窥知

2010美国儿童退热指南（英文）Clinical Report—Fever and Antipyretic Use in Children.pdf DOI: 10.1542/peds.2010-3852 ; originally published online February 28, 2011;Pediatrics Therapeutics, and Committee on Drugs Janice E. Sullivan, Henry C. Farrar and the Section on Clinical Pharmacology and Fever and Antipyretic Use in Children−−Clinical Report http://pediatrics.aappublications.org/content/early/2011/02/28/peds.2010-3852 located on the World Wide Web at: The online version of this article, along with updated information and services, is of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275. Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point publication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly by guest on July 14, 2011pediatrics.aappublications.orgDownloaded from Clinical Report—Fever and Antipyretic Use in Children abstract Fever in a child is one of themost common clinical symptomsmanaged by pediatricians and other health care providers and a frequent cause of parental concern. Many parents administer antipyretics even when there is minimal or no fever, because they are concerned that the child must maintain a “normal” temperature. Fever, however, is not the primary illness but is a physiologic mechanism that has beneficial effects in fighting infection. There is no evidence that fever itself wors- ens the course of an illness or that it causes long-term neurologic complications. Thus, the primary goal of treating the febrile child should be to improve the child’s overall comfort rather than focus on the normalization of body temperature. When counseling the parents or caregivers of a febrile child, the general well-being of the child, the importance of monitoring activity, observing for signs of serious ill- ness, encouraging appropriate fluid intake, and the safe storage of antipyretics should be emphasized. Current evidence suggests that there is no substantial difference in the safety and effectiveness of acetaminophen and ibuprofen 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 INTRODUCTION Fever 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 a child commonly leads to unscheduled physician visits, telephone calls by parents to their child’s physician for advice on fever control, and the wide use of over-the-counter antipyretics. Parents are frequently concernedwith the need tomaintain 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
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- Janice E. Sullivan, MD, Henry C. Farrar, MD, and the SECTION ON CLINICAL PHARMACOLOGY AND THERAPEUTICS, and COMMITTEE ON DRUGS KEY WORDS fever, antipyretics, children ABBREVIATIONS NSAID—nonsteroidal anti-inflammatory drug The guidance in this report does not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into account individual circumstances, may be appropriate. This document is copyrighted and is property of the American Academy of Pediatrics and its Board of Directors. All authors have filed conflict of interest statements with the American Academy of Pediatrics. Any conflicts have been resolved through a process approved by the Board of Directors. The American Academy of Pediatrics has neither solicited nor accepted any commercial involvement in the development of the content of this 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 Pediatrics automatically expire 5 years after publication unless reaffirmed, revised, or retired at or before that time. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2011 by the American Academy of Pediatrics Guidance for the Clinician in Rendering Pediatric Care 580 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on July 14, 2011pediatrics.aappublications.orgDownloaded from stand that dosing should be based on weight rather than age or height of fe- ver are much less likely to give an in- correct dose.4 Physicians and nurses are the primary source of information on fever man- agement for parents and caregivers, although there are some disparities between the views of parents and phy- sicians regarding antipyretic treat- ment.1 The most common indications for initiating antipyretic therapy by pe- diatricians are a temperature higher than 38.3°C (101°F) and improving the child’s overall comfort.5 Although only 13% of pediatricians specifically cite 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 child should not be awakened solely to be given antipyretics.5 Antipyretic therapy will remain a com- mon practice by parents and is gener- ally encouraged and supported by pe- diatricians. Thus, pediatricians and health care providers are responsible for the appropriate counseling of par- ents and other caregivers about fever and the use of antipyretics.7 PHYSIOLOGY OF FEVER It should be emphasized that fever is not an illness but is, in fact, a physio- logicmechanism that has beneficial ef- fects in fighting infection.8–10 Fever re- tards the growth and reproduction of bacteria and viruses, enhances neu- trophil production and T-lymphocyte proliferation, and aids in the body’s acute-phase reaction.11–14 The degree of fever does not always correlate with the severity of illness. Most fevers are of short duration, are benign, and may actually protect the host.15 Data show beneficial 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.11,16–18 Evidence is in- conclusive as to whether treating with antipyretics, particularly ibuprofen alone or in combination with acet- aminophen, increases the risks of complications with certain types of in- fections.19,20 Potential benefits of fever reduction include relief of patient dis- comfort and reduction of insensible water loss, which may decrease the occurrence of dehydration. Risks of lowering fever include delayed identifi- cation of the underlying diagnosis and initiation of appropriate treatment and drug toxicity. There is no evidence that children with fever, as opposed to hyperthermia, are at increased risk of adverse outcomes such as brain damage.7,9,21–23 Fever is a common and normal physiologic re- sponse that results in an increase in the hypothalamic “set point” in re- sponse to endogenous and exogenous pyrogens.9,23 In contrast, hyperthermia is a rare and pathophysiologic re- sponse with failure of normal ho- meostasis (no change in the hypotha- lamic set point) that results in heat production that exceeds the capability to dissipate heat.9,23 Characteristics of hyperthermia include hot, dry skin and central nervous system dysfunc- tion that results in delirium, convul- sions, or coma.23 Hyperthermia should be addressed promptly, be- cause at temperatures above 41°C to 42°C, adverse physiologic effects be- gin to occur.7,9,24 Studies of health care workers, including physicians, have revealed that most believe that the risk of heat-related adverse out- comes is increased with tempera- tures above 40°C (104°F), although this belief is not justified.5,23,25–27 A child with a temperature of 40°C (104°F) attributable to a simple febrile illness is quite different from a child with a temperature of 40°C (104°F) at- tributable to heat stroke. Thus, extrap- olating similar outcomes from these different illnesses is problematic. TREATMENT GOALS A discussion of the use of antipyretics in febrile children must begin with consideration of the therapeutic end points. When counseling families, phy- sicians should emphasize the child’s comfort and signs of serious illness rather than emphasizing normother- mia. A primary goal of treating the fe- brile child should be to improve the child’s overall comfort. Most pediatri- cians observe, with some supporting data from research, that febrile chil- dren have altered activity, sleep, and behavior in addition to decreased oral intake.28 Unfortunately, there is a pau- city of clinical research addressing the extent to which antipyretics improve discomfort associated with fever or ill- ness. It is not clear whether comfort improves with a normalized tempera- ture, because external cooling mea- sures, such as tepid sponge baths, can lower the body temperature without improving comfort.7,29 The use of alco- hol baths is not an appropriate cooling method, because there have been re- ported adverse events associated with systemic 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 exact mechanism of action, many physicians continue to encourage the use of anti- pyretics with the belief thatmost of the benefits are the result of improved comfort and the accompanying im- provements in activity and feeding, less irritability, and a more reliable sense of the child’s overall clinical con- dition. Because these are the most im- portant benefits of antipyretic therapy, it is of paramount importance that pa- rental counseling focus on monitoring of activity, observing for signs of seri- FROM THE AMERICAN ACADEMY OF PEDIATRICS PEDIATRICS Volume 127, Number 3, March 2011 581 by guest on July 14, 2011pediatrics.aappublications.orgDownloaded from ous illness, and appropriate fluid 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 simply lower the body temperature. It is well documented that there are significant concerns on the part of parents, nurses, and physicians about potential adverse effects of fever that have led to a description in the literature of “fever phobia.”31 The most consistently iden- tified serious concern of caregivers and health care providers is that high fevers, if left untreated, are associated with seizures, brain damage, and death.1,25,32,33 It is argued that by creat- ing undue concern over these pre- sumed risks of fever, for which there is no clearly established relationship, physicians are promoting an exagger- ated desire in parents to achieve nor- mothermia by aggressively treating fever in their children. There is no evidence that reducing fe- ver reduces morbidity or mortality from a febrile illness. Possible excep- tions to this could be children with un- derlying chronic diseases that may re- sult in limited metabolic reserves or children who are critically ill, because these 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 insufficient evidence, many pe- diatricians recommend the routine practice of pretreatment with acet- aminophen or ibuprofen before a pa- tient receives immunizations to de- crease the discomfort associated with the injections and subsequently at the injection sites and to minimize the fe- brile response.9,17,37–39 In addition, re- sults of 1 recent study suggested the possibility of decreased immune re- sponse to vaccines in patients treated early with antipyretics.40 Although the available literature is lim- ited on the actual risks of fever and the benefits of antipyretic therapy, it is recognized that improvement in pa- tient comfort is a reasonable thera- peutic objective. Furthermore, at this time, there is no evidence that temper- ature reduction, in and of itself, should be the primary goal of antipyretic therapy. Acetaminophen After sufficient evidence emerged of an association between salicylates and Reye syndrome, acetaminophen essentially replaced aspirin as the pri- mary treatment of fever. Acetamino- phen doses of 10 to 15 mg/kg per dose given 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 experience a decreased temperature within that time (Table 1). Although alternative dosing regimens have been suggested,41–43 no consis- tent evidence has indicated that the use of an initial loading dose by either the oral (30 mg/kg per dose) or rectal (40 mg/kg per dose) route improves antipyretic efficacy. The higher rectal dose is often used in intraoperative conditions but cannot be recom- mended for use in routine clinical care.44,45 The use of higher loading doses in clinical practice would add potential risks for dosing confusion leading to hepatotoxicity; therefore, such doses are not recommended. Although hepatotoxicity with acetamin- ophen at recommended doses has been reported rarely, hepatoxicity is most commonly seen in the setting of an acute overdose. In addition, there is significant concern over the possibility of acetaminophen-related hepatitis in the setting of a chronic overdose. The most commonly reported scenarios are those of children receiving multi- ple supratherapeutic doses (ie, 15 mg/kg per dose) or frequent adminis- tration of appropriate single doses at intervals of less than 4 hours, which has resulted in doses of more than 90 mg/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 hepatotoxicity had received adult preparations of acetaminophen. One safety concern is the effect of acetaminophen on asthma-related symptoms; although asthma has also been associated with acetamino- phen use, causality has not been demonstrated.48–51 Ibuprofen The use of ibuprofen to manage fever has been increasing, because it seems to have a longer clinical effect related to lowering of the body temperature TABLE 1 Antipyretic Information Variable Acetaminophen Ibuprofen Decline in temperature, °C 1–2 1–2 Time to onset, h 1 1 Time to peak effect, h 3–4 3–4 Duration of effect, h 4–6 6–8 Dose, mg/kg 10–15 every 4 h 10 every 6 h Maximum daily dose, mg/kg 90 mg/kga 40 mg/kg Maximum daily adult dose, g/d 4 2.4 Lower age limit, mob 3 6 Data represent approximate averages from referenced sources.42,43,52,54,71,82 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 examined by a health care provider. 582 FROM THE AMERICAN ACADEMY OF PEDIATRICS by guest on July 14, 2011pediatrics.aappublications.orgDownloaded from (Table 1). Studies in which the effec- tiveness of ibuprofen and acetamino- phen were compared have yielded variable results; the consensus is that both drugs aremore effective than pla- cebo in reducing fever and that ibupro- fen (10 mg/kg per dose) is at least as effective as, and perhaps more effec- tive than, acetaminophen (15 mg/kg per dose) in lowering body tempera- ture when either drug is given as a sin- gle or repetitive dose.52–57 Data also show that the height of the fever and the age of the child (rather than the specific medication used) may be the primary determinants of the efficacy of antipyretic therapy; those who have a higher fever and are older than 6 years show decreased efficacy or response to antipyretic therapy.54 Studies that com- pare the effect of ibuprofen versus acet- aminophen on children’s behavior and comfort are generally lacking. There is no evidence to indicate that there is a significant difference in the safety of standard doses of ibuprofen versus acetaminophen in generally healthy children between 6 months and 12 years of age with febrile illness- es.58 Similar to other nonsteroidal anti- inflammatory drugs (NSAIDs), ibupro- fen can potentially cause gastritis,59,60 although no data suggest that this is a common occurrence when used on an acute basis, such as during a febrile illness.58 However, there have been case reports of bleeding, gastritis, and ulcers of the stomach, duodenum, and esophagus associated with many NSAIDs, including ibuprofen, even when used in typical antipyretic and analgesic doses.59,60 Ibuprofen does not seem to worsen asthma symptoms. Concern has been raised over the nephrotoxicity of ibuprofen. In numer- ous case reports, children with febrile illnesses developed renal insufficiency when treated with ibuprofen or other NSAIDs. Thus, caution is encouraged when using ibuprofen in children with dehydration or with complex medical illnesses.61–63 In children with dehydra- tion, prostaglandin synthesis becomes an increasingly important mechanism for maintaining appropriate renal blood flow. The use of ibuprofen or any NSAID interferes with the renal effects of prostaglandins, which reduces re- nal blood flow and potentially precipi- tates or worsens renal dysfunction.61,63 However, it is not possible to deter- mine the actual incidence of ibuprofen-related renal insufficiency after short-term use, because it has not been systematically investigated or reported.64 Children who are at greatest risk of ibuprofen-related re- nal toxicity are those with dehydration, cardiovascular disease, preexisting renal disease, or the concomitant use of other nephrotoxic agents.62 Another potential group at risk is infants younger than 6 months because of the possibility of differences in ibuprofen pharmacokinetics and developmental differences in renal function.65 Data are inadequate to support a specific recommendation for the use of ibupro- fen for fever or pain in infants younger than 6 months (there are dosing data for neonatal closure of patent ductus arteriosus66,67), although the package insert states to “ask a doctor” for guid- ance on its use in this population. An- other potential risk associated with the use of ibuprofen is the possible as- sociation between ibuprofen and varicella-related invasive group A streptococcal infection.68,69 However, at the time of this report, data were insufficient to support a causal rela- tionship between ibuprofen and inva- sive group A streptococcal disease. Alternating or Combination Therapy A practice frequently used to control fever is the alternating or combined use of acetaminophen and ibuprofen. In a convenience sample survey of 256 parents or caregivers, 67% reported alternating acetaminophen and ibu- profen for fever control, 81% of whom stated that they had followed the ad- vice of their health care provider or pediatrician.70 Although 4 hours was the most frequent interval, parents re- ported alternating therapy every 2, 3, 4, and 6 hours, which suggests that there is no consensus on dosing instructions. At the time of this report, 5 studies had been identified that compared alter- nating ibuprofen and acetaminophen versus either acetaminophen or ibu- profen as single agents.71–75 Initially, changes in temperature were similar for all groups in these studies, regard- less of therapy. However, 4 or more hours after the initiation of treat- ment, lower temperature was consis- tently observed in the combination- treatment groups. For example, 6 and 8 hours after the initiation of the study, a greater percentage of children were afebrile in the combination group (83% and 81%, respectively) compared with those in the group that received ibuprofen alone (58% and 35%, respec- tively).71 Only 1 study72 evaluated is- sues related to stress and comfort and found lower stress scores and less time missed from child care in the combination-treatment group. An- other study73 showed a trend toward a normalization 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 studies provide some evidence that combina- tion therapy may be more effective at lowering temperature, questions re- main regarding the safety of this prac- tice as well as the effectiveness in im- proving discomfort, which is the primary treatment end point. The pos- sibility that parents will either not re- ceive or not understand dosing in- structions, combined with the wide array of formulations that contain FROM THE AMERICAN ACADEMY OF PEDIATRICS PEDIATRICS Volume 127, Number 3, March 2011 583 by guest on July 14, 2011pediatrics.aappublications.orgDownloaded from ...