Fever in infants and children: Pathophysiology and management

INTRODUCTION — Fever is an abnormal elevation of body temperature that occurs as part of a specific biologic response that is mediated and controlled by the central nervous system.

The pathophysiology and treatment of fever in infants and children will be reviewed here. Other causes of elevated body temperature in children and the evaluation and management of fever in specific populations of infants and children are discussed separately:

●(See "Heat stroke in children" and "Heat illness (other than heat stroke) in children".)

●(See "The febrile infant (29 to 90 days of age): Outpatient evaluation" and "Fever without a source in children 3 to 36 months of age: Evaluation and management".)

●(See "Evaluation and management of fever in children and adults with sickle cell disease".)

●(See "Fever of unknown origin in children: Etiology" and "Fever of unknown origin in children: Evaluation".)

●(See "Evaluation of children with non-chemotherapy-induced neutropenia and fever" and "Management of children with non-chemotherapy-induced neutropenia and fever".)

●(See "Fever in children with chemotherapy-induced neutropenia".)

TEMPERATURE MEASUREMENT

Site and method of measurement — The most common sites of temperature measurement in clinical practice are the rectum, mouth, and axilla; in addition, parents and caregivers may measure temperature at the tympanic membrane or forehead (temporal artery). Each of these sites has its own range of normal values [1].

●Rectal thermometry – Rectal thermometry is generally considered the reference standard for measurement of core body temperature [2], but there is a lag between changes in core body temperature and temperature in the rectal vault [3]. Rectal thermometry is usually performed in infants and young children if the result has clinical implications. The majority of studies establishing the risk of serious infections in febrile infants and young children have relied on rectal temperatures. Rectal thermometry is contraindicated in patients with neutropenia.

●Oral thermometry – Oral thermometry generally is preferred in children who are old enough to cooperate. Oral temperature is typically 0.6°C (1.0°F) lower than rectal temperature because of mouth breathing, which is particularly important in patients with tachypnea. Oral temperatures also may be affected by recent ingestion of hot or cold liquids [1,4].

Opinions differ about the best site of temperature measurement for young children who cannot cooperate with oral thermometry. The Bright Futures Guidelines for Health Supervision suggest rectal thermometry for children younger than four years of age [5]. In contrast, the National Institute for Health and Care Excellence recommends electronic axillary thermometry for children younger than four weeks, and axillary (electronic or chemical dot) or infrared tympanic membrane (TM) thermometry for children four weeks to five years of age because these methods are quicker, easier to use, and better accepted by children and their caregivers [6].

●Axillary thermometry – Axillary temperature is consistently lower than rectal temperature, but the absolute difference varies too widely for a standard conversion [7]. Axillary temperatures may be measured in neutropenic patients who are unable to use an oral thermometer.

●Contact and noncontact infrared thermometry – Infrared TM thermometers measure the amount of heat produced by the TM. Temperature readings are close to core temperature, although the infrared TM reflective devices commonly used in homes, hospitals, and offices are less accurate than TM thermistors used in research and by anesthesiologists [3,8-12]. Individual studies comparing TM and rectal temperatures in children have had contradictory results. Although newer-generation infrared TM thermometers appear to have improved accuracy compared with older models (using rectal thermometry as the standard) [13], results should be verified in situations where detection of fever has clinical implications (eg, laboratory evaluation of the febrile neonate or young infant) [2].

Infrared contact and noncontact forehead thermometers measure the amount of heat produced by the temporal arteries. The accuracy of such measurements may be affected by sweating or vascular changes [1]. As with tympanic temperature measurement, studies comparing temporal artery and rectal temperatures have contradictory results, and temporal artery temperatures should not be used to make clinical decisions [2,3,14-26]. Readings may be greater or lower than rectal temperature.

●Smart phones – Apps for smart phones that permit tracking of fever are available. They require an external sensor, with accuracy commensurate with that of the sensor. In the absence of adequate study, they cannot be recommended for use.

Converting between Fahrenheit and Celsius — Fahrenheit and Celsius temperature equivalents are provided in the table (table 1) or can be calculated (calculator 1).

●To convert a temperature measured in Fahrenheit to Celsius:

●To convert a temperature measured in Celsius to Fahrenheit:

TEMPERATURE HOMEOSTASIS — Body temperature is controlled by the thermoregulatory center of the hypothalamus. The thermoregulatory center balances heat production, derived primarily from metabolic activity in muscle and the liver, with heat dissipation from the skin and lungs. The thermoregulatory center is able to maintain a fairly steady body temperature in normal temperature environments. However, at environmental temperatures higher than approximately 35°C (95°F), the body's ability to dissipate heat is overwhelmed, and core temperature rises. (See "Heat stroke in children", section on 'Pathophysiology'.)

NORMAL BODY TEMPERATURE — The mean normal temperature is generally considered to be 37°C (98.6°F) [27]. This value usually is attributed to studies dating to the 19^th century. In a more recent study of young adults, the upper limit of normal body temperature (measured orally) was 37.2°C (98.9°F) in the morning and 37.7°C (99.9°F) overall [28]. Normal body temperature varies with age, time of the day, level of activity, and phase of the menstrual cycle, among other factors [1,4].

Infants and young children generally have higher temperatures than older children and adults. This relates to the greater surface-area-to-body-weight ratio and the higher metabolic rate of infants and small children. In the newborn period (age 0 to 28 days), the mean normal temperature (measured rectally) is 37.5°C, with an upper limit of normal (ie, two standard deviations above the mean) of 38°C (100.4°F) [29].

Normal temperature varies daily, with a morning nadir and late afternoon/early evening peak. The mean amplitude of variation is 0.5°C (0.9°F) [28]. During a febrile illness, daily low and high temperature readings are maintained, but at higher-than-normal levels. Daily variation can be as high as 1°C (1.8°F) in some individuals recovering from a febrile illness.

ELEVATED BODY TEMPERATURE — Elevated body temperature may result from fever (increased body temperature with elevated hypothalamic set-point) or hyperthermia (increased body temperature with normal hypothalamic set-point) (figure 1). It is important to differentiate between these conditions because they have different clinical implications and management strategies. (See 'Management of fever' below and "Heat stroke in children", section on 'Hospital management'.)

Fever — Fever is an abnormal elevation of body temperature that occurs as part of a specific biologic response that is mediated and controlled by the central nervous system. (See 'Pathogenesis' below.)

The temperature elevation that is considered "abnormal" depends upon the age of the child and the site of measurement. The temperature elevation that may prompt clinical investigation for infection depends upon the age of the child and the clinical circumstances (eg, immune deficiency, sickle cell disease, ill-appearance, etc); in most scenarios, the height of the fever is less important than other signs of serious illness (eg, irritability, meningismus) [30-33].

●In the otherwise healthy infant younger than three months of age, fever of concern generally is defined by rectal temperature ≥38.0°C (100.4°F). (See "The febrile infant (younger than 90 days of age): Definition of fever", section on 'Definition of fever'.)

●In children 3 to 36 months, fever generally is defined by rectal temperatures ranging from ≥38.0 to 39.0°C (100.4 to 102.2°F) and fever of concern by rectal temperatures ≥39.0°C (102.2°F) if there is no focus of infection on examination. (See "Fever without a source in children 3 to 36 months of age: Evaluation and management", section on 'Fever of concern'.)

●In older children and adults, fever may be defined by oral temperatures ranging from ≥37.8 to 39.4°C (100.0 to 103.0°F) and fever of concern by oral temperatures ≥39.5°C (103.1°F).

●The temperature thresholds of concern for children with underlying conditions (eg, sickle cell disease, neutropenia) are discussed separately:

•Sickle cell disease (see "Evaluation and management of fever in children and adults with sickle cell disease")

•Neutropenia (see "Fever in children with chemotherapy-induced neutropenia" and "Management of children with non-chemotherapy-induced neutropenia and fever", section on 'Definitions')

Pathogenesis — Fever is the result of a highly coordinated series of events that begins peripherally with the synthesis and release of interleukin (IL)-1, IL-6, tumor necrosis factor, interferon-alpha, and other endogenous pyrogenic cytokines by phagocytic cells in the blood or tissues (figure 2) [34]. These cytokines enter the blood and are carried to the anterior hypothalamus, where they induce an abrupt increase in the synthesis of prostaglandins, especially prostaglandin E2 (PGE2). The induction of PGE2 in the brain raises the hypothalamic set-point for body temperature (figure 1).

After the set-point is raised, the thermoregulatory center recognizes current body temperature to be too low and initiates a series of events to raise body temperature to the new set-point. This involves augmentation of heat production by increased metabolic rate and increased muscle tone and activity, and decreased heat loss through diminished perfusion of the skin. Body temperature rises until a new equilibrium is achieved at the elevated set-point. The upper limit of temperature due to fever appears to be 42°C (107.6°F), but it is unusual for temperature to exceed 41°C (106°F) without some element of concomitant hyperthermia [1,35,36].

In addition to causing fever, pyrogenic cytokines increase the synthesis of acute-phase proteins by the liver, decrease serum iron and zinc levels, provoke leukocytosis, and accelerate skeletal muscle proteolysis. IL-1 also induces slow-wave sleep, perhaps explaining the somnolence frequently associated with febrile illnesses. The increase in peripheral PGE2 may account for the myalgias and arthralgias that often accompany fever. Increased heart rate is a normal physiologic response to fever.

Benefits and harms — Whether fever is beneficial or harmful is disputed [36]. Fever is an integral part of the inflammatory response and, as such, may have a role in fighting infection. However, defense mechanisms can go awry. Even if fever does have a role in defending the host against infection, it may still be that, in some circumstances, fever does more harm than good [37,38].

●Potential benefits – Potential benefits of fever include retardation of the growth and reproduction of some bacteria and viruses (perhaps related to decreased serum iron) and enhanced immunologic function at moderately elevated temperatures (although some of the benefits are reversed at temperatures approaching 40°C [104°F]) [36,39-45]. Some animal studies have demonstrated enhanced survival with fever [46,47]. However, as with immune function, the benefits may be diminished or even reversed as temperature increases [47,48]. Whether these findings apply to humans is not known.

●Potential harms – Fever can make patients uncomfortable. It is associated with increased metabolic rate, oxygen consumption, carbon dioxide production, and demands on the cardiovascular and pulmonary systems. For the normal child, these stresses are of little or no consequence. However, for the child in shock or for the child with a pulmonary or cardiac abnormality, the increased demands can be detrimental and may offset any immunologic benefit from the fever.

In experimental studies, fever has been associated with impaired immunologic responses (eg, phagocytosis of staphylococci and lymphocyte transformation in response to mitogens) and cerebral injury (including edema and hemorrhage) [49-51]. Whether these findings apply to humans is not known.

There is no evidence to suggest that fever ≥40°C (104°F) is associated with increased risk of adverse outcome (eg, brain damage), although this belief is held by many caregivers and clinicians [39,52,53].

Hyperthermia — Hyperthermia is an abnormal elevation of body temperature that occurs without a change in the thermoregulatory set point in the hypothalamus (figure 1). This failure of normal homeostasis results in heat production that exceeds the body's capacity for dissipation [39]. Body temperature in patients with hyperthermia does not respond to antipyretic agents.

Characteristic clinical features of hyperthermia include a history of environmental heat exposure or use of drugs that interfere with normal thermoregulation (eg, anticholinergics); hot, dry skin; and central nervous system dysfunction (eg, delirium, convulsions, coma). Hyperthermia can be rapidly fatal; adverse physiologic effects begin to occur at temperatures >41°C (105.8°F). (See "Heat stroke in children", section on 'Clinical features' and "Heat illness (other than heat stroke) in children", section on 'Clinical manifestations and treatment'.)

EVALUATION OF FEVER — Fever is a sign of underlying disease, the cause of which should be evaluated, particularly if the child is ill-appearing or the fever persists. The response of fever to an antipyretic agent does not help to distinguish bacterial from viral infection [54-56]. When determining whether the child needs to be seen by a health care provider, caregivers' concern about their child's appearance is more important than the response of fever to antipyretic agent(s). In most cases, the febrile child has additional symptoms and signs of an acute infection, which can be managed as indicated. However, in some children, particularly children with underlying disease, fever may be a sign of a more serious or even life-threatening process.

The evaluation of fever in specific populations of children is discussed separately:

●(See "The febrile infant (29 to 90 days of age): Outpatient evaluation" and "Fever without a source in children 3 to 36 months of age: Evaluation and management".)

●(See "Fever of unknown origin in children: Etiology" and "Fever of unknown origin in children: Evaluation".)

●(See "Evaluation and management of fever in children and adults with sickle cell disease".)

●(See "Evaluation of children with non-chemotherapy-induced neutropenia and fever" and "Evaluation of children with non-chemotherapy-induced neutropenia and fever", section on 'Evaluation'.)

●(See "Fever in children with chemotherapy-induced neutropenia".)

MANAGEMENT OF FEVER — Fever is an important clinical sign. The first step in the management of fever is to determine its cause (see 'Evaluation of fever' above). Once the cause is known, the main reason to treat fever is to improve the child's comfort [39,57].

Anticipatory guidance — Patients, parents, and other caregivers frequently make the decision to treat fever without consulting a health care provider. Many patients and caregivers believe that fever is harmful and that temperature elevation requires treatment regardless of its cause or effects [52,58-60]. Education of patients, parents, and caregivers is required to counter these beliefs [4,36,39]. Such education should be provided at health supervision visits and reinforced during acute visits for acute febrile illnesses. A systematic review of eight studies evaluating anticipatory guidance for fever and common infections concluded that educational interventions provided before the illness episodes had the potential to improve medication management and parental health care-seeking behavior when the child became ill [61].

Important components of the anticipatory guidance for fever include [4,6,36,39,54-56]:

●Fever is not an illness but a physiologic response.

●In otherwise healthy children, most fevers are self-limited and benign, provided that the cause is known and fluid loss is replaced; fever does not cause brain damage. If there are signs of serious illness, a health care provider should be consulted.

●There is no evidence that fever makes the illness worse.

●Initial measures to reduce the child's temperature include provision of extra fluids and reduced activity.

●Fever may merit treatment with an antipyretic agent if the child is uncomfortable (as indicated by decreased activity level, decreased fluid intake, etc).

●Decreased temperature after receiving an antipyretic agent does not help to determine whether the child has a bacterial or viral infection.

●Children who are receiving treatment for fever do not need to be awakened to receive the antipyretic agent.

●Children who are receiving antipyretic medications should not be given combination cough and cold preparations, which often contain antipyretic medications; giving both medications may lead to inadvertent overdose.

●Antipyretic medications should be dosed according to weight, rather than age. When suggesting the use of antipyretic medications, the risk of under- or overdosing antipyretics can be minimized if the clinician provides written dosing instructions and a measuring device, such as a properly marked syringe (for liquid formulations); the dosing directions and measuring devices that are included with over-the-counter medications are variable and inconsistent [62]. The instructions should include which formulation (or which concentration of a liquid formulation); how to measure the appropriate volume (for liquid formulation); how often to administer; how to monitor the response; when to discontinue; and when to contact the health care provider.

●Instructions for safe storage of antipyretic medications.

Antipyretic agents — Antipyretic agents treat fever by restoring the thermoregulatory set-point to normal. The most commonly used antipyretic agents in children and adolescents are acetaminophen and ibuprofen. Aspirin should not be used because of its association with Reye syndrome [39].

Indications — Routine treatment of fever in otherwise normal children is not warranted [1,6]. Decisions regarding the treatment of fever in children should be made on a case-by-case basis depending upon the clinical circumstances (eg, underlying disease, level of discomfort, desire to monitor fever curve).

There is no evidence that reducing fever reduces the morbidity or mortality from a febrile illness (with the possible exception of children with underlying conditions that limit the ability to tolerate increased metabolic demands). The role of antipyretic therapy in recurrence of febrile seizures is discussed separately. (See "Treatment and prognosis of febrile seizures", section on 'Antipyretics'.)

Potential benefits of treating fever with antipyretics include improvement of discomfort and decrease in insensible water loss, which may decrease the risk of dehydration [39]. Antipyretic agents also have analgesic effects, which may enhance their overall effect. Potential downsides of treating fever include delayed identification of an underlying illness and drug toxicity; it is uncertain whether treating fever increases the risk for or complications of certain types of infections. (See 'Benefits and harms' above.)

Indications for the short-term treatment of fever may include [1,36]:

●Shock

●Underlying neurologic or cardiopulmonary disease, or other condition with increased metabolic rate (eg, burn, postoperative state)

●Alteration in fluid and electrolyte balance

●High fever (ie, ≥40°C [104°F])

●Discomfort

●Major head trauma

●Postcardiac arrest

Children with temperature elevation and the possibility of hyperthermia also require treatment, but the treatment of hyperthermia differs from that of fever. Antipyretic medications are ineffective in children with heat stroke and may exacerbate concomitant liver injury or coagulopathy. (See "Heat stroke in children", section on 'Hospital management' and "Heat illness (other than heat stroke) in children", section on 'Clinical manifestations and treatment'.)

Suggested approach — The choice of antipyretic agent for children with underlying medical conditions may be influenced by the underlying medical conditions (eg, avoidance of acetaminophen in children with liver failure) or desire to avoid drug interactions with chronic medications (eg, selective serotonin reuptake inhibitors may enhance the antiplatelet effect of ibuprofen).

When antipyretic therapy is indicated for children without underlying medical conditions, or with underlying medical conditions that do not influence the choice of antipyretic, we suggest beginning treatment with oral acetaminophen. Oral ibuprofen is an alternative to acetaminophen, particularly if anti-inflammatory effect is desired in addition to antipyresis. Patient/caregiver preference is a major factor in the choice of antipyretic because patients/caregivers frequently make the decision to treat fever without consulting a health care provider. In randomized trials, acetaminophen and ibuprofen are more effective than placebo in reducing temperature; ibuprofen is slightly more effective and longer-lasting than acetaminophen [63,64]. However, we prefer acetaminophen because of its long track record of safety with therapeutic dosing [1]. (See 'Acetaminophen' below and 'Ibuprofen' below.)

We do not suggest combining or alternating acetaminophen with ibuprofen because of the potential for dosing confusion, increased toxicity, and contribution to fever phobia [39,57,65,66]. Although combining or alternating acetaminophen and ibuprofen may be more effective than either agent alone in reducing fever, it is not clear that this temperature reduction is clinically significant [67,68]. In addition, there is little information about the effects on the child's discomfort or the safety of combining or alternating antipyretic therapy, and there are theoretic concerns of liver or kidney injury, particularly for children with volume depletion [67,69-71]. (See 'Combining or alternating therapy' below.)

If the temperature remains elevated and the child's discomfort is not improved three to four hours after administration of acetaminophen or ibuprofen, it is reasonable to switch from acetaminophen to ibuprofen or ibuprofen to acetaminophen [6]. (See 'Treatment response' below.)

Antipyretic regimens

Acetaminophen — For most children with fever who are treated with an antipyretic agent, we suggest oral acetaminophen because of its long track record of safety at therapeutic doses [1]. Although oral acetaminophen is preferred to rectal acetaminophen because the drug concentration is more predictable, short-term (ie, <48 hours) rectal administration is an option for children who cannot take acetaminophen orally [72].

Acetaminophen generally is not recommended for infants younger than three months of age without prior consultation with a health care provider because fever may be the only sign of serious infection in such infants. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Invasive bacterial infection' and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Invasive bacterial infection'.)

The dose of acetaminophen is 10 to 15 mg/kg per dose (maximum dose 1 g) orally every four to six hours (with no more than five doses in a 24-hour period) with a maximum daily dose of 75 mg/kg per day up to 4 g/day (some formulations suggest a lower maximum daily dose). We do not recommend a "loading dose" (eg, an initial dose of 30 mg/kg) of acetaminophen for routine clinical care because it may increase the risk of dosing confusion [39].

Approximately 80 percent of febrile children who are treated with acetaminophen have a reduction in temperature of 1 to 2°C (1.8 to 3.6°F) [39,73]. Acetaminophen begins to work in 30 to 60 minutes and has its peak effect in three to four hours. The duration of action is four to six hours.

When administered at appropriate doses, acetaminophen is remarkably free of side effects [74,75]. In August 2013, the US Food and Drug Administration (FDA) issued a safety communication about serious and potentially fatal acetaminophen-associated skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis that can occur with the first exposure to acetaminophen or at any time during use [76]. These reactions are rare (the FDA review found a total of only 107 cases between 1969 and 2012) and can occur with other antipyretic agents. Children who develop skin lesions while using acetaminophen should discontinue acetaminophen and seek prompt medical attention. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis" and "Acute generalized exanthematous pustulosis (AGEP)".)

An association between acetaminophen and asthma has been described, but causality has not been demonstrated. (See "Risk factors for asthma", section on 'Acetaminophen'.)

Overdose of acetaminophen may be lethal. Overdose may occur if acetaminophen is administered simultaneously with combination cough and cold remedies that contain acetaminophen, with unsupervised ingestion, and with unclear instructions for administration [39,77]. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Epidemiology'.)

Ibuprofen — For children ≥6 months of age in whom antipyretic and anti-inflammatory activity are desired (eg, in children with juvenile arthritis) and who are well hydrated, we suggest oral ibuprofen as the initial antipyretic agent [1].

The dose of ibuprofen is 10 mg/kg per dose (maximum dose 600 mg) orally every six hours with a maximum daily dose of 40 mg/kg up to 2.4 g/day [39]. Ibuprofen begins to work in <60 minutes and has its peak effect (decline in temperature of 1 to 2°C [1.8 to 3.6°F]) in three to four hours. The duration of action is six to eight hours [39,73].

Ibuprofen generally is not recommended for infants <3 months of age without prior consultation with a health care provider because fever may be the only sign of serious infection in such infants. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Invasive bacterial infection' and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Invasive bacterial infection'.)

Recommendations for ibuprofen in infants between three and six months of age vary geographically [78]. In the United States, ibuprofen suspension is approved for antipyresis in infants ≥6 months of age. In other countries, it may be approved for infants ≥3 months of age who weigh ≥5 kg. Infants <6 months of age are potentially at increased risk for renal toxicity because they have limited renal function relative to older infants and children [39]. Few studies have directly evaluated the risk of renal toxicity when ibuprofen is used to treat fever in infants <6 months of age, and the magnitude of risk is uncertain [63,78-82].

Adverse effects of ibuprofen may include gastritis and gastrointestinal bleeding [83]. When administered at appropriate doses and taken with food, ibuprofen usually is safe [75,84]. However, acute kidney injury has been reported following appropriate doses of ibuprofen [85]. Anecdotal reports have linked nonsteroidal anti-inflammatory drugs with the development or more rapid progression of necrotizing fasciitis due to group A streptococci in children with varicella [86,87]. However, a review of the literature, including five prospective studies, did not demonstrate a correlation [88].

Overdose may occur if ibuprofen is administered simultaneously with combination cough and cold remedies that contain ibuprofen, with unsupervised ingestion, and unclear instruction for administration [39]. Overdose of ibuprofen appears more easily managed than overdose of acetaminophen [89]. (See "Nonsteroidal antiinflammatory drug (NSAID) poisoning", section on 'Pediatrics'.)

Combining or alternating therapy — We do not suggest combining or alternating therapy with acetaminophen and ibuprofen to treat fever in children. Although combining or alternating acetaminophen and ibuprofen may be more effective than either agent alone in reducing fever, it is not clear that this reduction is clinically significant [67,68]. In addition, there is little information about the effects on the child's discomfort or the safety of combining or alternating antipyretic therapy, and there are theoretic concerns of liver or kidney injury, particularly for children with volume depletion [67,69-71].

A 2013 systematic review included six randomized trials (915 patients) evaluating combination or alternating versus single agent antipyretic therapy in children [67]. The individual trials used different thresholds for fever, sites of temperature measurement (eg, rectal, axillary), dosing regimens, and periods of observation for outcome assessment [68,80,90-94].

●In pooled analysis, combination therapy resulted in decreased mean temperature one hour after treatment (mean difference -0.27°C [-0.48°F], 95% CI -0.45 to -0.08°C [-0.81°F to -0.14°F]; two trials, 163 patients) and four hours after treatment (mean difference -0.70°C [-1.26°F], 95% CI -1.05 to -0.35°C [-1.89°F to -0.63°F]; two trials, 173 patients) although the mean temperature in the single-agent group one and four hours after treatment was <38°C (100.4°F) [67]. Fewer children receiving combination therapy remained or became febrile four hours after treatment (2 versus 23 percent; risk ratio [RR] 0.08, 95% CI, 0.02-0.42; two trials, 196 patients).

In pooled analysis, alternating therapy was associated with decreased mean temperature one hour after the second agent (mean difference -0.60°C [-1.08°F], 95% CI -0.94 to -0.26°C [-1.69°F to -0.47°F]; two trials, 78 patients) although the mean temperature in the single-agent group was ≤38°C (100.4°F) [67]. Fewer children receiving alternating therapy remained or became febrile three hours after the second agent (11 versus 45 percent; RR 0.25, 95% CI 0.11-0.55; two trials, 109 patients).

One trial compared combination with alternating therapy and found no difference in mean temperature reduction or proportion of children who remained or became febrile [94].

●Among the trials that assessed measures other than temperature, one found no difference in child discomfort between combination and single-agent therapy [93]; one found that caregivers perceived no difference in efficacy despite greater temperature reduction with alternating therapy [68]; and one found that children who received alternating antipyretic therapy had lower scores on a pain checklist than those who received single agent therapy, although it was not clear that the assigned antipyretic regimens were followed appropriately (children assigned to the alternating group received a lower mean number of doses of antipyretic than those assigned to single-agent therapy), making the results difficult to interpret [91].

●No serious adverse events were observed in the trials that reported serious adverse events of combining or alternating therapy [68,91-93]. In one trial, mild, transient elevation of liver enzymes and mildly abnormal renal function occurred in 1.7 and 3 percent of participants, respectively, but did not differ between groups [91].

The American Academy of Pediatrics (AAP) clinical report on fever and antipyretic use in children suggests that combined treatment with acetaminophen and ibuprofen may increase the possibility of inaccurate dosing and may contribute to "fever phobia" [39]. Similarly, the Italian Pediatric Society guidelines for the management of fever in children recommend against the combined use of acetaminophen and ibuprofen [57]. The National Institute for Health and Care Excellence advises against the simultaneous use of acetaminophen and ibuprofen and suggests that alternating these agents be considered only if the child's distress or discomfort persists or recurs before the next dose is due [6]. If the decision is made to use combined or alternating therapy, dosing instructions and intervals must be thoroughly explained. (See 'Anticipatory guidance' above.)

Duration — The duration of administration of antipyretic therapy depends upon the child's response; the end-point is the child's comfort [39]. Prolonged use of antipyretic agents generally is not necessary because most febrile illnesses in children are self-limited viral infections. Re-evaluation for secondary bacterial infection may be warranted in children whose fever and discomfort persist for more than two to three days.

Treatment response — Treatment with antipyretic agents should make the febrile child more comfortable. It is more important for caregivers to monitor the child's general appearance (for signs of serious illness such as lethargy, stiff neck, altered mental status, petechial or purpuric rash, etc), activity level, and fluid intake than to monitor the temperature curve and to seek medical care if they are concerned about their child's appearance. With either acetaminophen or ibuprofen, a response should be seen within 60 minutes; the response peaks in three to four hours [39]. If the temperature remains elevated and the child's discomfort is not improved three to four hours after administration of acetaminophen or ibuprofen, some experts would suggest switching from acetaminophen to ibuprofen or ibuprofen to acetaminophen [6]. There are no published studies to evaluate the safety or efficacy of this practice; however, in theory, some fevers may respond better to one antipyretic agent than another.

Persistence of a febrile illness beyond four or five days, a marked increase in the height of the maximum fever during the course of the illness, or the development of new localizing symptoms should raise concerns about alternative diagnoses or bacterial superinfection, which should be evaluated by a health care provider (or re-evaluated by a health care provider if the child was seen at the onset of illness) [39].

Use in young infants — The AAP clinical report on fever and antipyretic use in children suggests that acetaminophen not be administered to infants younger than three months and that ibuprofen not be administered to children younger than six months without evaluation by a clinician [39]. Fever may be the only sign of serious infection in a young infant, and such infections should be excluded before symptomatic treatment of fever is initiated. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Invasive bacterial infection' and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Invasive bacterial infection'.)

Decisions regarding the use of acetaminophen in infants younger than three months after serious infection has been excluded should be made on a case-by-case basis. The safety of acetaminophen in young infants can be extrapolated from its use as an analgesic in this population (see "Management and prevention of pain in neonates"). However, there is little information about its efficacy as an antipyretic.

External cooling — External cooling is the treatment of choice for heat stroke and other forms of heat illness in which rapid cooling is necessary to prevent end-organ damage. (See "Heat stroke in children", section on 'Rapid cooling' and "Heat illness (other than heat stroke) in children", section on 'Clinical manifestations and treatment'.)

We do not routinely suggest external cooling for temperature reduction in previously well infants and children with a febrile illness. In randomized trials comparing the combination of tepid sponging and antipyretic therapy to antipyretic therapy alone, the added benefit of tepid sponging in temperature reduction was short-lived, and sponging was associated with increased discomfort [95-97].

External cooling may be used as an adjunct to antipyretic therapy for children in whom more rapid and greater reduction of body temperature is necessary than can be achieved with antipyretic agents alone. In such cases, antipyretic agents should be administered at least 30 minutes before external cooling [4]. Antipyretic agents are necessary to reset the thermoregulatory set-point, without which external cooling will result in an increase in heat production [1].

Possible indications for concomitant antipyretic administration and mechanical cooling in children include:

●Uncertainty about the cause of elevated temperature (heat illness versus fever) (see 'Hyperthermia' above)

●Fever combined with a component of heat illness (eg, from over-wrapping, hypovolemia, or drugs such as atropine)

●Underlying neurologic disorder, in which the child may have abnormal temperature control and poor response to antipyretic agents

When mechanical cooling is necessary to treat fever, we suggest sponging with comfortably warm or tepid water (generally around 30°C [85°F]). Sponging is more effective than immersion because evaporation from the skin augments heat loss. Although temperature reduction may be faster with cold water, sponging with cold water is also more uncomfortable. Alcohol should not be used because its fumes are absorbed across the alveolar membrane and possibly across the skin, resulting in central nervous system toxicity [98].

Cooling blankets can be useful in hospitalized children who are critically ill or who have problems with temperature control (eg, children with acute head injury).

Alternative therapies — Practitioners of complementary and alternative therapy may suggest a number of remedies for fever in infants and children (eg, calcium lactate). These remedies have not been studied in clinical trials, and there is little to no information about their efficacy or safety. We do not recommend their use.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fever in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topic (see "Patient education: Giving your child over-the-counter medicines (The Basics)")

●Beyond the Basics topic (see "Patient education: Fever in children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Terminology – Fever is an abnormal increase in body temperature that results from elevation of the hypothalamic set-point (figure 2). The magnitude of temperature increase that prompts evaluation depends upon the age of the child and the clinical circumstances. (See 'Fever' above.)

●Evaluation of fever – The cause of fever should be evaluated, particularly in infants younger than three months of age and infants and children with underlying medical conditions that increase the risk of serious infection (eg, sickle cell disease, neutropenia). (See 'Evaluation of fever' above.)

●Indications for treatment – Decisions regarding the treatment of fever in children should be made on a case-by-case basis. Indications for the treatment of fever may include shock, underlying medical conditions that would be exacerbated by increased metabolic demand, fluid or electrolyte imbalance, temperature ≥40°C (104°F), and discomfort. (See 'Indications' above.)

●Suggested approach – The choice of antipyretic agent for children with underlying medical conditions may be influenced by the underlying medical condition and chronic medications. (See 'Suggested approach' above.)

•When the decision is made to use an antipyretic agent in a child without an underlying medical condition, or with an underlying medical condition that does not influence the choice of antipyretic, we suggest beginning treatment with acetaminophen (Grade 2B). The dose is 10 to 15 mg/kg per dose (maximum dose 1 g) orally every four to six hours (with no more than five doses in a 24-hour period; maximum daily dose: 75 mg/kg per day up to 4 g/day). (See 'Acetaminophen' above.)

Ibuprofen is an alternative to acetaminophen, particularly if anti-inflammatory effect is desired. The dose of ibuprofen is 10 mg/kg per dose (maximum dose 600 mg) orally every six hours (maximum daily dose: 40 mg/kg up to 2.4 g/day). (See 'Ibuprofen' above.)

•We suggest not combining or alternating acetaminophen with ibuprofen (Grade 2B). (See 'Combining or alternating therapy' above.)

•If the temperature remains elevated and the child's discomfort is not improved three to four hours after administration of acetaminophen or ibuprofen, some experts suggest switching from acetaminophen to ibuprofen or ibuprofen to acetaminophen. (See 'Treatment response' above.)

•Prolonged use of antipyretic agents generally is not necessary. Persistence of fever beyond four or five days, a marked increase in the height of the fever during the course of illness, or the development of new localizing symptoms should raise concerns about alternative diagnoses or bacterial superinfection, which should be evaluated. (See 'Duration' above.)

•For previously well infants and children with a febrile illness, we suggest not using external cooling for temperature reduction (Grade 2A). (See 'External cooling' above.)