Treatment of the Febrile Child: Treatment of the Febrile Child: What is the Evidence?What is the Evidence?

Mona Nabulsi-Khalil, MD MScMona Nabulsi-Khalil, MD MSc

Associate Professor of PediatricsAssociate Professor of Pediatrics

Department of PediatricsDepartment of Pediatrics

American University of BeirutAmerican University of Beirut

OUTLINEOUTLINE

Fever: Friend or FoeFever: Friend or Foe

Fever phobiaFever phobia

Why do we treat fever?Why do we treat fever?

Non-pharmacologic RxNon-pharmacologic Rx

Pharmacologic RxPharmacologic Rx

Adverse effects of RxAdverse effects of Rx

Historical PerspectiveHistorical Perspective

• Hippocrates: Fever as beneficial sign Hippocrates: Fever as beneficial sign during infectionduring infection

• Thomas Sydenham (1624-1689): “…Thomas Sydenham (1624-1689): “…nature’s engine …to remove her nature’s engine …to remove her enemy…”enemy…”

• Liebermeister (1800’s): fever as Liebermeister (1800’s): fever as regulation of body temp. at higher levelregulation of body temp. at higher level

Fever: Friend or Foe?Fever: Friend or Foe?

Beneficial host response:Beneficial host response:

– Animal studiesAnimal studies

– Human studiesHuman studies

Fever: Friend or foe?Fever: Friend or foe?

Harmful consequences:Harmful consequences:

• ↑↑OO2 2 consumption & COconsumption & CO22 production production

• ↑↑Cardiac output & fluid requirementCardiac output & fluid requirement

• Febrile seizures in predisposed childrenFebrile seizures in predisposed children

• Delirium, coma Delirium, coma death > 41 death > 4100 C C

FeverFever phobiaphobia

• Barton Schmitt: Unrealistic concerns Barton Schmitt: Unrealistic concerns about fever causing harm about fever causing harm

• Scmitt (AJDC 1980): Scmitt (AJDC 1980): – 94% of parents believed fever had side 94% of parents believed fever had side

effectseffects– 63% worried about serious harm63% worried about serious harm– 18% brain damage at T<38.918% brain damage at T<38.900 C C– 16% lethal & reaches 48.916% lethal & reaches 48.90 0 if untreatedif untreated

Fever phobiaFever phobia

• Crocetti, et al, Pediatrics 2001Crocetti, et al, Pediatrics 2001– 91% of parents: fever harmful91% of parents: fever harmful– 21%: brain damage; 14%: death21%: brain damage; 14%: death– >50%: check fever hourly>50%: check fever hourly– 25%: gave antipyretics for temp <3825%: gave antipyretics for temp <380 0 CC– 85%: awaken child from sleep to give 85%: awaken child from sleep to give

antipyreticantipyretic

Fever phobiaFever phobia

• Crocetti, et al:Crocetti, et al:

– 14-44% gave acetaminophen or ibuprofen 14-44% gave acetaminophen or ibuprofen at more frequently than indicatedat more frequently than indicated

– Phobic parents were more likely to have Phobic parents were more likely to have doctors that worry about feverdoctors that worry about fever

Why do we treat fever?Why do we treat fever?

• Relieve child Relieve child expert opinion

• Decrease on metabolic cost (cardiac, Decrease on metabolic cost (cardiac, pulmonary dis.) 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)!!

Non-pharmacologic Treatment of Non-pharmacologic Treatment of FeverFever

Non-pharmacologic RxNon-pharmacologic Rx

• Remove excessive clothing/blankets Remove excessive clothing/blankets heat heat dissipation (Exp. Op.)dissipation (Exp. Op.)

• Avoid excessive activity Avoid excessive activity heat production (Exp. heat production (Exp. Op.)Op.)

• Hydration Hydration insensible losses; blood flow (Exp. Op.)insensible losses; blood flow (Exp. Op.)

• Physical methods Physical methods ((Evidence level 1a)Evidence level 1a)

Physical methods of antipyresisPhysical methods of antipyresis

Heat loss:Heat loss: conduction, convection, conduction, convection, evaporationevaporation

• Tepid water spongingTepid water sponging Alexander the GreatAlexander the Great

• Cooling blanketsCooling blankets

• Circulating fansCirculating fans

Physical methods of antipyresisPhysical methods of antipyresis

Meremikwu & Oyo-Ita. Cochrane Meremikwu & Oyo-Ita. Cochrane Database Syst Rev 2003Database Syst Rev 2003

• Benefits & harms of physical methodsBenefits & harms of physical methods

• RCT’s; Physical method vs placebo/no RCT’s; Physical method vs placebo/no Rx; ± antipyreticRx; ± antipyretic

• 1 RCT (n=30): physical methods vs 1 RCT (n=30): physical methods vs placeboplacebo

similar % afebrile at 1 hrsimilar % afebrile at 1 hr

Meremikwu & Oyo-Ita. Meremikwu & Oyo-Ita. Cochrane Database Syst Rev 2003Cochrane Database Syst Rev 2003

2 RCTs (n=125): physical methods + 2 RCTs (n=125): physical methods + antipyretic vs antipyreticantipyretic vs antipyretic

RR (% afebrile at 1 hr): RR (% afebrile at 1 hr):

11.76; 95%CI 3.39-40.7911.76; 95%CI 3.39-40.79

1RCT (n=130): 1RCT (n=130): no diff.no diff.

AE in 3 trials: AE in 3 trials:

Shivering & goose pimplesShivering & goose pimples

RR 5.09; 95%CI 1.56-16.60RR 5.09; 95%CI 1.56-16.60

Pharmacologic AntipyresisPharmacologic Antipyresis

• Centrally-acting drugs: hypothalamic Centrally-acting drugs: hypothalamic thermoregulatory center; inhibit thermoregulatory center; inhibit synthesis of PG’ssynthesis of PG’s

• Two main families:Two main families:1.1. Paracetamol: Central antipyretic action Paracetamol: Central antipyretic action

(acetaminophen)(acetaminophen)

2.2. NSAID’s: Central antipyretic action and NSAID’s: Central antipyretic action and peripheral anti-inflammatory action peripheral anti-inflammatory action (ibuprofen)(ibuprofen)

AcetaminophenAcetaminophen

• 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 Toxicity: large doses fulminant fulminant hepatic failure hepatic failure death death

AcetaminophenAcetaminophen

• Meremikwu & Oyo-Ita. Cochrane Meremikwu & Oyo-Ita. Cochrane Database Syst Rev 2002Database Syst Rev 2002

• RCTs: ACE vs. placebo/no RxRCTs: ACE vs. placebo/no Rx OROR vs. vs. physical methodsphysical 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=1202 RCTs; n=120RR=1.84; 95%CI 0.94-3.61RR=1.84; 95%CI 0.94-3.61

No AENo AE

Rectal AcetaminophenRectal Acetaminophen

• Absorption: Absorption: Irregular, variable, Irregular, variable, prolongedprolonged

• Peak [serum]: 3.5 hrsPeak [serum]: 3.5 hrs

• Dose: 30-45 mg/kg; Q4-6 hrsDose: 30-45 mg/kg; Q4-6 hrs

Rectal vs. Oral AcataminophenRectal vs. Oral Acataminophen

Scolnick et al. Pediatrics 2002Scolnick et al. Pediatrics 2002

• 70 children (6m-6y); ambulatory (T70 children (6m-6y); ambulatory (T00 ≥≥

393900C)C)

• Oral ACE (15mg/kg), rectal ACE (15 Oral ACE (15mg/kg), rectal ACE (15 mg/kg), rectal ACE (30 mg/kg)mg/kg), rectal ACE (30 mg/kg)

• 3-hr F/U: no diff. in max 3-hr F/U: no diff. in max ΔΔ in temp. in temp.

Rectal vs. Oral AcataminophenRectal vs. Oral Acataminophen

Nabulsi et al. BMC Pediatrics 2005Nabulsi et al. BMC Pediatrics 2005• Double-dummy, D-B, P-C RCTDouble-dummy, D-B, P-C RCT

• 51 children (6m-13y); inpatients (T51 children (6m-13y); inpatients (T0 0 ≥≥ 38.5 38.500C)C)

• 15mg/kg oral, 15mg/kg rectal, 35 mg/kg rectal15mg/kg oral, 15mg/kg rectal, 35 mg/kg rectal• Hourly THourly T00 x 6h x 6h• Similar antipyresis (ITT)Similar antipyresis (ITT)

Time to max antipyresis: 3.6h; 95%CI (3.2-Time to max antipyresis: 3.6h; 95%CI (3.2-4.0)4.0)

Time to reduction by Time to reduction by ≥≥ 1 100C: 2.4h; 95%CI (1.8-C: 2.4h; 95%CI (1.8-3.1)3.1)

ΔΔ T T0 0 each hr (P=0.25; two-way ANOVA)each hr (P=0.25; two-way ANOVA)

IbuprofenIbuprofen

• 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, Toxicities: Renal, GI bleeding, anaphylaxisanaphylaxis

Ibuprofen vs. AcetaminophenIbuprofen vs. Acetaminophen

Perrot, et al. Arch Pediatr Adolsc Med Perrot, et al. Arch Pediatr Adolsc Med 20042004

• Meta-anlaysis: RCTs single-dose ACE & Meta-anlaysis: RCTs single-dose ACE & IBU IBU

• Fever or pain; <18 yrsFever or pain; <18 yrs

• IBU (5-10mg/kg) > ACE (10-15mg/kg) IBU (5-10mg/kg) > ACE (10-15mg/kg) at 2, 4, 6 hrs post doseat 2, 4, 6 hrs post dose

Perrot, et al. Arch Pediatr Adolsc Med 2004Perrot, et al. Arch Pediatr Adolsc Med 2004

Fever: 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

Ibuprofen vs. Acetaminophen: SafetyIbuprofen vs. Acetaminophen: Safety

Lesko & Mitchell. Pediatrics 1999Lesko & 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), IBU (5mg/kg), IBU (10mg/kg), ACE (12mg/kg) ACE (12mg/kg)

• 4-week F/U: similar rates of 4-week F/U: similar rates of hospitalizationshospitalizations

1.4%; 95% CI 1.3%-1.6% 1.4%; 95% CI 1.3%-1.6%

Lesko & Mitchell. Pediatrics 1999Lesko & Mitchell. Pediatrics 1999

• No serious AE:No serious AE:– Acute renal failureAcute renal failure– AnaphylaxisAnaphylaxis– Reye’s syndromeReye’s syndrome– AsthmaAsthma– BronchiolitisBronchiolitis– Vomiting/gastritisVomiting/gastritis

• GI bleeding: 3 (IBU)GI bleeding: 3 (IBU)

• Short-term assessment!!Short-term assessment!!

Alternating Ibuprofen-ActeminophenAlternating Ibuprofen-Acteminophen

• Common practice: physicians & care Common practice: physicians & care giversgivers

Mayoral, et al. Pediatrics 2000Mayoral, et al. Pediatrics 2000– 50% of physicians50% of physicians– Young physicians (fever phobia!!)Young physicians (fever phobia!!)

Alternating Ibuprofen-ActeminophenAlternating Ibuprofen-Acteminophen

Nabulsi, et al. BMC Medicine 2006Nabulsi, et al. BMC Medicine 2006- 38.5% of parents- 38.5% of parents

- 84.3%: physician’s advice- 84.3%: physician’s advice

- 13.7%: self-initiated- 13.7%: self-initiated

- 71.7%: “very effective”- 71.7%: “very effective”

Alternating Ibuprofen-ActeminophenAlternating Ibuprofen-Acteminophen

Wright & Liebelt. Clin Pediatr 2007Wright & Liebelt. Clin Pediatr 2007

- 44% of parents- 44% of parents

- 81%: physician’s advice- 81%: physician’s advice

- 8%: self-initiated- 8%: self-initiated

- Frequency : 9% (2 hrs)- Frequency : 9% (2 hrs)

16% (3 hrs)16% (3 hrs)

43% ( 4 hrs) 43% ( 4 hrs)

- 61%: written instructions- 61%: written instructions

Combined Ibuprofen-ActeminophenCombined Ibuprofen-Acteminophen

Erlewyn-Lajeunesse, et al. Arch Dis Child Erlewyn-Lajeunesse, et al. Arch Dis Child 20062006

• O-L RCTO-L RCT

• 123 children (6m-10y); ER (T123 children (6m-10y); ER (T0 0 ≥≥ 38.0 38.0 00C)C)

• Tympanic TTympanic T00, T, T11, T, T22

• Paracetamol 15mg/kg, IBU 5mg/kg, bothParacetamol 15mg/kg, IBU 5mg/kg, both

• ΔΔ at T at T11::

Both>Paracetam. 0.35 Both>Paracetam. 0.35 00C; 95%CI 0.10-0.60C; 95%CI 0.10-0.60

Both=IBU 0.25 Both=IBU 0.25 00C; 95%CI -0.01-0.50C; 95%CI -0.01-0.50

Alternating Ibuprofen-ActeminophenAlternating Ibuprofen-Acteminophen

Sarrell, et al. Arch Pediatr Adolesc Med Sarrell, et al. Arch Pediatr Adolesc Med 20062006

• 464 children (6-36m), outpatients (T464 children (6-36m), outpatients (T0 0 ≥≥ 38.4 38.4 00C)C)

• ??D-B RCT??D-B RCT• ACE 12.5mg/kg Q6h, IBU 5mg/kg Q8h, ACE 12.5mg/kg Q6h, IBU 5mg/kg Q8h,

ACE/IBU Q4h (??blinding)ACE/IBU Q4h (??blinding)• 3-day T, stress score, 3-day T, stress score, amount of drug, days amount of drug, days

absent from day care/work, fever recurrence, absent from day care/work, fever recurrence, no. ED visitsno. ED visits

Alternating Ibuprofen-ActeminophenAlternating Ibuprofen-Acteminophen

Sarrell, et al. Arch Pediatr Adolesc Med Sarrell, et al. Arch Pediatr Adolesc Med 20062006

• 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 Tlower mean T

more rapid ↓Tmore rapid ↓T

less stress scoreless stress score

less absenteeismless absenteeism• No AE in all groups No AE in all groups

Alternating Ibuprofen-ActeminophenAlternating Ibuprofen-Acteminophen

Nabulsi, et al. BMC Medicine 2006Nabulsi, et al. BMC Medicine 2006• D-B, P-C RCTD-B, P-C RCT

• 70 children (6m-12.8y); inpatients (T70 children (6m-12.8y); inpatients (T0 0 ≥≥ 38.8 38.8 00C)C)

• IBU 10mg/kg at TIBU 10mg/kg at T00 , placebo at T , placebo at T44

IBU 10mg/kg at TIBU 10mg/kg at T00 , ACE 15mg/kg at T , ACE 15mg/kg at T44

• TT00, T, T4-8 4-8

IBU & ACETN = 36

IBUN = 33

P VALUE

Afebrile at 6 hoursN (%)30 (83.3)19 (57.6)0.018

Afebrile at 7 hoursN (%)31 (86.1)14 (45.2)0.000

Afebrile at 8 hoursN (%)29 (80.6)11 (35.5)0.000

Maximum temperature decline

Mean (SD)2.2 (0.7)2.1 (1.2)0.793

Time to fever recurrenceMean (SD)7.4 (1.3)5.7 (2.2)0.000

HypothermiaN (%)5 (13.9)6 (18.2)0.627

Nabulsi, et al. BMC Medicine 2006Nabulsi, et al. BMC Medicine 2006

-2.5

-2

-1.5

-1

-0.5

0

4 5 6 7 8

Time (hrs)

Chan

ge in

Tem

pera

ture

(C)

Combined

Ibuprofen Only

Nabulsi, et al. BMC Medicine 2006Nabulsi, et al. BMC Medicine 2006

Combined antipyretics: ?risksCombined antipyretics: ?risks

• Potentiation of renal toxicity: case Potentiation of renal toxicity: case reportsreports

IbuprofenIbuprofen reduces glutathione reduces glutathione production +acetaminphenproduction +acetaminphen renal renal toxicity (tubular necrosis)toxicity (tubular necrosis)

Antipyretics AE: controversies!Antipyretics AE: controversies!

1.1. Asthma & IBU: Risk similar to ACE Asthma & IBU: Risk similar to ACE Lesko et al. Pediatrics 2002Lesko et al. Pediatrics 2002

2.2. Febrile sz & IBU or ACE: No Febrile sz & IBU or ACE: No ↓↓ in in recurrences recurrences

van Stuijvenberg, et al. Pediatrics 1998van Stuijvenberg, et al. Pediatrics 1998

Baumann RJ. Pediatrics 1999Baumann RJ. Pediatrics 1999

Antipyretics AE: controversies!Antipyretics AE: controversies!

3.3. Invasive group A strep and NSAIDs:Invasive group A strep and NSAIDs:

- No ↑ risk necrotising GAS infections- No ↑ risk necrotising GAS infections

- ? Association with non-invasive GAS - ? Association with non-invasive GAS infections and IBU infections and IBU

OR= 3.9; 95% CI 1.3-12 (Subgroup of OR= 3.9; 95% CI 1.3-12 (Subgroup of combined antipyretic)combined antipyretic)

Lesko et al. Pediatrics 2001Lesko et al. Pediatrics 2001

Should we treat fever?Should we treat fever?

“ “ .. antipyretics should not be given .. antipyretics should not be given routinely to children with fever in routinely to children with fever in developing countries; they should be developing countries; they should be reserved for the treatment of children reserved for the treatment of children with severe discomfort or high fever..”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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