50

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Section A fever

Temperature Regulation and the Pathogenesis of Fever

PHILIP A. MACKOWIAK

form inscriptions from the 6th century bc, most likely derived from an ancient Sumerian pictogram of a flaming brazier used to symbolize both fever and the local warmth of inflammation.1 Theoretical constructs of the pathogenesis of fever did not emerge until several centuries later, when hippocratic physicians proposed that body temperature, and physiologic harmony in general, involved a delicate balance among four corporal humorsblood, phlegm, black bile, and yellow bile.2 Fever was then believed to result from an excess of yellow bile, a concept in concert with the fact that many infections of that era caused both fever and jaundice. During the Middle Ages, demonic possession was added to the list of mechanisms thought to be responsible for fever. By the 18th century, Harveys discovery of the circulation of blood and the birth of clinical chemistry led iatrophysicists and iatrochemists to hypothesize alternatively that body heat and fever resulted from friction associated with the flow of blood through the vascular system and that they resulted from fermentation and putrefaction occurring in the blood and intestines.3 Ultimately, as a result of the work of Claude Bernard, the metabolic processes occurring within the body came to be recognized as the true source of body heat. Subsequent work established that body temperature is tightly controlled within a narrow range by mechanisms regulating the rate at which such heat is allowed to dissipate from the body. The origin of the practice of monitoring body temperature as an aid to diagnosis is uncertain. The oldest known references to devices used to measure temperature date to the 1st or 2nd century bc, when Philo of Byzantium and Hero of Alexandria are believed to have invented several such devices.4 It is reasonably certain that Galileo manufactured a primitive (air) thermometer at about the time that he assumed the chair in mathematics at Padua in 1592.5 However, thermometry was not fully assimilated into medical practice until 1868, when Carl Reinhold August Wunderlich published a magnum opus entitled Das Verhalten der Eigenwrme in Krankenheiten (The Course of Temperature in Diseases).6 Through Das Verhalten der Eigenwrme in Krankenheiten, Wunderlich gave 37C (98.6F) special significance with respect to normal body temperature.7 He described the diurnal variation of body temperature and, in the process, alerted clinicians to the fact that normal body temperature is actually a temperature range, rather than a specific temperature.

The oldest known written reference to fever exists in Akkadian cunei-

thermia, in which inflammatory cytokines play only a minor role. Thermophysiologists define the term hyperthermia as the condition of a temperature regulator when core temperature is above the range specified for the normal active state of the species.8 It may be regulated, as in fever, or forced, as in heat stroke, when heat production exceeds the capacity of heat loss. Heat stroke and other forms of forced hyperthermia are characterized by a sustained elevation in core temperature lacking the diurnal fluctuation typical of fever and normal body temperature, and do not respond to antipyretic therapy.9 In the clinical setting, fever is typically defined as a pyrogen-mediated rise in body temperature above the normal range. Although consistent with the publics perception of fever, the definition ignores the fact that a rise in body temperature is but one component of this multifaceted response. This standard clinical definition is further flawed, because it implies that body temperature is a single entity when, in fact, it is a pastiche of many different temperatures, each representative of a particular body part, and each varying throughout the day in response to activities of daily living and the influence of endogenous diurnal rhythms.

Clinical Thermometry
For over a century, the thermometer has been preeminent among clinical instruments used to distinguish health from disease and to monitor the course of illness. Unfortunately, thermometric measurements are influenced by a host of variables, all too frequently ignored when interpreting the significance of clinical temperature readings. ANATOMIC VARIABILITY Although clinicians frequently regard temperature readings from various anatomic sites as equivalent approximations of body temperature,1 no one temperature characterizes the thermal status of the human body. This is because the body has many different temperatures, each representative of a particular body part. Nevertheless, within the body, there are two basic thermal compartments worthy of special considerationthe core and the shell.10 The shell, which consists of skin and subcutaneous fat, insulates the core from the external environment. The core, of which the viscera and muscles are major components, although insulated by the shell, has temperature gradients of its own resulting from differences in the metabolic rates and blood flow patterns of the various organs contained therein. Even during baseline conditions, organs with higher metabolic rates have slightly higher temperatures than those with lower metabolic rates; in general, tissues close to the skin have lower temperatures than those at deeper locations.11 Although such differences are normally small, muscle temperatures rise during vigorous exercise markedly in comparison with those of less metabolically active organs. During shock and under extreme environmental conditions, regional anatomic variations in temperature may also be exaggerated. Rectal measurements were once regarded as the most practical and accurate means of obtaining routine estimates of core temperature. Benzinger and Benzinger, however, have pointed out that no known thermoregulatory system exists at this particular anatomic site.11 Rectal

Terminology
According to the International Union of Physiological Sciences Commission for Thermal Physiology, fever is a state of elevated core temperature, which is often, but not necessarily, part of the defensive responses of multicellular organisms (host) to the invasion of live (microorganisms) or inanimate matter recognized as pathogenic or alien by the host.8 The febrile response, of which the temperature rise is a component, is a complex physiologic reaction to disease, involving not only a cytokine-mediated rise in core temperature but also the generation of acute-phase reactants and the activation of numerous physiologic, endocrinologic, and immunologic systems. The regulated rise in temperature during fever is to be distinguished from that occurring during episodes of heat stroke and other forms of forced hyper-

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temperature readings are consistently higher than those obtained at other sites (even pulmonary artery blood), which some authorities have suggested might be caused by heat generated as a result of the metabolic activity of fecal bacteria.11 However, an early study showed no significant decrease in the rectal temperature after a reduction in the colonic bacterial content.11 There is also concern that stool in the rectum acts as a heat sink to delay or mitigate changes in the rectal temperature, particularly if the thermometer is inserted directly into stool.12 During shock, perfusion of the rectum may be markedly impaired, causing the rectal temperature to lag significantly behind a rapidly rising or falling core temperature.13 For this reason, Houdas and Ring have concluded that the rectal temperature provides a reliable approximation of the core temperature only if the patient is in thermal balance.14 In neonates, even in the absence of shock, the rectal temperature measured by standard technique has been reported to correlate poorly with the core temperature as measured by a deep rectal probe.15 The right atrium is the ideal site for measuring core temperature, because it is the nexus at which venous blood from all anatomic regions joins. However, because it is relatively inaccessible, the temperatures of other sites are more often used as approximations of core temperature. The tympanic membrane (TM) temperature is thought by some to be particularly useful in this regard, because the TM is perfused by a tributary of the artery that supplies the bodys thermoregulatory center.22 This fact, and the ease with which TM measurements can be obtained using modern infrared TM thermometers, have made these instruments the thermometers of choice in many clinics and intensive care units. There are two basic types of infrared TM thermometers. One type detects radiant energy emitted from the TM and portions of the ear canal, processes the information, and then displays a value representing tissue temperature in the ear canal (unadjusted mode).23 The other displays an (adjusted) estimate of the core temperature (e.g., pulmonary arterial blood temperature) based on comparison data obtained from selected study samples. Readings obtained using the former type of TM thermometer tend to be lower than simultaneously obtained oral readings, whereas those obtained with the latter type are generally higher.22 Unfortunately, numerous studies of many different TM thermometers have shown that although convenient, such instruments tend to give highly variable readings that correlate poorly with simultaneously obtained oral or rectal readings.19,23-26 Several studies have shown that monitoring the skin temperature using temperature-sensitive crystals incorporated into plastic strips placed on the forehead is an insensitive technique for detecting elevations in the core temperature.32,33 The detection of fever by palpation is similarly insensitive. Bergeson and Stienfeld found that 42% of 138 febrile children (as defined by a body temperature of 38C or higher) were judged to be afebrile by nurse assistants using palpation to detect fever.34 Only 1.8% of over 1000 afebrile children were judged to be febrile using this same technique. In an evaluation of a mothers ability to assess the temperature of her child by palpation, Banco and Veltri found mothers to have a sensitivity of 73.9% and a specificity of 85.6% for detecting fever higher than 38C (100.4F).35 Thus, palpation by mothers was more sensitive than that by nurse assistants but was less specific for detecting the febrile state. Finally, Bonadio and co-workers have reported that among infants younger than 2 months presenting to the emergency room with a history of fever, those in whom fever had been documented at home by rectal thermometer were twice as likely to be febrile on presentation or during hospitalization than those whose fever had been documented by palpation alone (92% vs. 46%; P < .001).36 Because the temperature of the rectum, mouth, and tympanic membrane are related but not identical, it would be useful to have a reliable formula for converting data from one site to another. In a study of healthy young adults, Rabinowitz and associates determined that on average, rectal readings exceed concurrent oral readings by 0.4C (0.8F) and exceed TM readings (obtained with the IVAC Core) by 0.8C (1.6F).19 However, these relationships were extremely variable.

Their findings concerning the relationship between rectal and oral readings were in agreement with those of several earlier investigations.37-40 Their findings with respect to the relationship between oral and TM readings, however, differed from earlier reports,12 which had generally shown TM readings to be higher than simultaneously obtained oral measurements. This discrepancy most likely reflected the fact that unadjusted-mode TM thermometersfor example, the IVAC Coregenerally give lower readings than adjusted-mode TM thermometers, such as those used in earlier studies.23 PHYSIOLOGIC VARIABLES Wunderlich and Seguin41 believed that old people have lower body temperatures than younger persons, and their views in this regard were corroborated by Howell in a report published in Lancet in 1948.42 There is also a substantial body of data suggesting that thermoregulation is impaired in older persons because of various effects of aging on the autonomic nervous system.43 Nevertheless, more recent work has not shown lower average core temperatures among healthy older subjects (mean age, 80.3 years; range, 62 to 99 years) than among healthy younger subjects.44 Comparisons of simultaneous oral, axillary, and rectal temperature readings from these subjects have shown lower average oral and axillary readings in older persons but comparable average rectal temperatures in older and younger subjects. It has long been known that women exhibit increases in body temperature of about 0.5C (0.9F) at the time of ovulation.14 Wunderlich and Seguin also maintained that women have slightly higher normal temperatures than men overall and often show greater and more sudden changes in temperature.41 Two other studies have corroborated Wunderlich and Seguins former but not latter observation.45,46 Body temperature, like most physiologic functions, exhibits circadian rhythmicity that is linked to the sleep-wake cycle.47 During normal sleep-wake cycles (i.e., asleep during the night and awake during the day), the core temperature reaches its zenith in the late afternoon or early evening and its nadir in the early morning.45 Adaptation to night shift work causes a reversal of this pattern. Thermoregulation has also been reported to be altered in patients with neuropsychiatric disorders, such as chronic depression.48 Therefore, when interpreting clinical thermometric measurements, it is important to consider not only the time of the measurement and the site at which the temperature was taken, but also the sleep-wake cycle and mental health of the subject being studied. In addition to these physiologic variables, exercise, digestion, and underlying disorders such as chronic renal failure, shock, and local inflammation at the site of the thermometric measurement (e.g., proctitis, external otitis, or stomatitis) may alter thermoregulatory responses, local temperature, or both. It has, for example, been shown that the core temperature varies by as much as 3C (36 to 39C) in states ranging from sleep to moderately high levels of sustained exercise, and this continuum of body temperature is related to a continuum of activity.49 Ambient temperature and humidity have been shown experimentally to affect both human sleep stages and body temperature,50 suggesting that body temperature might also vary according to the time of year and local climate. It is pertinent in this regard that Cheng and Partridge have shown that bundling and warm environments can elevate rectal temperatures of newborns to the febrile range.51 Normal Body Temperature A survey of physicians perceptions of body temperature published in 1995 indicated widespread confusion regarding key features of the human body temperature.52 Of 268 physicians and medical students surveyed, 75% gave 37C (98.6F) as their definition of normal body temperature. An additional 13% defined the normal temperature as a narrow range of temperatures about a mean of 37C (98.6F). Only 10 (4%) subjects in the group as a whole specified a particular body site (e.g., oral or rectal) for temperature measurements in their definition. Also, 98% percent thought that the normal temperature varies

50 Temperature Regulation and the Pathogenesis of Fever

767

0.125 Females 0.1 Relative frequency Males

0.075

0.05 0.025

Figure 50-1 Frequency distribution of 700 baseline oral temperatures obtained during 2 consecutive days of observation in 148 healthy young volunteers. Arrow indicates the location of 98.6F (37C). (From Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA. 1992;268: 1578-1580.)

96

97

98

99

100

101

Temperature (F)

during the day, with quantitative estimates of such diurnal variability ranging from 0.2C (0.4F) to 2.8C (5F) (mean SD, 0.8 0.4C [1.6 0.8F]). The origin of these perceptions of body temperature is uncertain, but in all likelihood it lies in Carl Wunderlichs 1868 book on clinical thermometry (see earlier), which many regard to this day as the definitive work on the subject.6 Unfortunately, several of Wunderlichs dictums concerning body temperature, such as the perceptions of modern-day physicians, appear to be in error. A 1992 descriptive analysis of 700 baseline oral temperature observations from 148 healthy men and women found a range of 35.6C (96.0F) to 38.2C (100.8F), with an overall mean of 36.8 0.4C (98.2 [0.7F]); 37C (98.6F) accounted for only 56 (8%) of the 700 oral temperature observations recorded (Fig. 50-1).45 The mean temperature varied diurnally, with a 6 am nadir and a 4 to 6 pm peak (Fig. 50-2). The maximal temperature (as reflected by the 99th percentile) varied from a low of 37.2C (98.9F) at 6 am to a high of 37.7C (99.9F) at 4 pm. Age did not significantly influence temperature within the age range studied (18 to 40 years) (linear regression, P = .99). Women had a slightly higher average oral temperature than men (36.9C [98.4F] vs. 36.7C [98.1F]; t test, P < .001, degrees of freedom [df ] = 698) but did not exhibit higher average diurnal temperature oscillations than male counterparts (0.56C [1.0F] vs. 0.54C [0.97F]). There was a statistically significant linear relationship between temperature and pulse rate (regression analysis, P < .001), with an average increase in heart rate of 4.4 beats/min for each

1C (2.44 beats/min for each 1F) rise in temperature over the range of temperatures examined (96.0 to 100.8F). According to Wunderlich and Seguin, When the organism (man) is in a normal condition, the general temperature of the body maintains itself at the physiologic point: 37C = 98.6F.41 Although several subsequent investigations have recorded mean temperatures of normal adult populations closer to 36.6C (98.0F),53 Wunderlichs intimation that 37C (98.6F) is the most normal of temperatures54 persists to this day in lay thinking, although to a lessening extent in the thinking of health care workers. The data reviewed earlier suggest that 37C (98.6F) has no special significance vis--vis body temperature in healthy young adults when such temperature is measured orally using modern thermometers. In the population examined, 37C (98.6F) was not the overall mean temperature, the mean temperature of any of the time periods studied, the median temperature, or the single most frequent temperature recorded. Furthermore, it did not fall within the 99.9% confidence limits for the sample mean (36.7 to 36.8C; 98.1 to 98.2F). Wunderlich identified 38.0C (100.4F) as the upper limit of normal body temperature in his patient population and therefore regarded any temperature higher than 38.0C (100.4F) as fever.41 However, the upper limit of normal body temperature varies among individuals, thereby limiting the applicability of mean values derived from population studies (even those as large as Wunderlichs) to individual subjects. However, the maximal temperature, like the mean temperature, exhibited by a population varies according to the time of day and the

Temperature (C)

Figure 50-2 Mean oral temperatures and temperature ranges in 148 healthy young volunteers according to time of day. The four temperatures shown at each sample time are the 99th percentile (top), 95th percentile (second), mean (third), and fifth percentile (bottom) for each sample set. (The numbers in parentheses are the temperatures in degrees Fahrenheit.) The numbers in parentheses on the x-axis indicate the number of observations analyzed at each sample time. (From Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA. 1992;268:1578-1580.)

37.1 (98.9) 37.1 (98.9) 36.4 (97.5) 36.0 (96.8) 38

37.5 (99.5) 37.2 (99.0) 36.5 (97.7) 35.7 (96.3)

37.6 (99.6) 27.4 (99.3) 36.8 (98.2) 36.1 (97.0)

37.7 (99.9) 37.4 (99.4) 39.9 (98.4) 36.3 (97.3)

37.7 (99.8) 37.6 (99.6) 36.9 (98.5) 36.3 (97.4)

37.6 (99.6) 37.3 (99.2) 36.8 (98.2) 37.1 (97.0)

37

36 (19) 35 6 AM (144) 8 AM (41) 12 Noon (157) 4 PM (57) 6 PM (262) 12 Mid

Time of day

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site at which the temperature measurement is taken. Because of such variability, no single temperature can be designated as the upper limit of normal. In the study population considered earlier, 37.2C (98.9F) was the maximal oral temperature (i.e., the 99th percentile) recorded at 6 am, whereas at 4 pm, the maximal oral temperature observed reached 37.7C (99.9F). Thus, these data suggest that when modern thermometers are used to monitor oral temperature in young or middle-aged adults, fever is roughly defined as an early-morning temperature of 37.2C (99.0F) or higher or a temperature of 37.8C (100F) or higher at any time during the day. Wunderlich wrote in 1868 that [temperature] oscillates even in healthy persons according to time of day by 0.5C = 0.9F. The next year, Wunderlich and Reeve wrote, The lowest point is reached in the morning hours between two and eight, and the highest in the afternoon between four and nine.55 Modern authorities have generally concurred with these observations. However, Tauber has suggested that the amplitude of diurnal variation might be as high as 1C (1.8F).56 The data described earlier are more consistent with the views of Wunderlich and colleagues. Nevertheless, the subjects examined in that study exhibited considerable individual variability, with some having daily temperature oscillations as wide as 1.3C (2.4F) and others having oscillations as narrow as 0.1C (0.2F). According to Wunderlich and Seguin, women have slightly higher normal temperatures than men and often show greater and more sudden changes of temperature.41 In a study of nine healthy young adults (six male and three female), Dinarello and Wolff corroborated both observations.46 The investigation described earlier, which did not control for the effects of ovulation on thermal observations, was able to corroborate only the former observation of Wunderlich and Seguin.45 It has been maintained for over a century that older persons have lower body temperatures than younger persons.41 Howells 1948 study (see earlier) seemed to substantiate this belief.42 Although there are considerable data suggesting that thermoregulation is impaired in older persons because of various effects of aging on the autonomic system,43 as noted, more recent investigation has not shown lower average core temperatures among healthy older persons than among healthy young people.44 As a result of work conducted earlier this century,38,57 it is widely believed that the heart rate increases 10 beats/min for each 1F rise in body temperature. More recent data (see earlier) indicate that the heart rate increases only 2.44 beats/min for each 1F rise in temperature.45 The difference between the earlier and more recent investigations most likely reflects the fact that in the latter study, subjects were afebrile and were examined seated, whereas those examined in earlier investigations were mostly febrile and rested reclining on a couch for 20 minutes before examination. The normal range of body temperature in children is not well delineated. Lorin has written that the range is higher in children than in adults and that a decrease toward adult levels begins at about 1 year of age, continues through puberty, and stabilizes at 13 to 14 years of age in girls and at 17 to 18 years of age in boys.58 He has offered a 1937 publication by Bayley and Stolz as documentation of his views on the matter.59 Unfortunately, these early investigators did not control for variables such as the time of day, bundling, and the thermometer dwell time, each of which might have significantly affected the results of their survey. It has also been maintained that the circadian rhythm that characterizes body temperature in the adult is less evident in the first few months of life, is well established by the second birthday, and tends to be more pronounced during childhood than during adulthood.58 This concept, like many concerned with the normal temperature of children, is difficult to substantiate with published data.

convert adenosine diphosphate to adenosine triphosphate (ATP). At rest, more than half of the bodys heat is generated as a result of the inefficiency of the biochemical processes that convert food energy into the free energy pool (e.g., ATP). Even if no external work is being performed, heat is generated as a result of both internal work (e.g., peristalsis, myocardial contractions, and the circulation of blood) and biochemical reactions involved in maintaining the structural and functional integrity of the various organ systems (i.e., the uptake and resynthesis of ATP). When external work is performed, additional heat is generated as a byproduct of skeletal muscle contractions. In adult humans and most other large mammals, shivering is the primary means whereby heat production is enhanced. Nonshivering thermogenesis is more important in smaller mammals, newborns (including humans), and cold-acclimated mammals.60,61 Although several tissues (e.g., the heart, respiratory muscles, and adipose tissue) contribute to the process, brown adipose tissue has been most closely associated with nonshivering thermogenesis. This highly specialized form of adipose tissue located near the shoulder blades, neck, adrenals, and deep blood vessels (adjacent to vital organs) is characterized by its brownish color, a profuse vascular system, and an abundance of mitochondria.60,62 Heat generated primarily in vital organs lying deep within the body core is distributed throughout the body via the circulatory system. In response to input from the nervous system, the circulatory system determines both the temperature of the various body parts and the rate at which heat is lost from body surfaces to the environmentby conduction, convection, radiation, and evaporation.63 In a warm environment, or in response to an elevation in the core temperature resulting from exercise, cutaneous blood flow increases so that heat is transported from the core to be dissipated at the skin surface. Simultaneous activation of sweating enhances such heat loss via evaporation. In anesthetized animals, increases in cutaneous blood flow in response to hypothalamic warming are offset by concomitant reductions in gastrointestinal blood flow.64 In a cold environment or in response to a reduction in core temperature, cutaneous blood flow normally decreases as a means of conserving heat within the body core. Thermoregulation is a process that involves a continuum of neural structures and connections extending to and from the hypothalamus and limbic system through the lower brain stem and reticular formation to the spinal cord and sympathetic ganglia (Fig. 50-3).60 Nevertheless, an area of the brain located in and near the rostral hypothalamus

RF Septal Preoptic nucleus nucleus OVLT Anterior hypothalamus STt

Thermoregulation
Heat is derived from biochemical reactions occurring in all living cells.60 At the mitochondrial level, energy derived from the catabolism of metabolites such as glucose is used in oxidative phosphorylation to

Figure 50-3 Sagittal view of the brain and upper spinal cord showing the multisynaptic pathway of skin and spinal thermoreceptors through the spinothalamic tract (STt) and reticular formation (RF) to the anterior hypothalamus, preoptic region, and the septum. OVLT, organum vasculosum of the lamina terminalis. (From Mackowiak PA. Concepts of fever. Arch Intern Med. 1998;158:1870-1881.)

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appears to be especially important to the process of thermoregulation. Although generally referred to as the preoptic area, it actually includes the medial and lateral aspects of the preoptic area, anterior hypothalamus, and septum. Numerous studies extending over 60 years have established that a synaptic network of neurons located in this area exerts at least partial control over physiologic and behavioral thermoregulatory responses.63,65 The network encompasses four different types of neuronswarm-sensitive, temperature-insensitive, heat loss, and heat production effector neuronsthat regulate core temperature. Hypothalamic warm-sensitive neurons integrate core and peripheral thermal information, orienting their dendrites medially and laterally to receive afferent input from cutaneous thermoreceptors. Temperature-insensitive neurons have a different dendritic orientation and appear to provide constant reference signals that determine thermoregulatory setpoints. The temperature-sensitive and temperature-insensitive neurons send mutually antagonistic inputs to effector neurons controlling thermoregulatory responses, with warm-sensitive neurons exciting heat loss through effector neurons and inhibiting heat production neurons.65 Many, although not all, thermophysiologists believe that the temperature-sensitive preoptic area regulates body temperature by integrating thermal input signals from thermosensors in the skin and core areas, including the central nervous system.66 One of the more widely held theories is that such integration involves a designated thermal setpoint for the preoptic area that is maintained by a negative feedback system. According to this theory, if the preoptic temperature rises above its setpoint, for whatever reason (e.g., during exercise), heat loss responses are activated to lower the body temperature and return the temperature of the preoptic area to the thermal setpoint (e.g., 37C).67 The thermal setpoint of a particular heat loss response is thus the maximal temperature tolerated by the preoptic area before the heat loss response is evoked. If, on the other hand, the preoptic temperature falls below its thermal setpoint (e.g., as a result of cold exposure), various heat retention and heat production responses are activated to raise body temperature and, with it, the temperature of the preoptic area, to its thermal setpoint. The thermal setpoint of a particular heat production response is thus the minimal temperature tolerated by the preoptic area before the response is evoked. Although a convenient explanation of the means whereby temperature elevations are coordinated during fever, the concept of a single central setpoint temperature is regarded by many thermophysiologists as oversimplified. At least some physiologists prefer to think of body temperature as regulated within a narrow range of temperatures by a composite setpoint of several thermosensitive areas and several different thermoregulatory responses.68-70 Various endogenous substances and drugs appear to affect temperature regulation by altering the activity of hypothalamic neurons. Perhaps the best examples of such substances are the pyrogenic cytokines (see later). These are released by mononuclear phagocytes in response to a wide array of stimuli and have the capacity to raise the thermoregulatory centers thermal setpoint. Whether they cross the blood-brain barrier to do so71,72 or act by evoking the release of other mediators (e.g., prostaglandin E2 [PGE2]) in circumventricular organs, such as the organum vasculosum of the lamina terminalis (OVLT),71 is uncertain. Whatever the precise endogenous mediators of fever, their primary effect appears to be to decrease the firing rate of preoptic warm-sensitive neurons, leading to the activation of responses designed to decrease heat loss and increase heat production.

Endogenous Pyrogens
Traditionally, pyrogens have been divided into two general categories, those that originate outside the body (exogenous pyrogens) and those that are derived from host cells (endogenous pyrogens). Exogenous pyrogens are, for the most part, microorganisms and toxins or other products of microbial origin, whereas endogenous pyrogens are host cellderived (pyrogenic) cytokines that are the principal central mediators of the febrile response.73 According to traditional concepts, exog-

enous pyrogens, regardless of their physicochemical structure, initiate fever by inducing host cells (primarily macrophages) to produce endogenous pyrogens. Such concepts notwithstanding, certain endogenous molecules also have the capacity to induce endogenous pyrogens. These include, among others, antigen-antibody complexes in the presence of complement,74,75 certain androgenic steroid metabolites,76-78 inflammatory bile acids,79 complement,80 and various lymphocyte-derived molecules.81,82 Similarly, data recently obtained from guinea pig studies have suggested that bacterial lipopolysaccharide (LPS) induces fever directly (rather than indirectly through the induction of pyrogenic cytokines) by interacting with Kupffers cells, thereby initiating pyrogenic signals that are transmitted to the preoptic area of the hypothalamus via the hepatic branch of the vagus nerve.83 Thus, the distinction between endogenous and exogenous pyrogens is artificial at best. Complete understanding of the function of individual pyrogenic cytokines has been hampered by the fact that one cytokine often influences the expression of other cytokines, their receptors, or both, and may also induce more distal co-mediators of cytokine-related bioactivities (e.g., prostaglandins and platelet-activating factor).84 In short, cytokines function within a complex regulatory network in which information is conveyed to cells by combinations, and perhaps by sequences, of a host of cytokines and other hormones.85 Like the words of human communication, individual cytokines are basic units of information. On occasion, a single cytokine, like a single word, may communicate a complete message. More often, however, complete messages received by cells probably resemble sentences, in which combinations and sequences of cytokines convey information. Because of such interactions, it has been difficult to ascertain the direct in vivo bioactivities of particular cytokines. Nevertheless, several cytokines have the capacity to induce fever in common. On the basis of this characteristic, they have been codified together as so-called pyrogenic cytokines. The list of currently recognized pyrogenic cytokines includes interleukin-1 (IL-1 [IL-1 and IL-]), tumor necrosis factor- (TNF-), IL-6, ciliary neurotropic factor (CNF), and interferon (IFN).86-94 Even among these few cytokines, complex relationships exist, with certain members upregulating the expression of other members or their receptors in certain situations and downregulating them in others.84 The four major pyrogenic cytokines have monomeric molecular masses that range from 17 to 30kDa. Undetectable under basal conditions in healthy subjects, they are produced by many different tissues in response to appropriate stimuli. Once released, pyrogenic cytokines have short intravascular half-lives. They are pleiotropic, in that they interact with receptors present on many different host cells. They are active in picomolar quantities, induce maximal cellular responses even at low receptor occupancy, and exert local (autocrine-paracrine) as well as systemic (endocrine) effects.84 It has long been suspected that interactions between pyrogenic cytokines and their receptors in the preoptic region of the anterior hypothalamus activate phospholipase A2, liberating plasma membrane arachidonic acid as a substrate for the cyclooxygenase (COX) pathway. Some cytokines appear to do so by increasing COX expression directly, causing liberation of the arachidonate metabolite PGE2. Because this small lipid molecule easily diffuses across the blood-brain barrier, it is thought by some to be the local mediator that activates thermosensitive neurons. In the case of fever induced by circulating IL-6, the cytokines pyrogenic effect appears to be mediated by PGE2 produced by nuclear signal transducer and activator of transcription (STAT)3 positive cells involved in the COX-2dependent fever pathway in the cerebral microvasculature.95 Although it is not yet widely accepted, additional studies have indicated that the C5a component of the complement cascade is integral to LPS-induced fever96 and that in some situations, thermal information involved in the febrile response is transmitted from the periphery to the thermoregulatory center via vagal pathways (see earlier).97 Figure 50-4 depicts the current hypothetical model for the febrile response,98 in which pyrogenic cytokines released by phagocytic leu-

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TABLE

50-1

Acute-Phase Physiologic Reactions

Exogenous pyrogen

Activated leukocytes Temperaturedependent feedback on cytokine expression

IL-6

Pyrogenic cytokines (IL-1, TNF-, IFN-) IL-6

Neuroendocrine Changes Fever, somnolence, and anorexia Increased secretion of corticotropin-releasing hormone, corticotropin, and cortisol Increased secretion of arginine vasopressin Decreased production of insulin-like growth factor I Increased adrenal secretion of catecholamines Hematopoietic Changes Anemia of chronic disease Leukocytosis Thrombocytosis Metabolic Changes Loss of muscle and negative nitrogen balance Decreased gluconeogenesis Osteoporosis Increased hepatic lipogenesis Increased lipolysis in adipose tissue Decreased lipoprotein lipase activity in muscle and adipose tissue Cachexia Hepatic Changes Increased metallothionein, inducible nitric oxide synthase, heme oxygenase, manganese superoxide dismutase, and tissue inhibitor of metalloproteinase-1 Decreased phosphoenolpyruvate carboxykinase activity Changes in Nonprotein Plasma Constituents Hypozincemia, hypoferremia, and hypercupremia Decreased plasma retinol concentrations Increased plasma glutathione concentrations
From Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448-454. Copyright 1999 Massachusetts Medical Society. All rights reserved.

Circumventricular organs PGE2 103 F Fever Figure 50-4 Hypothetical model for the febrile response. (From Mackowiak PA. Concepts of fever. Arch Intern Med. 1998;158: 1870-1881.)

vidual cytokines in response to various stimuli; or how the upper limit of the febrile range is set.84

Acute-Phase Response
As noted, a cytokine-mediated rise in the core temperature is but one of many features of the febrile response. Numerous other physiologic reactions, collectively referred to as the acute-phase response, are mediated by members of the same group of pyrogenic cytokines that activate the thermal response of fever. Such reactions include a host of behavioral, physiologic, biochemical, and nutritional alterations (Table 50-1).101 Stimuli capable of inducing an acute-phase response include bacterial and (to a lesser extent) viral infections, trauma, malignant neoplasms, burns, tissue infarction, immunologically mediated and crystal-induced inflammatory states, strenuous exercise, and childbirth.85,102 There is also evidence that major depression,103 schizophrenia,104 and psychological stress105 are capable of inducing an acutephase response. Traditionally, the term acute-phase response has been used to denote changes in plasma concentrations of a number of secretory proteins derived from hepatocytes. Acute-phase proteins, of which there are many (Table 50-2),101 exhibit increased synthesis (positive acute-phase proteins) or decreased synthesis (negative acute-phase proteins) during the acute-phase response. IL-6 is the chief stimulator of the production of most acute-phase proteins. Other pyrogenic cytokines, however, also influence the production of various subgroups of these proteins.101 Many of the acute-phase proteins are believed to modulate inflammation and tissue repair.106 A major function of C-reactive protein (CRP), for example, is presumed to involve binding of phosphocholine on pathogenic microorganisms, as well as phospholipid constituents on damaged or necrotic host cells. Through such binding, CRP might activate the complement system and promote phagocyte adherence, thereby initiating the process whereby pathogenic microbes or necrotic

kocytes into the bloodstream in response to exogenous pyrogens find their way to the OVLT, where they induce synthesis of prostaglandins mediating the febrile response. The model has several shortcomings that have caused thermophysiologists to suspect that multiple pathways might be involved in the induction of fever (e.g., the vagal pathways referred to earlier, local production of pyrogenic cytokines in the hypothalamus itself, participation of membrane-bound cytokines as mediators, and Toll-like receptor signal transduction), with different pathways or combinations of pathways being responsible for fever in different situations.97,99,100 All the models proposed to date have been concerned with mechanisms responsible for the induction phase of fever. None has considered the plateau or ascending phases of fever or explained why a disorder such as endocarditis, in which exogenous pyrogens (i.e., bacteria) are present continuously in the blood, is associated with a remittent rather than a continuous fever pattern. As a consequence, our understanding of the febrile response remains incomplete and largely speculative. As noted, the following are not yet clear: whether circulating cytokines cross the blood-brain barrier or have to be produced within the central nervous system to activate thermosensitive neurons; whether each of the pyrogenic cytokines is capable of raising the thermoregulatory setpoint independently or must exert this effect through some final common pathway (see Fig. 50-4); whether PGE2 or other local mediators are a sine qua non of the febrile response; what determines the magnitude of expression of indi-

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TABLE

50-2

Human Acute-Phase Proteins

Proteins Whose Plasma Concentrations Increase Complement system C3 C4 C5 C9 MAC Factor B C1 inhibitor C4b-binding protein Mannose-binding lectin Coagulation and fibrinolytic system Fibrinogen Plasminogen Tissue plasminogen activator Urokinase Protein S Vitronectin Plasminogen-activator inhibitor I Kininogen Antiproteases 1-Protease inhibitor 1-Antichymotrypsin Pancreatic secretory trypsin inhibitor Inter--trypsin inhibitors Transport proteins Ceruloplasmin Haptoglobin Hemopexin Participants in inflammatory responses Secreted phospholipase A2 Lipopolysaccharide-binding protein Interleukin-1 receptor antagonist Granulocyte colony-stimulating factor Others C-reactive protein Serum amyloid A 1-Acid glycoprotein Fibronectin Ferritin Angiotensinogen Proteins Whose Plasma Concentrations Decrease Albumin Transferrin Transthyretin 2-HS glycoprotein Alpha-fetoprotein Thyroxine-binding globulin Insulin-like growth factor I Factor XII Retinol-binding protein
Adapted from Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999;340:448-454. Copyright 1999 Massachusetts Medical Society. All rights reserved.

play important roles in modulating inflammation. However, the functional capacity of such proteins is broad. There is also a growing literature concerned with the acute-phase protein LPS-binding protein, which appears both to enhance and neutralize the biologic activity of LPS through its interaction with the CD14 receptor on macrophages.115 Although closely associated with fever, the acute-phase response is not an invariable component of the febrile response.101 Some febrile patients (e.g., those with certain viral infections) have normal blood levels of CRP. Moreover, patients with elevated blood levels of CRP are not always febrile. The acute-phase response, like the febrile response, is a complex response consisting of numerous integrated, though separately regulated, components. The particular components expressed in response to a given disease process more than likely reflect the specific cytokines induced by the disease.

Endogenous Antipyretics
Hippocrates maintained that heat is the immortal substance of life endowed with intelligence. However, heat must also be refrigerated by respiration and kept within bounds if the source or principle of life is to persist; for if refrigeration is not provided, the heat will consume itself.116 Modern-day clinicians also generally subscribe to the notion that the febrile range has an upper limit but do not agree on a precise temperature defining this limit.52 The lack of a consensus in this regard is understandable, because body temperature profiles exhibit considerable individual, anatomic, and diurnal variability. Thus, the upper limit of the febrile range cannot be defined as a single temperature applicable to all body sites of all people at all times during the day. Nevertheless, the febrile response is a regulated physiologic response, in which the temperature is maintained within a specific range, the upper limit of which almost never exceeds 41C in adult humans, regardless of the cause of the fever or the site at which the temperature measurement is taken.117 The physiologic necessity of this upper limit is supported by considerable experimental data demonstrating adverse physiologic consequences of core temperatures higher than 42C (107.6F).118 The mechanisms regulating fevers upper limit have yet to be fully elucidated. They could lie with the intrinsic properties of the neurons themselves or involve the release of endogenous antipyretic substances that antagonize the effects of pyrogens on thermosensitive neurons. With regard to the former possibility, plots of the firing rates of neurons coordinating thermoregulatory responses and heat production tend to converge at 42C (107.6F; Fig. 50-5).118 At this temperature, the sustained firing rates of warm-sensitive neurons reach their zenith and cannot be increased further in response to higher temperatures. Similarly, the firing rates of cold-sensitive neurons reach their nadir at 42C (107.6F) and cannot decrease further, even if the temperature continues to increase. Thus, regardless of the pyrogen concentration, thermosensitive neurons appear to be incapable of providing additional thermoregulatory signals once the temperature reaches 42C (107.6F). These same thermosensitive neurons are influenced by various endogenous substances, at least some of which appear to function as endogenous antipyretics.118 One such substance is arginine vasopressin. Studies from several laboratories using various animal models have established that arginine vasopressin is present in the fibers and terminals of the ventral septal area of the hypothalamus, is released into the ventral septal area during fever, reduces fever by its action at type 1 vasopressin receptors when introduced into the ventral septal area, and, when inhibited, prolongs fever.119-121 Melanocyte-stimulating hormone (-MSH) is another neuropeptide exhibiting endogenous antipyretic activity.122 Unlike some of the other antipyretic peptides, -MSH has not been identified in fibers projecting into the dorsolateral septal area.123 It does, nevertheless, reduce pyrogen-induced fever when administered to experimental animals in doses below those affecting the basal body temperature.124-128 When given centrally, -MSH is more than 25,000 times more potent

cells are cleared from the host. Such activities are most likely potentiated by CRP-induced production of inflammatory cytokines107 and tissue factor108 by monocytes. Nevertheless, the ultimate function of CRP is uncertain, in that several in vivo studies have shown it to have anti-inflammatory properties.109-111 Another major human acute-phase protein, serum amyloid A, has been reported to potentiate adhesiveness and chemotaxis of phagocytic cells and lymphocytes.112 There is also evidence that macrophages bear specific binding sites for serum amyloid A; serum amyloid Arich, high-density lipoproteins mediate the transfer of cholesterol to macrophages at sites of inflammation;113 and serum amyloid A enhances low-density lipoprotein oxidation in arterial walls.114 Complement components, many of which are acute-phase reactants, induce pyrogenic cytokines and PGE2; modulate chemotaxis, opsonization, vascular permeability, and vascular dilation; and have cytotoxic effects.101 Haptoglobin, hemopexin, and ceruloplasmin are all antioxidants. It is therefore reasonable to assume that, like the antiproteases 1-antichymotrypsin and C1-esterase inhibitor, they

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Pyrogen Maximum A FR w N P2 Th 37 C 42 C FR c P1 N P2 P1

Vertebrata Mammalia Aves Reptilia Amphibia Pisces

Arthropoda Crustacea Chelicerata Insecta

Chordata Urochordata Aechinodermata

Th 37 C 42 C Heat production P1 N P2 Annelida Hirudinea

Brachiopoda Ectoprocta Phoronidea Sipunculida Coelenterata Ctenophora

Th 37 C 42 C Mollusca Figure 50-5 Model showing responses (A, B) of the neuronal firing rate (FR) in the preoptic region and anterior hypothalamus and whole-body metabolic heat production (C) during changes in hypothalamic temperature (Th). Thermosensitivity is reflected by the slope of each plot. The letters inside the cells indicate a warm-sensitive (w) neuron and cold-sensitive (c) neuron. With increases in Th, warmsensitive neurons raise their FRs and heat production decreases. Pyrogens inhibit () the FRs of warm-sensitive neurons, thereby resulting in accelerated FRs of cold-sensitive neurons and increased heat production. The plots show FR and heat production responses during normal conditions in the absence of pyrogens (N) and in the presence of low concentrations (P1) and high concentrations (P2) of pyrogens. (From Mackowiak PA, Boulant JA. Fevers glass ceiling. Clin Infect Dis. 1996;22:525-536.) Gastropoda Platyhelminthes

ANIMALIA Figure 50-6 Evolutionary tree of animals. A febrile response has been documented in the Vertebrata, Arthropoda, and Annelida. These observations suggest that the febrile response evolved more than 400,000,000 years ago at about the time that evolutionary lines leading to arthropods and annelids diverged.

as an antipyretic than acetaminophen.122 Repeated central administration of -MSH does not induce tolerance to its antipyretic effect.129 In addition, injection of anti-MSH antiserum into the cerebral ventricles has augmented the febrile response of experimental animals to IL-1.130 Glucocorticoids and their inducers (e.g., corticotropin-releasing hormone [CRH] and corticotropin) inhibit the synthesis of pyrogenic cytokines such as IL-6 and TNF-.131-133 Through such effects, they are believed to exert inhibitory feedback on LPS-induced fever.134 Lipocortin 1, a putative mediator of glucocorticoid function, has also been shown to inhibit the pyrogenic actions of IL-1 and IFN.135 Injection of CRH into the third ventricle of experimental animals produces similar antipyretic effects.136 Thyrotropin-releasing hormone,137 gastric-inhibitory peptide,138 neuropeptide Y,139 nitric oxide,140 carbon monoxide,141 and bombesin142 similarly exhibit antipyretic properties under certain conditions. Of these, bombesin has exhibited the highest potency in that it consistently produces hypothermia associated with changes in heat dissipation and heat production when injected into the preoptic area or anterior hypothalamus of conscious goats and rabbits.142-144 Bombesin is believed to exert its hypothermic effect by decreasing the sensitivity of warm-sensitive neurons.144 IL-10 has been shown to mediate defervescence of fever evoked by both LPS-induced and Staphylococcus aureusinduced inflammation in rats.145 Moreover, pyrogenic cytokines, the mediators of the febrile response, might themselves have a role in determining fevers upper limit, in that under certain conditions (e.g., with intracerebral injection of recombinant human TNF- in Zucker rats), TNF- acts to lower rather than raise body temperature,146,147 although only in the presence of LPS. Thus, it is possible that at certain concentrations or

in the appropriate physiologic milieu, pyrogenic cytokines function paradoxically as endogenous antipyretics. A growing body of literature has indicated that the release of pyrogenic cytokines such as IL-1 is followed by increased shedding of soluble receptors for such cytokines, which function as endogenous scavengers of these pyrogens.148 In the case of IL-1, a 22- to 25-kDa molecule identified in supernates of human monocytes blocks binding of IL-1 to its receptors.149 The IL-1 receptor antagonist is structurally related to IL-1 and IL-1150 and binds to types I and II receptors on various target cells without inducing a specific biologic response.151,152 Shedding of soluble receptors of TNF- that bind to circulating TNF- and thereby inhibit binding to cell-associated receptors has also been described.153-157 The precise biologic function of such circulating receptor antagonists and soluble receptors is not known. However, it is possible that one function is to serve as a natural braking system for the febrile response.

Risk-Benefit Considerations
Questions concerning fevers risk-benefit quotient have generated considerable controversy.158 The controversy arises because of data indicating both potentiating and inhibitory effects of the response on resistance to infection. As a result, there is as yet no consensus as to the appropriate clinical situations (if any) in which fever or its mediators should be suppressed. Evidence illustrating fevers beneficial effects originate from several sources. Studies of the phylogeny of fever have shown the response to be widespread within the animal kingdom.159 With few exceptions, mammals, reptiles, amphibians, and fish, as well as several invertebrate species, have been shown to elevate their core temperature in response

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to a challenge with microorganisms or other known pyrogens (Fig. 50-6). It has been assumed, although not established conclusively, that such elevations in temperature are the poikilothermic corollary of fever. The prevalence of such febrile responses has been offered as some of the strongest evidence that fever is an adaptive response, based on the argument that the metabolically expensive increase in body temperature that accompanies the febrile response would not have evolved and been so faithfully preserved in the animal kingdom unless fever had some net benefit to the host. Further evidence of fevers beneficial effects can be found in numerous investigations demonstrating enhanced resistance of animals to infection with increases in body temperature within the physiologic range.159 In classic studies involving experimental infection of the reptile Dipsosaurus dorsalis with Aeromonas hydrophila, Kluger and associates demonstrated a direct correlation between body temperature and survival.160,161 They also showed in their model that suppression of the febrile response with sodium salicylate is associated with a substantial increase in mortality.161 Covert and Reynolds corroborated these findings in an experimental model involving goldfish.162 In mammalian experimental models, increasing the body temperature by artificial means has been reported to enhance the resistance of mice to herpes simplex virus,163 poliovirus,164 coxsackie B virus,165 rabies virus,166 and Cryptococcus neoformans167 but to decrease resistance to Streptococcus pneumoniae.168 Increased resistance of rabbits to S. pneumoniae169 and C. neoformans,170 dogs to herpesvirus,171 piglets to gastroenteritis virus,172 and ferrets to influenza virus173 has also been observed after the induction of artificial fever. Unfortunately, because raising the body temperature by artificial means does not duplicate the physiologic alterations that occur during fever in homeotherms (and, indeed, entails a number of opposite physiologic responses174), evidence obtained using mammalian experimental models must be interpreted with caution when used to understand the febrile response. Clinical data supporting an adaptive role for fever have accumulated slowly. Like animal data, clinical data include evidence of the beneficial effects of fever and adverse effects of antipyretics on the outcome of infections. In a retrospective analysis of 218 patients with gram-negative bacteremia, Bryant and associates reported a positive correlation between maximal temperature on the day bacteremia was diagnosed and survival.175 A similar relationship has been observed in patients with polymicrobial sepsis and mild (but not severe) underlying diseases.176 In an examination of factors influencing the prognosis of spontaneous bacterial peritonitis, Weinstein and co-workers identified a positive correlation between a temperature reading higher than 38C (100.4F) and survival.177 It has been reported that children with chickenpox who are treated with acetaminophen have a longer time to total crusting of lesions than placebo-treated controls.178 Stanley and colleagues have reported that adults infected with rhinovirus exhibit more nasal viral shedding when they receive aspirin than when given placebo.179 Furthermore, Graham and colleagues have reported a trend toward a longer duration of rhinovirus shedding in association with antipyretic therapy and have shown that the use of aspirin or acetaminophen is associated with suppression of the serum-neutralizing antibody response and with increased nasal symptoms and signs.180 A more recent retrospective observational analysis of studies of human volunteers infected with influenza A has found a relationship between antipyretic therapy and prolonged illness.181 These data, like those reviewed earlier, are subject to several interpretations and do not prove a causal relationship between fever and improved prognosis during infection. Nevertheless, they are consistent with such a relationship and, when considered in concert with the phylogeny of the febrile response and the animal data summarized earlier, constitute strong circumstantial evidence that fever is an adaptive response in most situations. Whereas many of the foregoing investigations examined the relationship between elevation of the core temperature and outcome of infection, others have considered the endogenous mediators of the febrile response. In such studies, all the principal pyrogenic cytokines have been shown to have immune-potentiating capabilities, which

might theoretically enhance resistance to infection.84,182 In vitro and in vivo investigations of these cytokines have provided evidence of a protective effect of IFN, TNF-, or IL-1, or all of these, against Plasmodium,183-185 Toxoplasma gondii,186 Leishmania major,187 Trypanosoma cruzi,188 and Cryptosporidium.189 Several reports have also shown enhancement of resistance to viral190-192 and bacterial infections193,194 by pyrogenic cytokines. Treatment of normal and granulocytopenic animals with IL-1 has been shown to prevent death in some gram-positive and gram-negative bacterial infections.194 However, IL-1 is effective only if administered an appreciable time (e.g., 24 hours) before the initiation of infections having rapidly fatal courses. In less acute infections, IL-1 administration can be delayed until shortly after the infectious challenge. Such observations suggest that those physiologic effects of the febrile response that enhance resistance to infection might be limited to localized infections or systemic infections of only mild to moderate severity. The febrile responses potential for harm was reflected in a flurry of reports suggesting that IL-1, TNF-, IL-6, and IFN mediate the physiologic abnormalities of certain infections. Although proof of an adverse effect of fever on the clinical outcome of these infections has yet to be established, the implication is that if pyrogenic cytokines contribute to the pathophysiologic burden of infections, both the mediators themselves and the febrile response are potentially deleterious. The most persuasive evidence in this regard derives from studies of gram-negative bacterial sepsis.195 It has long been suspected that bacterial LPS is involved in the pathophysiology of the syndrome. Purified LPS induces a spectrum of physiologic abnormalities similar to those occurring in patients with gram-negative bacterial sepsis. In experimental animals, challenge with LPS causes TNF- and IL-1 to be released into the bloodstream coincident with the appearance of signs of sepsis.196 Furthermore, patients with the septic syndrome have detectable levels of circulatory TNF-, IL-1, and IL-6 independent of culture-documented infection, and these levels correlate inversely with survival.197 IL-1, alone or in combination with other cytokines, induces many of the same physiologic abnormalities (e.g., fever, hypoglycemia, shock, and death) seen after the administration of purified LPS.198 In a murine experimental model for septic shock, IFN administered before or as long as 4 hours after LPS challenge increases mortality, whereas pretreatment with anti-IFN antibody significantly reduces mortality.199 In several investigations, the adverse effects of gramnegative bacterial sepsis, LPS injections, or both, have been attenuated by pretreating experimental animals with IL-1 antagonists200,201 and monoclonal antibodies directed against TNF-.202,203 Furthermore, animals rendered tolerant to TNF- by repeated injections of the recombinant cytokine are protected against the hypotension, hypothermia, and lethality of gram-negative bacterial sepsis.204 The theory derived from these observationsthat death from sepsis is the consequence of cytokine-mediated overstimulation of the immune systemunfortunately correlates only loosely with the clinical picture in humans, most likely because the studies cited used large doses of endotoxin or bacteria that induced levels of circulating pyrogenic cytokines exponentially higher than those detected in patients with sepsis.205 Thus, the cytokine storm created in such animals most likely has only limited relevance for human sepsis. This perhaps explains why in clinical trials, inhibition of pyrogenic cytokines in septic patients has had only modest success, improving outcome in patients with a high risk for death but not those with a low risk.206

Antipyretic Therapy
Although clinicians have long had at their disposal effective means of lowering the core temperature in febrile patients, the actual benefit of such reductions in temperature is still uncertain. Moreover, it has yet to be shown in humans that increases in the core temperature encountered during fever are actually harmful. Certainly, during the course of heat stroke and other forms of hyperthermia, the core temperature

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can, and frequently does, rise to levels that are inherently harmful.207 However, as noted, such levels are almost never reached during fevers regulated rise in temperature, which probably never exceeds 41C (105.8F) in humans.118 Nevertheless, whereas healthy volunteers have been reported to withstand core temperatures of 42C (107.6F) for periods of as long as 4 hours without apparent ill effects,208 the possibility remains that in certain patients, even the relatively modest increases in core temperature encountered during fever are deleterious and should therefore be suppressed. One such category of patients includes children, primarily those between the ages of 3 months and 5 years. In such children, seizures have been reported to occur during episodes of fever at a frequency as high as 14% in select populations.209 Although most children with febrile seizures have temperatures of 39C (102.2F) or higher at the time of their seizure,210 many tolerate even higher fevers at later dates without convulsing.211 Unfortunately, antipyretic therapy has not been shown to protect against recurrences of febrile seizures in the few controlled trials conducted thus far (see later).212 It has also been suggested that patients with underlying cardiovascular or pulmonary disorders might be especially susceptible to the adverse effects of fever because of metabolic demands imposed by the elevated temperature.213 Such demands are particularly high during the chill phase if shivering is present, as evidenced by increases in the sympathetic tone,174 oxygen consumption, respiratory minute volume, and respiratory quotient.214 As a result of the associated increase in metabolic demand, the chill phase of fever might be expected to add to the burden of cardiac or pulmonary disorders. Although this possibility has been offered as justification for antipyretic therapy in patients with these disorders, the risk-benefit ratio of such therapy has yet to be determined. Antipyretic therapy might also be justified, at least in theory, if fevers physiologic benefit exceeded its metabolic cost, if the treatment provided symptomatic relief without adversely affecting the course of the febrile illness, or if the toxicity (side effects) of the antipyretic regimen were appreciably lower than its beneficial effects. Unfortunately, although clinicians have long argued the validity of each of these propositions as justification for antipyretic therapy, few scientific data exist to support any of these arguments. Antipyretic drugs can be grouped into three general categories on the basis of their mechanisms of action. These include corticosteroids, aspirin and the other nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen. Each exerts its effects at different points in the febrile response pathway. Although not generally used for antipyresis, corticosteroids suppress fever through direct and indirect mechanisms. They block the transcription of pyrogenic cytokines and inducible COX via interactions involving the glucocorticoid receptor.73,215 They downregulate the synthesis of cytokine receptors and, by inducing lipocortin-1, they secondarily inhibit the activity of phospholipase A2, a critical enzyme in the prostaglandin synthetic pathway.215 Acetaminophen and aspirin and the other NSAIDs all inhibit COXmediated synthesis of inflammatory thromboxanes and prostaglandins from arachidonic acid. Cyclooxygenase has at least two distinct isoforms, COX-1 and COX-2. The former was long regarded as a constitutively expressed cellular enzyme involved in various housekeeping functions, whereas the latter was touted as an inducible enzyme responsible for hypothalamus-mediated fever and produced as part of the inflammatory process by various cell lines, including macrophages, synoviocytes, and endothelial cells. However, this dichotomous concept of a constitutive COX-1 and an inducible proinflammatory COX-2 has proved to be oversimplified. Not only do some cells express COX-2 constitutively but, under certain conditions, COX-2 has also been shown to promote healing of mucosal lesions and resolution of inflammation.216 The distinctive affinities of the various categories of antipyretic drugs for the different COX variants are thought to determine their relative antipyretic and analgesic potencies. Acetaminophen and aspirin, for example, are equally potent inhibitors of central COX but

only 10% as potent in this regard as indomethacin. Acetaminophen selectively inhibits a third COX variant, a close relative of COX-1 derived from the same gene and referred to as COX-3.217 The importance of the discovery of COX-3 is that it explains the pharmacologic actions of acetaminophen and other antipyretic analgesic drugs, which are weak inhibitors of COX-1 and COX-2 but penetrate easily into the central nervous system. NSAIDs such as diclofenac or ibuprofen are also potent inhibitors of COX-3 expressed in cultured cells but, being highly polar, are unlikely to reach brain COX-3 in effective concentrations.218 Only aspirin irreversibly inhibits COX via acetylation within the active site of the enzyme. Other NSAIDs and acetaminophen inhibit COX reversibly.219 Studies have shown that aspirin and the NSAIDs also have COXindependent antipyretic activity. Aspirin induces cytochrome P-450, which might augment its antipyretic effect by shifting arachidonic acid metabolism toward cytochrome P-450mediated production of antipyretic epoxyeicosanoids. Additionally, acetylation of COX-2 by aspirin increases the production of 15R-hydroxyeicosatetraenoic acid, which neutrophils use to form aspirin-triggered lipoxins. These lipoxins have potent anti-inflammatory activity independent of aspirin. Heat shock proteins have been shown to reduce the transcription of IL-1B in vitro, and therapeutic doses of aspirin and certain NSAIDs increase heat shock factor 1 concentration in vitro. These same drugs also diminish the activity of transcriptional activator nuclear factor kappa B (NF-B),219 which is involved in the transcription of pyrogenic cytokines, adhesion molecules, inducible nitric oxide synthase, and COX-2 in certain cell lines. Production of adenosine, an antiinflammatory mediator produced by leukocytes, is enhanced by aspirin and NSAIDs. The clinical implications of these alternative antipyretic pathways remain to be determined. PHYSICAL METHODS OF ANTIPYRESIS Various physical techniques are used to cool febrile patients. These include sponging with various solutions (e.g., tepid water or alcohol), the application of ice packs or cooling blankets, and exposure to circulating fans (most often in conjunction with sponging). With the latter method, Helox (80% helium, 20% oxygen) has been shown to be superior to air in lowering core temperature, at least in experimental animals, because of the greater thermal conductivity of helium compared with that of nitrogen.220 In contrast to antipyretic drugs, external cooling lowers the temperature of febrile patients by overwhelming effector mechanisms that have been evoked by an elevated thermoregulatory setpoint, rather than by lowering that setpoint. Therefore, unless concomitant antipyretic agents are used, or shivering is inhibited by other pharmacologic means, external cooling is vigorously opposed in the febrile patient by thermoregulatory mechanisms endeavoring to maintain the elevated body temperature. Physical methods of antipyresis promote heat loss by conduction, convection, and evaporation. Evaporative methods have traditionally been touted as the most effective physical means of promoting heat loss in febrile patients, because these methods are deemed to be least likely to induce shivering.221 However, carefully designed comparative trials have not yet established any one physical method of antipyresis as superior. Similarly, direct comparisons of pharmacologic and physical methods of antipyresis are all but nonexistent. In the only extant controlled study, Wenzel and Werner reported that salicylates reduced the second phase of endotoxin-induced fever in rabbits, whereas abdominal cooling increased heat production and did not lower the core temperature unless the animals were simultaneously exposed to environmental hyperthermia.222 Neither antipyretic modality abolished the initial febrile response. The few available clinical studies of the efficacy of physical methods of antipyresis have differed in their conclusions. Interpretation of the results of these studies has been difficult, because pharmacologic agents have almost invariably been administered concomitantly with external cooling. Steele and co-workers found acetaminophen (in age-

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adjusted dosages ranging from 80 to 320 mg) and sponging to be equally effective in lowering fever in children admitted to a pediatric hospital because of fever.223 However, when combined, the two modalities produced more rapid cooling than either alone. By contrast, Newman found that tepid water sponging in combination with acetaminophen (5 to 10mg/kg) was no more effective than acetaminophen alone in lowering the temperature of febrile children.224 ODonnell and colleagues have concluded that in adults, although hypothermia blanket therapy adds little to the action of pharmacologic agents in lowering temperature, it induces wider temperature fluctuations and more episodes of rebound hyperthermia.221 DIAGNOSTIC CONSIDERATIONS Numerous investigators have observed a direct correlation between the height of fevers and the rate of serious bacterial infections in children, with the maximal incidence of such infections at temperatures in excess of 40C (104F).225-228 It has also been suggested that the response of a fever to antipyretic therapy might have diagnostic implications, in that a drop in temperature, improvement in the appearance of a febrile child, or both generally indicates that the fever is not the result of a serious illness.229 This conclusion, however, is not supported by numerous investigations comparing the temperature response of bacteremic and nonbacteremic infections to antipyretic therapy in children.230-235 Several studies have suggested that an antipyretic response to NSAIDs can distinguish fevers of infectious origin from those caused by cancer by virtue of the fact that the latter fevers are more readily suppressed by such agents. Naproxen was the first such agent to be studied in this regard.236 Subsequent randomized comparisons have shown naproxen, indomethacin, and diclofenac to be equally effective in inhibiting cancer-induced fever,237 although the sensitivity and specificity of the naproxen test for differentiating neoplastic from infectious fevers are not yet known. Moreover, there is no physiologic rationale to explain why NSAIDs might be more effective in reducing fever caused by cancer than that caused by infection. BENEFITS VERSUS RISKS Two critical assumptions are made when prescribing antipyretic therapy. One is that fever is, at least in part, noxious, and the other is that suppressing fever will reduce if not eliminate fevers noxious effects. Neither assumption has been validated experimentally. In fact, there is considerable evidence that fever is an important defense mechanism that contributes to the hosts ability to resist infection.238 However, even if fever (or its mediators) does adversely affect the course of certain disordersfor example, bacterial sepsis158it does not necessarily follow that inhibiting fever using current modes of antipyretic therapy will obviate this effect, especially if such therapy has intrinsic toxicity of its own. One of the reasons commonly given to justify suppressing fever is that the metabolic cost of fever exceeds its clinical benefit. The metabolic cost of fever is substantial, especially during the chill phase of the response, with its shivering-induced increase in metabolic rate, norepinephrine-mediated peripheral vasoconstriction, and increased arterial blood pressure.174 Because of the potential adverse consequences of these metabolic effects on cardiovascular and pulmonary function, fever has been attacked with particular vigor in patients with underlying cardiovascular and pulmonary diseases.239 Although antipyretic therapy has theoretical merit in this regard, if it does not induce shivering,240 the detrimental effects of fever and the salutary effects of antipyretic therapy have yet to be critically evaluated. External cooling, which is widely used in critically ill patients to suppress fevers unresponsive to antipyretic drugs, has been shown to decrease oxygen consumption by as much as 20% if shivering is prevented by therapeutic paralysis.240 If shivering is not inhibited, external cooling causes a rise, rather than a fall, in oxygen consumption.240 Perhaps more important to febrile patients with underlying cardiovas-

cular disease, external cooling has the capacity to cause vasospasm of diseased coronary arteries by inducing a cold pressor response.241,242 For all these reasons, it has been suggested that a more rational strategy for treating fevers unresponsive to antipyretic drugs is to warm rather than to cool selected skin surfaces (e.g., the forehead), thereby reducing the vasoconstriction and shivering thresholds dictated by the elevated hypothalamic thermal setpoint and, in turn, effecting a decrease in the core temperature.243 Unfortunately, certain antipyretic drugs also appear to cause coronary vasoconstriction in patients with coronary artery disease. Friedman and associates observed significant increases in the mean arterial pressure, coronary vascular resistance, and myocardial arteriovenous oxygen difference after IV indomethacin (0.5mg/kg) in such patients.244 Coronary blood flow decreased simultaneously from 181 29 to 111 14mL/min (P < .05). Thus, in this investigation, myocardial oxygen demand increased in the face of a fall in coronary blood flow after indomethacin administration. The authors believe that indomethacins vasoconstrictor effect most likely derives from to its capacity to block the synthesis of vasodilatory prostaglandins. Perhaps even more disturbing are reports suggesting that compared with other NSAIDS, COX-2selective NSAIDS seem to increase the risk for cardiovascular thrombotic events in patients not taking aspirin.245 Antipyretic therapy is also commonly administered to enhance patient comfort.239 General experience with antipyretic drugs, which are usually also analgesic agents, seems to support this contention. However, carefully controlled efficacy studies have not yet established the validity of this contention. Moreover, the relative cost of such symptomatic relief, in terms of drug toxicity and adverse effects of antipyretic agents on the course of the illness responsible for the fever, have never been determined. The importance of such information is underscored by reports that acetaminophen prolongs the time to crusting of lesions in children with chickenpox,178 both acetaminophen and aspirin increase viral shedding and nasal signs and symptoms while suppressing the serum-neutralizing antibody response in adults with rhinovirus infections,179,180 and antipyretic drugs might prolong the course of influenza A infections.181 Antipyretic therapy is also occasionally given to prevent febrile seizures in children and prevent or reverse fever-induced mental dys function in frail elderly patients. Beisel and co-workers have shown that aspirin (in combination with propoxyphene) ameliorates feverinduced decrements in mental work performance in young volunteers infected with sandfly fever virus, even in the face of only partial relief of the fever or other symptoms of the illness.246 In view of these observations, antipyretic therapy might be expected to have a beneficial effect on fever-induced mental dysfunction in frail elderly patients. However, studies designed to test this hypothesis have not yet been reported. Unfortunately, antipyretic therapy does not appear to be effective in preventing febrile seizures.212 Camfield and colleagues have conducted a randomized double-blind study comparing a single daily dose of phenobarbital plus antipyretic instruction to placebo plus antipyretic instruction to prevent recurrent seizure after an initial simple febrile seizure.247 In children treated with phenobarbital and antipyretics, the febrile seizure recurrence rate was 5%, whereas in those given placebo with antipyretics, the rate was 25%, suggesting that a single daily 5-mg/kg dose of phenobarbital is more effective than counseling parents about antipyretic therapy in preventing recurrent febrile seizures. More recently, acetaminophen has been given to children with fever as prophylaxis against febrile seizure recurrences. Whether given in moderate dosage (10mg/kg dose four times daily)248 or in relatively high doses (15 to 20 mg/kg dose every 4 hours),249 acetaminophen failed to reduce the rate of febrile seizure recurrence. Finally, there has been mounting interest in the use of certain antipyretic drugs to modulate the activity of pyrogenic cytokines during bacterial sepsis.250 In some animal models of sepsis, antipyretic drugs that inhibit COX confer protection when given soon after bacterial challenge, presumably by blunting the adverse effects of TNF- and IL-1. In a large clinical trial, Bernard and associates reported that 48

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hours of IV therapy with the COX inhibitor ibuprofen lowered the core temperature, heart rate, oxygen consumption, and lactic acid blood levels but did not decrease the incidence of organ failure or mortality at 30 days.251 In a more recent retrospective analysis of sepsis trials, Eichacker and co-workers found evidence of a beneficial effect of antipyretic agents only in septic patients with a high risk for death (see earlier).206 Thus, in spite of promising results obtained in some experimental models, antipyretic agents have been shown to be of only limited value clinically for the treatment of bacterial sepsis. INDICATIONS Although clinicians have long resorted to various forms of antipyretic therapy, there is a dearth of scientific data concerning the actual benefits and relative risks of such treatments.252 Nevertheless, several tentative conclusions regarding antipyretic therapy seem warranted in light of the limited data available. It is clear, for example, that short courses of approved doses of standard antipyretic drugs carry a low risk for toxicity. Most of these drugs have analgesic as well as antipyretic properties. Therefore, if not otherwise contraindicated (e.g., aspirin in young children because of the risk for Reyes syndrome), such drugs can be prescribed to provide symptomatic relief in febrile patients, reduce the metabolic demands of fever in patients with underlying

cardiovascular and pulmonary disorders, and possibly prevent or alleviate fever-induced mental dysfunction in older patients. To minimize antipyretic-induced fluctuations in temperature, as well as the risk for recurrent shivering with its associated increased metabolic demands, antipyretic agents should be administered to febrile patients at regular intervals that preclude abrupt recurrences of fever, rather than as needed for temperatures above some arbitrary level. Whenever such medications are prescribed, it should also be recognized that each carries its own risk for toxicity and might prolong the course of the illness responsible for the fever while reducing the intensity of its symptoms. In view of the capacity of external cooling measures to induce a cold pressor response, it is questionable whether this form of antipyretic therapy should ever be administered to febrile patients, much less to intensive care unit patients for whom it is so frequently prescribed. If external cooling is used to treat fever, care must be taken to prevent shivering because of its associated increased oxygen consumption. Unfortunately, even if shivering is prevented, there is no guarantee that a cold pressor response will be averted. In view of indomethacins capacity to cause coronary vasoconstriction in patients with coronary artery disease and the possible increased risk for cardiovascular thrombotic events associated with COX-2selective NSAIDs, it should be used cautiously to suppress fever in such patients.

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