A 15 month old boy is brought to the office by his very concerned mother who reports that he has a high fever which doesn't come down even with double doses of acetaminophen and a cold water bath. He has had fever for 24 hours. His temperature has been measured as high as 40.8 degrees (105.4 degrees F). His mother and grandmother have given acetaminophen as directed on the package. When his fever remained over 40 degrees (104 F), they gave a second dose one hour after the first during every 4 hour period over the past day. His last dose was 1 hour prior to your exam. He has also been placed in a cold water bath but he objected so forcefully that it lasted only 5 minutes. Despite the fever he has been playing with his toys but has refused solid foods. He has had some juice. He has urinated slightly less often than usual. He has not vomited, had one normal formed stool today, and does not appear to be in pain although he is more fussy than usual and he appears tired. His mother notes that he is getting a new molar.
His past medical history, family history and review of systems are unremarkable.
Exam: VS T 40.7 (105.3 degrees F), P 185, R 24, BP 95/56, oxygen saturation 99%. He is alert and active, sitting on the exam table playing with a toy car. His movements appear jerky. He cries immediately when touched with a stethoscope and vigorously resists examination. The physical exam is otherwise unremarkable except for the fever and tachycardia.
Your nurse urgently requests permission to give him a dose of ibuprofen and a cold water bath to lower his temperature. His mother is crying, saying, "Do something! The temperature keeps going up. He will go into convulsions or develop brain damage!" What should you do?
Fever is a fascinating phenomenon, highly conserved throughout the animal kingdom as a response to infection and inflammation. Fever in children is associated with many myths and fears which are widely shared by lay people and medical professionals alike. This chapter will review what is known about this "hot topic" and suggests an approach to the questions and concerns above.
Fever is a state of elevated core temperature caused by a complex and highly regulated host response involving cytokines and numerous other acute phase reactants with activation of physiologic, endocrine and immune systems. It is stimulated by the presence of an infectious or inflammatory trigger. The interactions of these triggered host factors result in a change in the normal temperature range which is usually tightly controlled. Fever as a response to an infectious or inflammatory stimulus must be distinguished from hyperthermia caused by exposure to extreme environmental conditions or pathologic responses to anesthetics or drugs.
The measurement of true core temperatures is too invasive for routine clinical use. Core temperatures are best measured in the pulmonary artery or by a deep colonic probe. Even these invasive measurements are not accurate for all parts of the body. For example, in shock or other poor peripheral perfusion states, the temperature of the peripheral sites may be much lower than the core. Conversely, during vigorous exercise the muscle temperature may be considerably higher than the core. There are accuracy problems with all of the proposed formulas for converting a measured temperature at any one site with the temperature at another site or with the theoretical core temperature. Therefore conversion is neither necessary nor appropriate.
The oral temperature as measured under the tongue is the most accurate and practical site for thermometry. Rectal temperature measurements are preferred in infants and children who are too young to cooperate with oral measurements. Rectal temperature measurements are a mean of 0.4 C (0.7 F) degrees higher than oral temperatures. As rectal temperature readings may be affected by the presence or absence of stool in the rectum and peculiarities of local blood flow, oral temperature readings are considered to be the best reflector of core temperature. Tympanic temperature measured with a probe against the tympanic membrane as commonly employed by anesthesiologists is very accurate compared with other core temperature measurements. Recently infrared ear thermometers have become popular because they give very rapid readings. However these commonly available infrared ear thermometers used in clinics, hospital wards, and homes are somewhat inaccurate and show significant variation between measurements. They may read falsely low if the seal in the ear canal is poor (1). I have also encountered falsely elevated readings in multiple patients especially when the instrument is older or malfunctioning. Therefore, an unexpected elevated reading from an infrared ear thermometer should be confirmed with an oral or rectal measurement before embarking on an investigation of fever. Once it is proven that the patient has a fever, infrared ear readings may be used to measure trends in temperature associated with therapy of the basic process as long as one remembers that ear readings are variable and less accurate. Axillary temperature measurements are less accurate. Axillary temperature accuracy can be improved by keeping the thermometer in place for 5 to 12 minutes and holding the arm flexed against the body for the entire period. Skin temperature as measured with temperature sensitive crystals implanted in a strip can approximate the body's temperature, but should not be relied upon to give an accurate temperature.
In two studies, elevated tactile temperatures as measured at home by mothers touching their child's forehead had moderate (46% to 73%) correlation with later documentation of fever in the ED or hospital (2,3). Therefore if tactile fever is reported, later confirmation of either elevated temperature or an abnormal clinical appearance is needed before embarking on an etiologic investigation (4).
The first comprehensive study of temperature variation was published in 1868 by Carl Wunderlich (5,6). It is still the most comprehensive study and involved nearly one million observations in 25,000 subjects. He demonstrated that normal individuals have a range of temperature readings and that there is a diurnal variation with the lowest daily reading falling between 2 and 8 a.m. and the highest readings recorded from 4 to 9 p.m. These studies established the definitions of 37 C (98.6 F) degrees as the normal mean value and 38 C (100.4 F) as the fever threshold. More recent studies using more modern instruments found normal oral temperature to vary between 35.6 C (96.0 F) to 38.2 C (100.8 F) in 700 observations of a sample of 148 normal well young adults. In these adults, the 99th percentile of readings was 37.7 C (99.9 F), the median was 36.8 C (98.2 F), the mode was 36.7 C (98.0 F), and only 8% of the readings were at Wunderlich's normal temperature point of 37 (98.6) (6). These studies confirmed Wunderlich's finding of diurnal variation. Temperature was lowest at 0600 hours and peaked in late afternoon between 1600-1800. The mean difference between lowest and highest daily temperatures in these adult subjects was 0.5 degree C (0.9 degree F). For each individual, there existed a characteristic narrow range or normal set-point of body temperature showing diurnal variation of 0.1 to 1.3 degree C. Body temperature is affected very little by environmental conditions but to a greater degree by vigorous exercise. For a population of normal adults, the range of oral body temperature measurements is wider than the individual variation of 0.5 C, spanning 35.6 to 37.8 C (96.0 to 99.9 F) (the 1st to 99th percentiles) (6). A systematic review of articles published from 1939-1990 showed the range for normal oral temperatures to be somewhat wider 33.2 to 38.2 C, (men: 35.7 to 37.7 C, women: 33.2 to 38.1 C) (7).
There has been less systematic study of normal temperatures in children. It has been suggested that preschool children have a more exaggerated diurnal difference in than adults with higher temperatures late in the afternoon or after physical activity (8). A study of rectal temperatures taken once throughout the day in 671 well infants < 3 months old demonstrated (9):
The eruption of new teeth was shown to be associated with a slight increase in temperature within the normal range in 2 studies (10,11). A third study found no evidence for temperature elevation with tooth eruption or the 5 days preceding (12). There is no evidence that teething causes an elevation into the febrile range. The idea that teething causes fever is a widespread folk belief shared by a majority of parents and pediatric dentists but by less than 10% of pediatricians (13).
It remains somewhat uncertain exactly where the febrile range begins but oral temperatures greater than 37.7 degrees C (99.9 F) are greater than the 99th percentile for normal adults. Many lay people and health care professionals regard oral temperature readings between 37 and 38 degrees C (98.6 to 100.4 F) as "low grade fever." This is inappropriate as these values fall within the normal adult range in multiple studies. Temperature readings above the range of 38 to 38.2 C (100.4 -100.8 F) by any route suggest the presence of fever. This definition of the fever threshold is convenient and generally accepted. Certain individuals may have temperature elevations greater than this while being entirely well especially in late afternoon or after vigorous exercise. The presence of sustained fever of any degree indicates a problem which may need evaluation. Recognizing the presence of fever is of significance, but concern about the height of the fever is of less importance since the height of fever by itself is of limited diagnostic value.
Physiology of Fever: Fever producing substances are divided into two categories: those produced outside the body (exogenous pyrogens) and those produced inside the body (endogenous pyrogens). Exogenous pyrogens are usually microorganisms, their components or their extracellular products. Endogenous pyrogens are host cell derived cytokines which are the principal central mediators of the febrile response. The secretion of endogenous pyrogens is induced by both exogenous pyrogens and many endogenous molecules such as antigen-antibody complexes, complement, steroid metabolites, certain bile acids, and many lymphocyte derived molecules. The most prominent currently recognized pyrogenic "pro-inflammatory" cytokines include interleukin-1, tumor necrosis factor alpha, and interferon gamma. Regulation of cytokine secretion is very complex with many interactions between individual molecules and classes of molecules. The initial cytokine mediated rise of core temperature is only one facet of the febrile response. Other physiologic changes which are together called the acute phase response are somnolence, anorexia, changes in plasma proteins, altered synthesis of the hormones ACTH, glucagon, insulin, cortisol, catecholamines, growth hormone, TSH, thyroxin, aldosterone and vasopressin. Hematologic alterations include changes in leukocytes, lymphocytes, platelets and decreased red blood cell formation. Many acute phase proteins are secreted during the febrile response, some of which play a role in modulating inflammation and tissue repair. Pyrogenic cytokines act upon the preoptic region of the anterior hypothalamus of the central nervous system and upon peripheral tissues through specific receptors and pathways which are not yet delineated to produce changes in body temperature and also to limit the height of the fever rise. Thermoregulatory neurons involved in the febrile response are known to be completely inhibited at 41 to 42 C (105.8 to 107.6 F), the ceiling of the natural febrile range. Pyrogenic cytokines are balanced or "braked" by anti-inflammatory cytokines, arginine vasopressin, hypothermic neurochemicals, hypothermic peptides and even some of their shed soluble receptors. Thus, there is a complex and changing interplay of factors influencing the thermoregulatory set-point which causes it to change frequently resulting in the frequent changes in body temperature characteristic of most fevers.
Patterns of Fever: In the febrile state, the temperature is not controlled as tightly as the 0.5 degree C (0.9 degree F) variation that normal adults show during the day. There are several patterns of fever, some of which are associated with particular disease processes. Intermittent fevers are characterized by temperature patterns which dip into the normal range one or more times per day. Remittent fevers demonstrate wide swings in temperature but always remain above 38 (100.4). Hectic or "septic" or "high spiking" fevers show wide swings between highs and lows and may be either intermittent or remittent depending upon whether the low is in the normal range. Sustained fevers have temperatures that are always in the febrile range but vary less than 0.5 C (1 F). Relapsing fevers are recurrent over days to weeks. The pattern of fever has some value in diagnosis although exceptions to the associations are very common. Intermittent fever is associated with the systemic form of juvenile rheumatoid arthritis (Still's disease), miliary tuberculosis, mixed malarial infections, and may be produced with antipyretic therapy. Remittent fevers are associated with many viral infections, acute rheumatic fever, endocarditis with lower grade pathogens and Kawasaki syndrome. Hectic fevers suggest bacterial septicemia, endocarditis with high grade pathogens, occult or deep tissue abscesses, peritonitis, toxic shock syndrome and Kawasaki syndrome. Sustained fevers are associated with typhoid fever, nosocomial infection of devices such as intravenous lines and cerebral spinal fluid shunts. Relapsing fevers are characteristic of malaria, dengue, brucellosis and rat-bite fever.
Knowledge of the patterns of fever is useful in documentation and in describing the patient to others. It is sometimes of value in diagnosis and prognosis. It is important not to describe a patient as "afebrile" unless the temperature is in the normal range for at least an entire 24 hour period. Afebrile literally describes a patient with the "absence of fever," not just a patient whose temperature has briefly fallen into the normal range before it rises again. It is also imprecise to describe a "spiking fever" or a fever "spike" unless the temperature rises several degrees in a short period of time such as 4 hours or less.
Height of Fever and Response to Antipyretics: There is a weak correlation between height of fever and the severity of infection or whether it is viral or bacterial. However, this correlation is so weak that it is not clinically useful, because there is too much overlap between the viral and bacterial infection groups. The overwhelming majority of high fevers are caused by viral agents. Some highly lethal infections such as gram-negative bacterial septicemia may have only modest fever or even, most ominously, hypothermia. Conversely, the very benign and universal Human Herpesvirus (HHV) 6 and 7 or roseola infantum infections are characterized by fevers near the febrile ceiling, 40.5 C (104.9 F) or greater. There is a slightly increased likelihood (from about 4% to 8%) of occult bacteremia in young (6-18 months) children with temperatures over 40.0 C (104 F). However the overwhelming majority of children with high fever have non focal and presumed viral infections. Whether viral or bacterial, serious or trivial, five prospective studies in children have shown that temperature elevations had the same degree of response to antipyretic therapy (14-18). Therefore response or lack of temperature response to antipyretics usually does not distinguish between viral or bacterial infection or between trivial or serious infection. The child's clinical appearance, especially his level of alertness and appropriate social behavior, does help in determining if serious illness is present. Children with severe bacteremic infection still appeared clinically ill after successful fever reduction while the clinical appearance of children with non-severe infections improved (18). Thus the focus for parents and physicians should be on the child's appearance and behavior, not the height of the fever or presence or absence of response to antipyretics.
A temperature rise is accomplished by increasing heat generation primarily through shivering and decreasing heat dissipation by shunting blood away from the skin surface. Non-shivering thermogenesis is accomplished through many other metabolic processes especially those in brown fat. Patients with a rising temperature are hyperalert, feel jumpy or jittery, complain of cold sensations and have shivering, chills or violent rigors. Temperature lowering is associated with increased heat dissipation at the skin surface with dilatation of surface vessels and sweating which causes further evaporative cooling. Patients feel hot and have profound lassitude which inhibits muscle activity and prevents heat generation. These states alternate as the body temperature rises and falls. The rate at which the temperature changes determines the severity of these symptoms. Chills and shivering are increased and made much more uncomfortable if external cooling is applied.
Is fever harmful? To date there is no clear evidence that fever causes harm to the host. Temperatures of up to 41.5 C (106.7 F) are tolerated without any reported evidence of damage to the brain or other organs (19). Temperature elevations higher than this are not caused by response to an infecting agent but are usually associated with profound failure of thermoregulation such as exposure to extreme heat (heat stroke), severe brain injury with damage to the thermoregulatory center, and adverse reactions to anesthetics or neuroleptic drugs (malignant hyperthermia). There are no reports of brain damage caused by fever as a response to infection in a previously normal individual. Concerns have been expressed that fever may pose an increased stress in seriously ill individuals by increasing metabolic activity, heart rate, and respiratory rate. There is little evidence on this point. One large placebo controlled study of febrile adult ICU patients demonstrated that ibuprofen reduced fever and metabolic rate but had no beneficial effect on survival (20).
Is fever beneficial? There is limited evidence that fever is beneficial. Some animal infection studies have demonstrated a direct association between fever and survival (21-25). Other animal model infection studies demonstrated an increase in mortality if fever was suppressed with antipyretics (26-28). These types of studies have flaws which reduce their applicability to humans especially because some are done in cold blooded animals, some induce elevated temperature with external warming and some use uncommon pathogens. Some studies of patients with severe bacterial infections have shown a direct positive correlation between height of fever and survival (29-34). A controlled study in children with varicella demonstrated both a shorter duration of fever and more rapid healing of lesions in placebo recipients than those treated with acetaminophen. The magnitude of the effect was approximately equal to the effect of antiviral therapy on varicella (35). Two common cold studies showed more severe respiratory symptoms and longer duration of rhinovirus shedding when fever was suppressed with aspirin or acetaminophen (36,37).
Should Fever be treated with Antipyretics? Current clinical practice is that fever reducing drugs are employed routinely, often before any investigation as to the nature or cause of the fever is carried out. The rationale supporting this practice is that it is harmless and increases patient comfort. Indeed, antipyretics are often requested for and given to patients who are perfectly comfortable and have very modest temperature elevation. Patients often initiate antipyretic therapy on their own without medical consultation. It would be unreasonable to seek medical evaluation for all fevers so some degree of discretion needs to be permitted to patients. Some precautions need to be considered when recommending routine antipyretic treatment:
1. Aspirin therapy for fevers of varicella and influenza caused an epidemic of life-threatening Reye's Syndrome.
2. Acetaminophen is an extraordinarily safe drug within its dosing range. However, fatal liver damage from unintentional overdose of acetaminophen for fever has been reported.
3. Case control studies indicate that treatment of the fever of streptococcal toxic shock syndrome with ibuprofen is associated with increased mortality (38-39).
4. Ibuprofen causes platelet inhibition and upon occasion, significant gastrointestinal hemorrhage. Routine use of ibuprofen amplifies this risk.
If patients appear to be very uncomfortable from fever, it is reasonable to administer antipyretics. Antipyretic therapy may also be useful in a febrile child who appears slightly ill with a non-focal examination suggesting a benign illness. The administration of antipyretics with temperature normalization may result in improvement of the patient's behavior and appearance, thus avoiding unnecessary laboratory testing, antibiotics or hospitalization.
Another rationale for the routine use of antipyretic therapy in children under 5 years is that it will reduce the likelihood of febrile seizures. Many febrile seizures occur early in the course of illness with the seizure being the first sign that the child is febrile. In these cases, there is no opportunity for antipyretics to lower the temperature. A study of children with a history of febrile seizures found the recurrent seizure rate to be 5% in children treated with phenobarbital and antipyretics while 25% of those treated with placebo and antipyretics had a recurrent seizure (40). Two placebo controlled studies using standard and high dose acetaminophen during fever failed to show a benefit for the active drug in preventing seizure recurrence (41,42). We have no way of determining which normal child will be affected, but all children do not appear to be at equal risk for febrile seizures. Only 2% of children ever have a seizure while exposure to high body temperature is virtually universal by age 5 years. Although the literature fails to provide evidence that antipyretic therapy prevents recurrent febrile seizures, these seizures are very emotionally distressing to parents. Parents may feel more comfortable if antipyretic therapy is employed. When seizures occur despite appropriate use of antipyretics, parents should be counseled that they did all that was appropriate so that they will not employ excessive treatment with the next febrile illness or suffer unnecessary grief.
Approach to the febrile child: There are several clinical decision rules that are commonly employed in pediatric practice. Following these decision rules constitutes a conservative approach. Highly experienced clinicians may be able to identify low risk individuals who may fit the decision rule, but are unlikely to benefit from their recommendations.
Fever in infants under 8 weeks of age: This generally prompts a sepsis work-up consisting of a CBC, blood culture, catheterized urine culture, urinalysis, chest X-ray (if respiratory symptoms are present), and lumbar puncture. Empiric antibiotics and hospitalization are recommended routinely for this age group; however, children in the 4 to 8 week range have been treated as outpatient in some patient series if the following conditions are met: 1) the sepsis work-up is negative, 2) empiric antibiotics (e.g., ceftriaxone) are given, 3) the infant is feeding well, is not fussy and appears well clinically, 4) parents are assessed to be reliable observers, and 5) a source of reliable primary care is identified. A positive RSV ELISA may be considered to be the source of the fever which would make the infant less likely to benefit from the urine and cerebrospinal fluid studies, however, hospitalization may still be necessary.
Occult urinary tract infection: UTI may be difficult to diagnose in young children. Girls under 24 months of age and boys under 6 months of age with temperatures greater than 39 degrees C (102.2 F) are at modest risk for UTI. Most experts have recommended catheterized urine cultures for this group. Uncircumcised males are at a higher risk (although the magnitude of this additional risk is controversial). Some experts have recommended that uncircumcised boys be checked for UTI up until 24 months of age. Some children in this age group present with predominant respiratory symptoms (e.g., bronchiolitis), which point to a respiratory source of the fever. One study demonstrated that such patients are at reduced risk for UTI, but it still occurs, therefore urine testing may still be valid even for those with respiratory symptoms (43).
Occult bacteremia: Children from 3 months to 36 months of age with a temperature greater than 39 degrees C (102.2 F) are at risk for occult bacteremia. The risk of this is less than 4% and most cases, result in spontaneous resolution, even without antibiotic therapy. The risk of occult bacteremia is further modified by H. influenzae vaccine, pneumococcal vaccine, age and other factors making this decision complex and the management options controversial.
Otitis media is often diagnosed in febrile children, but it is likely that most cases of otitis media cause only mild degrees of fever. Thus, assuming that a diagnosis of otitis media accounts for the fever, may result in missing a UTI. Although antibiotic treatment for otitis media will frequently treat the UTI as well, if a vesicourinary anomaly is responsible for the UTI, then the patient will be at risk for subsequent recurrent pyelonephritis in the future until the vesicourinary anomaly is identified.
The utility of routine CBCs to identify septic patients has been studied extensively. Because of the excessive overlap of WBC results, CBCs are only occasionally indicative of a serious condition and generally not helpful in identifying septic patients. Clinical appearance (does the child appear to be toxic, lethargic, excessively irritable, or very ill appearing) is the most reliable clinical predictor of sepsis after 2 to 3 months of age.
Fever is a complex and highly regulated host response to a microbial or inflammatory stimulus. Fever is most often related to infection but is also seen prominently in auto-immune and neoplastic disease. Controlling fever should not be a major objective in itself. Although fever is often uncomfortable, it is not medically harmful to the host and may be beneficial. With that in mind we can now answer our mother and the nurse's concerns outlined in the vignette which introduced this chapter. Her son will not become brain-damaged as a result of his fever which is a natural and possibly helpful response to an as yet undiagnosed infection. It is unlikely that her son will have a seizure or "go into convulsions" both because it is statistically unlikely and because he has been febrile for several hours without having had a seizure. His fever will not continue to rise much as he has already approached the natural ceiling for the febrile response. It is more important at this point to assess the cause of the fever with a physical examination and any diagnostic testing which may be indicated, rather than to administer antipyretics. Drastic external cooling measures such as a cooling blanket or a cold water bath are absolutely not indicated and will certainly make the child feel worse (44). He should not be given another dose of acetaminophen as he has already received double doses. His mother must be told that giving more acetaminophen than indicated in future illnesses could cause liver damage. Acetaminophen and ibuprofen appear to be equally effective and safe in fever reduction in children (45,46). There is no reported clinical trial of the safety and efficacy of combining these agents in the symptomatic treatment of fever in children. Since our patient does not appear to be uncomfortable, it is not necessary to give him ibuprofen at this time. Simply dressing him minimally and offering him extra fluids without expecting him to eat solid foods is all that is required for fever treatment. Since he has a normal physical examination and has been previously immunized with Haemophilus influenzae b and pneumococcal conjugate vaccines, he is at very low risk for serious bacterial infection. Once his underlying illness has been fully addressed, ibuprofen therapy may be offered if he appears uncomfortable. It should be stressed that antipyretic therapy is entirely optional and should be given only if he needs relief of noxious fever related symptoms. Given his normal physical exam and age appropriate behavior, he most likely has an HHV 6 or 7 roseola related illness. Considering all that is known about temperature regulation in the febrile response, the control of the typically high fever characteristic of this illness rests more with the patient's physiology than with the influence of his mother or the medical profession. In evaluating any patient with fever it is of paramount importance to remember that fever is a sign of disease and not the disease process itself.
Acetaminophen is generically also called APAP (abbreviation) and paracetamol (other countries).
The formula to convert degrees F to degrees C is TempC = (TempF - 32)/1.8
The formula to convert degrees C to degrees F is TempF = (TempC X 1.8) + 32
1. True/False: Defining an elevated temperature is difficult and variable because the "normal" core temperature is not a fixed value, and the methods of measuring temperature have varying degrees of accuracy.
2. Which of the following is true?
. . . . . a. Treating fever with antipyretics is clearly harmful and should be always discouraged.
. . . . . b. Treating fever with antipyretics is clearly beneficial, without adverse effects and should always be recommended.
. . . . . c. Treating fever with antipyretics is optional.
. . . . . d. None of the above.
3. True/False: Temperatures above 40 degrees C (104 F) result in febrile seizures in most patients.
4. True/False: Ibuprofen has a superior antipyretic effect compared to acetaminophen.
5. Febrile children at risk for occult urinary tract infection include those with a temperature above 39 degrees C. What is the commonly used age ceiling for boys and for girls?
6. True/False: Teething is known to cause fever.
7. True/False: The diagnosis of acute otitis media is a reliable explanation for a high fever, thus eliminating the need to for other diagnostic considerations in a patient with an otherwise benign examination.
8. True/False: High fever may cause brain damage.
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Answers to questions
5. 6 months for boys, 24 months for girls.
6. False. At the most, teething might causes a very slight temperature elevation.
7. False. Otitis media is not considered to be a reliable source of causing a high fever. Other conditions, such as UTI, need to be considered.