Treatment of the Febrile Child: What is the Evidence?

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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

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OUTLINE

• Fever Friend or Foe
• Fever phobia
• Why do we treat fever?
• Non-pharmacologic Rx
• Pharmacologic Rx
• Adverse effects of Rx

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Historical Perspective

• Hippocrates Fever as beneficial sign during
  infection
• Thomas Sydenham (1624-1689) natures engine
  to remove her enemy
• Liebermeister (1800s) fever as regulation of
  body temp. at higher level

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Fever Friend or Foe?

• Beneficial host response
• Animal studies
• Human studies

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Fever Friend or foe?

• Harmful consequences
• ?O2 consumption CO2 production
• ?Cardiac output fluid requirement
• Febrile seizures in predisposed children
• Delirium, coma ? death gt 410 C

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Fever phobia

• 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 Tlt38.90 C
• 16 lethal reaches 48.90 if untreated

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Fever phobia

• Crocetti, et al, Pediatrics 2001
• 91 of parents fever harmful
• 21 brain damage 14 death
• gt50 check fever hourly
• 25 gave antipyretics for temp lt380 C
• 85 awaken child from sleep to give antipyretic

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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

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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)!!

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Non-pharmacologic Treatment of Fever
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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)

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Physical methods of antipyresis

• Heat loss conduction, convection, evaporation
• Tepid water sponging Alexander the Great
• Cooling blankets
• Circulating fans

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Physical methods of antipyresis

• Meremikwu Oyo-Ita. Cochrane Database Syst Rev
  2003
• Benefits harms of physical methods
• RCTs Physical method vs placebo/no Rx
  antipyretic
• 1 RCT (n30) physical methods vs placebo
• similar afebrile at 1 hr

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Meremikwu Oyo-Ita. Cochrane Database Syst Rev
2003

• 2 RCTs (n125) physical methods antipyretic vs
  antipyretic
• RR ( afebrile at 1 hr)
• 11.76 95CI 3.39-40.79
• 1RCT (n130) no diff.
• AE in 3 trials
• Shivering goose pimples
• RR 5.09 95CI 1.56-16.60

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Pharmacologic Antipyresis

• Centrally-acting drugs hypothalamic
  thermoregulatory center inhibit synthesis of
  PGs
• Two main families
• Paracetamol Central antipyretic action
  (acetaminophen)
• NSAIDs Central antipyretic action and
  peripheral anti-inflammatory action (ibuprofen)

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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

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Acetaminophen

• Meremikwu Oyo-Ita. Cochrane Database Syst Rev
  2002
• RCTs ACE vs. placebo/no Rx OR vs. physical
  methods
• Few studies, limited data, heterogeneity
• afebrile at 2 hrs (vs. sponging)
• 2 RCTs n120
• RR1.84 95CI 0.94-3.61
• No AE

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Rectal Acetaminophen

• Absorption Irregular, variable, prolonged
• Peak serum 3.5 hrs
• Dose 30-45 mg/kg Q4-6 hrs

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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 ? in temp.

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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 95CI (3.2-4.0)
• Time to reduction by 10C 2.4h 95CI
  (1.8- 3.1)
• ? T0 each hr (P0.25 two-way ANOVA)

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Ibuprofen

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

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Ibuprofen vs. Acetaminophen

• Perrot, et al. Arch Pediatr Adolsc Med 2004
• Meta-anlaysis RCTs single-dose ACE IBU
• Fever or pain lt18 yrs
• IBU (5-10mg/kg) gt ACE (10-15mg/kg) at 2, 4, 6 hrs
  post dose

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Perrot, et al. Arch Pediatr Adolsc Med 2004

• Fever
• IBU (5-10mg/kg) gt 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

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Ibuprofen vs. Acetaminophen Safety

• Lesko Mitchell. Pediatrics 1999
• Incidence of serious AE
• Children lt 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

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Lesko Mitchell. Pediatrics 1999

• No serious AE
• Acute renal failure
• Anaphylaxis
• Reyes syndrome
• Asthma
• Bronchiolitis
• Vomiting/gastritis
• GI bleeding 3 (IBU)
• Short-term assessment!!

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Alternating Ibuprofen-Acteminophen

• Common practice physicians care givers
• Mayoral, et al. Pediatrics 2000
• 50 of physicians
• Young physicians (fever phobia!!)

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Alternating Ibuprofen-Acteminophen

• Nabulsi, et al. BMC Medicine 2006
• - 38.5 of parents
• - 84.3 physicians advice
• - 13.7 self-initiated
• - 71.7 very effective

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Alternating Ibuprofen-Acteminophen

• Wright Liebelt. Clin Pediatr 2007
• - 44 of parents
• - 81 physicians advice
• - 8 self-initiated
• - Frequency 9 (2 hrs)
• 16 (3 hrs)
• 43 ( 4 hrs)
• - 61 written instructions

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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
• ? at T1
• BothgtParacetam. 0.35 0C 95CI 0.10-0.60
• BothIBU 0.25 0C 95CI -0.01-0.50

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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

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Alternating Ibuprofen-Acteminophen

• Sarrell, et al. Arch Pediatr Adolesc Med 2006
• Loading doses 25mg/kg ACE, 10mg/kg IBU
• ACE/IBU (plt0.001)
• lower mean T
• more rapid ?T
• less stress score
• less absenteeism
• No AE in all groups

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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

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Nabulsi, et al. BMC Medicine 2006
P VALUE IBU N 33 IBU ACET N 36
0.018 19 (57.6) 30 (83.3) Afebrile at 6 hours N ()
0.000 14 (45.2) 31 (86.1) Afebrile at 7 hours N ()
0.000 11 (35.5) 29 (80.6) Afebrile at 8 hours N ()
0.793 2.1 (1.2) 2.2 (0.7) Maximum temperature decline Mean (SD)
0.000 5.7 (2.2) 7.4 (1.3) Time to fever recurrence Mean (SD)
0.627 6 (18.2) 5 (13.9) Hypothermia N ()
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Nabulsi, et al. BMC Medicine 2006
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Combined antipyretics ?risks

• Potentiation of renal toxicity case reports
• Ibuprofen? reduces glutathione production
  acetaminphen? renal toxicity (tubular necrosis)

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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

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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

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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

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Thank You