Treatment of the Febrile Child: What is the Evidence?

1. Treatment of the Febrile Child: What is the Evidence? Mona Nabulsi-Khalil, MD MSc Associate Professor of Pediatrics Department of Pediatrics American University of Beirut

2. OUTLINE Fever: Friend or Foe Fever phobia Why do we treat fever? Non-pharmacologic Rx Pharmacologic Rx Adverse effects of Rx

3. Historical Perspective • Hippocrates: Fever as beneficial sign during infection • Thomas Sydenham (1624-1689): “…nature’s engine …to remove her enemy…” • Liebermeister (1800’s): fever as regulation of body temp. at higher level

4. Fever: Friend or Foe? Beneficial host response: • Animal studies • Human studies

5. Fever: Friend or foe? Harmful consequences: • ↑O2 consumption & CO2 production • ↑Cardiac output & fluid requirement • Febrile seizures in predisposed children • Delirium, coma  death > 410 C

6. Feverphobia • Barton Schmitt: Unrealistic concerns about fever causing harm • Scmitt (AJDC 1980): • 94% of parents believed fever had side effects • 63% worried about serious harm • 18% brain damage at T<38.90 C • 16% lethal & reaches 48.90 if untreated

7. Fever phobia • Crocetti, et al, Pediatrics 2001 • 91% of parents: fever harmful • 21%: brain damage; 14%: death • >50%: check fever hourly • 25%: gave antipyretics for temp <380 C • 85%: awaken child from sleep to give antipyretic

8. Fever phobia • Crocetti, et al: • 14-44% gave acetaminophen or ibuprofen at more frequently than indicated • Phobic parents were more likely to have doctors that worry about fever

9. Why do we treat fever? • Relieve child expert opinion • Decrease on metabolic cost (cardiac, pulmonary dis.) expert opinion • Avoid febrile seizure (not true) Evidence level Ia • Relieve parental anxiety (fever phobia)!!

10. Non-pharmacologic Treatment of Fever

11. Non-pharmacologic Rx • Remove excessive clothing/blankets heat dissipation (Exp. Op.) • Avoid excessive activity heat production (Exp. Op.) • Hydration insensible losses; blood flow (Exp. Op.) • Physical methods (Evidence level 1a)

12. Physical methods of antipyresis Heat loss:conduction, convection, evaporation • Tepid water spongingAlexander the Great • Cooling blankets • Circulating fans

13. Physical methods of antipyresis Meremikwu & Oyo-Ita. Cochrane Database Syst Rev 2003 • Benefits & harms of physical methods • RCT’s; Physical method vs placebo/no Rx; ± antipyretic • 1 RCT (n=30): physical methods vs placebo similar % afebrile at 1 hr

14. Meremikwu & Oyo-Ita. Cochrane Database Syst Rev 2003 2 RCTs (n=125): physical methods + antipyretic vs antipyretic RR (% afebrile at 1 hr): 11.76; 95%CI 3.39-40.79 1RCT (n=130): no diff. AE in 3 trials: Shivering & goose pimples RR 5.09; 95%CI 1.56-16.60

15. Pharmacologic Antipyresis • Centrally-acting drugs: hypothalamic thermoregulatory center; inhibit synthesis of PG’s • Two main families: • Paracetamol: Central antipyretic action (acetaminophen) • NSAID’s: Central antipyretic action and peripheral anti-inflammatory action (ibuprofen)

16. Acetaminophen • Absorption: 30-60 min • Maximum antipyresis: 3-4 hrs • Dose (oral): 10-15 mg/kg; Q4-6 hrs • Toxicity: large doses  fulminant hepatic failure  death

17. Acetaminophen • Meremikwu & Oyo-Ita. Cochrane Database Syst Rev 2002 • RCTs: ACE vs. placebo/no RxORvs. physical methods • Few studies, limited data, heterogeneity • % afebrile at 2 hrs (vs. sponging): 2 RCTs; n=120 RR=1.84; 95%CI 0.94-3.61 No AE

18. Rectal Acetaminophen • Absorption: Irregular, variable, prolonged • Peak [serum]: 3.5 hrs • Dose: 30-45 mg/kg; Q4-6 hrs

19. Rectal vs. Oral Acataminophen Scolnick et al. Pediatrics 2002 • 70 children (6m-6y); ambulatory (T0≥ 390C) • Oral ACE (15mg/kg), rectal ACE (15 mg/kg), rectal ACE (30 mg/kg) • 3-hr F/U: no diff. in max Δ in temp.

20. Rectal vs. Oral Acataminophen Nabulsi et al. BMC Pediatrics 2005 • Double-dummy, D-B, P-C RCT • 51 children (6m-13y); inpatients (T0 ≥ 38.50C) • 15mg/kg oral, 15mg/kg rectal, 35 mg/kg rectal • Hourly T0 x 6h • Similar antipyresis (ITT) Time to max antipyresis: 3.6h; 95%CI (3.2-4.0) Time to reduction by ≥ 10C: 2.4h; 95%CI (1.8- 3.1) Δ T0 each hr (P=0.25; two-way ANOVA)

21. Ibuprofen • Absorption: 1-2 hrs • Maximum antipyresis: 4 hrs • Oral dose: 5-10 mg/kg; Q 6-8 hrs • Toxicities: Renal, GI bleeding, anaphylaxis

22. Ibuprofen vs. Acetaminophen Perrot, et al. Arch Pediatr Adolsc Med 2004 • Meta-anlaysis: RCTs single-dose ACE & IBU • Fever or pain; <18 yrs • IBU (5-10mg/kg) > ACE (10-15mg/kg) at 2, 4, 6 hrs post dose

23. Perrot, et al. Arch Pediatr Adolsc Med 2004 Fever: • IBU (5-10mg/kg) > ACE (10-15mg/kg) • Weighted effect sizes: • 0.19 SD; 95% CI 0.05-0.33 (at T2) • 0.31 SD; 95% CI 0.19-0.44 (at T4) • 0.33 SD; 95% CI 0.19-0.47 (at T6) • AE: similar to placebo

24. Ibuprofen vs. Acetaminophen: Safety Lesko & Mitchell. Pediatrics 1999 • Incidence of serious AE • Children < 2 yrs • D-B, practitioner based RCT • IBU (5mg/kg), IBU (10mg/kg), ACE (12mg/kg) • 4-week F/U: similar rates of hospitalizations 1.4%; 95% CI 1.3%-1.6%

25. Lesko & Mitchell. Pediatrics 1999 • No serious AE: • Acute renal failure • Anaphylaxis • Reye’s syndrome • Asthma • Bronchiolitis • Vomiting/gastritis • GI bleeding: 3 (IBU) • Short-term assessment!!

26. Alternating Ibuprofen-Acteminophen • Common practice: physicians & care givers Mayoral, et al. Pediatrics 2000 • 50% of physicians • Young physicians (fever phobia!!)

27. Alternating Ibuprofen-Acteminophen Nabulsi, et al. BMC Medicine 2006 - 38.5% of parents - 84.3%: physician’s advice - 13.7%: self-initiated - 71.7%: “very effective”

28. Alternating Ibuprofen-Acteminophen Wright & Liebelt. Clin Pediatr 2007 - 44% of parents - 81%: physician’s advice - 8%: self-initiated - Frequency : 9% (2 hrs) 16% (3 hrs) 43% ( 4 hrs) - 61%: written instructions

29. Combined Ibuprofen-Acteminophen Erlewyn-Lajeunesse, et al. Arch Dis Child 2006 • O-L RCT • 123 children (6m-10y); ER (T0 ≥ 38.0 0C) • Tympanic T0, T1, T2 • Paracetamol 15mg/kg, IBU 5mg/kg, both • Δ at T1: Both>Paracetam. 0.35 0C; 95%CI 0.10-0.60 Both=IBU 0.25 0C; 95%CI -0.01-0.50

30. Alternating Ibuprofen-Acteminophen Sarrell, et al. Arch Pediatr Adolesc Med 2006 • 464 children (6-36m), outpatients (T0 ≥ 38.4 0C) • ??D-B RCT • ACE 12.5mg/kg Q6h, IBU 5mg/kg Q8h, ACE/IBU Q4h (??blinding) • 3-day T, stress score, amount of drug, days absent from day care/work, fever recurrence, no. ED visits

31. Alternating Ibuprofen-Acteminophen Sarrell, et al. Arch Pediatr Adolesc Med 2006 • Loading doses: 25mg/kg ACE, 10mg/kg IBU • ACE/IBU (p<0.001): lower mean T more rapid ↓T less stress score less absenteeism • No AE in all groups

32. Alternating Ibuprofen-Acteminophen Nabulsi, et al. BMC Medicine 2006 • D-B, P-C RCT • 70 children (6m-12.8y); inpatients (T0 ≥ 38.8 0C) • IBU 10mg/kg at T0 , placebo at T4 IBU 10mg/kg at T0 , ACE 15mg/kg at T4 • T0, T4-8

33. Nabulsi, et al. BMC Medicine 2006

34. Nabulsi, et al. BMC Medicine 2006

35. Combined antipyretics: ?risks • Potentiation of renal toxicity: case reports Ibuprofen reduces glutathione production +acetaminphen renal toxicity (tubular necrosis)

36. Antipyretics AE: controversies! • Asthma & IBU: Risk similar to ACE Lesko et al. Pediatrics 2002 • Febrile sz & IBU or ACE: No ↓ in recurrences van Stuijvenberg, et al. Pediatrics 1998 Baumann RJ. Pediatrics 1999

37. Antipyretics AE: controversies! • Invasive group A strep and NSAIDs: - No ↑ risk necrotising GAS infections - ? Association with non-invasive GAS infections and IBU OR= 3.9; 95% CI 1.3-12 (Subgroup of combined antipyretic) Lesko et al. Pediatrics 2001

38. Should we treat fever? “ .. antipyretics should not be given routinely to children with fever in developing countries; they should be reserved for the treatment of children with severe discomfort or high fever..” WHO Programme for the Control of Acute Respiratory Infections. The management of fever in young children with acute respiratory infections in developing countries. Geneva: World Health Organization, WHO/ARI/93.30,1993

39. Thank You