Guidance for the Clinician in Rendering Pediatric Care Clinical Report— and Antipyretic Use in Children

Janice E. Sullivan, MD, Henry C. Farrar, MD, and the abstract SECTION ON CLINICAL PHARMACOLOGY AND THERAPEUTICS, and COMMITTEE ON DRUGS Fever in a child is one of the most common clinical symptoms managed by pediatricians and other health care providers and a frequent cause KEY WORDS fever, antipyretics, children of parental concern. Many parents administer antipyretics even when ABBREVIATIONS there is minimal or no fever, because they are concerned that the child NSAID—nonsteroidal anti-inflammatory drug must maintain a “normal” temperature. Fever, however, is not the The guidance in this report does not indicate an exclusive primary illness but is a physiologic mechanism that has beneficial course of treatment or serve as a standard of medical care. effects in fighting infection. There is no evidence that fever itself wors- Variations, taking into account individual circumstances, may be ens the course of an illness or that it causes long-term neurologic appropriate. complications. Thus, the primary goal of treating the febrile child This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors should be to improve the child’s overall comfort rather than focus on have filed conflict of interest statements with the American the normalization of body temperature. When counseling the parents Academy of Pediatrics. Any conflicts have been resolved through or caregivers of a febrile child, the general well-being of the child, the a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any importance of monitoring activity, observing for signs of serious ill- commercial involvement in the development of the content of ness, encouraging appropriate fluid intake, and the safe storage of this publication. antipyretics should be emphasized. Current evidence suggests that there is no substantial difference in the safety and effectiveness of acetaminophen and in the care of a generally healthy child with fever. There is evidence that combining these 2 products is more effective 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 promote patient safety by advocating for simplified formulations, dosing in- structions, and dosing devices. Pediatrics 2011;127:580–587 www.pediatrics.org/cgi/doi/10.1542/peds.2010-3852 INTRODUCTION doi:10.1542/peds.2010-3852 Fever is one of the most common clinical symptoms managed by pedi- All clinical reports from the American Academy of Pediatrics atricians and other health care providers and accounts, by some esti- automatically expire 5 years after publication unless reaffirmed, mates, for one-third of all presenting conditions in children.1 Fever in a revised, or retired at or before that time. child commonly leads to unscheduled physician visits, telephone calls PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). by parents to their child’s physician for advice on fever control, and the Copyright © 2011 by the American Academy of Pediatrics wide use of over-the-counter antipyretics. Parents are frequently concerned with the need to maintain a “normal” temperature in their ill child. Many parents administer antipyretics even though there is either minimal or no fever.2 Approximately one- half of parents consider a temperature of less than 38°C (100.4°F) to be a fever, and 25% of caregivers would give antipyretics for tempera- tures of less than 37.8°C (100°F).1,3 Furthermore, 85% of parents (n ϭ 340) reported awakening their child from sleep to give antipyretics.1 Unfortunately, as many as one-half of parents administer incorrect doses of antipyretics; approximately 15% of parents give suprathera- peutic doses of acetaminophen or ibuprofen.4 Caregivers who under-

580 FROM THE AMERICAN ACADEMY OF PEDIATRICS Downloaded from www.aappublications.org/news by guest on September 28, 2021 FROM THE AMERICAN ACADEMY OF PEDIATRICS stand that dosing should be based on more quickly from viral infections, al- tributable to heat stroke. Thus, extrap- weight rather than age or height of fe- though the fever may result in discom- olating similar outcomes from these ver are much less likely to give an in- fort in children.11,16–18 Evidence is in- different illnesses is problematic. correct dose.4 conclusive as to whether treating with Physicians and nurses are the primary antipyretics, particularly ibuprofen TREATMENT GOALS source of information on fever man- alone or in combination with acet- A discussion of the use of antipyretics agement for parents and caregivers, aminophen, increases the risks of in febrile children must begin with although there are some disparities complications with certain types of in- consideration of the therapeutic end between the views of parents and phy- fections.19,20 Potential benefits of fever points. When counseling families, phy- sicians regarding antipyretic treat- reduction include relief of patient dis- sicians should emphasize the child’s ment.1 The most common indications comfort and reduction of insensible comfort and signs of serious illness for initiating antipyretic therapy by pe- water loss, which may decrease the rather than emphasizing normother- diatricians are a temperature higher occurrence of dehydration. Risks of mia. A primary goal of treating the fe- than 38.3°C (101°F) and improving lowering fever include delayed identifi- brile child should be to improve the the child’s overall comfort.5 Although cation of the underlying diagnosis and child’s overall comfort. Most pediatri- only 13% of pediatricians specifically initiation of appropriate treatment cians observe, with some supporting cite discomfort as the primary indi- and drug toxicity. data from research, that febrile chil- cation for antipyretic use,6 this in- There is no evidence that children with dren have altered activity, sleep, and tent is generally implied in their rec- fever, as opposed to , are behavior in addition to decreased oral ommendations. Most pediatricians at increased risk of adverse outcomes intake.28 Unfortunately, there is a pau- (80%) believe that a sleeping ill child such as brain damage.7,9,21–23 Fever is a city of clinical research addressing the should not be awakened solely to be common and normal physiologic re- extent to which antipyretics improve given antipyretics.5 sponse that results in an increase in discomfort associated with fever or ill- Antipyretic therapy will remain a com- the hypothalamic “set point” in re- ness. It is not clear whether comfort mon practice by parents and is gener- sponse to endogenous and exogenous improves with a normalized tempera- ally encouraged and supported by pe- pyrogens.9,23 In contrast, hyperthermia ture, because external cooling mea- diatricians. Thus, pediatricians and is a rare and pathophysiologic re- sures, such as tepid sponge baths, can health care providers are responsible sponse with failure of normal ho- lower the body temperature without for the appropriate counseling of par- meostasis (no change in the hypotha- improving comfort.7,29 The use of alco- ents and other caregivers about fever lamic set point) that results in heat hol baths is not an appropriate cooling and the use of antipyretics.7 production that exceeds the capability method, because there have been re- to dissipate heat.9,23 Characteristics ported adverse events associated with PHYSIOLOGY OF FEVER of hyperthermia include hot, dry skin systemic absorption of alcohol.30 Fur- It should be emphasized that fever is and central nervous system dysfunc- thermore, antipyretics have other clin- not an illness but is, in fact, a physio- tion that results in delirium, convul- ical outcomes, including analgesia, logic mechanism that has beneficial ef- sions, or coma.23 Hyperthermia which may enhance their overall clini- fects in fighting infection.8–10 Fever re- should be addressed promptly, be- cal effect. Regardless of the exact tards the growth and reproduction of cause at temperatures above 41°C to mechanism of action, many physicians bacteria and viruses, enhances neu- 42°C, adverse physiologic effects be- continue to encourage the use of anti- trophil production and T-lymphocyte gin to occur.7,9,24 Studies of health pyretics with the belief that most of the proliferation, and aids in the body’s care workers, including physicians, benefits are the result of improved acute-phase reaction.11–14 The degree have revealed that most believe that comfort and the accompanying im- of fever does not always correlate with the risk of heat-related adverse out- provements in activity and feeding, the severity of illness. Most are comes is increased with tempera- less irritability, and a more reliable of short duration, are benign, and may tures above 40°C (104°F), although sense of the child’s overall clinical con- actually protect the host.15 Data show this belief is not justified.5,23,25–27 A dition. Because these are the most im- beneficial effects on certain compo- child with a temperature of 40°C portant benefits of antipyretic therapy, nents of the immune system in fever, (104°F) attributable to a simple febrile it is of paramount importance that pa- and limited data have revealed that fe- illness is quite different from a child rental counseling focus on monitoring ver actually helps the body recover with a temperature of 40°C (104°F) at- of activity, observing for signs of seri-

PEDIATRICS Volume 127, Number 3, March 2011 581 Downloaded from www.aappublications.org/news by guest on September 28, 2021 ous illness, and appropriate fluid in- ited on the actual risks of fever and the leading to hepatotoxicity; therefore, take to maintain hydration. benefits of antipyretic therapy, it is such doses are not recommended. The desire to improve the overall com- recognized that improvement in pa- Although hepatotoxicity with acetamin- fort of the febrile child must be bal- tient comfort is a reasonable thera- ophen at recommended doses has anced against the desire to simply peutic objective. Furthermore, at this been reported rarely, hepatoxicity is lower the body temperature. It is well time, there is no evidence that temper- most commonly seen in the setting of documented that there are significant ature reduction, in and of itself, should an acute overdose. In addition, there is concerns on the part of parents, be the primary goal of antipyretic significant concern over the possibility nurses, and physicians about potential therapy. of acetaminophen-related hepatitis in adverse effects of fever that have led to Acetaminophen the setting of a chronic overdose. The a description in the literature of “fever most commonly reported scenarios phobia.”31 The most consistently iden- After sufficient evidence emerged of are those of children receiving multi- an association between salicylates tified serious concern of caregivers ple supratherapeutic doses (ie, Ͼ15 and , acetaminophen and health care providers is that high mg/kg per dose) or frequent adminis- essentially replaced as the pri- fevers, if left untreated, are associated tration of appropriate single doses at mary treatment of fever. Acetamino- with seizures, brain damage, and intervals of less than 4 hours, which 1,25,32,33 phen doses of 10 to 15 mg/kg per dose death. It is argued that by creat- has resulted in doses of more than 90 given every 4 to 6 hours orally are gen- ing undue concern over these pre- mg/kg per day for several days.46,47 Giv- erally regarded as safe and effective. sumed risks of fever, for which there is ing an adult preparation of acetamino- Typically, the onset of an antipyretic ef- no clearly established relationship, phen to a child may result in suprath- fect is within 30 to 60 minutes; approx- physicians are promoting an exagger- erapeutic dosing. In 1 case series,46 imately 80% of children will experience ated desire in parents to achieve nor- half of the children with hepatotoxicity mothermia by aggressively treating a decreased temperature within that time (Table 1). had received adult preparations of fever in their children. acetaminophen. There is no evidence that reducing fe- Although alternative dosing regimens One safety concern is the effect of ver reduces morbidity or mortality have been suggested,41–43 no consis- acetaminophen on asthma-related from a febrile illness. Possible excep- tent evidence has indicated that the symptoms; although asthma has also tions to this could be children with un- use of an initial loading dose by either been associated with acetamino- derlying chronic diseases that may re- the oral (30 mg/kg per dose) or rectal phen use, causality has not been sult in limited metabolic reserves or (40 mg/kg per dose) route improves demonstrated.48–51 children who are critically ill, because antipyretic efficacy. The higher rectal these children may not tolerate the in- dose is often used in intraoperative Ibuprofen creased metabolic demands of fever.34 conditions but cannot be recom- Finally, there is no evidence that anti- mended for use in routine clinical The use of ibuprofen to manage fever pyretic therapy decreases the recur- care.44,45 The use of higher loading has been increasing, because it seems rence of febrile seizures.22,35,36 doses in clinical practice would add to have a longer clinical effect related potential risks for dosing confusion to lowering of the body temperature Despite insufficient evidence, many pe- diatricians recommend the routine practice of pretreatment with acet- aminophen or ibuprofen before a pa- TABLE 1 Antipyretic Information tient receives immunizations to de- Variable Acetaminophen Ibuprofen crease the discomfort associated with Decline in temperature, °C 1–2 1–2 Ͻ Ͻ the injections and subsequently at the Time to onset, h 1 1 Time to peak effect, h 3–4 3–4 injection sites and to minimize the fe- Duration of effect, h 4–6 6–8 brile response.9,17,37–39 In addition, re- Dose, mg/kg 10–15 every 4 h 10 every 6 h sults of 1 recent study suggested the Maximum daily dose, mg/kg 90 mg/kga 40 mg/kg Maximum daily adult dose, g/d 4 2.4 possibility of decreased immune re- Lower age limit, mob 36 sponse to vaccines in patients treated Data represent approximate averages from referenced sources.42,43,52,54,71,82 early with antipyretics.40 a Label is for 75 mg/kg; 90 mg/kg per day should be limited to less than 3 consecutive days.83-85 b Unless specifically recommended by a health care provider for the younger patient and, then, only after the infant has been Although the available literature is lim- examined by a health care provider.

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(Table 1). Studies in which the effec- dehydration or with complex medical alternating acetaminophen and ibu- tiveness of ibuprofen and acetamino- illnesses.61–63 In children with dehydra- profen for fever control, 81% of whom phen were compared have yielded tion, synthesis becomes stated that they had followed the ad- variable results; the consensus is that an increasingly important mechanism vice of their health care provider or both drugs are more effective than pla- for maintaining appropriate renal pediatrician.70 Although 4 hours was cebo in reducing fever and that ibupro- blood flow. The use of ibuprofen or any the most frequent interval, parents re- fen (10 mg/kg per dose) is at least as NSAID interferes with the renal effects ported alternating therapy every 2, 3, effective as, and perhaps more effec- of , which reduces re- 4, and 6 hours, which suggests that tive than, acetaminophen (15 mg/kg nal blood flow and potentially precipi- there is no consensus on dosing per dose) in lowering body tempera- tates or worsens renal dysfunction.61,63 instructions. However, it is not possible to deter- ture when either drug is given as a sin- At the time of this report, 5 studies had 52–57 mine the actual incidence of gle or repetitive dose. Data also been identified that compared alter- ibuprofen-related renal insufficiency show that the height of the fever and nating ibuprofen and acetaminophen after short-term use, because it has the age of the child (rather than the versus either acetaminophen or ibu- not been systematically investigated specific used) may be the profen as single agents.71–75 Initially, or reported.64 Children who are at primary determinants of the efficacy changes in temperature were similar greatest risk of ibuprofen-related re- of antipyretic therapy; those who have for all groups in these studies, regard- nal toxicity are those with dehydration, a higher fever and are older than 6 years less of therapy. However, 4 or more cardiovascular disease, preexisting show decreased efficacy or response to hours after the initiation of treat- 54 renal disease, or the concomitant use antipyretic therapy. Studies that com- ment, lower temperature was consis- of other nephrotoxic agents.62 Another pare the effect of ibuprofen versus acet- tently observed in the combination- potential group at risk is infants aminophen on children’s behavior and treatment groups. For example, 6 and younger than 6 months because of the comfort are generally lacking. 8 hours after the initiation of the study, possibility of differences in ibuprofen There is no evidence to indicate that a greater percentage of children were pharmacokinetics and developmental there is a significant difference in the afebrile in the combination group differences in renal function.65 Data safety of standard doses of ibuprofen (83% and 81%, respectively) compared are inadequate to support a specific versus acetaminophen in generally with those in the group that received recommendation for the use of ibupro- healthy children between 6 months ibuprofen alone (58% and 35%, respec- fen for fever or pain in infants younger and 12 years of age with febrile illness- tively).71 Only 1 study72 evaluated is- than 6 months (there are dosing data es.58 Similar to other nonsteroidal anti- sues related to stress and comfort and for neonatal closure of patent ductus inflammatory drugs (NSAIDs), ibupro- found lower stress scores and less arteriosus66,67), although the package 59,60 fen can potentially cause gastritis, insert states to “ask a doctor” for guid- time missed from child care in the although no data suggest that this is a ance on its use in this population. An- combination-treatment group. An- 73 common occurrence when used on an other potential risk associated with other study showed a trend toward a acute basis, such as during a febrile the use of ibuprofen is the possible as- normalization of fever-related symp- 58 illness. However, there have been sociation between ibuprofen and toms by 24 and 48 hours after institu- case reports of bleeding, gastritis, varicella-related invasive group A tion of therapy, but these trends disap- and ulcers of the stomach, duodenum, streptococcal infection.68,69 However, peared by day 5. and esophagus associated with many at the time of this report, data were Although the aforementioned studies NSAIDs, including ibuprofen, even when insufficient to support a causal rela- provide some evidence that combina- used in typical antipyretic and tionship between ibuprofen and inva- tion therapy may be more effective at 59,60 doses. Ibuprofen does not seem to sive group A streptococcal disease. lowering temperature, questions re- worsen asthma symptoms. main regarding the safety of this prac- Concern has been raised over the Alternating or Combination tice as well as the effectiveness in im- nephrotoxicity of ibuprofen. In numer- Therapy proving discomfort, which is the ous case reports, children with febrile A practice frequently used to control primary treatment end point. The pos- illnesses developed renal insufficiency fever is the alternating or combined sibility that parents will either not re- when treated with ibuprofen or other use of acetaminophen and ibuprofen. ceive or not understand dosing in- NSAIDs. Thus, caution is encouraged In a convenience sample survey of 256 structions, combined with the wide when using ibuprofen in children with parents or caregivers, 67% reported array of formulations that contain

PEDIATRICS Volume 127, Number 3, March 2011 583 Downloaded from www.aappublications.org/news by guest on September 28, 2021 these drugs, increases the potential tions, physicians should encourage cians should advocate for a limited for inaccurate dosing or overdos- families to only use 1 formulation. number of formulations of acetamino- ing.76,77 Finally, this practice may only Acetaminophen is the most common phen and ibuprofen and for clear label- promote the fever phobia that already single ingredient implicated in emer- ing of dosing instructions and an in- exists. gency department visits for medica- cluded dosing device for antipyretic Although there is some evidence that tion overdoses among children, and products. combination therapy may result in a more than 80% of these emergency LEAD AUTHORS lower body temperature for a greater visits are a result of unsupervised 81 Janice E. Sullivan, MD period of time, there is no evidence ingestions ; therefore, proper han- Henry C. Farrar, MD dling and storage of antipyretics that combination therapy results in COMMITTEE ON DRUGS, 2009–2010 should be encouraged. overall improvement in other clinical Daniel A. C. Frattarelli, MD, Chairperson outcomes. Also, these studies have not SUMMARY Jeffrey L. Galinkin, MD contained adequate numbers of sub- Thomas P. Green, MD Appropriate counseling on the man- Mary A. Hegenbarth, MD jects to fully evaluate the safety of this Mark L. Hudak, MD agement of fever begins by helping practice. Therefore, there is insuffi- Matthew E. Knight, MD parents understand that fever, in and cient evidence to support or refute the Robert E. Shaddy, MD of itself, is not known to endanger a routine use of combination treatment FORMER COMMITTEE ON DRUGS generally healthy child. In contrast, fe- with both acetaminophen and ibupro- MEMBER ver may actually be of benefit; thus, the fen. Practitioners who choose to follow Wayne R. Snodgrass, MD, PhD real goal of antipyretic therapy is not this practice should counsel parents CONSULTANT simply to normalize body temperature carefully regarding proper formula- Robert M. Ward, MD but to improve the overall comfort and tion, dosing, and dosing intervals and LIAISONS well-being of the child. Acetaminophen emphasize the child’s comfort instead John J. Alexander, MD – Food and Drug and ibuprofen, when used in appropri- Administration of reduction of fever. ate doses, are generally regarded as Janet D. Cragan, MD – Centers for Disease Control and Prevention safe and effective agents in most clini- INSTRUCTIONS FOR CAREGIVERS George P. Giacoia, MD – National Institutes of cal situations. However, as with all Health It is critically important for pediatri- drugs, they should be used judiciously Michael J. Rieder, MD – Canadian Paediatric cians to clearly describe the appropri- to minimize the risk of adverse drug Society Adelaide Robb, MD – American Academy of ate use (ie, formulation, dose, and dos- effects and toxicity. Combination ther- Child and Adolescent Psychiatry ing interval) of acetaminophen and apy with acetaminophen and ibupro- Hari C. Sachs, MD – Food and Drug ibuprofen to caregivers (Table 1). Child fen may place infants and children at Administration safety will be further enhanced by increased risk because of dosing er- STAFF clear labeling and the development of rors and adverse outcomes, and these Raymond J. Koteras, MHA [email protected] simplified dosing methods, standard- potential risks must be carefully con- ized drug concentrations, and stan- sidered. When counseling a family on SECTION ON CLINICAL PHARMACOLOGY dardized delivery devices.78–80 Cough- the management of fever in a child, pe- AND THERAPEUTICS, 2009–2010 and-cold products that contain Janice E. Sullivan, MD, Chairperson diatricians and other health care pro- Glen S. Frick, MD acetaminophen and ibuprofen should viders should minimize fever phobia Lynne G. Maxwell, MD not be given to children because of the and emphasize that antipyretic use Ian M. Paul, MD possibility that parents may uninten- does not prevent febrile seizures. Pedi- John F. Pope, MD Thomas G. Wells, MD tionally give their child simultaneous atricians should focus instead on mon- doses of an antipyretic and a cough- itoring for signs/symptoms of serious FORMER EXECUTIVE COMMITTEE MEMBERS and-cold medication that contains the illness, improving the child’s comfort Charles J. Cote, MD same antipyretic. In addition, there is a by maintaining hydration, and educat- Henry C. Farrar, MD lack of proven efficacy for this class of ing parents on the appropriate use, Richard L. Gorman, MD combination products for children. For dosing, and safe storage of antipyret- STAFF children who require liquid prepara- ics. To promote child safety, pediatri- Raymond J. Koteras, MHA

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