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 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 infectionHippocrates: Fever as beneficial sign during infection Thomas Sydenham (1624-1689): “…nature’s engine …to remove her enemy…”Thomas Sydenham (1624-1689): “…nature’s engine …to remove her enemy…” Liebermeister (1800’s): fever as regulation of body temp. at higher levelLiebermeister (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? Fever: Friend or foe? Harmful consequences: ↑O 2 consumption & CO 2 production↑O 2 consumption & CO 2 production ↑Cardiac output & fluid requirement↑Cardiac output & fluid requirement Febrile seizures in predisposed childrenFebrile seizures in predisposed children Delirium, coma  death > 41 0 CDelirium, coma  death > 41 0 C

6. Fever phobia Barton Schmitt: Unrealistic concerns about fever causing harmBarton Schmitt: Unrealistic concerns about fever causing harm Scmitt (AJDC 1980):Scmitt (AJDC 1980): –94% of parents believed fever had side effects –63% worried about serious harm –18% brain damage at T<38.9 0 C –16% lethal & reaches 48.9 0 if untreated

7. Fever phobia Fever phobia Crocetti, et al, Pediatrics 2001Crocetti, et al, Pediatrics 2001 –91% of parents: fever harmful –21%: brain damage; 14%: death –>50%: check fever hourly –25%: gave antipyretics for temp <38 0 C –85%: awaken child from sleep to give antipyretic

8. Fever phobia Fever phobia Crocetti, et al: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 childRelieve child expert opinion Decrease on metabolic cost (cardiac, pulmonary dis.)Decrease on metabolic cost (cardiac, pulmonary dis.) expert opinion Avoid febrile seizure (not true)Avoid febrile seizure (not true) Evidence level Ia Relieve parental anxiety (fever phobia)!!Relieve parental anxiety (fever phobia)!!

10. Non-pharmacologic Treatment of Fever

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

12. Physical methods of antipyresis Heat loss: conduction, convection, evaporation Tepid water sponging Alexander the GreatTepid water sponging Alexander the Great Cooling blanketsCooling blankets Circulating fansCirculating fans

13. Physical methods of antipyresis Meremikwu & Oyo-Ita. Cochrane Database Syst Rev 2003 Benefits & harms of physical methodsBenefits & harms of physical methods RCT’s; Physical method vs placebo/no Rx; ± antipyreticRCT’s; Physical method vs placebo/no Rx; ± antipyretic 1 RCT (n=30): physical methods vs placebo1 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 RR 5.09; 95%CI 1.56-16.60

15. Pharmacologic Antipyresis Pharmacologic Antipyresis Centrally-acting drugs: hypothalamic thermoregulatory center; inhibit synthesis of PG’sCentrally-acting drugs: hypothalamic thermoregulatory center; inhibit synthesis of PG’s Two main families:Two main families: 1.Paracetamol: Central antipyretic action (acetaminophen) 2.NSAID’s: Central antipyretic action and peripheral anti-inflammatory action (ibuprofen)

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

17. Acetaminophen Meremikwu & Oyo-Ita. Cochrane Database Syst Rev 2002Meremikwu & Oyo-Ita. Cochrane Database Syst Rev 2002 RCTs: ACE vs. placebo/no Rx OR vs. physical methodsRCTs: ACE vs. placebo/no Rx OR vs. physical methods Few studies, limited data, heterogeneityFew studies, limited data, heterogeneity % afebrile at 2 hrs (vs. sponging):% 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, prolongedAbsorption: Irregular, variable, prolonged Peak [serum]: 3.5 hrsPeak [serum]: 3.5 hrs Dose: 30-45 mg/kg; Q4-6 hrsDose: 30-45 mg/kg; Q4-6 hrs

19. Rectal vs. Oral Acataminophen Scolnick et al. Pediatrics 2002 70 children (6m-6y); ambulatory (T 0 ≥ 39 0 C)70 children (6m-6y); ambulatory (T 0 ≥ 39 0 C) Oral ACE (15mg/kg), rectal ACE (15 mg/kg), rectal ACE (30 mg/kg)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.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 RCTDouble-dummy, D-B, P-C RCT 51 children (6m-13y); inpatients (T 0 ≥ 38.5 0 C)51 children (6m-13y); inpatients (T 0 ≥ 38.5 0 C) 15mg/kg oral, 15mg/kg rectal, 35 mg/kg rectal15mg/kg oral, 15mg/kg rectal, 35 mg/kg rectal Hourly T 0 x 6hHourly T 0 x 6h Similar antipyresis (ITT)Similar antipyresis (ITT) Time to max antipyresis: 3.6h; 95%CI (3.2-4.0) Time to reduction by ≥ 1 0 C: 2.4h; 95%CI (1.8- 3.1) Δ T 0 each hr (P=0.25; two-way ANOVA)

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

22. Ibuprofen vs. Acetaminophen Perrot, et al. Arch Pediatr Adolsc Med 2004 Meta-anlaysis: RCTs single-dose ACE & IBUMeta-anlaysis: RCTs single-dose ACE & IBU Fever or pain; <18 yrsFever or pain; <18 yrs IBU (5-10mg/kg) > ACE (10-15mg/kg) at 2, 4, 6 hrs post doseIBU (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)IBU (5-10mg/kg) > ACE (10-15mg/kg) Weighted effect sizes:Weighted effect sizes: 0.19 SD; 95% CI 0.05-0.33 (at T2)0.19 SD; 95% CI 0.05-0.33 (at T2) 0.31 SD; 95% CI 0.19-0.44 (at T4)0.31 SD; 95% CI 0.19-0.44 (at T4) 0.33 SD; 95% CI 0.19-0.47 (at T6)0.33 SD; 95% CI 0.19-0.47 (at T6) AE: similar to placeboAE: similar to placebo

24. Ibuprofen vs. Acetaminophen: Safety Lesko & Mitchell. Pediatrics 1999 Incidence of serious AEIncidence of serious AE Children < 2 yrsChildren < 2 yrs D-B, practitioner based RCTD-B, practitioner based RCT IBU (5mg/kg), IBU (10mg/kg), ACE (12mg/kg)IBU (5mg/kg), IBU (10mg/kg), ACE (12mg/kg) 4-week F/U: similar rates of hospitalizations4-week F/U: similar rates of hospitalizations 1.4%; 95% CI 1.3%-1.6%

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

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

27. Alternating Ibuprofen-Acteminophen 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 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) 16% (3 hrs) 43% ( 4 hrs) 43% ( 4 hrs) - 61%: written instructions

29. Combined Ibuprofen-Acteminophen Combined Ibuprofen-Acteminophen Erlewyn-Lajeunesse, et al. Arch Dis Child 2006 O-L RCTO-L RCT 123 children (6m-10y); ER (T 0 ≥ 38.0 0 C)123 children (6m-10y); ER (T 0 ≥ 38.0 0 C) Tympanic T 0, T 1, T 2Tympanic T 0, T 1, T 2 Paracetamol 15mg/kg, IBU 5mg/kg, bothParacetamol 15mg/kg, IBU 5mg/kg, both Δ at T 1 :Δ at T 1 : Both>Paracetam. 0.35 0 C; 95%CI 0.10-0.60 Both=IBU 0.25 0 C; 95%CI -0.01-0.50

30. Alternating Ibuprofen-Acteminophen Alternating Ibuprofen-Acteminophen Sarrell, et al. Arch Pediatr Adolesc Med 2006 464 children (6-36m), outpatients (T 0 ≥ 38.4 0 C)464 children (6-36m), outpatients (T 0 ≥ 38.4 0 C) ??D-B RCT??D-B RCT ACE 12.5mg/kg Q6h, IBU 5mg/kg Q8h, ACE/IBU Q4h (??blinding)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 visits3-day T, stress score, amount of drug, days absent from day care/work, fever recurrence, no. ED visits

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

32. Alternating Ibuprofen-Acteminophen Alternating Ibuprofen-Acteminophen Nabulsi, et al. BMC Medicine 2006 D-B, P-C RCTD-B, P-C RCT 70 children (6m-12.8y); inpatients (T 0 ≥ 38.8 0 C)70 children (6m-12.8y); inpatients (T 0 ≥ 38.8 0 C) IBU 10mg/kg at T 0, placebo at T 4IBU 10mg/kg at T 0, placebo at T 4 IBU 10mg/kg at T 0, ACE 15mg/kg at T 4 T 0, T 4-8T 0, T 4-8

33. P VALUEIBU N = 33 IBU & ACET N = 36 0.01819 (57.6)30 (83.3) Afebrile at 6 hours N (%) 0.00014 (45.2)31 (86.1) Afebrile at 7 hours N (%) 0.00011 (35.5)29 (80.6) Afebrile at 8 hours N (%) 0.7932.1 (1.2)2.2 (0.7) Maximum temperature decline Mean (SD) 0.0005.7 (2.2)7.4 (1.3) Time to fever recurrence Mean (SD) 0.6276 (18.2)5 (13.9) Hypothermia N (%) Nabulsi, et al. BMC Medicine 2006

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

36. Antipyretics AE: controversies! 1.Asthma & IBU: Risk similar to ACE Lesko et al. Pediatrics 2002 2.Febrile sz & IBU or ACE: No ↓ in recurrences van Stuijvenberg, et al. Pediatrics 1998 Baumann RJ. Pediatrics 1999

37. Antipyretics AE: controversies! 3.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