminophen –ibuprofen therapy in childhood fever- The only antipyretics advised in febrile children are ibuprofen and paracetamol (PCM), which show a high effectiveness and safety profile. A recent systematic literature review found that both medications are equally efficient in decreasing fever and discomfort in children, based on eight trials including 1,632 children. (3)

While it is advised that the choice of drugs in children should be based on age, underlying clinical problems, and co-medications (3). Parents and clinicians frequently manage fever in children with a mix of paracetamol and ibuprofen. (4)

Epidemiological research reveals that combination prescribing habits are common among physicians, nurses, pharmacists, and carers in many nations. In a recent Italian survey, 12 percent of doctors said they practiced combining drugs. Research across Switzerland (65 %), the United States (50 %),Turkey (91 %), and Spain (69 %) have reported higher proportions of doctors practicing combination therapies. (3)

How do they act?–The rationale behind combined therapy

The rationale for combining ibuprofen and paracetamol is that given their differing modes of action, a synergism between the two medications is possible. Given the fact that PCM –ibuprofen dual drug therapy has been effective in a variety of acute pain states in children, this combination has been of particular interest for alleviating discomfort and pain relief in fevers. (3)

Updated knowledge of these varied practice guidelines for febrile children is much needed among the medical fraternity. Thus, this article summarizes the global guidelines, while highlighting the relevant studies on the use of paracetamol-ibuprofen drug combination.

Summarising current guidelines on pediatric fever management-A first-of-its-kind comprehensive meta-analysis (1) investigating fever management recommendations across 55 countries and comparing them to the relevant studies has revealed some very interesting facts. The same has been elaborated below.

Temperature threshold for antipyresis: Study Evidence vs. clinical practice guidelines -

There is minimal consensus concerning the temperature in the various antipyresis guidelines, with numbers varying from 37.5 to 40.5 degrees Celsius and no justification stated.

Contrary to this, studies reveal that the majority of healthcare professionals believe that temperatures above 40 degrees Celsius increase the risk of heat-related adverse outcomes, and more than 90% of them administer antipyretic medication at temperatures above 39 degrees Celsius.

Pharmacologic treatment: Choice of drug, dosing, adverse effects-

High-quality evidence has revealed that paracetamol and ibuprofen both are effective in lowering high temperatures in children. Though Paracetamol is recommended widely across guidelines, there is no robust evidence supporting its superior effect or safety profile.

• The American Academy of Pediatrics state that the primary objective in treating pediatric fevers should be to promote comfort, and that there is insufficient evidence to support or contradict the routine use of combination therapy. (4)
• Antipyretics should only be administered when a fever is coupled with discomfort, according to the Italian Paediatric Society's guidelines. (4)

Analyzing the varied guidelines, it can be concluded that there is not a single piece of advice that all the recommendations agree on, rather many are contradictory to the currently available evidence-based study results–a fact that is true even for the most recent guidelines.

This lack of consensus among global guidelines places physicians in a dilemma regarding the management of pediatric fevers. Faced with such challenges, the medical fraternity is compelled to redirect focus on current studies comparing the potency of combined PCM –ibuprofen dual therapy vs monotherapy.

Quoting studies: What do studies reveal?

EFFECT ON TEMPERATURE

• A study aimed to evaluate the evidence surrounding the use of combinations of paracetamol and ibuprofen in the treatment of childhood fever, concluded that by 4 hours, a consistent difference in temperature decline was noted, with the group taking the dual therapy reporting a more rapid temperature fall than the group taking monotherapy. (4) Resonating with these findings, yet another study revealed that a single combined dose of PCM –ibuprofen was superior to ibuprofen alone at 4, 5 and 6 h (4). Mean temperature was also lower in the combined therapy group at 1 h after the initial administration of therapy (3).
• Examining the number of children who were afebrile at different time points, a study highlighted that by 7 and 8 hours, more children were afebrile in the combined than the ibuprofen group, the difference being 40.9% at 7 h and 45.1% at 8 h (4).
• Yet another study suggested a faster temperature drop in the combined group, compared with individual drugs. The team elaborated that a temperature >37.2°C was recorded among 36% of children in the paracetamol group, 15% for ibuprofen and only 9% for the combined group at 2 h; and the equivalent figures for 4 h being 29%, 15%, and 2% respectively. (4)
• Considering fever-free periods as the outcome, a study confirmed that those in the combined group had more time without fever in the first 24 h than those receiving paracetamol or ibuprofen alone. (4)
• Another study reported that in the first 24 hours, children given both drugs spent 4.4 hours less time with fever than those given paracetamol and 2.5 hours less time with fever than that given ibuprofen, confirming the benefits of combined therapy. (5)

EFFECT ON DISCOMFORT and associated symptoms

Studies assessing the fever-associated discomfort at 24 h, 48 h, and at 5 days in children noted that though PCM alone was superior on the 1st day, the combination therapy scored better in subsequent days. (4)

Key pointers-

• Antipyretic drug therapy in children with fever should be started only after careful consideration of age and the severity of associated symptoms.
• Global guidelines on managing pediatric fevers remain controversial and confusing to date.
• Study results support the evidence that giving both paracetamol and ibuprofen, in a combined form could be more effective in treating fever with associated discomfort and pain, compared to monotherapy alone.
• On a concluding note- Antipyretics are widely used in pediatric fevers, as parents have unwarranted anxieties of fever, and some healthcare professionals share these fears. (4)
• Paracetamol and ibuprofen are generally effective drugs in alleviating fever and associated symptoms and exhibit a good safety profile. Combining the two drugs for high fever, or fever that does not respond to one drug alone is a common practice. (4)
• With ample evidence supporting the potency of this drug combination in managing pediatric fevers, it is time that clinicians keep an open eye on ongoing trials, and not only on guidelines.

References

1. Green C, Krafft H, Guyatt G, Martin D (2021) Symptomatic fever management in children: A systematic review of national and international guidelines. PLoS ONE 16(6): e0245815. https://doi.org/10.1371/journal. pone.0245815

2. Chiappini E, Bortone B, Galli L, de Martino M. Guidelines for the symptomatic management of fever in children: systematic review of the literature and quality appraisal with AGREE II. BMJ Open. 2017; 7:e015404. https://doi.org/10.1136/bmjopen-2016-015404 PMID: 28760789

3. 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

4. Purssell, E. (2011). Systematic review of studies comparing combined treatment with paracetamol and ibuprofen, with either drug alone. Archives of disease in childhood, 96(12), 1175-1179.

5. Hollinghurst S, Redmond N, Costelloe C, Montgomery A, Fletcher M, Peters T J et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): economic evaluation of a randomised controlled trial BMJ 2008; 337 :a1490 doi:10.1136/bmj.a1490