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Antipyretic Strategies: Is Fever Clearance Enough To Justify Dual Therapy?
Pediatrics
October 1, 2024
Acetaminophen and ibuprofen are two widely used medications for children's pain and fever. When used sparingly and with correct dosage, these medications are generally regarded as safe. However, much remains unknown about their safety and efficacy when used in combination or alternating sequentially during a febrile illness. In this issue of Pediatrics, Florez et al, report a large network meta-analysis of 31 randomized controlled trials to compare a single treatment with either monotherapy (acetaminophen or ibuprofen), combined therapy (acetaminophen + ibuprofen together), or alternating therapy (acetaminophen followed by ibuprofen 2-4 hours later).1 Wide variation in efficacy and safety outcomes across studies complicated the analysis. Depending on available outcome data, efficacy was evaluated by either temperature change at 4 or 6 hours or proportion of children afebrile at 4 or 6 hours. Safety was based on the frequency of adverse events (AE) over the 6-hour window. Dual therapy strategies, either combined or alternating, appeared to be superior to acetaminophen monotherapy as judged by the higher proportion of afebrile children at 4 and 6 hours. There were no between group differences in frequency of AE. These findings are consistent with previous analyses.2,3 Despite this huge effort, pivotal questions remain: Is reducing temperature enough to justify dual therapy? Is dual therapy safe?American Academy of Pediatrics (AAP) guidance reminds pediatricians and parents alike that the primary goal of antipyretic therapy is to both improve the child's overall comfort and their ability to maintain hydration.4 Unfortunately, the study's aim to include child discomfort as a primary efficacy marker was not possible. Child discomfort was evaluated in only 6 studies, each using dissimilar metrics. To promote clinically meaningful patient-oriented outcomes, it must become standard study design to evaluate validated metrics of comfort, hydration, and activity level. Measures of hydration are particularly important when considering ibuprofen safety and potential adverse renal effects.The safety of combined or alternating acetaminophen and ibuprofen in febrile children remains elusive, particularly after repeated doses during febrile illness. Although Florez reports no significant differences in adverse event frequency, they acknowledge the serious limitations of single course therapy and the short AE monitoring window. Additionally, as is common in meta-analyses, safety outcome metrics varied widely across studies. Most studies did not include quantitative measures of liver enzymes, renal function, urinalysis, or drug concentrations. The limited data available in these trials highlight the need for more standardized and comprehensive research practices.Medication safety is best assessed using standardized outcome metrics, in a large number of participants, and over multiple medication doses. While uncommon, adverse drug reactions can occur with antipyretics. Acetaminophen can be associated with nausea and hepatotoxicity, and ibuprofen can be associated with gastrointestinal bleeding and renal injury.5 Both acetaminophen and ibuprofen have been associated with Stevens-Johnson syndrome.6 Adverse effects including liver and renal toxicity may present several hours to days after exposure. Even in cases of acetaminophen overdose, liver transaminase enzymes do not begin to rise until approximately 12 hours after ingestion.7 Measures of serum creatinine are only an indirect marker of renal function or injury.8 Evaluating adverse events during a febrile illness is particularly challenging since adverse effects of medication or illness may overlap. Endogenous and drug-specific safety biomarkers (eg, renal function or acetaminophen-protein adducts-a validated acetaminophen liver injury marker) measured across sufficient time are needed to standardize drug safety evaluations in pediatric research. Without comprehensive safety data over longer periods of time, it is essential to reiterate that similar AE frequency across groups is not necessarily evidence of safety.Finally, antipyretic medications are one of the most common medications associated with medication errors and overdose at home. Different medication concentrations and variable measurements tools complicate safe medication administration in the home. Dual and alternating regimens are more complicated and may increase the risk of errors given that acetaminophen can be given every four to six hours, and ibuprofen every eight hours. The AAP Clinical Report on Preventing Medication Errors provides valuable insight.9 Any recommendation for antipyretic therapy should come with detailed instruction and teach-back of medication dosing and time intervals. Teach-back is an essential tool in which caregivers explain the instructions in their own words, thereby demonstrating understanding and ensuring closed-loop communication. Proper handling and storage of antipyretics in the home is necessary to avoid unsupervised ingestion.Many questions remain:...
Journals & Publications
Commentary: Fever Is Your Friend
Pediatrics In Review
December 1, 2023
Fever, the theme of our 3 patient cases, is often looked on as a disease in itself, a misconception we have helped foster by the language we use: scarlet and yellow fevers, typhoid and Rocky Mountain spotted fevers, also rheumatic, hay, dengue, cat-scratch, and rat-bite fevers. Reinforcing this impression of fever as a disease, rather than as a symptom or sign of an underlying illness, contributes to parents' fear of fever and their frequent compulsion to treat it.An element of the human inflammatory response, fever in contrast to hyperthermia rarely threatens a child's well-being. Given that it is an energy-consuming process, metabolically costly, fever almost certainly has a protective effect or it would not have persisted through its long evolutionary history. A controlled rise in the body's temperature mediated by the anterior hypothalamus, fever is a reaction to any insult that sets off the body's inflammatory response. Akin to a thermostat, the hypothalamic set point regulates body temperature. Some inciting factor, a viral infection most often in children, stimulates the release of cytokines that act as pyrogens, which increase levels of prostaglandin E2 at the anterior hypothalamus, causing a rise in the set point. With actual body temperature lower than the new set point, the patient at the onset of fever feels chilled and the body's response is to shiver, generating more internal heat, and to vasoconstrict at the skin and close down sweat glands, reducing heat loss: in effect, a controlled turning up the furnace and shutting the windows.Hyperthermia is fundamentally different from fever. An unregulated rise in temperature above the set point, it can result from the body producing too much heat (thyroid storm), from the inability to disperse heat (an overbundled baby), or from a combination of both (inappropriate exertion on a hot, humid day). Instead of the chill accompanying the onset of fever, the body experiences intense flushing as blood vessels dilate and sweat glands go into overdrive to shed heat to the environment: the opposite of fever, the furnace is heating out of control and the windows are thrown wide open.Evidenced by the epidemic of heat stroke during this past summer's heat waves, hyperthermia can send body temperature dangerously high. But fever, a homeostatic process, is kept within physiologic limits, rarely rising above 106°F (41.1°C): a counter-acting element of the febrile response is the release of cryogens that check the effect of pyrogens as fever rises. In fact, only approximately 0.05% of pediatric emergency patients present with a temperature higher than 106°F (>41°C). And although it seems intuitive that the higher a child's fever the more likely is a serious bacterial infection, even at high temperatures a viral source is far more common. Temperature itself becomes dangerous only when it reaches 107°F or higher (≥41.7°C), in which case the underlying fever is likely to be exacerbated by a component of hyperthermia, often dehydration.Fever, it turns out, has a long history widespread among animals as a protective response. When they become infected, some fish and lizards, which are cold-blooded, seek out a warmer environment where their body temperatures rise, in effect an induced fever. This behavior has been shown to confer a survival benefit that can be reversed by the administration of antipyretic agents. Fever inhibits the growth of many viruses and bacteria, and hinders the absorption of iron, without which many pathogenic bacteria cannot survive. It promotes the activity of neutrophils and the production of superoxides, and it enhances the proliferation of T cells and the action of interferon. As a metabolically costly phenomenon that increases the expenditure of energy by 7% to 10% for each rise in temperature of approximately 2°F (-1.12°C), fever's long and widespread endurance argues for it as a protective process with survival benefit.Why then are we, both parents and pediatricians, so adamant about treating fever? Barton Schmitt coined the term fever phobia in his study reporting parents' overwhelming confusion about fever, their pervasive beliefs that it is harmful, can cause brain damage, and can rise to 110°F (43.3°C) or higher if not treated. Not surprising, then, that most parents worried 'lots' about fever, considered it high even at less than 102°F (<39°C), and treated even temperatures in the normal range with antipyretic agents. Frequently, parents cited doctors and nurses as their primary source of knowledge about fever, an assertion made credible by a survey of AAP members in Massachusetts, two-thirds of whom regularly suggested treating fevers less than 102°F (<39°C) because they can themselves be dangerous, and one-quarter of whom believed that a fever of 104°F (40°C) could cause brain damage and even death (Pediatrics. 1992;90:851-854).A temperature of 100.4°F (38°C) or greater is usually cited as signifying a fever. But as with any physiologic measure, the limit of normal is not defined by a single temperature but by a range of values that account for individual variations, fluctuations by time of day, and differences related to age as well as to how and where the temperature is taken. Body temperature varies throughout the day, being higher late in the afternoon and early in the evening than in the morning or at night. Infants have higher body temperature than older children and adults. Rectal temperature is the closest to core temperature, defined as blood's temperature in the pulmonary artery, but aside from the discomfort that limits its use in many children it can be inaccurate because of improper technique or the presence of stool. As a rule, oral temperature is approximately 1°F (-0.56°C) less than rectal temperature, but this difference varies from person to person, and its precision relies on the cooperation of the patient; recent intake of cold or hot liquids or foods can also affect its accuracy, as can tachypnea in an anxious child. Axillary temperature, although easy and convenient to take, does not have a reliable correlation with rectal temperature so can be difficult to interpret. Infrared thermometers, despite their convenience, do have limitations. Faulty placement in the ear canal and the presence of ear wax can limit the reliability of tympanic thermometers, and forehead thermometer readings can be affected by ambient conditions such as direct sunlight, cold room temperature, or sweaty skin. Least dependable are so-called fever strips and pacifier thermometers.The management of fever should begin before the child is febrile. In giving anticipatory advice, we pediatricians should acknowledge our role in generating fever phobia. When we recommend the routine use of antipyretics for any rise in temperature, we undermine our reassurance to parents that they need not worry about the fever itself. And that reassurance is less likely to be accepted when their child is febrile than as part of routine counseling: fever is actually a protective process, not in itself a threat that without treatment can climb to frightening heights; sensible care means simple measures such as adequate hydration, attention to ambient room temperature, and avoiding overbundling. Our message should be that it is the underlying illness, not the fever, that may put their child in jeopardy, and we need to teach about the symptoms and behaviors that should trigger concern and signal the need for professional involvement.When the illness underlying a fever puts a child at risk, clearly it must be treated; but how to deal with the fever, beyond attention to hydration and ambient conditions, is a question of judgment. Intervening to make a child more comfortable is certainly appropriate, and the decision to give an antipyretic should not be based on a specific temperature but rather on how the child looks and behaves: for many children, a fever of 104°F (40°C) or even higher is tolerated without ill effect, whereas others become droopy and upset when their temperature barely reaches the threshold of fever. Another reason often given for treating a fever is that lowering the temperature helps separate children with trivial illness from those with serious infections. In reality, how a febrile child responds to a dose of antipyretic drug does not reliably distinguish dangerous from nonthreatening disease. A healthy child with a transitory viral illness is not endangered by a fever, but a child with an underlying chronic illness or a serious acute infection may not deal well with the metabolic stress that fever can impose: tachycardia and tachypnea, as well as higher oxygen consumption and greater insensible water losses, can compromise a child who is anemic, septic, or in shock, or who is at special risk from a disease that strains homeostasis.Aside from antipyretic medication, another common approach to treating fever is physical cooling. Acetaminophen and nonsteroidal anti-inflammatory drugs are effective antipyretics because they inhibit the production of prostaglandin E2, which then lowers the hypothalamic set point back toward normal, turning off the stimulus for the body to generate heat. In contrast, physical measures such as cool baths or sponging do not affect the set point, which remains high. Instead, they draw heat from the body: rather than turning the furnace off, these measures open the windows wide. The hypothalamus detects a widening gap between its high set point and the body's lowering temperature, with the paradoxical effect that it responds by raising the set point still higher. Once the bath or sponging is done, the stimulus remains to produce more heat by raising the metabolic rate and causing muscles to shiver, which may cause the child discomfort and lead to a rebound in the fever. Physical cooling can have an appropriate role in the management of fever when the triggering illness makes the child dangerously vulnerable to the metabolic stress resulting from the rise in temperature. In such a case, the combination of cooling with an antipyretic brings the fever down quickly while also lowering the set point to prevent a rebound rise in temperature.A difficult issue is the role of antipyretic drugs in preventing febrile seizures, which are most common in children 6 months to 6 years of age, the same age group to most often have benign viral infections. Advising parents routinely to treat the fever of these self-limited illnesses to preve...
Journals & PublicationsFeverBody Temperature

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