pediatrics 2011 sullivan 580 7 (1)

Clinical ReportFever and Antipyretic Use inChildren

abstractFever in a child is one of themost common clinical symptomsmanagedby pediatricians and other health care providers and a frequent causeof parental concern. Many parents administer antipyretics even whenthere is minimal or no fever, because they are concerned that the childmust maintain a normal temperature. Fever, however, is not theprimary illness but is a physiologic mechanism that has benecialeffects in ghting infection. There is no evidence that fever itself wors-ens the course of an illness or that it causes long-term neurologiccomplications. Thus, the primary goal of treating the febrile childshould be to improve the childs overall comfort rather than focus onthe normalization of body temperature. When counseling the parentsor caregivers of a febrile child, the general well-being of the child, theimportance of monitoring activity, observing for signs of serious ill-ness, encouraging appropriate uid intake, and the safe storage ofantipyretics should be emphasized. Current evidence suggests thatthere is no substantial difference in the safety and effectiveness ofacetaminophen and ibuprofen in the care of a generally healthy childwith fever. There is evidence that combining these 2 products is moreeffective than the use of a single agent alone; however, there are con-cerns that combined treatment may be more complicated and contrib-ute to the unsafe use of these drugs. Pediatricians should also promotepatient safety by advocating for simplied formulations, dosing in-structions, and dosing devices. Pediatrics 2011;127:580587

INTRODUCTIONFever is one of the most common clinical symptoms managed by pedi-atricians and other health care providers and accounts, by some esti-mates, for one-third of all presenting conditions in children.1 Fever in achild commonly leads to unscheduled physician visits, telephone callsby parents to their childs physician for advice on fever control, and thewide use of over-the-counter antipyretics.

Parents are frequently concernedwith the need tomaintain a normaltemperature in their ill child. Many parents administer antipyreticseven though there is either minimal or no fever.2 Approximately one-half of parents consider a temperature of less than 38C (100.4F) to bea fever, and 25% of caregivers would give antipyretics for tempera-tures of less than 37.8C (100F).1,3 Furthermore, 85% of parents (n340) reported awakening their child from sleep to give antipyretics.1

Unfortunately, as many as one-half of parents administer incorrectdoses of antipyretics; approximately 15% of parents give suprathera-peutic doses of acetaminophen or ibuprofen.4 Caregivers who under-

Janice E. Sullivan, MD, Henry C. Farrar, MD, and theSECTION ON CLINICAL PHARMACOLOGY AND THERAPEUTICS,and COMMITTEE ON DRUGS

KEY WORDSfever, antipyretics, children

ABBREVIATIONSNSAIDnonsteroidal anti-inammatory drug

The guidance in this report does not indicate an exclusivecourse of treatment or serve as a standard of medical care.Variations, taking into account individual circumstances, may beappropriate.

This document is copyrighted and is property of the AmericanAcademy of Pediatrics and its Board of Directors. All authorshave led conict of interest statements with the AmericanAcademy of Pediatrics. Any conicts have been resolved througha process approved by the Board of Directors. The AmericanAcademy of Pediatrics has neither solicited nor accepted anycommercial involvement in the development of the content ofthis publication.

www.pediatrics.org/cgi/doi/10.1542/peds.2010-3852

doi:10.1542/peds.2010-3852

All clinical reports from the American Academy of Pediatricsautomatically expire 5 years after publication unless reafrmed,revised, or retired at or before that time.

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

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Guidance for the Clinician inRendering Pediatric Care

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stand that dosing should be based onweight rather than age or height of fe-ver are much less likely to give an in-correct dose.4

Physicians and nurses are the primarysource of information on fever man-agement for parents and caregivers,although there are some disparitiesbetween the views of parents and phy-sicians regarding antipyretic treat-ment.1 The most common indicationsfor initiating antipyretic therapy by pe-diatricians are a temperature higherthan 38.3C (101F) and improvingthe childs overall comfort.5 Althoughonly 13% of pediatricians specicallycite discomfort as the primary indi-cation for antipyretic use,6 this in-tent is generally implied in their rec-ommendations. Most pediatricians(80%) believe that a sleeping ill childshould not be awakened solely to begiven antipyretics.5

Antipyretic therapy will remain a com-mon practice by parents and is gener-ally encouraged and supported by pe-diatricians. Thus, pediatricians andhealth care providers are responsiblefor the appropriate counseling of par-ents and other caregivers about feverand the use of antipyretics.7

PHYSIOLOGY OF FEVER

It should be emphasized that fever isnot an illness but is, in fact, a physio-logicmechanism that has benecial ef-fects in ghting infection.810 Fever re-tards the growth and reproduction ofbacteria and viruses, enhances neu-trophil production and T-lymphocyteproliferation, and aids in the bodysacute-phase reaction.1114 The degreeof fever does not always correlate withthe severity of illness. Most fevers areof short duration, are benign, and mayactually protect the host.15 Data showbenecial effects on certain compo-nents of the immune system in fever,and limited data have revealed that fe-ver actually helps the body recover

more quickly from viral infections, al-though the fever may result in discom-fort in children.11,1618 Evidence is in-conclusive as to whether treating withantipyretics, particularly ibuprofenalone or in combination with acet-aminophen, increases the risks ofcomplications with certain types of in-fections.19,20 Potential benets of feverreduction include relief of patient dis-comfort and reduction of insensiblewater loss, which may decrease theoccurrence of dehydration. Risks oflowering fever include delayed identi-cation of the underlying diagnosis andinitiation of appropriate treatmentand drug toxicity.

There is no evidence that children withfever, as opposed to hyperthermia, areat increased risk of adverse outcomessuch as brain damage.7,9,2123 Fever is acommon and normal physiologic re-sponse that results in an increase inthe hypothalamic set point in re-sponse to endogenous and exogenouspyrogens.9,23 In contrast, hyperthermiais a rare and pathophysiologic re-sponse with failure of normal ho-meostasis (no change in the hypotha-lamic set point) that results in heatproduction that exceeds the capabilityto dissipate heat.9,23 Characteristicsof hyperthermia include hot, dry skinand central nervous system dysfunc-tion that results in delirium, convul-sions, or coma.23 Hyperthermiashould be addressed promptly, be-cause at temperatures above 41C to42C, adverse physiologic effects be-gin to occur.7,9,24 Studies of healthcare workers, including physicians,have revealed that most believe thatthe risk of heat-related adverse out-comes is increased with tempera-tures above 40C (104F), althoughthis belief is not justied.5,23,2527 Achild with a temperature of 40C(104F) attributable to a simple febrileillness is quite different from a childwith a temperature of 40C (104F) at-

tributable to heat stroke. Thus, extrap-olating similar outcomes from thesedifferent illnesses is problematic.

TREATMENT GOALS

A discussion of the use of antipyreticsin febrile children must begin withconsideration of the therapeutic endpoints. When counseling families, phy-sicians should emphasize the childscomfort and signs of serious illnessrather than emphasizing normother-mia. A primary goal of treating the fe-brile child should be to improve thechilds overall comfort. Most pediatri-cians observe, with some supportingdata from research, that febrile chil-dren have altered activity, sleep, andbehavior in addition to decreased oralintake.28 Unfortunately, there is a pau-city of clinical research addressing theextent to which antipyretics improvediscomfort associated with fever or ill-ness. It is not clear whether comfortimproves with a normalized tempera-ture, because external cooling mea-sures, such as tepid sponge baths, canlower the body temperature withoutimproving comfort.7,29 The use of alco-hol baths is not an appropriate coolingmethod, because there have been re-ported adverse events associated withsystemic absorption of alcohol.30 Fur-thermore, antipyretics have other clin-ical outcomes, including analgesia,which may enhance their overall clini-cal effect. Regardless of the exactmechanism of action, many physicianscontinue to encourage the use of anti-pyretics with the belief thatmost of thebenets are the result of improvedcomfort and the accompanying im-provements in activity and feeding,less irritability, and a more reliablesense of the childs overall clinical con-dition. Because these are the most im-portant benets of antipyretic therapy,it is of paramount importance that pa-rental counseling focus on monitoringof activity, observing for signs of seri-

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ous illness, and appropriate uid in-take to maintain hydration.

The desire to improve the overall com-fort of the febrile child must be bal-anced against the desire to simplylower the body temperature. It is welldocumented that there are signicantconcerns on the part of parents,nurses, and physicians about potentialadverse effects of fever that have led toa description in the literature of feverphobia.31 The most consistently iden-tied serious concern of caregiversand health care providers is that highfevers, if left untreated, are associatedwith seizures, brain damage, anddeath.1,25,32,33 It is argued that by creat-ing undue concern over these pre-sumed risks of fever, for which there isno clearly established relationship,physicians are promoting an exagger-ated desire in parents to achieve nor-mothermia by aggressively treatingfever in their children.

There is no evidence that reducing fe-ver reduces morbidity or mortalityfrom a febrile illness. Possible excep-tions to this could be children with un-derlying chronic diseases that may re-sult in limited metabolic reserves orchildren who are critically ill, becausethese children may not tolerate the in-creased metabolic demands of fever.34

Finally, there is no evidence that anti-pyretic therapy decreases the recur-rence of febrile seizures.22,35,36

Despite insufcient evidence, many pe-diatricians recommend the routinepractice of pretreatment with acet-aminophen or ibuprofen before a pa-tient receives immunizations to de-crease the discomfort associated withthe injections and subsequently at theinjection sites and to minimize the fe-brile response.9,17,3739 In addition, re-sults of 1 recent study suggested thepossibility of decreased immune re-sponse to vaccines in patients treatedearly with antipyretics.40

Although the available literature is lim-

ited on the actual risks of fever and thebenets of antipyretic therapy, it isrecognized that improvement in pa-tient comfort is a reasonable thera-peutic objective. Furthermore, at thistime, there is no evidence that temper-ature reduction, in and of itself, shouldbe the primary goal of antipyretictherapy.

Acetaminophen

After sufcient evidence emerged ofan association between salicylatesand Reye syndrome, acetaminophenessentially replaced aspirin as the pri-mary treatment of fever. Acetamino-phen doses of 10 to 15 mg/kg per dosegiven every 4 to 6 hours orally are gen-erally regarded as safe and effective.Typically, the onset of an antipyretic ef-fect is within 30 to 60 minutes; approx-imately 80% of childrenwill experiencea decreased temperature within thattime (Table 1).

Although alternative dosing regimenshave been suggested,4143 no consis-tent evidence has indicated that theuse of an initial loading dose by eitherthe oral (30 mg/kg per dose) or rectal(40 mg/kg per dose) route improvesantipyretic efcacy. The higher rectaldose is often used in intraoperativeconditions but cannot be recom-mended for use in routine clinicalcare.44,45 The use of higher loadingdoses in clinical practice would addpotential risks for dosing confusion

leading to hepatotoxicity; therefore,such doses are not recommended.

Although hepatotoxicity with acetamin-ophen at recommended doses hasbeen reported rarely, hepatoxicity ismost commonly seen in the setting ofan acute overdose. In addition, there issignicant concern over the possibilityof acetaminophen-related hepatitis inthe setting of a chronic overdose. Themost commonly reported scenariosare those of children receiving multi-ple supratherapeutic doses (ie, 15mg/kg per dose) or frequent adminis-tration of appropriate single doses atintervals of less than 4 hours, whichhas resulted in doses of more than 90mg/kg per day for several days.46,47 Giv-ing an adult preparation of acetamino-phen to a child may result in suprath-erapeutic dosing. In 1 case series,46

half of the children with hepatotoxicityhad received adult preparations ofacetaminophen.

One safety concern is the effect ofacetaminophen on asthma-relatedsymptoms; although asthma has alsobeen associated with acetamino-phen use, causality has not beendemonstrated.4851

Ibuprofen

The use of ibuprofen to manage feverhas been increasing, because it seemsto have a longer clinical effect relatedto lowering of the body temperature

TABLE 1 Antipyretic Information

Variable Acetaminophen Ibuprofen

Decline in temperature, C 12 12Time to onset, h 1 1Time to peak effect, h 34 34Duration of effect, h 46 68Dose, mg/kg 1015 every 4 h 10 every 6 hMaximum daily dose, mg/kg 90 mg/kga 40 mg/kgMaximum daily adult dose, g/d 4 2.4Lower age limit, mob 3 6

Data represent approximate averages from referenced sources.42,43,52,54,71,82a Label is for 75 mg/kg; 90 mg/kg per day should be limited to less than 3 consecutive days.83-85b Unless specically recommended by a health care provider for the younger patient and, then, only after the infant has beenexamined by a health care provider.


(Table 1). Studies in which the effec-tiveness of ibuprofen and acetamino-phen were compared have yieldedvariable results; the consensus is thatboth drugs aremore effective than pla-cebo in reducing fever and that ibupro-fen (10 mg/kg per dose) is at least aseffective as, and perhaps more effec-tive than, acetaminophen (15 mg/kgper dose) in lowering body tempera-ture when either drug is given as a sin-gle or repetitive dose.5257 Data alsoshow that the height of the fever andthe age of the child (rather than thespecic medication used) may be theprimary determinants of the efcacyof antipyretic therapy; those who havea higher fever and are older than 6 yearsshow decreased efcacy or response toantipyretic therapy.54 Studies that com-pare the effect of ibuprofen versus acet-aminophen on childrens behavior andcomfort are generally lacking.

There is no evidence to indicate thatthere is a signicant difference in thesafety of standard doses of ibuprofenversus acetaminophen in generallyhealthy children between 6 monthsand 12 years of age with febrile illness-es.58 Similar to other nonsteroidal anti-inammatory drugs (NSAIDs), ibupro-fen can potentially cause gastritis,59,60

although no data suggest that this is acommon occurrence when used on anacute basis, such as during a febrileillness.58 However, there have beencase reports of bleeding, gastritis,and ulcers of the stomach, duodenum,and esophagus associated with manyNSAIDs, including ibuprofen, even whenused in typical antipyretic and analgesicdoses.59,60 Ibuprofen does not seem toworsen asthma symptoms.

Concern has been raised over thenephrotoxicity of ibuprofen. In numer-ous case reports, children with febrileillnesses developed renal insufciencywhen treated with ibuprofen or otherNSAIDs. Thus, caution is encouragedwhen using ibuprofen in children with

dehydration or with complex medicalillnesses.6163 In children with dehydra-tion, prostaglandin synthesis becomesan increasingly important mechanismfor maintaining appropriate renalblood ow. The use of ibuprofen or anyNSAID interferes with the renal effectsof prostaglandins, which reduces re-nal blood ow and potentially precipi-tates or worsens renal dysfunction.61,63

However, it is not possible to deter-mine the actual incidence ofibuprofen-related renal insufciencyafter short-term use, because it hasnot been systematically investigatedor reported.64 Children who are atgreatest risk of ibuprofen-related re-nal toxicity are those with dehydration,cardiovascular disease, preexistingrenal disease, or the concomitant useof other nephrotoxic agents.62 Anotherpotential group at risk is infantsyounger than 6 months because of thepossibility of differences in ibuprofenpharmacokinetics and developmentaldifferences in renal function.65 Dataare inadequate to support a specicrecommendation for the use of ibupro-fen for fever or pain in infants youngerthan 6 months (there are dosing datafor neonatal closure of patent ductusarteriosus66,67), although the packageinsert states to ask a doctor for guid-ance on its use in this population. An-other potential risk associated withthe use of ibuprofen is the possible as-sociation between ibuprofen andvaricella-related invasive group Astreptococcal infection.68,69 However,at the time of this report, data wereinsufcient to support a causal rela-tionship between ibuprofen and inva-sive group A streptococcal disease.

Alternating or CombinationTherapy

A practice frequently used to controlfever is the alternating or combineduse of acetaminophen and ibuprofen.In a convenience sample survey of 256parents or caregivers, 67% reported

alternating acetaminophen and ibu-profen for fever control, 81% of whomstated that they had followed the ad-vice of their health care provider orpediatrician.70 Although 4 hours wasthe most frequent interval, parents re-ported alternating therapy every 2, 3,4, and 6 hours, which suggests thatthere is no consensus on dosinginstructions.

At the time of this report, 5 studies hadbeen identied that compared alter-nating ibuprofen and acetaminophenversus either acetaminophen or ibu-profen as single agents.7175 Initially,changes in temperature were similarfor all groups in these studies, regard-less of therapy. However, 4 or morehours after the initiation of treat-ment, lower temperature was consis-tently observed in the combination-treatment groups. For example, 6 and8 hours after the initiation of the study,a greater percentage of children wereafebrile in the combination group(83% and 81%, respectively) comparedwith those in the group that receivedibuprofen alone (58% and 35%, respec-tively).71 Only 1 study72 evaluated is-sues related to stress and comfort andfound lower stress scores and lesstime missed from child care in thecombination-treatment group. An-other study73 showed a trend toward anormalization of fever-related symp-toms by 24 and 48 hours after institu-tion of therapy, but these trends disap-peared by day 5.

Although the aforementioned studiesprovide some evidence that combina-tion therapy may be more effective atlowering temperature, questions re-main regarding the safety of this prac-tice as well as the effectiveness in im-proving discomfort, which is theprimary treatment end point. The pos-sibility that parents will either not re-ceive or not understand dosing in-structions, combined with the widearray of formulations that contain



these drugs, increases the potentialfor inaccurate dosing or overdos-ing.76,77 Finally, this practice may onlypromote the fever phobia that alreadyexists.

Although there is some evidence thatcombination therapy may result in alower body temperature for a greaterperiod of time, there is no evidencethat combination therapy results inoverall improvement in other clinicaloutcomes. Also, these studies have notcontained adequate numbers of sub-jects to fully evaluate the safety of thispractice. Therefore, there is insuf-cient evidence to support or refute theroutine use of combination treatmentwith both acetaminophen and ibupro-fen. Practitioners who choose to followthis practice should counsel parentscarefully regarding proper formula-tion, dosing, and dosing intervals andemphasize the childs comfort insteadof reduction of fever.

INSTRUCTIONS FOR CAREGIVERS

It is critically important for pediatri-cians to clearly describe the appropri-ate use (ie, formulation, dose, and dos-ing interval) of acetaminophen andibuprofen to caregivers (Table 1). Childsafety will be further enhanced byclear labeling and the development ofsimplied dosing methods, standard-ized drug concentrations, and stan-dardized delivery devices.7880 Cough-and-cold products that containacetaminophen and ibuprofen shouldnot be given to children because of thepossibility that parents may uninten-tionally give their child simultaneousdoses of an antipyretic and a cough-and-cold medication that contains thesame antipyretic. In addition, there is alack of proven efcacy for this class ofcombination products for children. Forchildren who require liquid prepara-

tions, physicians should encouragefamilies to only use 1 formulation.Acetaminophen is the most commonsingle ingredient implicated in emer-gency department visits for medica-tion overdoses among children, andmore than 80% of these emergencyvisits are a result of unsupervisedingestions81; therefore, proper han-dling and storage of antipyreticsshould be encouraged.

SUMMARY

Appropriate counseling on the man-agement of fever begins by helpingparents understand that fever, in andof itself, is not known to endanger agenerally healthy child. In contrast, fe-ver may actually be of benet; thus, thereal goal of antipyretic therapy is notsimply to normalize body temperaturebut to improve the overall comfort andwell-being of the child. Acetaminophenand ibuprofen, when used in appropri-ate doses, are generally regarded assafe and effective agents in most clini-cal situations. However, as with alldrugs, they should be used judiciouslyto minimize the risk of adverse drugeffects and toxicity. Combination ther-apy with acetaminophen and ibupro-fen may place infants and children atincreased risk because of dosing er-rors and adverse outcomes, and thesepotential risks must be carefully con-sidered. When counseling a family onthe management of fever in a child, pe-diatricians and other health care pro-viders should minimize fever phobiaand emphasize that antipyretic usedoes not prevent febrile seizures. Pedi-atricians should focus instead onmon-itoring for signs/symptoms of seriousillness, improving the childs comfortby maintaining hydration, and educat-ing parents on the appropriate use,dosing, and safe storage of antipyret-ics. To promote child safety, pediatri-

cians should advocate for a limitednumber of formulations of acetamino-phen and ibuprofen and for clear label-ing of dosing instructions and an in-cluded dosing device for antipyreticproducts.

LEAD AUTHORSJanice E. Sullivan, MDHenry C. Farrar, MD

COMMITTEE ON DRUGS, 20092010Daniel A. C. Frattarelli, MD, ChairpersonJeffrey L. Galinkin, MDThomas P. Green, MDMary A. Hegenbarth, MDMark L. Hudak, MDMatthew E. Knight, MDRobert E. Shaddy, MD

FORMER COMMITTEE ON DRUGSMEMBERWayne R. Snodgrass, MD, PhD

CONSULTANTRobert M. Ward, MD

LIAISONSJohn J. Alexander, MD Food and DrugAdministration

Janet D. Cragan, MD Centers for DiseaseControl and Prevention

George P. Giacoia, MD National Institutes ofHealth

Michael J. Rieder, MD Canadian PaediatricSociety

Adelaide Robb, MD American Academy ofChild and Adolescent Psychiatry

Hari C. Sachs, MD Food and DrugAdministration

STAFFRaymond J. Koteras, [email protected]

SECTION ON CLINICAL PHARMACOLOGYAND THERAPEUTICS, 20092010Janice E. Sullivan, MD, ChairpersonGlen S. Frick, MDLynne G. Maxwell, MDIan M. Paul, MDJohn F. Pope, MDThomas G. Wells, MD

FORMER EXECUTIVE COMMITTEEMEMBERSCharles J. Cote, MDHenry C. Farrar, MDRichard L. Gorman, MD

STAFFRaymond J. Koteras, MHA


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Clinical ReportFever and Antipyretic Use in ChildrenINTRODUCTIONPHYSIOLOGY OF FEVERTREATMENT GOALSAcetaminophenIbuprofenAlternating or Combination Therapy

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