Fever is common in ICUs: its incidence ranges from 28% to 70% of patients in general ICUs1, 2 and from 23% to 47% in neurologic and neurosurgical ICUs.3, 4 And although nurses employ various techniques in attempting to cool critically ill patients, no guidelines have been established for the pharmacologic and physical treatment of fever in this population. Should these patients be treated with physical methods of antipyresis—also known as external cooling methods—such as the application of cooling blankets or ice packs? And which techniques are best?

We reviewed original, controlled trials published in English, in which physical antipyresis was used in the treatment of adults in critical care settings. A total of 13 studies met these criteria: five compared physical antipyresis methods, six compared either pharmacologic with physical methods or a single method with a combination of methods, and two focused on the relationship between physical antipyresis and mortality rates. These 13 studies are detailed online in Table 1: http://links.lww.com/A456 . We discuss the findings of these studies, as well as other literature that did not meet these rigorous criteria, below.

Figure. Dana EchoHawk

PHYSICAL ANTIPYRESIS IN THE ICU: PROS AND (MOSTLY) CONS

Fever is usually treated initially with antipyretics. (For an in-depth discussion of the physiologic mechanisms involved, see The Causes of Fever and Other Forms of Temperature Elevation, page 42,5-14 and The Effects of Fever and Other Forms of Temperature Elevation, page 45.5, 12, 15–38) These include nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen (Tylenol), both of which inhibit the cyclooxygenase pathway and formation of prostaglandin E₂, thus accelerating the return of the thermoregulatory set point to normal.22 Conditions marked by nonfebrile temperature elevation, such as hyperthermia and malignant hyperthermia, are refractory to antipyretics, but may respond to other agents; for example, malignant hyperthermia is treated initially with dantrolene (Dantrium).

During fever, thermoregulatory mechanisms (such as shivering and vasoconstriction) remain intact and work to maintain the elevated core temperature. The hypothalamic set point relies on thermal signals from both core and peripheral structures (such as internal organs and skin, respectively), with skin thermoreceptors contributing about 20% of this information.39 The use of an external cooling method that significantly lowers skin temperature, then, will prompt an increase in shivering and vasoconstriction, which is counterproductive. Moreover, lowered skin temperature causes patients to feel uncomfortably cold. Peripheral vasoconstriction may be accompanied by increased arterial blood pressure and reduced urine output. And shivering can raise a patient's metabolic rate to three to five times its resting value.40

In a study by Lenhardt and colleagues, the use of air-flow cooling blankets by nine volunteers in whom moderate fever was induced significantly increased the incidence and duration of shivering, oxygen consumption, mean arterial pressure, and plasma epinephrine and norepinephrine concentrations.41 (Air-flow cooling blankets use circulating cooled air to lower body temperature by convection; water-flow cooling blankets use a layer of circulating cooled water to do so by conduction.) Particularly in patients with cardiovascular disease, external cooling may cause vasospasm of diseased coronary arteries by inducing a cold pressor response (an acute rise in arterial blood pressure in response to cold, which can increase the workload of the left ventricle). In such patients, warming (rather than cooling) selected skin surfaces to reduce vasoconstriction and shivering thresholds dictated by the elevated hypothalamic set point would be a safer and more effective strategy for promoting heat loss.42

When ICU patients are deeply sedated, shivering is inhibited and external cooling may ease the cardiorespiratory burden. In a study by Manthous and colleagues, air-flow cooling blankets were applied to 12 febrile, mechanically ventilated, sedated ICU patients.43 As temperature was reduced from a mean of 39.4°C to 37°C, oxygen consumption decreased from a mean of 359 mL/min to 295.1 mL/min, and energy expenditure decreased from a mean of 2,481 kcal/day to 1,990 kcal/day. In nonsedated patients, shivering during external cooling can be prevented by keeping the patient's extremities warm with insulating wraps (three layers of dry terry-cloth toweling or wadded, quilted cotton: wrapped from toes to groin and from fingertips to axillae).44, 45 Heat loss to the environment is then achieved by cooling the less-thermosensitive surface of the trunk. Various drugs, including meperidine, clonidine, physostigmine, and ondansetron, have been used to suppress shivering.46 But for many of these drugs such use is off label, and their effectiveness in suppressing shivering hasn't been proven in clinical trials.

More aggressive physical antipyresis hasn't been found to lower temperature more rapidly, and it results in a higher incidence of adverse effects. Caruso and colleagues used air-flow cooling blankets in a study of 89 febrile, hospitalized patients who were randomized to four cooling blanket–temperature groups: 7.2°C, 12.8°C, 18.3°C, and 23.9°C.47 (All patients also received acetaminophen.) There were no significant differences among groups in the mean time needed for core temperature to decrease to 38.9°C or lower; the cooling rate was found to be unaffected by blanket-temperature level. Patients exposed to the warmer blanket temperatures shivered less and reported being more comfortable.

Mortality rates. Especially among the critically ill, many factors will influence outcomes, making it difficult to determine the effects physical antipyresis has on death rates. We found only two studies investigating mortality rates. In a Swiss study by Gozzoli and colleagues, surgical ICU patients without neurotrauma or severe hypoxemia were randomized into two groups.48 One group received external cooling (via air-flow cooling blankets, ice packs, or cloths plunged into ice water) when core temperature exceeded 38.4°C; the second group received no antipyresis. No significant differences in comfort, fever recurrence, length of ICU stay, or mortality rates were noted. The authors concluded that “systematic suppression of fever may not be useful” in patients without neurotrauma or severe hypoxemia.

A study by Schulman and colleagues was conducted in trauma ICU patients who were randomized into two groups.49 Patients in the “aggressive” treatment group received pharmacologic antipyresis (acetaminophen) for temperatures higher than 38.5°C and physical antipyresis (air-flow cooling blanket) for temperatures higher than 39.5°C. Those in the “permissive” treatment group received no treatment until temperatures exceeded 40°C, when both acetaminophen and a cooling blanket were used. The study was stopped after the first interim analysis, after seven deaths occurred in the aggressive treatment group and only one death occurred in the permissive treatment group. Although this difference did not reach statistical significance, the researchers wrote that aggressive treatment “trended toward a higher mortality rate” and that “blunting the body's natural response to inflammation and infection inhibits its ability to recover from a severe insult.”

IS PHYSICAL ANTIPYRESIS SUPERIOR TO DRUGS?

Our review found that it's not clear which of the two approaches to antipyresis, physical or pharmacologic, is more effective. In a small, nonrandomized Swiss study by Poblete and colleagues, external cooling with cloths plunged into ice water and applied to “most of the body surface” of febrile, sedated, mechanically ventilated patients was more effective than treatment with either metamizol or propacetamol in decreasing core temperature and energy expenditure.50 (In the United States metamizol is known as dipyrone or noramidopyrine and is approved for veterinary use only; propacetamol is the prodrug for paracetamol, known in this country as acetaminophen.) But in another Swiss trial by Gozzoli and colleagues, 30 febrile, sedated, mechanically ventilated surgical patients were randomized to receive IV administration of metamizol, IV administration of propacetamol, or external cooling through the combined application of air-flow cooling blankets, cloths plunged into ice water, and ice packs.51 All three methods proved equally effective at lowering core temperature; however, for every 1°C reduction, the energy expenditure index (energy expenditure divided by body surface area) rose 5% in the external cooling group and fell 7% and 8% in the metamizol and propacetamol groups, respectively.

We found that combined pharmacologic and physical antipyretic treatments in ICU patients remain controversial. In a study involving 14 patients in liver-transplantation ICUs, Henker and colleagues evaluated the effectiveness of acetaminophen and a water-flow cooling blanket when used individually and in combination.52 The core temperature showed a mean decrease of 0.5°C in response to the combined treatment, compared with a mean decrease of 0.1°C when the blanket alone was used and a mean increase of 0.2°C when acetaminophen alone was given; although the differences did not reach statistical significance, that can be attributed to the small sample size. Shivering occurred in four of the six patients (67%) treated with the blanket alone and in one of the five (20%) treated with acetaminophen alone, but in none of the three patients treated with both.

Similarly, in a study by Mayer and colleagues involving 220 patients in a neurologic ICU, the combined use of acetaminophen and an air-flow cooling blanket was compared with the use of acetaminophen alone.53 After 24 hours of treatment, there was no significant difference between the patient groups in the proportion achieving core temperatures at or below 37.2°C (44% versus 36%, respectively). In this relatively large study, the lack of statistical significance could not be attributed to sample size; the authors concluded that more effective interventions are necessary to achieve and maintain normothermia in this population.

PHYSICAL ANTIPYRETIC METHODS—WHICH IS BEST?

There is scant research comparing methods of physical antipyresis. A South African laboratory study conducted in healthy volunteers with induced hyperthermia found that a combined evaporative– convective method (water splashed onto the body, followed by blown compressed air) was more effective at lowering temperature than a conductive method (application of ice packs).54 The authors also concluded that their “review of comparative studies unequivocally supports … enhanced evaporative cooling as the most effective method of reducing high body temperature,” perhaps because it is the least likely to induce shivering. But the studies they reviewed involved mainly marathon and “fun” runners, not ICU patients; whether their finding can be generalized is questionable.

Price and colleagues compared four external cooling methods in British patients with cerebral insult.55 An evaporative cooling method (cool cloths and sponging) was considered to be more effective than conductive (ice packs) and convective methods (air-flow cooling blankets or fans) in reducing patients' core temperatures below 38°C—but only when used in combination with paracetamol (acetaminophen). Design weaknesses included the study's small sample size, unequal group sizes, and the concomitant administration of antipyretics.

In a study among neurologic ICU patients, Morgan compared the efficacy of acetaminophen alone, water-flow cooling blankets with acetaminophen, and tepid water sponging with acetaminophen.56 Core temperatures took the most time to decrease to 37.8°C in the sponging-and-acetaminophen group (mean time, 144 minutes) and the least time in the blanket-and-acetaminophen group (mean time, 100 minutes). (The acetaminophen-only group had a mean time of 110 minutes.) The differences among the three groups were not significant. The blanket-and-acetaminophen group had a significantly higher incidence of shivering than either of the other groups (57%, versus 0% in both other groups). But the small sample size (21 patients allocated into three groups) and the concomitant administration of acetaminophen leave some question as to the validity of the findings.

Two recent randomized studies compared the effectiveness of convective cooling with that of conductive cooling. Creechan and colleagues found that air-flow cooling blankets were more effective than water-flow cooling blankets when used with critically ill adults with an infection-related fever.57 Core temperatures decreased significantly more rapidly in the air-flow blanket group than in the water-flow blanket group (0.377°C/hr versus 0.163°C/hr); more patients achieved a temperature of 38°C or lower after eight hours of cooling (75% versus 47%); and recurrence of fever took significantly longer (22.2 hr versus 6.6 hr). Similar findings emerged from a study by Loke and colleagues, conducted in a general ICU in Hong Kong. Significantly more patients in that study's air-flow blanket group achieved temperatures below 38°C after eight hours of treatment than did those in its water-flow blanket group (94% versus 60%).58Moreover, patients in the air-flow group cooled in significantly less time than did the other group (mean time, 3.1 versus 5.7 hours). It's worth noting that the use of water-flow cooling blankets has been implicated in cases of “zigzag” temperature fluctuations (fluctuations of 1.6°C or more within a 24-hour period) and rebound hypothermia (temperature decrease to below 36.1°C).59 Because water-flow blankets are heavy, patients are also at higher risk for pressure ulcer development resulting from vasoconstriction and poor tissue perfusion.60

Two new methods. Endovascular cooling involves intravascular catheter–based heat exchange. In the CoolGard/Cool Line catheter system, a catheter is placed in a large vein such as the internal jugular, subclavian, or femoral vein. Normal saline then circulates “through two balloons coaxially mounted on the catheter in a closed loop”; an external pump with cooling capability maintains the saline at the desired temperature.61 Heat transfer occurs as the patient's blood passes over each balloon; the saline isn't directly infused. The other catheter-based system that's currently available, the Celsius Control System, uses a similar design.

Two studies have compared endovascular cooling with other antipyretic methods. In a randomized, multicenter study conducted with neurologic ICU patients, Diringer and colleagues considered the effects of adding endovascular cooling to a conventional fever management protocol.61 One group received conventional antipyretic treatment (acetaminophen, ibuprofen, and air-flow cooling blankets, gastric lavage, and ice packs, as needed); another group received both conventional treatment and treatment with heat exchange catheters. Fever burden—calculated as the product of temperature elevation above 38°C and its duration in hours during the 72-hour study period, expressed in degree-hours—was found to be significantly lower in the endovascular cooling group than in the other group (2.87°C-hr versus 7.92°C-hr, respectively). And in a study with normothermic patients suffering from subarachnoid hemorrhage, Keller and colleagues compared the efficacy of endovascular cooling with conventional antipyresis using air- or water-flow cooling blankets and ice packs.62 The time needed to induce hypothermia (33°C to 34°C) was significantly shorter in the endovascular cooling group than in the conventional treatment group (a mean of 190 versus 370 minutes, respectively). However, although endovascular cooling is highly effective, it is invasive and thus carries a higher risk of complications associated with catheterization of a central vein, such as hemothorax, pneumothorax, and infection.

A second, recently developed method of physical antipyresis involves hydrogel-coated, water-circulating energy-transfer pads. In the Arctic Sun Temperature Management System, five pads are placed on the patient's back, abdomen, and thighs; a control unit circulates water through the pads and adjusts their temperature to the target level.63Mayer and colleagues compared the efficacy of this system to that of water-flow cooling blankets for treating febrile patients in a neurologic ICU.64 Fever burden (calculated as above, except using a temperature elevation above 37.2°C and its duration in hours during the 24-hour study period) was significantly lower in patients treated with the pads than in those treated with the blankets (median 4.1°C-hr versus 16.1°C-hr). Moreover, the patients treated with the pads were febrile for a smaller percentage of the study period (8% versus 42%) and “attained normothermia faster” (median 2.4 hr versus 8.9 hr). But more of those patients suffered from shivering than did those treated with the blankets (39% versus 8%).

IMPLICATIONS FOR NURSING PRACTICE

Fever (pyrexia) is an elevation in the core temperature (that of the blood in the heart, lungs, and brain stem) that results when infection or injury causes a rise in levels of endogenous pyrogens (in particular, certain cytokines). (Cytokines are proteins that function as immunoregulatory mediators; some cytokines, such as tumor necrosis factor-a, may have pyrogenic or antipyrogenic action, depending on the circumstances of release.5) This in turn causes the thermoregulatory set point in the hypothalamus to reset to a higher-than-normal level. (The core temperature can't be measured noninvasively; oral, axillary, rectal, urinary bladder, and tympanic membrane readings all provide close estimates. The normal range is generally considered to be from 36.5°C to 37.5°C.6, 7 To see how the body maintains normal core tempature, see Figure 1, at left.) The body reacts as though its core temperature is too low; vasoconstriction and shivering are activated to generate heat.8 The cytokines also act on specialized areas of the brain to induce the release of central mediators, mainly prostaglandin E₂.9 These too act on the hypothalamus (directly or through certain neurotransmitters) to raise the set point above normal. According to guidelines jointly developed by the Society of Critical Care Medicine and the Infectious Disease Society of America, a core temperature above 38.3°C in an ICU patient should be considered indicative of fever and should prompt clinical assessment.10

The human body has several mechanisms to maintain the normal core temperature of 36°C to 37°C. Sensory neurons sense internal body temperature using the blood and central nervous system and external body temperature from the skin. That information is integrated in the hypothalamus. If the temperature is too low, the body attempts to warm itself through vasoconstriction of the cutaneous beds and shivering. If the temperature is too high, the body attempts to lower temperatures through sweating and vasodilation.

The most common infectious causes of fever in the ICU are ventilator-associated pneumonia, sinusitis, and bloodstream infections.11, 12 Several noninfectious causes have also been identified, including postoperative stress, cerebral injury, drug administration, blood transfusion, adrenal insufficiency, myocardial infarction, and pulmonary embolism.11, 12 Other possible causes of temperature elevation include hyperthermia and malignant hyperthermia. However, these occur much more rarely than fever; for example, the incidence of malignant hyperthermia in adults given anesthesia has been estimated at one in 5,000 (0.02%) to one in 65,000 (0.0015%).13

Increased temperature is but one component of the acute phase reaction, which also involves increased secretion of glucocorticoids, aldosterone, and growth hormone; greater synthesis of liver proteins (mainly C-reactive protein); decreased secretion of vasopressin5; a shift in blood flow from cutaneous to deep vascular beds; decreased sweating and increased heart rate and blood pressure; and shivering, anorexia, somnolence, and malaise.

Fever involves three phases.8 In the chill phase (see Figure 2, at right), the initial rise in core temperature and resetting of the set point cause the patient to feel cold, triggering shaking chills (sometimes called rigors) and vasoconstriction. These responses elevate the core temperature, which is maintained at this higher level in the ensuing plateau phase. In the defervescent phase, the levels of circulating cytokines decline and the thermoregulatory set point returns to normal, prompting heat dissipation through such mechanisms as evaporation (diaphoresis) and radiation (vasodilation and flushing).

Figure 2. The Chill Phase of Fever

Malignant hyperthermia is a life-threatening condition that usually arises in genetically susceptible people during anesthesia; it's triggered by halogenated volatile anesthetics such as isoflurane (Forane) and by neuromuscular blockers such as succinylcholine (Anectine and others).14 It's characterized by a rapid and enormous increase in metabolic heat produced by internal organs and skeletal muscles; in some cases this is accompanied by peripheral vasoconstriction, which further impedes heat loss. The core temperature may rise as fast as 1°C every five minutes. Other signs include muscle rigidity (especially of the masseters), hypercarbia (more than double the normal end-tidal carbon dioxide level), and cyanosis related to increased oxygen consumption.

Central fever can be described as a prolonged fever resulting from damage to the thermoregulatory center in the hypothalamus, such as that caused by intracranial lesion or other trauma.11 It's a combination of fever (triggered by tissue damage) and hyperthermia (triggered by autonomic nervous system disruption or tissue damage). Most cases manifest in patients with preexisting cerebral injury. Temperature curves are usually plateaulike and fever may exceed 41°C; the condition is usually (but not always) unresponsive to antipyretic agents. Perspiration is “conspicuously absent”; relative bradycardia may or may not be present.11

The Effects of Fever and Other Forms of Temperature Elevation

The benefits. There is evidence from both animal and human studies that fever provides adaptive advantages. First, it's believed that fever inhibits bacterial growth. In laboratory studies with mice and sheep, an artificially induced increase in core temperature was followed by significantly improved survival rates after infection, while administration of antipyretics decreased survival.15, 16 (But because the temperature was elevated artificially, these findings may not be applicable to febrile humans.) In a small study of older adults with community-acquired pneumonia, patients who manifested leukocytosis and temperatures higher than 37.8°C on hospital admission were seven times less likely to die than those who did not, with mortality rates of 4% and 29% in the two groups, respectively.17 In a retrospective study of patients with polymicrobial sepsis and various underlying diseases, a positive correlation was observed between febrile response and survival.18 And one review has reported that human survival during sepsis “is reduced in the face of hypothermia … or a failure to generate a fever.”19 Furthermore, in reviewing what is known about fever from an evolutionary perspective, Hasday and colleagues observe that those immunologic processes that are usually active in the presence of fever “have evolved to function optimally at febrile rather than basal temperatures.”20 Hasday and Singh have proposed four mechanisms by which fever might be protective; in addition to the inhibition of pathogen growth and improved immune system response mentioned above, these include inducing the expression of cytoprotective proteins in host cells and stimulating their generation by pathogen cells.21

The adverse effects. The administration of antipyretic therapy is based on the assumptions that fever is noxious for patients and that suppression will reduce its detrimental effects.22, 23 But such effects have been confirmed only for specific groups of adult ICU patients. For example, in cases of traumatic brain injury, intracerebral or subarachnoid hemorrhage, and ischemic stroke, elevation of the core temperature by as little as 1°C may worsen cerebral damage.24 Possible mechanisms include increased cerebral metabolism, rising intracranial pressure, increased cerebral edema, altered neurotransmitter release, and further breakdown of the blood–brain barrier.25 In patients suffering from subarachnoid or intracerebral hemorrhage, the duration of fever has been found to be a significant predictor of death.26, 27 Treatment with hypothermia—in which the core temperature is lowered below normal for a given period—has been shown to hasten neurologic recovery in some patients with traumatic brain injury.28

It's been said that fever is metabolically costly. According to Bruder and colleagues, an increase in core temperature of 1°C results in a 10% mean increase in energy expenditure, independent of the presence of shivering.29 (In ICU patients, energy expenditure, a measure of metabolic rate, is typically measured using indirect calorimetry.) The subsequent increases in oxygen consumption, heart and respiration rates, and cardiac output add a considerable burden to patients with preexisting cardiopulmonary diseases, especially during the chill phase of fever.30 Hasday and colleagues agreed, noting that in such patients, these increased metabolic demands may raise the risk of ischemic hypoxia.20 Their review also cited the possibility that the “enhanced microbial killing mechanisms” seen with fever could cause collateral tissue damage.

Other rationales offered for suppression of fever in adult patients include relief of a patient's discomfort (caused by symptoms such as shivering, headache, malaise, and myalgia) and of fever-associated cognitive and emotional disturbances (such as confusion and anxiety, respectively).31 In critically ill patients, fever has been found to be an independent risk factor for the manifestation of agitation and delirium.32, 33

Kluger and colleagues suggested that fever isn't adaptive but, rather, maladaptive “when cytokines and other inflammatory mediators are overproduced,” leading to very high temperatures.34 Although there is no consensus regarding its upper limit, fever is regulated by endogenous antipyrogenic substances such as vasopressin, glucocorticoids, melanocortins, and cytochrome P-450 enzymes, as well as some cytokines.5, 35, 36 That antipyretic mechanisms have evolved suggests the importance of preventing the core temperature from reaching dangerously high levels. However, in cases of nonfebrile temperature elevation (such as hyperthermia), endogenous antipyretics aren't activated, and extremely high temperatures (above 41°C) can occur.

Marik states that in most cases, fever attributed to noninfectious processes rarely rises above 38.9°C; fever attributed to infectious processes usually does exceed that threshold.12 But there are exceptions. Fever associated with medication or with the transfusion of blood or blood products is often characterized by shaking chills and high, spiking temperatures.12 (Single, transient temperature spikes that follow transfusion and remain below 41°C usually require no treatment.37) Antibiotics, procainamide (Procanbid), and antigenic agents (such as amphotericin B) are the drugs most likely to trigger fever, which can exceed 41°C in such cases.

Besides cerebral damage, deleterious effects of very high temperature—regardless of its cause—include suppression of immune responses, denaturation of cell proteins, impaired release of oxygen to tissues, acid–base abnormalities, and organ dysfunction.20, 38

Physical Antipyresis Methods Used in ICU Patients

Convection

Evaporation

Selective cooling of the brain

Other

Newer methods

1. Circiumaru B, et al. A prospective study of fever in the intensive care unit. Intensive Care Med 1999;25(7):668–73. [Context Link]

2. Peres Bota D, et al. Body temperature alterations in the critically ill. Intensive Care Med 2004;30(4):811–6. [Context Link]

3. Commichau C, et al. Risk factors for fever in the neurologic intensive care unit. Neurology 2003;60(5):837–41. [Context Link]

4. Kilpatrick MM, et al. Hyperthermia in the neurosurgical intensive care unit. Neurosurgery 2000;47(4):850–6. [Context Link]

5. Mackowiak PA. Concepts of fever. Arch Intern Med 1998;158(17):1870–81. [Context Link]

6. Buggy DJ, Crossley AW. Thermoregulation, mild perioperative hypothermia and postanaesthetic shivering. Br J Anaesth 2000;84(5):615–28. [Context Link]

7. Guyton AC. Body temperature, temperature regulation and fever. In: Guyton AC, Hall JE, editors. Textbook of medical physiology. Philadelphia: W. B. Saunders; 1996. p. 911–22. [Context Link]

8. Holtzclaw BJ. The febrile response in critical care: state of the science. Heart Lung 1992;21(5):482–501. [Context Link]

9. Dinarello CA. Cytokines as endogenous pyrogens. J Infect Dis 1999;179 Suppl 2:S294–S304. [Context Link]

10. O'Grady NP, et al. Practice guidelines for evaluating new fever in critically ill adult patients. Task Force of the Society of Critical Care Medicine and the Infectious Diseases Society of America. Clin Infect Dis 1998;26(5):1042–59. [Context Link]

11. Cunha BA, Shea KW. Fever in the intensive care unit. Infect Dis Clin North Am 1996;10(1):185–209. [Context Link]

12. Marik PE. Fever in the ICU. Chest 2000;117(3):855–69. [Context Link]

13. Malignant Hyperthermia Association of the United States. What is malignant hyperthermia? 2007. http://medical.mhaus.org/index.cfm/fuseaction/OnlineBrochures.Display/BrochurePK/8AABF3FB-13B0-430F-BE20FB32516B02D6.cfm . [Context Link]

14. Gronert GA, et al. Malignant hyperthermia. In: Miller RD, editor. Miller's anesthesia. 6th ed. Philadelphia: Elsevier Churchill Livingstone; 2005. p. 1169–90. [Context Link]

15. Jiang Q, et al. Febrile core temperature is essential for optimal host defense in bacterial peritonitis. Infect Immunol 2000;68(3):1265–70. [Context Link]

16. Su F, et al. Fever control in septic shock: beneficial or harmful? Shock 2005;23(6):516–20. [Context Link]

17. Ahkee S, et al. Community-acquired pneumonia in the elderly: association of mortality with lack of fever and leukocytosis. South Med J 1997;90(3):296–8. [Context Link]

18. Mackowiak PA, et al. Polymicrobial sepsis: an analysis of 184 cases using log linear models. Am J Med Sci 1980;280(2):73–80. [Context Link]

19. Hasday JD, Garrison A. Antipyretic therapy in patients with sepsis. Clin Infect Dis 2000;31(5 Suppl):S234-S241. [Context Link]

20. Hasday JD, et al. The role of fever in the infected host. Microbes Infect 2000;2(15):1891–904. [Context Link]

21. Hasday JD, Singh I. Fever and the heat shock response: distinct, partially overlapping processes. Cell Stress Chaperones 2000;5(5):471–80. [Context Link]

22. Plaisance KI, Mackowiak PA. Antipyretic therapy: physiologic rationale, diagnostic implications, and clinical consequences. Arch Intern Med 2000;160(4):449–56. [Context Link]

23. Mackowiak PA. Physiological rationale for suppression of fever. Clin Infect Dis 2000;31(Suppl 5):S185–S189. [Context Link]

24. Busto R, et al. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987;7(6):729–38. [Context Link]

25. Cairns CJ, et al. Management of hyperthermia in traumatic brain injury. Curr Opin Crit Care 2002;8(1):106–10. [Context Link]

26. Oliveira-Filho J, et al. Fever in subarachnoid hemorrhage: relationship to vasospasm and outcome. Neurology 2001;56(10):1299–304. [Context Link]

27. Schwarz S, et al. Incidence and prognostic significance of fever following intracerebral hemorrhage. Neurology 2000;54(2):354–61. [Context Link]

28. Marion DW, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997;336(8):540–6. [Context Link]

29. Bruder N, et al. Influence of body temperature, with or without sedation, on energy expenditure in severe head-injured patients. Crit Care Med 1998;26(3):568–72. [Context Link]

30. Mackowiak PA, Plaisance KI. Benefits and risks of antipyretic therapy. Ann N Y Acad Sci 1998;856:214–23. [Context Link]

31. Greisman LA, Mackowiak PA. Fever: beneficial and detrimental effects of antipyretics. Curr Opin Infect Dis 2002;15(3):241–5. [Context Link]

32. Jaber S, et al. A prospective study of agitation in a medical–surgical ICU: incidence, risk factors, and outcomes. Chest 2005;128(4):2749–57. [Context Link]

33. Aldemir M, et al. Predisposing factors for delirium in the surgical intensive care unit. Crit Care Med 2001;5(5):265–70. [Context Link]

34. Kluger MJ, et al. Role of fever in disease. Ann N Y Acad Sci 1998;856:224–33. [Context Link]

35. Roth J, et al. Endogenous antipyretics: neuropeptides and glucocorticoids. Front Biosci 2004;9:816–26. [Context Link]

36. Tesfaigzi Y, et al. Clinical and cellular effects of cytochrome P-450 modulators. Respir Physiol 2001;128(1):79–87. [Context Link]

37. Cunha BA. Fever in the intensive care unit. Intensive Care Med 1999;25(7):648–51. [Context Link]

38. Mackowiak PA, Boulant JA. Fever's glass ceiling. Clin Infect Dis 1996;22(3):525–36. [Context Link]

39. Cheng C, et al. Increasing mean skin temperature linearly reduces the core-temperature thresholds for vasoconstriction and shivering in humans. Anesthesiology 1995;82(5):1160–8. [Context Link]

40. Holtzclaw BJ, Geer RT. Shivering after heart surgery: assessment of metabolic effects [abstract]. Anesthesiology 1986;65(3A):A18. [Context Link]

41. Lenhardt R, et al. The effects of physical treatment on induced fever in humans. Am J Med 1999;106(5):550–5. [Context Link]

42. Mackowiak PA. Diagnostic implications and clinical consequences of antipyretic therapy. Clin Infect Dis 2000;31(Suppl 5):S230-S233. [Context Link]

43. Manthous CA, et al. Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit Care Med 1995;151(1):10–4. [Context Link]

44. Abbey J, et al. A pilot study: the control of shivering during hypothermia by a clinical nursing measure. J Neurosurg Nurs 1973;5(2):78–88. [Context Link]

45. Sund-Levander M, Wahren LK. Assessment and prevention of shivering in patients with severe cerebral injury. A pilot study. J Clin Nurs 2000;9(1):55–61. [Context Link]

46. Holtzclaw BJ. Shivering in acutely ill vulnerable populations. AACN Clin Issues 2004;15(2):267–79. [Context Link]

47. Caruso CC, et al. Cooling effects and comfort of four cooling blanket temperatures in humans with fever. Nurs Res 1992;41(2):68–72. [Context Link]

48. Gozzoli V, et al. Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the effect of external cooling. Arch Intern Med 2001;161(1):121–3. [Context Link]

49. Schulman CI, et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect 2005;6(4):369–75. [Context Link]

50. Poblete B, et al. Metabolic effects of i.v. propacetamol, metamizol or external cooling in critically ill febrile sedated patients. Br J Anaesth 1997;78(2):123–7. [Context Link]

51. Gozzoli V, et al. Randomized trial of the effect of antipyresis by metamizol, propacetamol or external cooling on metabolism, hemodynamics and inflammatory response. Intensive Care Med 2004;30(3):401–7. [Context Link]

52. Henker R, et al. Comparison of fever treatments in the critically ill: a pilot study. Am J Crit Care 2001;10(4):276–80. [Context Link]

53. Mayer SA, et al. Clinical trial of an air-circulating cooling blanket for fever control in critically ill neurologic patients. Neurology 2001;56(3):292–8. [Context Link]

54. Kielblock AJ, et al. Body cooling as a method for reducing hyperthermia. An evaluation of techniques. S Afr Med J 1986;69(6):378–80. [Context Link]

55. Price T, et al. Cooling strategies for patients with severe cerebral insult in ICU (Part 2). Nurs Crit Care 2003;8(1):37–45. [Context Link]

56. Morgan SP. A comparison of three methods of managing fever in the neurologic patient. J Neurosci Nurs 1990;22(1):19–24. [Context Link]

57. Creechan T, et al. Cooling by convection vs cooling by conduction for treatment of fever in critically ill adults. Am J Crit Care 2001;10(1):52–9. [Context Link]

58. Loke AY, et al. Comparing the effectiveness of two types of cooling blankets for febrile patients. Nurs Crit Care 2005;10(5):247–54. [Context Link]

59. O'Donnell J, et al. Use and effectiveness of hypothermia blankets for febrile patients in the intensive care unit. Clin Infect Dis 1997;24(6):1208–13. [Context Link]

60. Shackell S. Cooling hyperthermic and hyperpyrexic patients in intensive care. Nurs Crit Care 1996;1(6):278–82. [Context Link]

61. Diringer MN, the Neurocritical Care Fever Reduction Trial Group. Treatment of fever in the neurologic intensive care unit with a catheter-based heat exchange system. Crit Care Med 2004;32(2):559–64. [Context Link]

62. Keller E, et al. Endovascular cooling with heat exchange catheters: a new method to induce and maintain hypothermia. Intensive Care Med 2003;29(6):939–43. [Context Link]

63. Carhuapoma JR, et al. Treatment of refractory fever in the neurosciences critical care unit using a novel, water-circulating cooling device. J Neurosurg Anesthesiol 2003;15(4):313–8. [Context Link]

64. Mayer SA, et al. Clinical trial of a novel surface cooling system for fever control in neurocritical care patients. Crit Care Med 2004;32(12):2508–15. [Context Link]