David H. Ahrenholz
As humans, we are homeothermic mammals who maintain our core temperature within a very narrow range, with a normal diurnal variation of about 1.5°C.1 Temperate climates present a range of temperatures that cause rapid loss of body heat to the environment, and three specific behaviors—fabrication of clothing, shelter-building, and control of fire—have allowed us to populate the earth. But hypothermia occurs when external heat loss exceeds the rate of endogenous thermogenesis. In the initial stages there are no irreversible changes as the metabolic rate slows about 50% for each 10°C drop in core temperature (Arrhenius’ law).2 Under rigidly controlled anesthesia, asystolic arrest occurs between 15–20°C, and a brief state of “suspended animation” can facilitate the completion of otherwise impossible surgical procedures in a relatively bloodless field.3
SYSTEMIC HYPOTHERMIA
Primary Accidental Hypothermia
Accidental nontraumatic hypothermia, with a core temperature below 35°C, occurs if a normal person is exposed to cool temperatures with inadequate clothing or shelter, and is most common during winter months.4 Initially there is an intense cutaneous vasoconstriction to reduce heat loss, and the exposed skin can rapidly cool to the ambient temperature. The patient experiences thermogenic shivering, which markedly increases oxygen consumption and depletes glycogen stores.5 As the temperature drops, metabolism progressively slows and shivering ceases. The patient becomes confused, lethargic, and cold to the touch. Urine production is profuse as the kidneys lose the ability to transport sodium and other ions. The patient exhibits bradycardia, hypotension, hypovolemia, and metabolic acidosis with elevated blood lactate. Agitation, irrational behavior, and combativeness are replaced by obtundation and finally coma. When cardiac arrest occurs, death is not immediate, but is inevitable without medical intervention.
Cooling is accelerated in windy conditions, but immersion in cold water will remove heat up to 25 times faster than air at the same temperature. Although exceptional athletes can swim for hours in cold water, an unconditioned person may become unconscious within 30 minutes of immersion in 4°C water. Children immersed in cold water quickly become hypothermic and comatose, but if the glottis closes and excludes water from the lungs, they may be resuscitated even if vital signs are undetectable. If a rescued child is given cardiopulmonary resuscitation (CPR) and rapidly rewarmed, survival without neurologic impairment is possible.6
For the responsive hypothermic patient with a core temperature above 34°C, passive rewarming measures with convective warming blankets and warm fluids are adequate.5 Severely hypothermic patients require warmed parenteral fluids to correct the cold-induced diuresis. Urine output will remain brisk during rewarming and is NOT an indicator of adequate intravascular volume. Subclavian or internal jugular catheter placement is avoided because the guide wire can easily trigger ventricular fibrillation of the cold myocardium. A Foley catheter with an integral temperature probe is optimal to monitor the core temperature. Comatose patients require endotracheal and nasogastric tubes to protect the airway and prevent aspiration. If any perfusing rhythm can be detected, administer pressor agents, but avoid chest compressions that may trigger intractable ventricular fibrillation.
If no perfusing cardiac activity is noted, begin CPR, and continue until the patient is rewarmed to a temperature that permits successful defibrillation (>30°C) (Figure 49-1). During rewarming monitor the patient for electrolyte imbalances, respiratory and renal complications, which may have delayed onset. Mortality of 17–27% is reported.7,8
FIGURE 49-1 Management algorithm for treatment of hypothermia. All patients should also be closely monitored for physiologic complications associated with hypothermia. (Reproduced with permission from Reed RL III, Gentilello LM. Temperature associated injuries and syndromes. In: Mattox KL, Moore EE, Feliciano DV, eds. Trauma. 6th ed. New York: McGraw-Hill; 2008:1071.)
Patients with hypothermia routinely present with a skin temperature more than 15°C lower than the core temperature,5 so that even in a warmed environment, the core temperature can continue to fall, a phenomenon referred to as “afterdrop.” Once shivering stops the patient has little capacity for thermogenesis.5 Immersion of the patient in 40°C water is the most rapid rewarming technique,9 but is contraindicated if the patient requires CPR, emergency surgery, or treatment of open wounds or unstable fractures. Extremely cold or even frozen extremities are not rewarmed until the core temperature reaches 33°C. Then each affected extremity is sequentially immersed as the patient is monitored for any temperature decrease.10
If immersion is not possible, the patient can be rewarmed by extracorporeal bypass11 or with a multiport central venous catheter designed to induce therapeutic hypothermia, usually placed via the femoral vein into the inferior vena cava. Balloons integral to the catheter are irrigated with warm saline via a closed circuit.
Secondary Metabolic Hypothermia
A number of pathophysiologic states can interfere with mechanisms to maintain normothermia. These occur in debilitated or elderly patients secondary to hypothyroidism, adrenal insufficiency, sepsis, or stroke.12 Trauma profoundly disrupts temperature homeostasis and is the most common cause of secondary hypothermia.
Hypothermia in Trauma
Hypothermia increases the mortality across all trauma age groups. Jurkovich et al.13 reported a 40% mortality in trauma patients with a core temperature <34°C, which increased to 100% in those patients with a core temperature <32°C. A larger retrospective study from the National Trauma Databank using stepwise logistic analysis found that hypothermia independently predicted mortality after trauma (odds ratio 1.54, 95% CI 1.40–1.71).14 Wang et al. reported similar data from analysis of 38,520 patients in Pennsylvania Trauma Outcome Study (odds ratio 3.03, 95% CI 2.62–3.51).15 Inaba et al. reviewed the mortality of trauma patients undergoing cavitary surgery. Postoperative hypothermia was an independent predictor of mortality (odds ratio 3.2 CI 1.9-5.3).16 Mortality was increased 7-fold for patients with a temperature <33°C versus >35°C. Gentilello et al. showed that hypothermic trauma patients who were aggressively rewarmed had a markedly improved survival compared to those treated with less aggressive methods (Figure 49-2).17
FIGURE 49-2 Adjusted cumulative survival (Kaplan–Meier) trauma of patients randomized to rapid or slow rewarming, demonstrating an increase in mortality during resuscitation with slow rewarming
. (Reproduced with permission from Gentilello LM, Jurkovich GJ, Stark MS, et al. Is hypothermia in the victim of major trauma protective or harmful? A randomized, prospective study. Ann Surg. 1997;226:439.)
Hypothermia and Metabolic Reserves
It is unclear if hypothermia causes increased mortality or if a falling core temperature is a preterminal event as the energy stores are exhausted. Blood adenosine triphosphate (ATP) levels are lower and remain depressed longer in hypothermic trauma patients compared to persons with hypothermia following elective surgery18 or patients with therapeutic hypothermia induced under anesthesia.19 This depletion may be hormonally mediated. Trauma and hypothermia induce profound stress by activating the adrenomedullary hormonal system, hypothalamic–pituitary–adrenocortical axis, and sympathetic nervous system.20
Hypothermia and Immunity
Hypothermia impairs immune function by a direct effect on leukocyte-mediated microbial killing. Intraoperative hypothermia is associated with an increase in superficial wound infections following elective surgery.21
Hypothermia and Cardiac Function
Hypothermia causes bradycardia, and cardiac output decreases about 7% for each 1°C drop in temperature. The cold myocardium is irritable and ventricular fibrillation is common if chest compressions are used in the presence of bradycardia. Defibrillation is difficult until the heart is rewarmed.22
Hypothermia and Coagulation
Cold exerts its most profound adverse effect on the coagulation system, with a marked increase in clinical bleeding even before a change in coagulation test values, which are routinely performed on blood samples warmed to 37°C.23A host of mechanisms have been implicated including depressed platelet function,24 impaired platelet delivery,25 slowed coagulation enzyme activation,26 activation of protein C,27and activation of fibrinolysis.28 All of these can contribute to traumatic bleeding, depending upon the temperature and degree of acidosis. The “trauma triad of death” has been defined as hypothermia, acidosis, and massive bleeding following trauma.29 The resulting exsanguination depletes calcium, platelets, and clotting factors and requires early replacement with whole blood. Trauma control laparotomy is optimal in these patients.30 Immediate control of surgical bleeding, packing of the body cavity and temporary closure, followed by intensive efforts to correct acidosis, hypothermia, and replace lost blood are lifesaving.31
THERAPEUTIC HYPOTHERMIA
Paradoxically, there is mounting evidence that the effects of cellular hypoxia caused by exsanguinating bleeding are attenuated by subsequent systemic hypothermia.32,33 Reperfusion normally is associated with the elaboration of oxidative metabolites, which increase the ischemic injury. If surgical control of hemorrhage is adequate, induced hypothermia may reduce the hypoxic neurologic sequelae, although the risk of rebleeding is presumably increased.34Whole body hypothermia has now been advocated to limit the neurologic deficits following treated cardiac arrest, traumatic head injuries35 and even hemorrhagic and ischemic stroke.36 Induced hypothermia is used only in the absence of persistent bleeding, with precise monitoring of vital signs and the core temperature. The combination of meperidine and buspirone is most effective to suppress the shivering response.37 The core temperature is maintained at 32–33°C for several days before gradually returning to normothermia. Large randomized clinical trials are planned to study induced hypothermia in carefully selected patients.38
LOCALIZED HYPOTHERMIA
Although surgeons describe every local cold injury as frostbite, ice formation in tissue can produce two distinct clinical injuries, frostbite or rapid freeze injury, and both can occur in the same patient (Table 49-1). For human tissue cryopreservation, split thickness skin grafts are slowly frozen, stored at −70°C and will remain viable for a decade or more. Similar slow cooling conditions cause a frostbite injury. But rapid freezing of the same tissue produces immediately nonviable skin, as large intracellular ice crystals rupture the cells (flash freeze injury).39
TABLE 49-1 Clinical Differences Between Potentially Reversible Frostbite and Irreversible Rapid Freeze Injuries
FROSTBITE
Frostbite occurs during moderate rates of tissue cooling, and at about −4°C, ice crystals form in the extracellular fluid. The ice removes water and increases the solute concentration around the cells, which begin to dehydrate and collapse. Cellular metabolism slows and oxygen delivery is reduced. Proximal vasoconstriction preserves core body heat as the distal body parts cool, so the injury is always circumferential, extending from distal to proximal in the digits, ears, and nose.10
The tissue is cold, stiff, pale, and insensate. Passive rewarming causes an ischemic injury as metabolism increases before the return of local blood flow. The optimal treatment for frozen digits is rapid rewarming in 40°C water to quickly restore blood flow to tissues as the metabolic rate increases. This is painful and requires parenteral narcotics.40
Immediately after thawing, the frozen tissue becomes bright pink. But the injured endothelial cells predispose to progressive vascular infarction.41 Damaged skin quickly blisters and hemorrhagic bullae indicate a deep injury. The digits turn purplish and mummify over a period of weeks. Traditional treatment includes deflation of blisters, gentle daily cleansing, elevation of the affected parts, and oral ibuprofen.42 Physical therapy is begun as the affected parts heal or demarcate.
At Regions Hospital Burn Center since 1994 we have used catheter directed thrombolytic agents in highly selected patients to treat angiographically documented intra-arterial thrombi caused by severe frostbite.43 The angiograms must be performed within 24 hours of rewarming, before a prolonged warm ischemia injury occurs. Arterial catheters are used to infuse thrombolytics to the affected digits and angiograms are repeated daily for a maximum of 72 hours. The infusion is terminated if there is complete return of blood flow to the affected digits or if there is no improvement in flow over 24 hours.
In our review of 63 treated patients, 482 digits showed impaired blood flow following frostbite injury. Of the 201 digits with complete resumption of blood flow, only 4 (2%) required an amputation. With partial return of flow, 64% (133/206) of digits were salvaged, but if no distal digit perfusion was obtained, only 5.3% of digits survived.
Evaluation and treatment in a burn center is recommended, because lytic therapy is contraindicated if the patient cannot consent, is combative, has a delayed presentation, or has experienced a hemorrhagic stroke, major solid organ injury, recent surgical procedures, or other trauma, freeze–thaw–refreeze injuries, or delay of greater than 24 hours after thawing. Severe arthritis and joint pain secondary to loss of articular cartilage are the most common sequelae of salvaged digits, associated with prolonged severe cold sensitivity or even Raynaud’s phenomenon.
Cold Contact or Flash Freeze Injuries
Exposure to cold or pressurized gases (like carbon dioxide, oxygen, nitrogen, or propane), or contact with a cold object, can produce an irreversible freeze injury.44 Plantar injury occurs when walking on ice or snow with unprotected feet. Huge ice crystals form both extracellularly and intracellularly, immediately rupturing the affected cells. The injury may have the appearance of a thermal burn and can affect any body part because escaping gas can pass through layers of clothing. The wounds are treated with topical antimicrobials and skin grafts are applied if the wounds granulate. Lytic agents have no benefit and are contraindicated in these patients.
Nonfreezing Cold Injuries
Rapid cooling of the exposed skin causes severe pain and pale skin color called frostnip, and have little clinical significance. Immediate rewarming prevents tissue freezing, but the tissue remains sensitive to changes in temperature. Repeated episodes of near freezing cause chilblains, with intense vasospasm and damage to local nerves. Subsequent cold exposure triggers marked pain with features of Raynaud’s syndrome, which increases the risk of a secondary freezing injury. Treatment is symptomatic.45
SYSTEMIC HYPERTHERMIA
Hyperthermia causes more deaths in the United States each year than accidental hypothermia, with epidemics reported in large cities following prolonged hot and humid weather.46 The “heat index” used by the National Weather Service combines environmental temperature and relative humidity to estimate the risk of overheating.
Exercise-induced Hyperthermia
Exercise increases heat production, which can exceed the cooling capacity of the body. Hyperthermia is common in military training or combat, and in strenuous contact sports or distance running. Certain drugs, especially antipsychotic and anticholinergic agents, block systemic thermoregulation mechanisms and increase the risk of hyperthermia.
Systemic hyperthermia begins as heat stress and progresses to heat exhaustion as fluid losses mount and core temperature increases. The hallmarks are intense thirst, weakness, confusion, slurred speech, and incoordination, progressing to weakness, muscle cramps, nausea, and vomiting. The patient is flushed, is sweating profusely, and feels acutely ill. Symptoms persist until the core temperature is lowered and lost fluids and electrolytes are replaced.47
Heat stroke results from a sudden failure of the normal cooling mechanisms as the cutaneous blood vessels paradoxically vasoconstrict and sweating stops.48 The core temperature rises catastrophically and the obtunded patient is unable to seek help. The clinical picture is easily mistaken for a cerebrovascular accident because the patient is pale, cool to the touch and disoriented, paretic, or comatose. Prolonged elevation of core temperature produces irreversible central nervous system injury.
Heat stroke accounts for 2% of sudden deaths among competitive athletes,49 and rapid cooling by every means is indicated. Immersion is an ice bath is optimal,50 but removal of clothing, and exposure to any cold object, followed by fluid and salt replacement, can be lifesaving. Heat stroke has been treated with activated protein C.51 Complications of heat stroke include disseminated intravascular coagulation and multiple organ failure, mediated by massive cytokine activation. An extremely high core temperature causes rhabdomyolysis and myoglobinuria, associated with compartment syndrome in affected muscles. Survival in such cases is rare.
Iatrogenic Hyperthermia Syndromes
Malignant hyperthermia is caused by exposure of susceptible individuals with a unique genetic composition to halogenated anesthetic agents. The prevalence is estimated as high as 1 in 3,000. There is an uncoupling of oxidative phosphorylation, and glucose is rapidly converted to lactate. The heat released causes a precipitous spike in the core temperature that can be rapidly lethal. The treatment follows several steps. First, stop the anesthetic agent and ventilate with pure oxygen to drive off the anesthetic, treat acidosis and reverse anaerobic metabolism. Immediately remove occlusive drapes and begin active cooling—an ice bath is ideal. Then infuse dantrolene to reverse the effects of the anesthetic, and administer glucose to replace the depleted glycogen reserves. Patients with the genetic abnormality can safely receive general anesthesia with alternative anesthetic agents, nitrous oxide and nondepolarizing muscle relaxants.52
The malignant neuroleptic syndrome (MNS) is a rare event in patients receiving antidepressant medications that block dopamine. It has been reported in trauma patients treated with haloperidol for agitation.53It is also caused by atypical antipsychotic agents, or sudden withdrawal of dopamine agonists such as levodopa. The risk is increased with lithium administration, dehydration, or low serum iron levels. The patient presents with high fever and intense muscle rigidity; lesser features include depressed mentation or coma, tremors, autonomic dysfunction, or dysphagia. The illness is easily mistaken for meningitis, malignant hyperthermia, or drug-induced delirium. Laboratory tests are not diagnostic, although creatinine kinase levels are elevated. The treatment is rapid cooling and rehydration, discontinuation of dopamine blocking agents or restoring dopamine agonists, and supportive measures in the ICU. The reported mortality is 10%.54
Serotonin syndrome is caused by serotonin uptake inhibitors, tricyclic and atypical antidepressants, and monoamine oxidase (MAO) inhibitors. The trauma surgeon encounters the syndrome in association with the use of cocaine, ecstasy, amphetamines, tramadol, fentanyl, or even linazolid. Nausea and diarrhea indicate a mild illness, but delirium, hyperthermia, and autonomic instability can be life threatening. These patients exhibit agitation rather than the stupor of MNS, and require benzodiazepines for sedation, combined with cessation of the causative agent and supportive measures.
REFERENCES
1. Bartfai T, Conti B. Fever. Sci World J. 2010;10:490–503.
2. Wolberg LS, Meng ZH, Monroe DM III, et al. A systematic evaluation of the effect of termperature on coagulation enzyme activity and platelet function. J Trauma. 2004;56:1221–1228.
3. Mossad EB, Machado S, Apostolakis J. Bleeding following deep hypothermia and circulatory arrest in children. Semin Cardiothorac Vasc Anesth. 2007;11(1):34–46.
4. Centers for Disease Control and Prevention (CDC). Hypothermia-related deaths--United States, 1999-2002 and 2005. MMWR Morb Mortal Wkly Rep. 2006;55(10):282–284.
5. Haman F, Scott CG, Kenny GP. Fueling shivering thermogenesis during passive hypothermic recovery. J Appl Physiol. 2007;103:1346–1351.
6. Biggart MJ, Bohn DJ. Effect of hypothermia and cardiac arrest on outcome of near-drowning accidents in children. J Pediatr. 1990;117 (2 pt 1):179–183.
7. Danzl DF, Pozos RS, Auerbach PS, et al. Multicenter hypothermia survey. Ann Emerg Med. 1987;16:1042–1055.
8. Ledingham IM, Mone JG. Treatment of accidental hypothermia: a prospective clinical study. Br Med J. 1980;280:1102–1105.
9. Vanggaard L, Eyolfson D, Xu X, et al. Immersion of distal arms and legs in warm water (AVA rewarming) effectively rewarms mildly hypothermic humans. Aviat Space Environ Med. 1999;70(11):1081–1088.
10. Mohr Wm J, Jenabzadeh K, Ahrenholz DH. Cold injury. Hand Clin. 2009;25:481–496.
11. Gregory JS, Bergstein JM, Aprahamian C, et al. Comparison of three methods of rewarming from hypothermia: advantages of extracorporeal blood warming. J Trauma. 1991;31:1247–1251.
12. Cooper KE, Ferguson AV, Pozos RS, et al. Thermoregulation and Hypothermia in the Elderly. Minneapolis, MN: University of Minnesota Press; 1983:35.
13. Jurkovich GJ, Greiser WB, Luterman A, et al. Hypothermia in trauma victims: an ominous predictor of survival. J Trauma. 1987;27:1019–1024.
14. Martin RS, Kilgo PD, Miller PR, et al. Injury-associated hypothermia: an analysis of the 2004 National Trauma Data Bank. Shock. 2005;24: 114–118.
15. Wang HE, Callaway CW, Peitzman AB, et al. Admission hypothermia and outcome after major trauma. Crit Care Med. 2005;33:1296–1301.
16. Inaba K, Teixeira PGR, Rhee P, et al. Mortality impact of hypothermia after cavitary explorations in trauma. World J Surg. 2009;33:864–869.
17. Gentilello LM, Jurkovich GJ, Stark MS, et al. Is hypothermia in the victim of major trauma protective or harmful? A randomized, prospective study. Ann Surg. 1997;226:439–447 (discussion 447–449).
18. Seekamp A, van Griensven M, Hildebrandt F, et al. Adenosine-triphosphate in trauma-related and elective hypothermia. J Trauma. 1999;47:673–683.
19. Pape HC. Pathophysiologic changes and effects of hypothermia on outcome in elective surgery and trauma patients. Am J Surg. 2004; 187(3):363–371.
20. Goldstein DS, Kopin IJ. Adrenomedullary, adrenocortical, and sympathoneural responses to stressors: a meta-analysis. Endocr Regul. 2008;42(4):111–119.
21. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med. 1996; 334:1209–1215.
22. Paton BC, Pozos RE, Wittmer LE. Cardiac Function During Accidental Hypothermia. Minneapolis, MN: University of Minnesota Press; 1983:133–142.
23. Reed R, Johnson T, Hudson J, et al. The disparity between hypothermic coagulopathy and clotting studies. J Trauma. 1992;33:465–470.
24. Valeri C, Feingold H, Cassidy G, et al. Hypothermia-induced reversible platelet dysfunction. Ann Surg. 1987;205:175–181.
25. Cosgriff N, Moore EE, Sauaia A, et al. Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited. J Trauma. 1997;42(5):857–862.
26. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007;13(6): 680–685.
27. Fries D, Innerhofer P, Schobersberger W. Time for changing coagulation management in trauma-related massive bleeding. Curr Opin Anaesthesiol. 2009;22(2):267–274.
28. Watts DD, Trask A, Soeken K, et al. Hypothermic coagulopathy in trauma: effect of varying levels of hypothermia on enzyme speed, platelet function, and fibrinolytic activity. J Trauma. 1998;44(5):846–854.
29. Mikhail J. The trauma triad of death: hypothermia, acidosis, and coagulopathy. AACN Clin Issues. 1999;10(1):85–94.
30. Stone HH, Strom PR, Mullins RJ. Management of the major coagulopathy with onset during laparotomy. Ann Surg. 1983;197:532.
31. Blackbourne LH. Combat damage control surgery. Crit Care Med. 2008;36(7 suppl):S304–S310.
32. Fukudome EY, Alam HB. Hypothermia in multisystem trauma. Crit Care Med. 2009;37(7 suppl):S265–S272.
33. Varon J. Therapeutic hypothermia: implications for acute care practitioners. Postgrad Med. 2010;122(1):19–27.
34. Kheirbek T, Kochanek AR, Alam HB. Hypothermia in bleeding trauma: a friend or a foe? Scand J Trauma Resusc Emerg Med. 2009;17(1):65.
35. Sinclair HL, Andrews PJD. Bench-to-bedside review: hypothermia in traumatic brain injury. Critical Care. 2010;14:204–214.
36. Linares G, Mayer SA. Hypothermia for the treatment of ischemic and hemorrhagic stroke. Crit Care Med. 2009;37(7 suppl):S243–S249.
37. Sessler DI. Defeating normal thermoregulatory defenses: induction of therapeutic hypothermia. Stroke. 2009;40(11):e614–e621.
38. van der Worp HB, Macleod MR, Kollmar R; European Stroke Research Network for Hypothermia (EuroHYP). Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J Cereb Blood Flow Metab. 2010;30(6):1079–1093.
39. Ahrenholz DH. Frostbite injuries. Probl Gen Surg. 2003;20:129–137.
40. Purdue GF, Hunt JL. Cold injury: a collective review. J Burn Care Rehabil. 1986;7(4):331–342.
41. Britt LD, Dascombe WH, Rodriguez A. New horizons in management of hypothermia and frostbite injury. Surg Clin North Am. 1991;71(2): 345–370.
42. McCauley RL, Hing DN, Robson MC, et al. Frostbite injuries: a rational approach based on the pathophysiology. J Trauma. 1983;23(2):143–147.
43. Jenabzadeh K, Ahrenholz DH, Mohr Wm III. Frostbite: a single institution’s twenty year experience with intra-arterial thrombolytic therapy. J Burn Care Res. 2009;30(2 suppl):S103.
44. Camp DF, Ateaque A, Dickson WA. Cryogenic burns from aerosol sprays: a report of two cases and review of the literature. Br J Plast Surg. 2003;56(8):815–817.
45. Prakash S, Weisman MH. Idiopathic chilblains. Am J Med. 2009;122 (12):1152–1155.
46. Semenza JC, Rubin CH, Falter KH, et al. Heat-related deaths during the July 1995 heat wave in Chicago. N Engl J Med. 1996;335:84–90.
47. Noakes TD. Hydration in the marathon: using thirst to gauge safe fluid replacement. Sports Med. 2007;37(4–5):463–466.
48. Bouchama A, Dehbi M, Chaves-Carballo E. Cooling and hemodynamic management in heatstroke: practical recommendations. Crit Care. 2007; 11(3):R54
49. Maron BJ, Doerer JJ, Haas TS, et al. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980–2006. Circulation. 2009;119(8):1085–1092.
50. McDermott BP, Casa DJ, Ganio MS, et al. Acute whole-body cooling for exercise-induced hyperthermia: a systematic review. J Athl Train. 2009;44(1):84–93.
51. Chen CC, Chen ZC, Lin MT, et al. Activated protein C improves heatstroke outcomes through restoration of normal hypothalamic and thermoregulatory function. Am J Med Sci. 2009;338(5):382–387.
52. Wappler F. Anesthesia for patients with a history of malignant hyperthermia. Curr Opin Anaesthesiol. 2010;23(3):417–422.
53. Bellamy CJ, Kane-Gill SL, Falcione BA, et al. Neuroleptic malignant syndrome in traumatic brain injury patients treated with haloperidol. J Trauma. 2009;66(3):954–958.
54. Nisijima K, Shioda K, Iwamura T. Neuroleptic malignant syndrome and serotonin syndrome. Prog Brain Res. 2007;162:81–104.