Antipyretic Therapy Physiologic Rationale, Diagnostic Implications, and Clinical Consequences

REVIEW ARTICLE Antipyretic Therapy Physiologic Rationale, Diagnostic Implications, and Clinical Consequences

Karen I. Plaisance, MD; Philip A. Mackowiak, MD

arious treatments have been used to suppress fever since antiquity. Surprisingly, few studies have been performed to ascertain the physiologic consequences of antipyresis and validate the rationale behind such therapy. More importantly, it has not been established conclusively that the benefits of antipyretic therapy outweigh its risks. The Vpresent review considers these issues in light of currently available data and formulates guidelines for antipyretic therapy based on these data. Arch Intern Med. 2000;160:449-456

Antipyretic agents have been used to lower picion that fever is inherently noxious. This febrile body temperature for well over two suspicion is reflected in the results of sur- millennia.1,2 AncientAssyrian,Egyptian,and veys reporting that approximately 40% of Greek physicians all apparently knew of parents and other caregivers regard tem- and exploited the antipyretic property of ex- peratures encountered during fever as tracts of the bark of the willow (Salix alba).2 harmful,11,12 and that 12% of physicians be- However, it was not until 1763 that the Rev- lieve that fever has the capacity to cause erend Edward Stone gave the first scientific brain damage.8 Perhaps most indicative of description of the clinical benefits of willow the medical profession’s inherent antipa- bark to the Royal Society of London.3 Less thy toward fever is the fact that an esti- than 80 years later, Piria4 succeeded in pre- mated 70% of nurses and 30% of physi- paring salicylic acid from salicin, a glycoside cians routinely use antipyretic drugs to component of willow bark. Salicylic acid suppress fever.8,9 was first synthesized by Gerland5 in 1852, The present review critically evalu- some 8 years before Kolbe and Lautemann,6 ates the physiologic rationale, the diag- who are frequently credited with this ac- nostic implications, and the clinical con- complishment, and just a year before von sequences of antipyretic therapy. The data Gerhardt7 developed acetylsalicylic acid (as- reviewed are also used to formulate rec- pirin) during efforts to find a more palatable ommendations regarding the appropri- form of salicylate. In 1899, the Bayer Com- ate clinical application of such therapy. pany launched the modern era of antipyretic therapy with the introduction of aspirin as DEFINITIONS the world’s first commercially available antipyretic drug.1 During this same period, Fever is “a state of elevated core tempera- acetanilideandphenacetinwerederivedfrom ture, which is often, but not necessarily, part para-aminophenol compounds in coal tar, of the defensive response of multicellular and pyrazolon compounds such as amino- organisms (hosts) to the invasion of live (mi- pyrine were developed.2 croorganisms) or inanimate matter recog- A little less than a century later, the nized as pathogenic or alien by the host.”13 marketplace is replete with drugs capable The febrile response, of which fever is but of suppressing fever. Their widespread ap- 1 component, is a complex physiologic re- plication by primary care physicians,8 emer- action to disease involving a cytokine- gency department nurses,9 pharmacists,10 mediated rise in core temperature, genera- parents, and other caregivers11,12 has been, tion of acute-phase reactants, and activation at least in part, motivated by a general sus- of numerous physiologic, endocrinologic, and immunologic systems.14 The rise in core From the University of Maryland School of Pharmacy (Dr Plaisance), the Medical temperature during fever is to be distin- Care Clinical Center, Veterans Affairs Maryland Health Care System guished from the unregulated rise that oc- (Dr Mackowiak), and the Department of Medicine, University of Maryland School curs during hyperthermia, in which pyro- of Medicine (Dr Mackowiak), Baltimore, Md. genic cytokines are not directly involved and

ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 449

Downloaded From: https://jamanetwork.com/ on 10/01/2021 never been shown in humans that in- ANTIPYRETIC DRUGS creases in core temperature encountered during fever, which rarely ex- The essential elements of the fever ceed 41°C (105.8°F), are harmful per physiologic pathway are release of py- 17 Exogenous Pyrogen se. Nevertheless, many clinicians rogenic cytokines by inflammatory believe that even the relatively mod- cells in response to some exogenous est increases in core temperature en- pyrogen (eg, infection), induction of countered during fever are delete- cyclooxygenase (COX) 2 activation rious to certain patients and should of the arachidonic acid cascade, and therefore be suppressed. enhanced biosynthesis of prostaglan-

Activated Leukocytes Children, primarily between din E2 (PGE2) by hypothalamic vas- ages 3 months and 5 years, are 1 such cular endothelial cells.28 Through its category of patients. In these chil- effect on thermoregulatory neurons Temperature- dren, seizures have occurred during located in the preoptic area of the an- Pyrogenic Cytokines Dependent α γ Feedback on episodes of fever at a frequency of terior hypothalamus, PGE2 acts to IL-6 (IL-1, TNF- , IFN- ) Cytokine from 2% to 5% in the United States raise the hypothalamic thermal set IL-6 Expression and Western Europe18,19 to as high as point (Figure) and thereby induce 14% in other selected countries.20 Al- peripheral and thermogenic mecha- though most children have tempera- nisms to increase core temperature. tures of 39.0°C or lower at the time Theoretically, antipyretic agents of their seizure,21 many tolerate might interrupt the fever response at higher fevers at later dates without any step along this pathway.29 convulsing.22 Unfortunately, antipy- The drugs most commonly used retic therapy has not been shown to today to suppress fever are the sa- Circumventricular Organs protect against recurrences of fe- licylates (eg, sodium salicylate and PGE2 brile seizure in the few controlled tri- acetylsalicylic acid), ibuprofen, and als conducted thus far.23 the other nonsteroidal anti-inflam- It has also been suggested that matory drugs (NSAIDs), and the patients with underlying cardiovas- para-aminophenol derivative acet- 39.5°C (103°F) cular or pulmonary disorders might aminophen. Until the 1970s, little Fever be especially susceptible to the ad- was known about mechanisms reverse effects of fever because of the sponsible for the antipyretic activity Hypothetical model for the fever response 28 increased metabolic demands im- of any of these compounds. In 1970, (reprinted from Mackowiak with permission). 24 30 IL indicates interleukin; TNF, tumor necrosis posed by the elevated temperature. Milton and Wendlandt demon- factor; IFN, interferon; and PGE2, Such demands, which peak during strated both that prostaglandins of the prostaglandin E2. the chill phase, largely as a result E series cause rapid onset of fever of shivering, include increases in sym- when injected into the cerebral ven- against which standard antipyretics pathetic tone,25 oxygen consump- tricles of cats and rabbits, and that are largely ineffective. Antipyretics tion, respiratory minute volume, and PGE2 is released within the brain dur- block or reverse fever’s cytokine- respiratory quotient.26 Although these ing fever. These observations, in con- mediated rise in core temperature, but have been proffered as prima facie junction with those of Vane31 show- do not affect body temperature in the justification for antipyretic therapy in ing that aspirin and other antipyretic afebrile state. They are to be distin- patients with underlying cardiopul- drugs inhibit synthesis of prostaglan- guished from hypothermia agents monary disorders, the risk-benefit dins, suggest that antipyretic drugs (cryogens), which are capable of low- ratio of such therapy has yet to be reduce fever primarily by inhibiting ering core temperature even in the ab- determined. the formation of PGE2 in the brain. sence of fever. Antipyretic therapy might also However, not all experimental data be justified, at least in theory, if fe- obtained since the early work of RATIONALE ver’s metabolic cost exceeded its Milton and Wendlandt30 and Vane31 physiologic benefit, if the treatment have supported this hypothesis. Two critical assumptions are made provided symptomatic relief with- Injection of PGE2 into appropriate when prescribing antipyretic ther- out adversely affecting the course of brain regions of animals capable of apy. One is that fever is, at least the febrile illness, and/or if the toxi- mounting a febrile response to en- in part, noxious, and the other, that cologic costs (adverse effects) of the dotoxin, for example, does not con- suppressing fever will reduce if not antipyretic regimen were apprecia- sistently cause fever in the ani- eliminate fever’s noxious effects. Nei- bly lower than its beneficial effects. mals.32 Moreover, salicylate infusions ther assumption has been validated Unfortunately, although clinicians into the ventral septal area of ex- experimentally. In fact, there is con- have long argued the validity of each perimental animals blocks the fe- siderable evidence that fever is an of these propositions as justification brile response caused by intraven- important defense mechanism that for antipyretic therapy, few experi- tricular injection of PGE,33 suggesting contributes to the host’s ability to re- mental observations exist to sup- that the mechanisms of action of at sist infection.15,16 Moreover, it has port any of these arguments.27 least some antipyretic drugs might

ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 450

Downloaded From: https://jamanetwork.com/ on 10/01/2021 involve more than simple inhibition eral COX.35-37 The relatively weak ac- ver are instructive.41,43-51 In the aggre- of PGE synthesis. tivity of acetaminophen against pe- gate, they suggest that orally admin- Acetaminophen, aspirin, and the ripheral COX most likely accounts for istered ibuprofen is a more potent other NSAIDs all seem to block con- its poor anti-inflammatory activity. antipyretic than oral acetamino- version of arachidonic acid to PGE2 The duration of action of an an- phen. However, the difference in po- by inhibiting COX.21 Production of tipyretic drug depends on both its tency is small, and the antipyretic ef- PGE2 at key sites within the hypo- concentration at the site of action fects of the 2 agents follow a similar thalamus is widely regarded as a criti- and whether it inhibits COX revers- time course, with both drugs exhib- cal step in the process by which the ibly or irreversibly. Because aspirin iting maximal activity 3 to 4 hours af- physiologic cascade responsible for inhibits COX irreversibly,38 its an- ter oral administration.41,43-51 raising core temperature during the tipyretic effect persists until new en- Pediatric studies of the relative febrile response is activated.34 Cy- zyme is generated at the site of ac- activity of other NSAIDs are sparse. clooxygenase has at least 2 distinct iso- tion. Other NSAIDs are reversible In those comparing oral (5 mg/kg per forms: a constitutive isoform, COX-1, inhibitors of COX, and as such day) and rectal (100-400 mg/d) nime- and a predominately inducible iso- would be expected to have activi- sulide with oral placebo and rectal form, COX-2, which is undetectable ties that vary directly with their con- acetaminophen (200-800 mg/d),52,53 in most resting cells.1 The former ini- centration at the site of action.38 the 2 formulations of nimesulide were tiates production of prostacyclin, However, many of the NSAIDs (eg, nearly equivalent. Moreover, 100 mg which has both antithrombogenic and the 2-arylpropionic acid deriva- of rectal nimesulide seemed to be at cytoprotective properties, whereas the tives, ibuprofen and ketoprofen) are least as effective as 200-mg acetami- latter is a principal mediator of the in- chiral compounds—that is, they ex- nophen suppositories when given in flammatory response. The anti- ist as both S- and R-enantiomers. The doses varying between 1 and 4 sup- inflammatory action of NSAIDs is be- R-enantiomer, which is 100- to 500- positories per day, depending on in- lieved to result from inhibition of fold less active against COX-2 than dividual needs.53 COX-2, and the unwanted adverse ef- the S-enantiomer, functions as a drug Few studies have compared the fects, such as gastric irritation, from depot by being converted to the S- antipyretic activity of NSAIDs in inhibition of COX-1. enantiomer in vivo. As a result, ra- adults. In endotoxin-challenged The structure and catalytic ac- cemic mixtures of the 2 enantiom- adult volunteers, ibuprofen (800 mg tivity of the two COX isoforms are ers, the form in which many NSAIDs orally) is an effective antipyretic if similar.35 Both contain approxi- are marketed, exhibit longer dura- given just before or simultaneously mately 600 amino acids, of which 63% tions of action than might be ex- with the endotoxin challenge,42,54 are in identical sequence. Their ac- pected based on the pharmacoki- and is superior to acetaminophen in tive sites are located at the apex of a netics of the S-enantiomer alone.39-41 lowering the temperature of pa- long, narrow, hydrophobic channel. Because it takes time for the fe- tients with sepsis.55 Intramuscular The amino acids forming the chan- ver cascade (Figure) to effectuate heat ketorolac (30 mg) was shown to be nel, as well as catalytic sites and neigh- retentionandproductionmechanisms, as effective as acetaminophen (650 boring residues, are identical in the 2 there is a necessary delay between the mg orally) in suppressing fever in en- isoforms with 2 exceptions. Valine in release of endogenous pyrogens and dotoxin-challenged adult volun- COX-1 is substituted for isoleucine at pyrogen-induced increases in core teers.56 In a single-dose crossover positions 434 and 523 in COX-2. temperature.Forsimilarreasons,there trial involving patients with vari- These variations account for many but is a delay between the time an antipy- ous febrile disorders, oral nimesu- not all of the differences in the reac- retic drug reaches its site of action and lide (200 mg) and dipyrone (500 tivities of the 2 isoforms. Aspirin, for core temperature begins to fall. This mg) were more effective than oral as- example, acetylates serine 530 of both antipyretic latency period might also pirin (500 mg) in lowering fever.57 isoforms. In COX-1, this blocks ac- be influenced by the capacity of ara- Finally, in clinical trials comparing cess of arachidonic acid to the cata- chidonic acid metabolites, such as rectal nimesulide (200 mg) with 58 lytic site, causing irreversible inhibi- PGE2, to down-regulate production of acetaminophen (500 mg rectally), tion of the enzyme. Because of the at least some pyrogenic cytokines.42 and diclofenac (100 mg rectally) 59 wider hydrophobic channel of COX-2, BysuppressingPGE2 production,COX with placebo, the 3 agents exhib- access of arachidonic acid to the ac- inhibitorscauseaparadoxicalincrease ited similar antipyretic activity. tive site persists after acetylation of in translation of pyrogenic cytokines. One of the most important char- serine 530 by aspirin. Studies of the relative potencies acteristics separating the various Acetaminophen and the NSAIDs of the various classes of antipyretic antipyretic drugs relates to toxic ef- differ with respect to their relative po- drugs have involved diverse clinical fects. Aspirin, for example, has a tencies as inhibitors of peripheral and settings, numerous dosages and for- unique capacity for causing Reye central nervous system COX. Acet- mulations of the antipyretic agents, syndrome,60,61 a children’s disorder aminophen, for example, is nearly as and differing measures of clinical ef- characterized by hepatic failure and effective as aspirin and 10% as effec- ficacy. As a result, a comprehensive encephalopathy due to inhibition of tive as indomethacin in inhibiting meta-analysis of the accumulated data mitochondrial oxidative phosphory- central COX, but only 5% as effec- set is not possible. Nevertheless, sev- lation.62 A welter of other adverse ef- tive as aspirin and 0.02% as effective eral studies comparing ibuprofen with fects have been attributed to NSAIDs as indomethacin in inhibiting periph- acetaminophen in children with fe- (Table 1),63 the most important of

ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 451

Downloaded From: https://jamanetwork.com/ on 10/01/2021 which, renal dysfunction and gastro- low-dose aspirin (650 mg twice daily) oracuterenalfailureamongthe55 785 intestinal bleeding, derive from their have been shown to repair aspirin- children receiving ibuprofen.67 capacity to inhibit COX.63 Nonselec- induced mucosal ulcers substan- Becauseacetaminophenhaslittle tive COX inhibitors are especially tially faster (median time to healing, activity against peripheral COX,35,37 prone to cause such toxic effects.35,64 1 week) than those receiving high- it causes little gastric or renal tox- Subjects who use piroxicam, a drug dose aspirin (650 mg 4 times daily; icity. While acetaminophen is meta- with a high affinity for COX-1, for ex- median time to healing, 5 weeks).66 bolized predominantly by glucu- ample, are approximately 11 times In a large survey examining an- ronidation and sulfation, it is also more likely to experience an adverse tipyretic drug toxic effects, Lesko and metabolized to a lesser extent via the gastrointestinal event than subjects Mitchell67 randomized over 84 000 p450 2E1 pathway to a highly elec- not using NSAIDs.35,64 By compari- children (aged 8 months to 10 years) trophilic metabolite, N-acetyl- son, those who use naproxen, a drug to oral ibuprofen (5 mg/kg or 10 p-benzoquinoneimine (NAPQ1). with a greater affinity for COX-2, have mg/kg) or acetaminophen (12 mg/kg) When the primary pathways are ex- only a 3 times higher risk of serious every 4 to 6 hours, later querying pa- ceeded, NAPQ1 accumulates and gastrointestinal toxic effects than non- rents about adverse medical events. binds covalently to cell proteins and users of NSAIDs.35,64 Other factors that The median duration of treatment in DNA.68 When such binding is ex- seem to increase the risk of gastro- their subjects was 3 days, during tensive and involves hepatocytes, intestinal toxic effects in users of which a median of 6 to 10 doses of acute hepatotoxicity ensue. Under NSAIDs include being older than 60 antipyretic drugs were adminis- normal circumstances, NAPQ1 is years, a history of a gastrointestinal tered. Approximately 1% of subjects detoxified by conjugation to gluta- disorder, concomitant corticoste- in each group were hospitalized dur- thione. If glutathione stores are de- roid therapy, and duration of NSAID ing the study, most for treatment of pleted, eg, during chronic ethanol consumption. Toxic effects occur infectious diseases. Four children, abuse or starvation, the risk of acet- most often during the initial month however, were hospitalized with gas- aminophen-induced hepatotoxicity of therapy.64 Findings of longitudi- trointestinal bleeding. All had been increases markedly.68,69 nal endoscopic evaluation of sub- treated with ibuprofen, 2 at each dose. Whereas acute liver failure in the jects treated with long-term aspirin The risk of hospitalization for acute setting of an attempted suicide with suggest that resistance of the gastric gastrointestinal bleeding in those acetaminophen is well recognized, mucosa to the toxic effects of NSAIDs receiving ibuprofen was 7.2 per only recently has attention been fo- increases with time.65 As a result, rates 100 000. Although no child had to be cused on the risk of hepatic injury due of adverse reactions associated with hospitalized for acute gastrointesti- to acetaminophen administered in chronic ingestion of nonselective nal bleeding in the acetaminophen doses within or slightly above the rec- COX inhibitors might underesti- group, hospitalization rates in the ommended range (4 g in 24 hours). mate the risk of serious complica- 2 treatment groups were not signifi- In a recent series of 71 cases of tions associated with sporadic use of cantly different. There were no epi- acetaminophen-induced hepatotox- such agents. Volunteers receiving sodes of Reye syndrome, anaphylaxis, icity, 30% of the cases were shown to resultfromaccidentaloverdosesinpa- tients using the drug for pain relief.68 Table 1. Adverse Effects Associated With Reasons for excessive dosing included Nonsteroidal Anti-inflammatory Drug Therapy too frequent dosing, simultaneous ingestion of multiple acetaminophen- System Adverse Effects containing compounds, and ingestion Gastrointestinal Peptic ulceration of cough and cold remedies not rec- Esophagitis and strictures Small- and large-bowel erosions ognized to contain acetaminophen. Renal Reversible acute renal failure PHYSICAL METHODS Fluid and electrolyte disturbances Chronic renal failure OF ANTIPYRESIS Interstitial nephritis External cooling has been used since Nephrotic syndrome antiquity to treat fever. Alexander Cardiovascular Exacerbation of hypertension the Great received external cooling Exacerbation of congestive cardiac failure Exacerbation of angina in the form of repeated cool baths as Hepatic Elevated transaminases his principal therapy for the febrile Fulminant hepatic failure (rare) illness to which he succumbed in 70 Central nervous system Headache 323 BC. External cooling contin- Drowsiness ues to be used, most often in combi- Confusion and behavior disturbance nation with antipyretic medica- Aseptic meningitis tions, to treat children with fevers Hematologic Thrombocytopenia refractory to such medications and Hemolytic anemia 71 Agranulocytosis and aplastic anemia adults in intensive care units. Other Exacerbation of asthma and nasal polyposis A variety of techniques are used Rash to cool patients by physical means. These include sponging with vari-

ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 452

Downloaded From: https://jamanetwork.com/ on 10/01/2021 ous solutions (eg, tepid water or al- increasedheatproductionanddidnot DIAGNOSTIC IMPLICATIONS cohol), application of ice packs or lower core temperature unless ani- cooling blankets, and exposure to cir- mals were simultaneously exposed to Numerousinvestigatorshaveobserved culating fans (most often in conjunc- a warm environment. Neither anti- a direct correlation between the height tion with sponging). In contrast to an- pyretic modality abolished the initial of fever and the rate of serious bacte- tipyretic drugs, external cooling phase of the febrile response. rialinfectionsinchildren,withthelike- lowers the temperature of febrile pa- The few clinical studies done of lihood of such infections increasing tients by overwhelming effector the efficacy of physical methods of an- sharply in children febrile to greater mechanisms that have been evoked tipyresis have differed in their con- than 40°C.74,75-78 It has also been sug- by an elevated thermoregulatory set clusions. Interpretation of these data gested that the response of a fever to point, rather than by lowering that set has been difficult because pharma- antipyretictherapymightbeimportant point. Therefore, unless concomi- cologic agents have almost invari- diagnostically, in that a drop in tem- tant therapy with antipyretic agents ably been administered concomi- perature and/or improvement in the has lowered the thermal set point or tantly with external cooling. Steele et general appearance of a febrile child shivering is inhibited by other phar- al73 found oral acetaminophen (in age- indicate that the fever is not due to a macologic means, external cooling is adjusted dosages ranging from 80 to seriousillness.79 Thisconclusion,how- vigorously opposed in the febrile pa- 320 mg) and sponging with ice wa- ever, is not supported by several inves- tient by thermoregulatory mecha- ter or with alcohol in water to be tigations comparing the response of nisms trying to maintain the el- equally effective in reducing fever in children to antipyretics (primarily oral evated body temperature. children. While less effective in low- acetaminophen) during bacteremic Physical methods promote heat ering febrile temperatures, spong- and nonbacteremic infections80-85 loss by conduction (eg, during immer- ing with tepid water has been re- (Table 2). Of 6 such investigations sion in cold water), convection (eg, ported to afford greater comfort than published in recent years, only 185 during passage of cool air over body sponging with either ice water or al- foundadifferenceintheantipyreticre- surfaces), and evaporation (eg, during cohol in water.73 When acetamino- sponsiveness of bacteremic and non- wateroralcoholspongebaths).Evapo- phen was combined with sponging, bacteremic fever. In that study, bacte- rative methods have traditionally been more rapid cooling occurred than remic fevers responded substantially touted as the most effective physical with either modality alone. New- less well to acetaminophen than non- meansofpromotingheatlossinfebrile man,74 on the other hand, reported bacteremic fevers. However, unlike 5 patients because such methods are that tepid-water sponging in combi- other prospective investigations that deemed to be the least likely method nation with 5 to 10 mg/kg of oral acet- showed no such difference, this inves- to induce shivering.71 However, care- aminophen is no more effective than tigation was a retrospective study. fully designed comparative trials have acetaminophen alone in lowering the Thus, with 1 retrospective exception, not yet established any 1 physical temperature of children with fever. published investigations suggest that method of antipyresis as superior. In a prospective observational study in children, fevers due to serious in- Direct comparisons of pharma- of adults with fever being treated in fections (ie, bacteremic) are as respon- cologic and physical methods of an- intensive care units, O’Donnell et al71 sive to antipyretic therapy as less se- tipyresis are likewise all but nonex- concluded that while hypothermia rious infections. istent. In the only controlled study, blanket therapy added little to the ac- Several studies have suggested WenzelandWerner72 reportedthatsa- tion of pharmacologic agents in low- that neoplastic fevers are more re- licylates reduced the second phase of ering temperature, it induced wider sponsive to NSAIDs than infectious endotoxin-induced fever in rabbits, temperature fluctuations and more fevers, and that this difference in an- whereas abdominal skin cooling episodes of hypothermia. tipyretic responsiveness can be used

Table 2. Studies in Children of the Oral Temperature Response of Bacteremic vs Nonbacteremic Infections to Antipyretic Agents

Temperature Response, °C

Bacteremic Nonbacteremic Antipyretic Age of

Authors Year Study Design Agent Subjects, y No.* TI † ↓T‡ No.* TI† ↓T‡ P § Torrey et al80 1985 Prospective/observational Acetaminophen/aspirin Յ2 16 40.1 1.3 239 39.9 1.05 .14 Baker et al81 1987 Prospective/observational Acetaminophen Յ6 10 40.1 1.5 225 39.6 1.0 NG࿣ Yamamoto et al82 1987 Prospective/observational Acetaminophen Յ2 17 40.5 1.6 216 40.4 1.6 .85 Weisse et al83 1987 Prospective/observational Acetaminophen Յ17 11 NG࿣ 1.4 16 NG࿣ 1.2 .37 Baker et al84 1989 Prospective/observational Acetaminophen Յ2 19 40.1 1.7 135 40.0 1.6 Ͼ.05 Mazur et al85 1989 Retrospective/case control Acetaminophen Յ6 34 39.8 1.0 68 39.8 1.5 Ͻ.001

*Number of subjects studied. †Mean initial temperature (T) (ie, T just prior to administration of antipyretic agent). ‡Mean decrease in T 60 to 120 minutes following treatment with antipyretic agent. ࿣ NG indicates not given. §Comparison of ↓T in “bacteremic” vs “nonbacteremic” subjects by t test.

ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 453

Downloaded From: https://jamanetwork.com/ on 10/01/2021 to distinguish fevers of infectious ori- reasons, it has been suggested that a ruses such as influenza virus as gin from those due to cancer.86-88 Un- more rational strategy for treating fe- well (K.I.P., S. Kudaravalli, MD, S. S. fortunately, because patients with ob- vers unresponsive to antipyretic drugs Wasserman, MD, and P.A.M., un- vious infections were excluded from is to warm rather than to cool se- published data, 1999). Finally, analysis in these studies, the results lected skin surfaces, thereby reduc- paracetamol has recently been re- may have been biased. Naproxen was ing the vasoconstriction and shiver- ported to prolong parasitemia in one of the first such drugs to be stud- ing thresholds dictated by the elevated children infected with Plasmodium ied in this regard.86 Subsequent ran- hypothalamic thermal set point, and, falciparum, presumably by decreas- domized comparisons have reported in this way, promoting heat loss.92 ing production of tumor necrosis naproxen, indomethacin, and diclof- Unfortunately, certain antipy- factor and oxygen radicals.98 enac to be equally effective in inhib- retic drugs also seem to cause coro- Antipyretic therapy is also oc- iting cancer-induced fever.88 No sat- nary vasoconstriction in patients casionally given to prevent febrile sei- isfactory explanation has been offered with coronary artery disease. Fried- zures in children and to prevent or to date as to why NSAIDs might be man et al93 observed significant in- to reverse fever-associated mental more effective in reducing fever due creases in mean arterial pressure, dysfunction in frail elderly patients. to cancer than that due to infection. coronary vascular resistance, and Beisel et al99 showed that aspirin (in myocardial arteriovenous oxygen combination with propoxyphene) RISK-BENEFIT difference after administration of ameliorates fever-associated decre- CONSIDERATIONS intravenous indomethacin (0.5 ments in mental work performance mg/kg) in such patients. Mean ± SEM in young volunteers infected with One of the reasons commonly given coronary blood flow decreased simul- sandfly fever virus, even in the face as justification for suppressing fever taneously from 181 ± 29 to 111 ± 14 of only partial relief of either the fe- is that the metabolic cost of fever ex- mL/min (PϽ.05). Thus, in this inves- ver or other symptoms of the ill- ceeds its clinical benefits. In fact, the tigation, myocardial oxygen de- ness. In view of these observations, metabolic and cardiovascular costs of mand increased in the face of a fall in antipyretic therapy might be ex- fever are substantial, especially dur- coronary blood flow following indo- pected to have a beneficial effect on ing the chill phase of the response with methacin administration. The au- fever-associated mental dysfunc- its shivering-induced increase in meta- thors speculated that indometha- tion in frail elderly patients. How- bolic rate, norepinephrine-mediated cin’s vasoconstrictor effect derives ever, studies designed to test this hy- peripheral vasoconstriction, and in- from its capacity to block the synthe- pothesis have not been conducted. creased arterial blood pressure.25 Be- sis of vasodilatory prostaglandins. Unfortunately, antipyretic cause of the potential adverse conse- Antipyretic therapy is also com- therapy has yet to prove effective in quences of these metabolic effects on monly administered to enhance pa- preventing febrile seizures.23 Cam- cardiovascular and pulmonary func- tient comfort.94 General experience field et al100 conducted a randomized tion, fever has been attacked with with antipyretic drugs, which are for double-blind study comparing single particular vigor in patients with un- the most part also analgesic agents, daily-dose phenobarbital plus anti- derlying cardiovascular and/or pul- seems to support this rationale. How- pyretic instruction with placebo plus monary diseases.71 Although antipy- ever, carefully controlled efficacy antipyretic instruction in preventing retic therapy has theoretical merit in studies have never quantified the de- recurrent febrile seizures following an this regard (if it does not induce shiv- gree to which antipyretic therapy en- initial simple febrile seizure. In chil- ering89), neither the detrimental ef- hances the comfort of patients with dren treated with phenobarbital and fects of fever nor the salutary effects fever. Moreover, the relative cost of antipyretics, the febrile seizure recur- of antipyretic therapy have been con- such symptomatic relief, in terms of rence rate was 5%, whereas in those firmed experimentally, even in pa- drug toxicity and adverse effects of receiving placebo and antipyretics, the tients with underlying cardiovascu- antipyretic agents on the course of the rate was 25%, suggesting that a single lar and pulmonary diseases. illness responsible for the fever, has daily dose of phenobarbital is more External cooling, which is never been determined. The impor- effective than counseling parents widely used in such patients to sup- tance of such information is under- about antipyretic therapy in prevent- press fevers unresponsive to antipy- scored by reports that acetamino- ing recurrent febrile seizures. More re- retic drugs, has been shown to de- phen prolongs the time to crusting cent studies in children have shown crease oxygen consumption by as of skin lesions in children with that whether given in moderate doses much as 20% in febrile critically ill chicken pox95 and that acetamino- (10 mg/kg per dose, 4 times a day)101 patients if shivering is prevented by phen and aspirin increase viral shed- or in relatively high doses (15-20 therapeutic paralysis.89 If shivering is ding and nasal signs and symptoms mg/kg per dose every 4 hours),102 acet- not inhibited, external cooling causes while suppressing the serum- aminophen fails to reduce the rate of a rise in oxygen consumption.89 Per- neutralizing antibody response in recurrence of febrile seizures. haps more important to febrile pa- adults with rhinovirus infec- Finally, there has been consid- tients with underlying cardiovascu- tions.96,97 Findings of studies in hu- erable recent interest in the use of an- lar disease, external cooling has the man volunteers imply further that the tipyretic drugs to modulate the activ- capacity to cause vasospasm of dis- capacity of antipyretic agents to pro- ity of pyrogenic cytokines during eased coronary arteries by inducing long the course of rhinovirus and vari- bacterial sepsis.103 In certain animal a cold pressor response.90,91 For these cella infections might extend to vi- models, antipyretic drugs that in-

ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 454

Downloaded From: https://jamanetwork.com/ on 10/01/2021 hibit COX confer protection when evidence that such medications are ef- 11. Kramer MS, Niamark L, Leduc DG. Parental fever phobia and its correlates. Pediatrics. 1985; given soon after bacterial challenge, fective in suppressing febrile seizures, 75:1110-1113. presumably by blunting the adverse even if given prophylactically. 12. Kelly L, Morin K, Young D. Improving caretak- ␣ In view of the capacity of exter- ers’ knowledge of fever management in pre- effects of tumor necrosis factor and school children: is it possible? J Pediatr Health interleukin 1. In a recent large clini- nal cooling measures to induce a cold Care. 1996;10:167-173. cal trial, Bernard et al55 reported that pressor response,89,91 it is question- 13. IUPS Thermal Commission. Glossary of Terms for Thermal Physiology. 2nd ed. Pflu¨gers Arch. 48 hours of intravenous therapy with able whether this form of antipy- 1987;410:567-587. the COX inhibitor ibuprofen low- retic therapy should ever be admin- 14. Mackowiak PA, Bartlett JG, Borden EC, et al. Con- ered core temperature, heart rate, oxy- istered to patients with fever (much cepts of fever. Clin Infect Dis. 1997;25:119-138. 15. Kluger MJ, Kozak W, Conn CA, et al. The adap- gen consumption, and lactic acid less to patients in the intensive care tive value of fever. In: Mackowiak PA, ed. Fever: blood levels, but did not decrease the unit, for whom it is most commonly Basic Mechanisms and Management. 2nd ed. prescribed). If external cooling is used Philadelphia, Pa: Lippincott-Raven Publishers; incidence of organ failure or 30-day 1997:255-266. mortality rate in patients with sepsis. to treat fever, care must be taken to 16. Mackowiak PA. Fever: blessing or curse? a uni- Thus, in spite of promising results ob- prevent shivering because of its as- fying hypothesis. Ann Intern Med. 1994;120: 1037-1040. tained in some experimental mod- sociated increase in oxygen consump- 17. Mackowiak PA, Boulant JA. Fever’s glass ceil- els, the antipyretic agent ibuprofen has tion. Unfortunately, even if shivering. Clin Infect Dis. 1996;22:525-536. not yet been shown to be of clinical ing is prevented, there is no guarantee 18. Hirtz DG. Generalized tonic clonic and febrile seizures. Pediatr Clin North Am. 1989;36:375-382. value in treating bacterial sepsis. that a cold pressor response will be 19. Berg AT. Febrile seizures and epilepsy: the con- averted. In view of indomethacin’s ca- tributions of epidemiology. Pediatr Perinatal Epi- pacity to cause coronary vasocon- demiol. 1992;6:145-152. CONCLUSIONS 20. Lessell S, Torres JM, Kurland LT. Seizure dis- striction in patients with coronary ar- orders in a Guamanian village. Arch Neurol. 1962; Although clinicians have used various tery disease,93 NSAIDs should be used 7:37-44. 21. Aicardi J. Febrile convulsions. In: Aicardi J, ed. forms of antipyretic therapy since with caution, if at all, to suppress fe- Epilepsy in Children, 2nd ed. New York, NY: time immemorial, there is a dearth of ver in such patients. Raven Press; 1994:253-275. data concerning the benefits and rela- 22. Lennox-Buchthal MA. Febrile Convulsions: A Re- appraisal. Amsterdam, the Netherlands: Elsevier tive risks of such treatments. Never- Accepted for publication June 30, 1999. Science Inc; 1973:1-138. theless, several tentative conclusions This work was supported by the 23. Rosman NP. Febrile convulsions. In: Mackow- iak PA, ed. Fever: Basic Mechanisms and Man- regarding antipyretic therapy seem Department of Veterans Affairs, Wash- agement. 2nd ed. Philadelphia, Pa: Lippincott- justified in light of the limited data ington, DC. Raven Publishers; 1997:267-277. available. It is clear, for instance, that The authors wish to thank Shel- 24. Styrt B, Sugarman B. Antipyresis and fever. Arch Intern Med. 1990;150:1589-1597. short courses of approved doses of don E. Greisman, MD, for his helpful 25. Greisman SE. Cardiovascular alterations during standard antipyretic drugs carry a low advice. fever. In: Mackowiak PA, ed. Fever: Basic Mecha- riskoftoxiceffects.Mostofthesedrugs Reprints: Philip A. Mackowiak, nisms and Management. 2nd ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1997:143-165. have analgesic as well as antipyretic MD, the Medical Care Clinical Cen- 26. Horwath SM, Spurr GB, Hutt BK, Hamilton LH. properties. Therefore, if not otherwise ter, Veterans Affairs Maryland Health Metabolic cost of shivering. J Appl Physiol. 1956; contraindicated (eg, aspirin in young 8:595-602. Care System, 10 N Greene St, Balti- 27. Mackowiak PA, Plaisance KI. The benefits and children because of the risk of Reye more, MD 21201. risks of antipyretic therapy. Ann N Y Acad Sci. syndrome), such drugs can be used to 1998;856:214-223. provide symptomatic relief in patients 28. Mackowiak PA. Concepts of fever. Arch Intern REFERENCES Med. 1998;158:1870-1881. with fever, to reduce the metabolic de- 29. Grundmann MJ. Studies on the Action of Anti- mands of fever in chronically debili- pyretic Substances [doctor of philosophy the- 1. Vane JR, Botting RM. Mechanism of action of sis]. Oxford, England: University of Oxford; 1969. tated patients, and possibly to prevent nonsteroidal anti-inflammatory drugs. Am J Med. 30. Milton AS, Wendlandt S. Effects on body tem- oralleviatefever-associatedmentaldys- 1998;104(suppl):2S-8S. perature of prostaglandins of the A, E and F se- function in the elderly. To minimize 2. Jack DB. One hundred years of aspirin. Lancet. ries on injection into the third ventricle of unan- 1997;350:437-439. aesthetized cats and rabbits. J Physiol (Lond). antipyretic-induced fluctuations in 3. Cooper KE. Fever and Antipyresis: The Role of 1971;218:325-336. temperature (and the risk of recurrent the Nervous System. Cambridge, Mass: Cam- 31. Vane JR. Inhibition of prostaglandin synthesis shivering and its increased metabolic bridge University Press: 1995:100-105. as a mechanism of action for aspirin-like drugs. 4. Piria R. Sur des nouveaux produits extraits de Nature New Biol. 1971;231:232-235. demands) antipyretic agents should la salicin. C R Acad Sci Paris. 1838;6:620-624. 32. Mitchell D, Laburn H, Cooper KE, Hellon RF, be administered to patients with fever 5. Gerland H. New formation of salicylic acid. Cranston WI, Townsend Y. Is prostaglandin E the J Chem Soc. 1852;5:133. neural mediator of the febrile response? The case at regular intervals to preclude abrupt 6. Kolbe H, Lautemann E. Über die Constitution und against a proven obligatory role. Yale J Biol Med. recurrences of fever, rather than as Basicita¨t der Salicylsa¨ure. Justus Liebigs An- 1986;59:159-168. needed for temperatures above some nals Chem. 1860;115:157-206. 33. Alexander SJ, Cooper KE, Veale WL. Sodium sa- 7. von Gerhardt C. Untersuchungen u¨ber die licylate: alternate mechanism of central antipy- arbitrary level. When prescribing such wasserfreien organischen Sa¨ren. Justus Leibig retic action in the rat. Pflu¨gers Arch. 1989;413: medications, physicians must recog- Annals Chem. 1853;87:149-178. 451-455. nize that each carries its own risk of 8. Ipp M, Jaffe D. Physicians’ attitudes toward the 34. Blatteis CM, Sehic E. Prostaglandin E2: a puta- diagnosis and management of fever in children tive fever mediator. In: Mackowiak PA, ed. Fe- toxic effects, and might prolong the 3 months to 2 years of age. Clin Pediatr. 1993; ver: Basic Mechanisms and Management. 2nd course of at least some infections. It 32:66-70. ed. Philadelphia, Pa: Lippincott-Raven Publish- 9. Thomas V, Riegel B, Andrea J, Murray P, Gerhart ers; 1997:117-145. should be noted further that there is A, Gocka I. National survey of pediatric fever man- 35. Vane JR, Bakhle YS, Botting RM. Cyclooxygen- nocompellingevidencethataresponse agement practices among emergency depart- ases 1 and 2. Annu Rev Pharmacol Toxicol. 1998; to antipyretic medications is useful di- ment nurses. J Emerg Nurs. 1994;20:505-510. 38:97-120. 10. Eskerud JR, Andrew M, Stromnes B, Toverud EL. 36. Vane JR, Botting RM. New insights into the mode agnostically in distinguishing serious Pharmacy personnel and fever. Pharm World Sci. of action of anti-inflammatory drugs. Inflamm from self-limited illnesses, nor is there 1993;15:156-160. Res. 1995;44:1-10.

ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 455

Downloaded From: https://jamanetwork.com/ on 10/01/2021 37. Flower RJ, Vane JR. Inhibition of prostaglandin treatment of fever: a double-blind, crossover clini- 81. Baker MD, Fosarelli PD, Carpenter RO. Child- synthetase in brain explains the antipyretic ac- cal trial. J Int Med Res. 1984;12:102-107. hood fever: correlation of diagnosis with tem- tivity of paracetamol (4-acetamidophenol). Na- 58. Cunietti E, Monti M, Vigano A, et al. Nimesulide perature response to acetaminophen. Pediat- ture. 1972;240:410-411. in the treatment of hyperpyrexia in the aged: rics. 1987;80:315-318. 38. Insel PA. Analgesic-antipyretic and antiinflam- double-blind comparison with paracetamol. Ar- 82. Yamamoto LT, Wigder HN, Fligner DJ, et al. Re- matory agents and drugs employed in the treat- zneim-Forsch Drug Res. 1993;43:160-162. lationship of bacteremia to antipyretic therapy ment of gout. In: Hardman JG, Limbird LE, eds. 59. Reiner M, Cereghetti S, Haeusermann M, Monti in febrile children. Pediatr Emerg Care. 1987;3: Goodman and Gilman’s The Pharmacological Ba- T. Antipyretic activity of nimesulide supposito- 223-227. sis of Therapeutics. 9th ed. New York, NY: Mc- ries: double blind versus diclofenac and pla- 83. Weisse ME, Miller G, Brien JH. Fever response Graw-Hill Co; 1996:617-657. cebo. Int J Clin Pharmacol Ther Toxicol. 1985; to acetaminophen in viral vs. bacterial infec- 39. Carabaza A, Cabre F, Rotllan E, et al. Stereos- 23:673-677. tions. Pediatr Infect Dis J. 1987;6:1091-1094. elective inhibition of inducible cyclooxygenase 60. Hurwitz ES, Barrett MJ, Bregman D, et al. Pub- 84. Baker RC, Tiller T, Bausher JC, et al. Severity of by chiral nonsteroidal antiinflammatory drugs. lic health service study on Reye’s syndrome and disease correlated with fever reduction in fe- J Clin Pharmacol. 1996;36:505-512. medications: report of the pilot phase. N Engl J brile infants. Pediatrics. 1989;83:1016-1019. 40. Evans AM. Pharmacodynamics and pharmacoki- Med. 1985;313:849-857. 85. Mazur LJ, Jones TM, Kozinetz CA. Temperature netics of the profens: enantioselectivity, clinical im- 61. Hurwitz ES, Marret MJ, Bregman D, et al. Pub- response to acetaminophen and risk of occult plications, and special reference to S(+)-ibuprofen. lic health service study of Reye’s syndrome and bacteremia: a case-control study. J Pediatr. 1989; J Clin Pharmacol. 1996;36(suppl):7s-15s. medications: report of the main study. JAMA. 115:888-891. 41. Kelley MT, Walson PD, Edge JH, Cox S, Mortensen 1987;257:1905-1911. 86. Chang JC, Gross HM. Utility of naproxen in the ME. Pharmacokinetics and pharmacodynamics of 62. Rahwan GL, Rahwan RG. Aspirin and Reye’s syn- differential diagnosis of fever of undetermined ibuprofen isomers and acetaminophen in febrile drome: the change in prescribing habits of health origin in patients with cancer. Am J Med. 1984; children. Clin Pharmacol Ther. 1992;52:181-189. professionals. Drug Intell Clin Pharm. 1986;20: 76:597-603. 42. Spinos GA, Bloesch D, Keller U, Zimmerli W, 143-145. 87. Chang JC. NSAID test to distinguish between in- Cammisuli S. Pretreatment with ibuprofen aug- 63. Brooks P. Use and benefits of nonsteroidal anti- fectious and neoplastic fever in cancer patients. ments circulating tumor necrosis factor-␣, in- inflammatory drugs. Am J Med. 1998;104 Postgrad Med. 1988;84:71-72. terleukin-6 and elastase during acute endotox- (suppl 3A):9S-13S. 88. Tsavaris N, Zinelis A, Karabelis A, et al. A random- inemia. J Infect Dis. 1991;163:89-95. 64. Gabriel SE, Jaakkimainen L, Bombardier C. Risk ized trial of the effect of three non-steroidal anti- 43. Nahata MC, Powell DA, Durrell DE, Miller MA, for serious gastrointestinal complications re- inflammatory agents in ameliorating cancer- Gupta N. Efficacy of ibuprofen in pediatric pa- lated to use of nonsteroidal anti-inflammatory induced fever. J Intern Med. 1990;228:451-455. tients with fever. Int J Clin Pharmacol Ther Toxi- drugs: a meta-analysis. Ann Intern Med. 1991; 89. Manthores CA, Hall JB, Olson D, et al. Effect of col. 1992;30:94-96. 115:787-796. cooling on oxygen consumption in febrile criti- 44. Autret E, Breart G, Jonville AP, Courcier S, Las- 65. Graham DY, Smith JL. Aspirin and the stom- cally ill patients. Am J Respir Crit Care Med. 1995; sale C, Goehrs JM. Comparative efficacy and tol- ach. Ann Intern Med. 1986;104:390-398. 151:10-14. erance of ibuprofen syrup in children with py- 66. Graham DY, Smith JL, Spjut HJ, Torres E. Gas- 90. Raizner AE, Chahine RA, Ishimori T, et al. Provo- rexia associated with infectious diseases and tric adaptation: studies in humans during con- cation of coronary artery spasm by the cold pres- treated with antibiotics. Eur J Clin Pharamcol. tinuous aspirin administration. Gastroenterol- sor test: hemodynamic, arteriographic and quan- 1994;46:197-201. ogy. 1988;95:327-333. titative arteriographic observations. Circulation. 45. Walson PD, Galletta G, Braden NJ, Alexander L. 67. Lesko SM, Mitchell AA. An assessment of the safety 1980;62:925-932. Ibuprofen, acetaminophen, and placebo treat- of pediatric ibuprofen: a practitioner-based ran- 91. Nobel EG, Gang P, Gordon JB, et al. Dilation of ment of febrile children. Clin Pharmacol Ther. domized clinical trial. JAMA. 1995;273:929-933. normal and constriction of atherosclerotic coro- 1989;46:9-17. 68. Schiodt FV, Rochling FA, Casey DL, Lee WM. nary arteries caused by the cold pressor test. Cir- 46. Wilson JT, Brown RD, Kearns GL, et al. Single- Acetaminophen toxicity in an urban county hos- culation. 1987;77:43-52. dose, placebo-controlled comparative study of pital. N Engl J Med. 1997;337:1112-1117. 92. Lenhardt R, Kurz A, Sessler DI. Thermoregula- ibuprofen and acetaminophen antipyresis in chil- 69. Whitcomb DC, Block GD. Association of acet- tion and hyperthermia. Acta Anaesthesiol Scand dren. J Pediatr. 1991;119:803-811. aminophen hepatotoxiicty with fasting and al- Suppl. 1996;109:34-38. 47. McIntyre J, Hull D. Comparing efficacy and tol- cohol use. JAMA. 1994;272:1845-1850. 93. Friedman PL, Brown EJ Jr, Gunther S, et al. Coro- erability of ibuprofen and paracetamol in fever. 70. Oldach DW, Richard R, Borza EN, Benitez RM. nary vasoconstrictor effect of indomethacin in Arch Dis Child. 1996;74:164-167. “A mysterious death.” N Engl J Med. 1998;338: patients with coronary artery disease. N Engl J 48. Kauffman RE, Sawyer LA, Scheinbaum ML. An- 1764-1769. Med. 1981;305:1171-1175. tipyretic efficacy of ibuprofen vs acetamino- 71. O’Donnell J, Axelrod P, Fisher C, Lorber B. Use 94. Isaacs SN, Axelrod PI, Lorber B. Antipyretic or- phen. AJDC. 1992;146:622-625. and effectiveness of hypothermia blankets for fe- ders in a university hospital. Am J Med. 1990;88: 49. Walson PD, Galletta G, Chomilo F, Braden NJ, Saw- brile patients in the intensive care unit. Clin In- 31-35. yer LA, Scheinbaum ML. Comparison of mul- fect Dis. 1997;24:1208-1213. 95. Dorna TF, DeAngelis C, Baumgardner RA, et al. tidose ibuprofen and acetaminophen therapy in 72. Wenzel C, Werner J. Physical versus pharma- Acetaminophen: more harm than good for febrile children. AJDC. 1992;146:626-632. cological counter-measures. Eur J Appl Physiol. chicken pox? J Pediatr. 1989;114:1045-1048. 50. Marriott SC, Stephenson TJ, Hull D, Pownall R, 1988;57:81-88. 96. StanleyED,JacksonGG,PanusarnC,etal.Increased Smith CM, Butler A. A dose ranging study of ibu- 73. Steele RW, Tanaka PT, Lara RP, Bass JW. Evalu- viral shedding with aspirin treatment of rhinovirus profen susupension as an antipyretic. Arch Dis ation of sponging and of oral antipyretic therapy infection. JAMA. 1975;231:1248-1251. Child. 1991;66:1037-1041. to reduce fever. J Pediatr. 1970;77:824-829. 97. Graham MH, Burrell CJ, Douglas RM, et al. Ad- 51. Van Esch A, Van Stennsel-Moll HA, Steyerberg EW, 74. Newman J. Evaluation of sponging to reduce verse effects of aspirin, acetaminophen, and ibu- Offringa M, Habbema JDF, Derksen-Lubsen G. An- body temperature in febrile children. CMAJ. 1985; profen on immune function, viral shedding, and tipretic efficacy of ibuprofen and acetaminophen 132:641-642. clinical status in rhinovirus-infected volun- in children with febrile seizures. Arch Pediatr Ado- 75. McCarthy PL, Grundy GW, Spiesel SZ, Dolan TF. teers. J Infect Dis. 1990;162:1277-1282. lesc Med. 1995;149:632-637. Bacteremia in children: an outpatient clinical re- 98. Brandts CH, Ndjave´ M, Graninger W, Kremsner 52. Lecomte J, Monti T, Pochobradsky MG. Antipy- view. Pediatrics. 1976;57:861-868. PG. Effect of paracetamol on parasite clearance retic effects of nimesulide in paediatric prac- 76. McGowan JE, Bratton L, Klein JO, Finland M. Bac- time in Plasmodium falciparum malaria. Lan- tice: a double-blind study. Curr Med Res Opin. teremia in febrile children seen in a “walk-in” pe- cet. 1997;350:704-709. 1991;12:296-303. diatric clinic. N Engl J Med. 1973;288:1309- 99. Beisel WR, Morgan BB Jr, Bartelloni PJ, et al. 53. D’Apuzzo V, Monti T. Pilot study of the antipyretic 1312. Symptomatic therapy in viral illness. A con- and analgesic activity of nimesulide paediatric sup- 77. Teele DW, Pelton SI, Grant MJ, et al. Bactere- trolled study of effects on work performance. positories. Drugs Exp Clin Res. 1992;18:63-68. mia in febrile children under 2 years of age: re- JAMA. 1974;228:581-584. 54. Michie HR, Manouge KR, Spriggs DR, et al. De- sults of cultures of blood of 600 consecutive fe- 100. Camfield PR, Camfield CS, Shapiro SH, et al. The tection of circulating tumor necrosis factor af- brile children seen in a “walk-in” clinic. J Pediatr. first febrile seizure: antipyretic instruction plus ter endotoxin administration. N Engl J Med. 1988; 1975;87:227-230. either phenobarbital or placebo to prevent re- 318:1481-1486. 78. Bonadio WA, Romine K, Gyuro J. Relationship of currence. J Pediatr. 1980;5:719-737. 55. Bernard GR, Wheller AP, Russell JA, et al. The fever magnitude to rate of serious bacterial infec- 101. Uhari M, Rantala H, Vainionpa¨a¨ L, et al. Effect effects of ibuprofen on the physiology and sur- tions in neonates. J Pediatr. 1990;116:733-735. of acetaminophen and of low intermittent doses vival of patients with sepsis. N Engl J Med. 1997; 79. McCarthy PL. Fever in infants and children. In: of diazepam on prevention of recurrences of fe- 336:912-918. Mackowiak PA, ed. Fever: Basic Mechanisms and brile seizures. J Pediatr. 1995;126:991-995. 56. Vargas R, Maneatis T, Bynum L, Peterson C, Mc- Management. 2nd ed. Philadelphia, Pa: Lippin- 102. Schnaiderman D, Lahat E, Sheefer T, et al. An- Mahon FG. Evaluation of the antipyretic effect of cott-Raven Publishers; 1997:351-362. tipyretic effectiveness of acetaminophen in fe- ketorolac, acetaminophen, and placebo in en- 80. Toney SB, Henretig F, Fleisher G, et al. Tempera- brile seizures: ongoing prophylaxis versus spo- dotoxin-induced fever. J Clin Pharmacol. 1994; ture response to antipyretic therapy in children: radic usage. Eur J Pediatr. 1993;152:747-749. 34:848-853. relationship to occult bacteremia. Am J Emerg 103. Warren HS. Strategies for the treatment of sep- 57. Reiner M, Massera E, Magni E. Nimesulide in the Med. 1985;3:190-192. sis. N Engl J Med. 1997;336:952-953.

ARCH INTERN MED/ VOL 160, FEB 28, 2000 WWW.ARCHINTERNMED.COM 456

Downloaded From: https://jamanetwork.com/ on 10/01/2021