We hypothesized that hydroxyethyl starch (HES), which maintains colloid osmotic pressure and potentially "seals" capillary leaks, would ameliorate circulatory shock and cerebral ischemia during heatstroke in a rat model. Animals under urethane anesthesia were exposed to high ambient temperature (Ta) of 42 degrees C until mean arterial pressure and local cerebral blood flow in the striatum began to decrease from peak level, which was arbitrarily defined as the onset of heatstroke. Control rats were exposed to 24 degrees C. In rats treated with 1 mL/kg, 11 mL/kg, or 22 mL/kg of normal saline (NS) immediately after the onset of heatstroke, the values for survival time (interval between the initiation of heatstroke and animal death) were found to be 21 +/- 2, 36 +/- 9, or 92 +/- 7 min, respectively. Intravenous administration of 11 mL/kg of HES (about 5 times the volume-expanding effect of 11 mL/kg of NS), but not 2 mL/kg of HES (about the same volume-expanding effect as 11 mL/kg NS), significantly increased the survival time from the control values of 36 +/- 9 min to new values of 181 +/- 13 min. In NS (11 mL/kg)-treated or HES (2 mL/kg)-treated rats after heatstroke onset, the values for mean arterial pressure, stroke volume, total peripheral resistance, cerebral blood flow, blood pH, Paco2, Pao2, and brain Po2 were significantly lower than those of rats kept at Ta 24 degrees C. In contrast, the values for colonic temperature and the extracellular concentrations of glutamate, glycerol, and lactate/pyruvate ratio obtained in striatum were significantly higher than those of controls. The heatstroke-induced arterial hypotension, decreased stroke volume and total peripheral resistance, decreased blood pH and Pao2, decreased brain Po2, and increased levels of striatal glutamate, glycerol, and lactate/pyruvate ratio in NS-treated rats were all attenuated significantly by increasing the volume expansion with 11 mL/kg of HES administered immediately at the onset of heatstroke. Our data suggest that HES therapy seems superior to NS treatment during heatstroke. The benefit of HES therapy during heatstroke might have something to do with volume expansion rather than capillary permeability.

Unless immediately recognized and treated, heat stroke is often lethal, and victims who do survive may sustain permanent neurological damage.1) The clinical diagnosis of heat stroke is demonstrated when hyperthermia is accompanied with circulatory shock (arterial hypotension), intracranial hypertension, and cerebral ischemia and injury. 2,3) Meanwhile, the heat stroke-induced central nervous system dysfunction includes delirium, convulsion, or coma. 4) Hence, prolonging survival time in heat stroke victims may offer more sufficient time for urgent treatment, thereby ameliorating the heat stroke-induced damage.Several lines of evidence indicate that rodents share with humans almost the same heat stroke syndromes, such as arterial hypotension, activated inflammation, and multiorgan dysfunction (in particular, cerebral ischemia, injury, and dysfunction. [5][6][7] In the rodents heat stroke model, significant decrements in both mean arterial pressure (MAP) and cerebral blood flow (CBF), but increments of cerebral monoamines levels and free radical productions are obtained in urethane-anaesthetized rats after heat stroke. 8,9) These pathophysiological changes are known to aggravate the conditions of cerebral ischemia and neuronal damage during heat stroke in rats.10,11) Activated inflammation is evidenced by overproduction of pro-inflammatory cytokines (e.g., tumor necrosis factor-a (TNF-a)) in plasma of heat stroke rats.12,13) High levels of TNF-a in the peripheral blood stream, as well as excessive accumulation of glutamate, hydroxyl radicals, dopamome (DA) and serotonin (5-HT) in the central brain, correlate with the severity of circulatory shock, cerebral ischemia and neuronal damage during heat stroke in rats. 6,9,11,14,15) Various clinical and experimental investigations have shown that single doses of dexamethasone (DXM; exogenous glucocorticoids) or mannitol are extensively used in the treatment of cerebral ischemia and/or cerebral injury. [16][17][18] In the studies of heat stroke, pretreatment with DXM attenuated serum IL-1b levels and improved survival in heat stroke. 19) Additionally, pretreatment with mannitol before the onset of heat stroke caused significant reduction of the heat strokeinduced the increased free radical formation and intracranial hypertension. 20) Although, many therapeutic agent show potential promise in many animal models, the results of most single-agent clinical trials are sobering. Consequently, various authors advocate studies to estimate the efficacy of combined therapeutic approaches. 21,22) Hence, the mannitol that acts to decrease intracranial pressure and radical formation, and a potent inflammatory agent (such as DXM) might be combined to develop an improved fluid therapy for attenuation or amelioration of heat stroke-induced damage. Furthermore, there is less attention to evaluate immediate effects of both DXM and mannitol (the combined agent) on heat stroke-induced pathophysiological changes, let alone their neuroprotective underlying influences, especially in the aspects...

BackgroundIncreased systemic cytokines and elevated brain levels of monoamines, and hydroxyl radical productions are thought to aggravate the conditions of cerebral ischemia and neuronal damage during heat stroke. Dexamethasone (DXM) is a known immunosuppressive drug used in controlling inflammation, and hydroxyethyl starch (HES) is used as a volume-expanding drug in cerebral ischemia and/or cerebral injury. Acute treatment with a combined therapeutic approach has been repeatedly advocated in cerebral ischemia experiments. The aim of this study is to investigate whether the combined agent (HES and DXM) has beneficial efficacy to improve the survival time (ST) and heat stroke-induced cerebral ischemia and neuronal damage in experimental heat stroke.MethodsUrethane-anesthetized rats underwent instrumentation for the measurement of colonic temperature, mean arterial pressure (MAP), local striatal cerebral blood flow (CBF), heart rate, and neuronal damage score. The rats were exposed to an ambient temperature (43 degrees centigrade) to induce heat stroke. Concentrations of the ischemic and damage markers, dopamine, serotonin, and hydroxyl radical productions in corpus striatum, and the serum levels of interleukin-1 beta, tumor necrosis factor-alpha and malondialdehyde (MDA) were observed during heat stroke.ResultsAfter heat stroke, the rats displayed circulatory shock (arterial hypotension), decreased CBF, increased the serum levels of cytokines and MDA, increased cerebral striatal monoamines and hydroxyl radical productions release, and severe cerebral ischemia and neuronal damage compared with those of normothermic control rats. However, immediate treatment with the combined agent at the onset of heat stroke confers significant protection against heat stroke-induced circulatory shock, systemic inflammation; cerebral ischemia, cerebral monoamines and hydroxyl radical production overload, and improves neuronal damage and the ST in rats.ConclusionsOur results suggest that the combination of a colloid substance with a volume-expanding effect and an anti-inflammatory agent may provide a better resuscitation solution for victims with heat stroke.

Abstract. In this study, we investigated the acute hemodynamic effects of an infusion of the endothelin-1 (ET-1)-A-selective receptor antagonists BQ-610 and BQ-123 in heatstroke rats with circulatory shock and cerebral ischemia. Heatstroke was induced by putting the anesthetized adult Sprague-Dawley rats into an ambient temperature of 42°C. The moment in which the mean arterial pressure dropped irreversibly from the peak for an extent of 25 mmHg was taken as the onset of heatstroke. The interval between initiation of heat exposure and heatstroke onset was found to be about 80 min for rats treated with vehicle solution. When the animals were exposed to 42°C for 80 min, hyperthermia, arterial hypotension, decrement of cardiac output (due to decreased stroke volume and decreased total peripheral resistance), increment of plasma ET-1 and tumor necrosis factor-a , and increment of cerebral ischemia and injury markers were manifested. Prior antagonism of ET-1 A receptors with BQ-610 (0.5 mg / kg, i.v.) or BQ-123 (1 mg / kg, i.v.), but not ET-1B receptors with BQ-788 (0.5 mg / kg, i.v.), 60 min before the initiation of heat exposure, appreciably alleviated hyperthermia, arterial hypotension, decreased cardiac output, increment of tumor necrosis factor-a , and increment of cerebral ischemia (e.g., glutamate and lactate / pyruvate ratio) and injury (e.g., glycerol) markers exhibited during heatstroke. The data indicates that ET-1A receptor antagonism may maintain appropriate levels of mean arterial pressure and cerebral circulation during heatstroke by reducing production of tumor necrosis factor-a .

Dexamethasone (DXM) is known as an immunosuppressive drug used for inflammation control. In the present study, we attempted to examine whether DXM administration could attenuate the hypercoagulable state and the overproduction of pro-inflammatory cytokines, improve arterial hypotension, cerebral ischemia and damage, and vital organ failure in a rat model of heat stroke. The results indicated that all the rats suffering from heat stroke showed high serum levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), accompanied with increased prothrombin time, activated partial thromboplastin time and D-D dimer, and decreased protein C. During the induction period of heat stroke, plasma levels of blood urea nitrogen (BUN), creatinine, glutamic oxaloacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), and alkaline phosphatase (ALP), were consistently increased. High striatal levels of glycerol, glutamate, and lactate/pyruvate were simultaneously detected. On the contrary, the mean arterial pressure, plasma levels of interleukin-10 (IL-10), and local cerebral blood flow at the striatum were all decreased. Importantly, intravenous administration of DXM substantially ameliorated the circulatory dysfunction, systematic inflammation, hypercoagulable state, cerebral ischemia and damage during the induction period of heat stroke. These findings demonstrated that DXM may be an alternative therapy that can ameliorate heat stroke victims by attenuating activated coagulation, systemic inflammation, and vital organ ischemia/injury during heat stroke.