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Pathophysiology and Management of Fever Revisited

e read with interest the paper by Drs. Dalal and Zhukovsky,1 as well as the associated commentary by Dr. Mackowiak,2 and wish to question a number of the statements made about the pathophysiology and treatment of hyperthermia and/or fever. These authors may not have been familiar with the signicant body of data regarding this subject that has been developed both clinically and preclinically. Ironically, these data exist primarily in the oncologic literature. A few basic principles regarding thermal regulation that were not highlighted in the article have signicant implications for the treatment of high-grade fevers or hyperthermia. At room temperature, a 70 kg human produces 84 W of basal metabolic heat; of these, 48 W are lost from radiant heat exchange, 8 W from evaporation, and 27 W from insensible losses. As body temperature increases, skin temperature rises and radiant heat loss increases dramaticallyeg, 107 W when core temperature is 41.8C. Radiant heat exchange is also a fourth power function. Hence, in the absence of evaporative heat loss, radiant heat exchange is the major determinant of thermal regulation.35 Conductive heat exchange is extremely inefcient. Therefore, we agree that maximizing evaporative heat losses and radiant heat losses by exposing the patients skin and fanning or sprinkling a patient with water is the optimal approach to cooling. (The use of sponging alcohol can create enough fumes to become toxic; water is actually more efcient for evaporative heat loss as it has a greater specic heat.) We argue, however, that cooling blankets, cold-water immersion, ice packs, and cold compresses are relatively contraindicated. Although they have been used in the past, we believe that such measures can actually inVOLUME 4, NUMBER 6

terfere with efcient patient cooling. Relative to this discussion, we wish to further emphasize that the rise in core body temperature that occurs in the absence of evaporative heat losses (eg, with dehydration/heatstroke), often at an elevated environmental temperature, represents both predictable and reproducible physiology. The following equation describes the non-linear increase in basal metabolic rate (BMR) as core temperature increases6,7: BMR T Core = 85 1.07(T Core) 0.5 Robins et al have conrmed this relationship in a series of large mammal and human studies.35 This relationship between metabolic rate and core temperature makes thermal control fragile at core temperatures above 41C. Above 42C, thermal compensatory mechanisms are maximal, assuming evaporative heat losses are minimal. Thus, a patient will enter a thermal runaway state due to what is essentially a self-perpetuating metabolic heat pump (in sharp distinction to malignant hyperthermia). The concept emphasized here is that control mechanisms are being saturated, not disabled. In their discussion of fever/hyperthermia management, Drs. Dalal and Zhukovsky1 did not emphasize the crucial importance of correcting electrolyte imbalance and providing adequate hydration to maintain cardiac output and optimal sweating during high-grade fevers. Most physicians would intuitively recognize the formidable cardiac stress of fever, which occurs at 42C. What maybe somewhat surprising is the observation that cardiac stress becomes maximal at temperatures between 39.5C and 40.0C35; thus, physicians should be as concerned about the cardiac status of patients in this less dramatic fever range. At a temperature of 40C, a pa-

tients heart rate invariably doubles, and if stroke volume is maintained with adequate uids, the patients cardiac output also doubles.35 Therefore, we suggest supplemental nasal oxygen for any patient who may have a compromised cardiac status. Further, as cardiac status in patients with high-grade fevers can be quite brittle, the suggestion of cool uids administered intraperitoneally, gastric lavage, enzymes with ice water, or even extracorporeal circulation8 may well be contraindicated. The use of cooling intravenous uids makes no physiologic sense, which a simple caloric calculation can conrm. A great deal more is known about the implications of fever at a pathophysiologic level than is alluded to in Dr. Mackowiaks peer viewpoint.2 For example, the hormonal changes that occur within association of fever have been well described.9,10 Additionally, fever-/ hyperthermia-induced changes in cytokines and receptors at both peripheral and bone marrow levels have all been described in detail.1114 Further, the effects on core body temperature relative to chemotherapy, radiotherapy, and immunotherapy have been widely investigated.1523 Finally, his suggestion that we have not scientically explored variables regarding anatomic site, gender, activity, etc., is incorrect. Such variables have been studied in depth.35,2429
Professor, Department of Medicine, Neurology and Human Oncology University of Wisconsin School of Medicine Madison, Wisconsin Nurse Manager, Department of Human Oncology University of Wisconsin Hospitals and Clinics Madison, Wisconsin Professor, Department of Medicine University of Wisconsin School of Medicine Madison, Wisconsin

H. Ian Robins, MD, PhD

Kimberly Brandt, RN, MBA

Walter L. Longo, MD

REFERENCES
1. Dalal S, Zhukovsky DS. Pathophysiology and management of fever. J Support Oncol 2006;4:916. 2. Mackowiak PA. Pathophysiology and management of feverwe know less than we should. J

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Support Oncol 2006;4:2122. 3. Robins HI, Grossman J, Davis TE, Dennis WH, AuBuchon JP. A preclinical trial of a radiant heat device for whole body hyperthermia using a porcine model. Cancer Res 1983;43:20182022. 4. Robins HI, Dennis WH, Neville AJ, et al. A nontoxic system for 41.8C whole body hyperthermia: results of a phase I study using a radiant heat device. Cancer Res 1985;45:39373944. 5. Robins HI,Woods JP, Schmitt CL, Cohen JD. A new technological approach to radiant heat whole body hyperthermia. Cancer Letters 1994;79:137145. 6. Law HT, Pettigrew RT. Heat transfer in whole body hyperthermia. Ann N Y Acad Sci 1980;335:298 310. 7. Keele CA, Neil E, eds. Samson Wrights Applied Physiology. 12th ed. New York: Oxford University Press; 1971. 8. Wiedemann GJ, Katschinski D, Menzel M, Mulkerin D, Robins HI. Extracorporeal whole body hyperthermia: toxicity assessment. Int J Hyperthermia 1997;13:249250. 9 . R o b i n s H I , K a l i n N , Sh e l to n S E, e t a l . Neuroendocrine changes in patients undergoing whole body hyperthermia. Int J Hyperthermia 1987;3:99105. 10. Robins HI, Kalin NH, Shelton SE, et al. Rise in plasma beta-endorphin, ACTH, and cortisol in cancer patients undergoing whole body hyperthermia. Horm Metab Res 1987;19:441443. 11. d'Oleire F, Robins HI, Cohen JD, Schmitt CL, Spriggs D. Cytokine induction in humans by 41.8C whole body hyperthermia. J Natl Cancer Inst 1993;93:833834. 12. Robins HI, Kutz M, Wiedemann G, et al. Cytokine induction by 41.8C whole body hyperthermia. Cancer Letters 1995;97:195201. 13. Cohen JD, Robins HI. Hyperthermia enhancement of carboplatin in human leukemia cells in vitro. Cancer Res 1987;47:43354337. 14. Robins HI, Grosen EG, Katschinski DM, et al. Whole body hyperthermia induction of soluble tumor necrosis factor receptors: implications for rheumatoid diseases. J Rheumatol 1999;26:25132516. 15. Katschinski DM, Wiedemann GJ, dOleire FR, Longo W, Robins HI. Whole body hyperthermia cytokine induction: a review, and unifying hypothesis for myeloprotection in the setting of cytotoxic therapy. Cytokine Growth Factor Rev 1999;10:9397. 16. Robins HI, Sielaff KM, Storer B, Hawkins MJ, Borden EC. A phase I trial of interferon-a with whole body hyperthermia in advanced cancer. Cancer Res 1989;49:16091615. 17. Robins HI, Longo WL, Steeves RA, et al. Adjunctive therapy (whole body hyperthermia versus lonidamine) to total body irradiation for the treatment of favorable B cell neoplasms: a report of two pilot clinical trials and laboratory investigations. Int J Radiat Oncol Biol Phys 1990;18:909920.

18. Wiedemann G, Robins HI, Gutsche S, et al. Ifosfamide, carboplatin and etoposide (ICE) combined with 41.8C whole body hyperthermia in patients with refractory sarcoma. Eur J Cancer 1996;32A:888892. 19. Robins HI, Rushing D, Kutz M, et al. A phase I trial of 41.8C whole body hyperthermia and melphalan in cancer patients. J Clin Oncol 1997;15:158164. 20. Katschinski DM, Benndorf R, Wiedemann GJ, et al. Heat shock protein antibodies in sarcoma patients undergoing 41.8C whole body hyperthermia. J Immunotherapy 1999;22:6770. 21. Robins HI, Katschinski DM, Longo W, et al. A pilot study of melphalan, tumor necrosis factor-a and 41.8C whole body hyperthermia. Cancer Chemother Pharmacol 1999;43:409414. 22. Westermann AM, Weidemann GJ, Jager E, et al. A systemic hyperthermia oncologic working group phase II trial: ifosfamide , carboplatin and etoposide combined with 41.8C whole body hyperthermia for metastatic soft tissue sarcoma. Oncology 2003;64:312321. 23. Robins HI, Longo WL, Steeves RA, et al. A pilot study of whole body hyperthermia and local irradiation for advanced non-small cell lung cancer conned to the thorax. Int J Radiat Oncol Biol Phys 1988;15:427431. 24. Robins HI, Cohen JD, Schmitt CL, et al. A phase I clinical trial of carboplatin and 41.8C whole body hyperthermia in cancer patients. J Clin Oncol 1993;11:17871794. 25. Martin PA, Robins HI, Dennis WH. Monitoring body site temperatures during systemic hyperthermia. Crit Care Med 1987;15:163164. 26. Woods JP, Schmitt CL, Rosenthal RC, dOleire FR, Robins HI. Canine bone marrow as a potential thermal sanctuary during the plateau phase of whole body hyperthermia. Int J Hyperthermia 1995;11:4957. 27. Robins HI, Cohen JD, Neiville AJ. Whole-Body Hyperthermia: Biological, Physical and Clinical Aspects. Berlin: Springer-Verlag; 1992. 28. Katschinski DM, Wiedemann GJ, Mentzel M, et al. Influence of circadian rhythm on 41.8C whole body hyperthermia induced induction of hematopoietic growth factors. Int J Hyperthermia 1997;13:571576. 29. Katschinski DM, Jelkmann W, Widemann GJ, et al. Dynamic changes in serum erythropoietin levels in solid tumor patients undergoing whole body hyperthermia and/or chemotherapy. Int J Hyperthermia 1997;13:563570.

the pathophysiology and management of fever. We fully agree that meticulous supportive care with attention to cardiac, respiratory, uid, and electrolyte status is integral in the management of patients who present with fever and hyperthermia, as bets the goals of care, and appreciate the authors reiteration of such. Prompt reversal of hyperthermia by immediate initiation of rapid and effective cooling techniques is the cornerstone of management and should begin as soon as the diagnosis is suspected. As mentioned in our article, initial measures should involve external methods such as removal of clothing, tepid water sponging, and use of fans to maximize evaporative heat loss. Other measures of physical cooling, such as immersion in ice water, cooling blankets, use of cool uids intravenously or via intraperitoneal administration, gastric lavage, and enemas with ice water can be options in extreme cases; these methods should be carefully monitored to avoid overshooting to hypothermia. We respect Dr. Robins experience with the management of hyperthermia, as controversy still remains over the optimal method; controlled head-to-head studies comparing times or outcomes between the various methods are lacking. Controversy persists for the management of fever as well. Physical methods with tepid-water sponging, fans, and use of antipyretics may improve comfort; however, the impact of fever control with antipyretics on the outcome of underlying infectious processes remains unclear. Shalini Dalal, MD Donna S. Zhukovsky, MD, FACP
Department of Palliative Care & Rehabilitation Medicine The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Authors Response
We would like to thank Dr. Robins and colleagues for their comments on our recently published article regarding

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