Renoprotective effect of oral rehydration solution III in exertional heatstroke rats.

AIM: Exertional heastroke (EHS) can lead to acute kidney injury. Oral rehydration solution III (ORS III), recommended by WHO in 2004, is used to rehydrate children with gastroenteritis. This study aimed to characterize the renoprotective effect of ORS III in EHS rats. METHODS: Rats were randomly divided into Group Control, Group EHS, Group EHS + Water, and Group EHS + ORS. Thirty minutes before the experiment, ORS III was orally administrated to Group EHS + ORS, Water was given to Group EHS + Water. Rats from Group EHS, Group EHS + Water and Group EHS + ORS were then forced to run until they fatigued. Core temperature (Tc) was monitored and 40.5 °C was considered as the onset of heatstroke. Serum creatinine (SCr), blood urea nitrogen (BUN) were measured using an automated biochemical analyzer. Serum neutrophil gelatinase-associated lipocalin (NGAL) was measured using an NGAL ELISA Kit. Light microscopy was used for kidney structural analysis. RESULTS: SCr level in Group EHS was no different from Group Control (p > .05), while BUN and NGAL levels in Group EHS were higher than Group Control (p <.001, p < .001). SCr, BUN and NGAL concentrations in group EHS + Water were no different from Group EHS (p > .05). SCr, BUN levels in Group EHS + ORS were no different from Group EHS (p > .05). But NGAL levels were significant in these two groups (p = .012). Renal histopathologies of rats in Group EHS and Group EHS + Water showed flattened lumens filled with eosinophilic materials. The damage was milder in Group EHS + ORS, in which injured tubules showed degeneration of the tubular epithelium and sloughing of the brush border membrane. CONCLUSION: ORS III could alleviate the kidney injury in EHS rats.

Heat stroke during long-term clozapine treatment: should we be concerned about hot weather?

OBJECTIVE: To describe the case of a patient with schizophrenia on clozapine treatment who had an episode of heat stroke. CASE DESCRIPTION: During a heat wave in January and February 2014, a patient with schizophrenia who was on treatment with clozapine was initially referred for differential diagnose between systemic infection and neuroleptic malignant syndrome, but was finally diagnosed with heat stroke and treated with control of body temperature and hydration. COMMENTS: This report aims to alert clinicians take this condition into consideration among other differential diagnoses, especially nowadays with the rise in global temperatures, and to highlight the need for accurate diagnosis of clinical events during pharmacological intervention, in order to improve treatment decisions and outcomes.

Heat stroke during long-term clozapine treatment: should we be concerned about hot weather? / Heat stroke durante tratamento de longo prazo com clozapina: devemos nos preocupar com o tempo quente?

Objective To describe the case of a patient with schizophrenia on clozapine treatment who had an episode of heat stroke. Case description During a heat wave in January and February 2014, a patient with schizophrenia who was on treatment with clozapine was initially referred for differential diagnose between systemic infection and neuroleptic malignant syndrome, but was finally diagnosed with heat stroke and treated with control of body temperature and hydration. Comments This report aims to alert clinicians take this condition into consideration among other differential diagnoses, especially nowadays with the rise in global temperatures, and to highlight the need for accurate diagnosis of clinical events during pharmacological intervention, in order to improve treatment decisions and outcomes.

Objetivo Descrever o caso de um paciente com esquizofrenia em tratamento com clozapina acometido por um episódio de heat stroke. Descrição do caso Durante uma onda de calor em janeiro e fevereiro de 2014, um paciente com esquizofrenia em tratamento com clozapina foi inicialmente encaminhado para diagnóstico diferencial de infecção sistêmica e síndrome neuroléptica maligna, tendo obtido o diagnóstico final de heat stroke, tratado com controle de temperatura corporal e hidratação. Comentários Este relato de caso tem como objetivo alertar os clínicos para este diagnóstico diferencial, que pode surgir com mais frequência à medida que as temperaturas globais continuarem a aumentar, e também destacar a importância da realização de um diagnóstico mais acurado, que possa melhorar as decisões de tratamento e os desfechos clínicos para os pacientes.

Association of plasma diamine oxidase and intestinal fatty acid-binding protein with severity of disease in patient with heat stroke.

OBJECTIVES: The aim of this study was to describe the role of intestinal fatty acid-binding protein (iFABP) and allergy-related diamine oxidase (DAO) in patients with heat stroke (HS). METHODS: A total of 10 patients with HS in intensive care unit and 10 healthy volunteers were enrolled in this study. The plasma intestinal permeability markers iFABP and DAO were measured since the time of admission. The whole blood endotoxin was also assessed. The associations between iFABP, DAO, and endotoxin level were analyzed. Then, white blood cell count, procalcitonin, and C-reactive protein were examined. In addition, we also determined the levels of proinflammatory cytokines such as IL-1α, IL-6, and TNF-α. RESULTS: Comparing with the healthy control, the plasma iFABP and DAO level in patients with HS increased significantly (P < .05). The kinetic curve showed that plasma iFABP and DAO level reached peak value at day 3 and day 4 after admission, respectively. The endotoxin level was positively correlated with iFABP and DAO level. We also observed a significantly increased level of procalcitonin and C-reactive protein but not white blood count in patients with HS. After treatment, the iFABP and DAO level decreased significantly (P < .05). A significant increase in level of IL-1α and IL-6 was also found in patients with HS. CONCLUSIONS: The plasma concentrations of DAO and iFABP could reflect a better function of the intestinal mucosa barrier in patients with HS. Plasma iFABP and DAO level decreased significantly after the treatment and, thus, might be a predictor for the severity of HS.

Xuebijing injection reduces organ injuries and improves survival by attenuating inflammatory responses and endothelial injury in heatstroke mice.

BACKGROUND: The pathogenesis of heatstroke is a multi-factorial process involved with an interplay among subsequent inflammation, endothelial injury and coagulation disturbances, which makes pharmacological therapy of heatstroke a challenging problem. Xuebijing injection (XBJ), a traditional Chinese medicine used to sepsis, has been reported to suppress inflammatory responses and restore coagulation disturbances. However, little is known about the role of XBJ in heatstroke. METHODS: Mice were treated with indicated dose of XBJ before and/or after the induction of heatstroke. Serum inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and endothelial markers, von Willebrand Factor (vWF) and E-selectin, were measured by ELISA. Liver, kidney and heart profiles including alanine aminotransferase, aspartic aminotransferase, creatinine, blood urea nitrogen, and lactate dehydrogenase, were evaluated by UniCel DxC 800 Synchron Clinical Systems, and troponin was measured by ELISA. Coagulation profiles, including thrombin time, prothrombin time, activated partial thromboplastin time, international normalized ratio, and fibrinogen were examined by STA Compact® Hemostasis System. Jejunum injury was evaluated with H&E staining. Changes in mitochondrial structure in cardiac tissue were assesed by electron microscopy. RESULTS: Pretreatment with XBJ decreased serum pro-inflammatory cytokines including TNF-α and IL-6, as well as endothelial injury markers, vWF and E-selectin, in a dose-dependent manner in heatstroke mice. Similar protective effects were observed when XBJ was administered after, or both before and after heat insult. These protective effects lasted for over 12 h in mice receiving XBJ before and after heat insult. XBJ also improved survival rates in heatstroke mice, ameliorated liver, heart, and kidney injuries, including mitochondrial damage to the heart, and reduced coagulation disturbances. CONCLUSIONS: XBJ prevents organ injuries and improves survival in heatstroke mice by attenuating inflammatory responses and endothelial injury. XBJ may be a potentially useful in the prevention and treatment of heatstroke.

Transplantation of human dental pulp-derived stem cells protects against heatstroke in mice.

Stem cells from human exfoliated deciduous tooth pulp (SHED) is a promising approach for the treatment of stroke and spinal cord injury. In this study, we investigated the therapeutic effects of SHED for the treatment of multiple organ (including brain, particularly hypothalamus) injury in heatstroke mice. ICR male mice were exposed to whole body heating (WBH; 41.2°C, relative humidity 50-55%, for 1 h) and then returned to normal room temperature (26°C). We observed that intravenous administration of SHED immediately post-WBH exhibited the following therapeutic benefits for recovery after heatstroke: (a) inhibition of WBH-induced neurologic and thermoregulatory deficits; (b) reduction of WBH-induced ischemia, hypoxia, and oxidative damage to the brain (particularly the hypothalamus); (c) attenuation of WBH-induced increased plasma levels of systemic inflammatory response molecules, such as tumor necrosis factor-α and intercellular adhesion molecule-1; (d) improvement of WBH-induced hypothalamo-pituitary-adrenocortical (HPA) axis activity (as reflected by enhanced plasma levels of both adrenocorticotrophic hormone and corticosterone); and (e) attenuation of WBH-induced multiple organ apoptosis as well as lethality. In conclusion, post-WBH treatment with SHED reduced induction of proinflammatory cytokines and oxidative radicals, enhanced plasma induction of both adrenocorticotrophic hormone and corticosterone, and improved lethality in mouse heatstroke. The protective effect of SHED may be related to a decreased inflammatory response, decreased oxidative stress, and an increased HPA axis activity following the WBH injury.

Clearance of serum solutes by hemofiltration in dogs with severe heat stroke.

BACKGROUND: We have previously reported that hemofiltration (HF) may be an effective additional means of treating heat stroke when rapid cooling is not effective. METHODS: Dogs were assigned to a heat stroke (control) or heat stroke + hemofiltration (HF) group (n = 8 each group). After heat stroke induction, dogs in the HF group received HF for 3 h. Serum concentrations of interleukin (IL)-10, tumor necrosis factor (TNF)-α, IL-6, blood urea nitrogen (BUN) and creatinine were measured at baseline and 1, 2, and 3 h after heat stroke. Clearance rates of solutes were determined 1, 2, and 3 h after the start of HF. RESULTS: Serum concentrations of all solutes tended to increase with time after heat stroke in the control group, but decreased (BUN, creatinine) or remained relatively unchanged (TNF-α, IL-6, IL-10) with time in the HF group. Concentrations of all solutes were significantly lower in the HF group compared with the control group at 2 and 3 h (P < 0.05). Clearance rates for small molecular weight solutes were high, while those for larger molecular weight solutes were low. CONCLUSION: HF prevents heat stroke-induced increases in serum cytokine concentrations and is effective for clearing small molecular weight solutes from serum, but less effective for clearing larger molecular weight solutes, including TNF-α, IL-6, and IL-10.

Vascular endothelial cell injury partly induced by mesenteric lymph in heat stroke.

Animal models have shown that mesenteric lymph plays important roles in the pathogenesis of endothelium injury in many critical ill states. Gut-derived septicemia and endothelium injury are the two key pathogenesis of heat stroke (HS); however, it is unclear whether mesenteric lymph is cytotoxic to endothelium in HS. HS rat models were prepared in a prewarmed incubator. Mesenteric lymph, collected pre-, during, and post-HS, was analyzed for biological activity on human umbilical vein endothelial cell (HUVEC) in vitro. The effect of HS lymph on the production of von Willebrand factor (vWF), thrombomodulin (TM), and IL-6 by HUVEC was investigated. In vivo, vascular endothelium injury biomarkers, circulating endothelial cell (CEC), as well as serum soluble vWF and TM were tested in rats of HS and HS with mesenteric lymph duct ligation (HS-LDL). HS but not heat stroke sham mesenteric lymph-injured endothelial cells showed significantly increased HUVEC cytotoxicity and enhanced HUVEC monolayer permeability as well as elevated levels of vWF and TM production by HUVEC. IL-6 production by HUVEC was augmented by HS lymph in vitro. The effects of HS lymph on IL-6 production had a time course resembling that of the toxic effects of HS lymph on HUVEC. In vivo, when compared with HS rats, decreased CEC counts as well as lower serum vWF and TM concentrations were detected in HS-LDL rats. HS mesenteric lymph is probably harmful to vascular endothelium, which indicates that the modulation of mesenteric lymph may have some potential benefits to HS.

Flutamide, an androgen receptor antagonist, improves heatstroke outcomes in mice.

Flutamide has been used as an adjunct for decreasing the mortality from subsequent sepsis. Heatstroke resembles septic shock in many aspects. We hypothesized that heat-induced multiple organ dysfunction syndromes and lethality could be reduced by flutamide therapy. In heatstroke groups, mice were exposed to whole body heating (41.2°C, for 1h) in a controlled-environment chamber. The heat-stressed mice were returned to normal room temperature (24°C) after whole body heating. Mice still alive on day 4 of WBH treatment were considered survivors. Physiological and biochemical parameters were monitored for 2.5h post-WBH. Heatstroke mice were subcutaneously treated with flutamide (12.5-50mg/kg body weight in 0.05 ml) or vehicle solution (0.05 ml/kg body weight) once daily for 3 consecutive days post-WBH. We evaluated the effect of flutamide in heatstroke mice and showed that flutamide significantly (i) attenuated hypothermia, (ii) reduced the number of apoptotic cells in the hypothalamus, the spleen, the liver, and the kidney, (iii) attenuated the plasma index of toxic oxidizing radicals (e.g., nitric oxide metabolites and hydroxyl radicals), (iv) diminished the plasma index of the organ injury index (e.g., lactate dehydrogenase), (v) attenuated plasma systemic inflammation response molecules (e.g., tumor necrosis factor-α and interleukin-6), (vi) reduced the index of infiltration of polymorphonuclear neutrophils in the lung (e.g., myeloperoxidase activity), and (vii) allowed three times the fractional survival compared with vehicle. Thus, flutamide appears to be a novel agent for the treatment of mice with heatstroke or patients in the early stage of heatstroke.

Hypobaric hypoxia preconditioning attenuates experimental heatstroke syndromes via preinduction of heat shock protein 70.

INTRODUCTION: Heatstroke has been defined as a form of hyperthermia associated with a systemic inflammatory response that leads to multiple organ dysfunction syndrome (MODS). It has also been documented that heat shock protein 70 (HSP70) preconditioning is able to induce thermotolerance. Here, the authors further investigated whether hypobaric hypoxia preconditioning (HHP) improved the MODS in heatstroke by up-regulation of HSP70. METHODS: Anesthetized rats were randomly assigned to (a) non-HHP + nonheated group, (b) non-HHP + heated group, (c) HHP + heated group and (d) HHP + HSP70 antibodies (Abs) + heated groups. All heated groups were exposed to heat stress (43°C, 70 minutes) to induce heatstroke. For HHP, animals were exposed to 0.66 atmosphere absolute (18.3% O2) for 5 hours daily for consecutive 5 days per week for 2 weeks before the start of heat exposure. RESULTS: HHP significantly (i) attenuated hypotension, (ii) reduced plasma index of the toxic oxidizing radicals and the organ injury indicator, (iii) attenuated plasma systemic inflammatory response molecules, (iv) reduced an index of infiltration of polymorphonuclear neutrophils in the lung like myeloper-oxidase activity, (v) promoted plasma levels of an anti-inflammatory cytokine, interleukin-10, (vi) promoted the survival time to fourfold compared with non-HHP group and (vii) promoted the overexpression of HSP70 in different organs (eg, the lung) during heatstroke. The beneficial effects of HHP could be significantly attenuated by HSP70 Ab preconditioning. CONCLUSION: Our results show that HHP protects rats from heat-induced MODS via up-regulating HSP70. Thus, HHP could be a novel strategy for the prevention of heatstroke animals or patients before heat exposure.

High-dose antithrombin III prevents heat stroke by attenuating systemic inflammation in rats.

OBJECTIVE: Systemic inflammatory mediators, including the high mobility group box 1 (HMGB1) protein, play important roles in the development of various inflammatory conditions. Although anticoagulants, such as antithrombin III (AT III), inhibit inflammation resulting from various causes, their anti-inflammatory mechanism of action is not well understood. Nevertheless, as heat stroke is a severe inflammatory response disease, we hypothesized that AT III would inhibit inflammation and prevent heat stress-induced acute heat stroke. METHODS: Male Wistar rats received a bolus injection of saline or 250 U of AT III per kg of body weight into the tail vein, followed by heat stress (exposure to 42 degrees C for 30 min). Levels of cytokines (interleukin-1 beta, interleukin-6, and TNF-alpha), NOx, and HMGB1 were measured in serum and tissue at regular intervals for 6 h after the heat stress induction. RESULTS: Levels of cytokines, NOx, and HMGB1 in serum decreased over time in AT III-treated rats. AT III pretreatment also reduced NOx levels during heat stress-induced inflammation. As a result, AT III pretreatment improved survival in a rat model of heat stress-induced acute inflammation. CONCLUSIONS: Our data suggest that AT III pretreatment inhibited the secretion of cytokines, NOx, and HMGB1, and prevented heat stress-induced acute inflammation.

Pre-existing lipopolysaccharide may increase the risk of heatstroke in rats.

BACKGROUND: : We attempted to ascertain whether pre-existing inflammatory state [caused by exogenous administration of lipopolysaccharide (LPS)] exacerbated multiorgan dysfunction in experimental heatstroke. DESIGN: : Immediately after the start of heat stress (42 degrees C), anesthetized rats were divided into 2 major groups and given 0.9% NaCl solution (10 mL/kg of body weight, intravenously) or LPS (10 mg/kg of body weight, intravenously). On heat exposure, the occurrence of both hyperthermia (>42.0 degrees C) and hypotension (mean arterial pressure <50 mm Hg) was taken as the time point for heatstroke onset. RESULTS: : The LPS-treated, but not the saline-treated, animals underwent the heat stress for 52 minutes, displayed heatstroke syndromes. As compared with those of the saline controls, the LPS-treated rats had higher extent of activated inflammation (evidenced by increased plasma levels of interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6), hypercoagulable state (evidenced by increased levels of prothrombin time, activated partial thromboplastin time, and D-dimer, but decreased levels of both protein C and platelet counts), and multiorgan apoptosis and dysfunction (evidenced by increased plasma levels of creatinine, blood urea nitrogen, alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase). CONCLUSION: : Our results suggest that pre-existing inflammatory state may exacerbate the multiorgan injury during heat exposure. This tends to promote that pre-existing infection or sepsis may increase the risk of heatstroke.

Recombinant activated protein C attenuates endothelial injury and inhibits procoagulant microparticles release in baboon heatstroke.

OBJECTIVE: We tested the hypothesis that the antithrombotic and cytoprotective effects of recombinant human activated protein C (rhAPC) protect baboons against the lethal effects of heatstroke. METHODS AND RESULTS: Fourteen anesthetized baboons assigned randomly to rhAPC (n=7) or control group (n=7) were heat-stressed in a prewarmed incubator at 44 to 47 degrees C until systolic blood pressure fell below 90 mm Hg, which signaled severe heatstroke. rhAPC was administered intravenously (24 microg/kg/h) for 12 hours at onset of heatstroke. Heat stress induced coagulation and fibrinolysis activation as evidenced by a significant increase from baseline levels in plasma levels of thrombin-antithrombin (TAT) complexes, tissue plasminogen activator, and D-dimer. Heat stress elicited cell activation/injury as assessed by the release of interleukin (IL)-6, soluble thrombomodulin, and procoagulant microparticles (MPs). rhAPC did not significantly reduce heatstroke-induced thrombin generation, and D-dimer and had no effect on fibrinolytic activity. In contrast, rhAPC infusion attenuated significantly the plasma rise of IL-6 and inhibited the release of soluble thrombomodulin and MPs as compared with control group. No difference in survival was observed between rhAPC-treated and control group. CONCLUSIONS: rhAPC given to heatstroke baboons provided cytoprotection, but had no effect on heatstroke-induced coagulation activation and fibrin formation. Inhibition of MPs by rhAPC suggested a novel mechanism of action for this protein.

Human umbilical cord blood-derived CD34+ cells cause attenuation of multiorgan dysfunction during experimental heatstroke.

Multiorgan dysfunction ensuing from severe heatstroke includes hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. We attempted to assess whether human umbilical cord blood-derived CD34+ cell therapy improves survival during experimental heatstroke by attenuating multiorgan dysfunction. Anesthetized rats, immediately after the onset of heatstroke, were divided into 2 major groups and given CD34- or CD34+ cells (1 x 10(5)-5 x 10(5)/mL/kg body weight) i.v. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats were exposed to room temperature (26 degrees C) and used as normothermic controls. Hypotension, hepatic and renal failure (evidenced by increased serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels in plasma), hypercoagulable state (evidenced by increased prothrombin time, activated partial thromboplastin time, and D-dimer, and decreased platelet count and protein C in plasma), activated inflammation (evidence by increased TNF-alpha levels in serum), and cerebral dysfunction (evidenced by intracranial hypertension, cerebral hypoperfusion and hypoxia, and cerebral ischemia and injury) were monitored. When the CD34- cell-treated or untreated rats underwent heat stress, their survival time values were found to be 19 to 23 min. Resuscitation with CD34+ cells significantly improved survival time (duration, 63-291 min). As compared with normothermic controls, all CD34- cell-treated heatstroke animals displayed hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. However, CD34+ cell therapy significantly caused attenuation of all the above-mentioned heatstroke reactions. In addition, the levels of IL-10 in plasma and glial cell line-derived neurotrophic factors in brain were all significantly increased after CD34+ cell therapy during heatstroke. Our data indicate that CD34+ cell therapy may resuscitate persons who had a heatstroke by reducing multiorgan dysfunction or failure.

Glucocorticoids do not protect against the lethal effects of experimental heatstroke in baboons.

The mortality and neurological morbidity in heatstroke have been attributed to the host's inflammatory responses to heat stress, suggesting that anti-inflammatory therapy may improve outcome. We tested the hypothesis that a high dose of dexamethasone protects baboons against the lethal effects of heatstroke. Ten anesthetized baboons (Papio hamadryas) were assigned randomly to dexamethasone (n = 5) or control group (n = 5). Dexamethasone (2 mg/kg i.v.) was administered in four divided doses every 6 h starting immediately before heat stress and continuing during cooling. All animals were heat-stressed in a prewarmed neonatal incubator at 44 degrees C to 47 degrees C until systolic blood pressure fell less than 90 mmHg and then cooled passively at the ambient temperature. Mortality and neurological morbidity were noted, and biochemical markers of tissue injury/organ dysfunction were determined. Circulating interleukin (IL) 6 and complement components (C3 and C4) were measured sequentially. All heat-stressed animals had systemic inflammation indicated by increased plasma IL-6 and decreased C3 and C4 levels. Dexamethasone attenuated the complement system activation and maintained a higher plasma concentration of IL-6, with a significant augmentation of arterial blood pressure. Dexamethasone did not prevent the occurrence of severe heatstroke but unexpectedly aggravated significantly the tissue injury and multiorgan system dysfunction. Two animals (40%) in the control group and one in the steroid group survived (P > 0.05). Dexamethasone failed to protect the baboons from the lethal effects of heatstroke. These results do not support clinical testing of corticosteroids as beneficial in preventive or therapeutic strategies for the treatment of heatstroke in humans.

Resuscitation from experimental heatstroke by brain cooling therapy.

We have used hypothermic retrograde jugular venous flush to cool the brain previously and to provide better resuscitation than peripheral cold saline infusion during heatstroke in the rat. The current study was performed to assess the effects of brain cooling further on production of reactive nitrogen species, reactive oxygen species, tumor necrosis factor-alpha, and interleukin-10 in both serum and brain during heatstroke. Rats, under general anaesthesia, were randomized into the following groups and given: (a) 36 degrees C or (b) 4 degrees C saline infusion in the external jugular vein immediately after onset of heatstroke. They were exposed to an ambient temperature of 43 degrees C for exactly 70 min to induce heatstroke. When the 36 degrees C saline-treated rats underwent heat stress, their survival time values were found to be 21-25 min. Immediately after the onset of heatstroke, resuscitation with an i.v. dose of 4 degrees C saline greatly improved survival (226-268 min). Compared with the normothermic controls, the 36 degrees C saline-treated heatstroke rats displayed higher levels of brain temperature, intracranial pressure, serum and hypothalamic nitric oxide metabolite, tumor necrosis factor-alpha and dihydroxybenzoic acid as well as hypothalamic inducible nitric oxide synthase immunoreactivity. In contrast, the values of mean arterial pressure, cerebral perfusion pressure, and hypothalamic levels of local blood flow, and partial pressure of oxygen were all significantly lower during heatstroke. The cerebrovascular dysfunction, the increased levels of nitric oxide metabolites, tumor necrosis factor-alpha, and dihydroxybenzoic acid in both the serum and the hypothalamus, and the increased levels of hypothalamic inducible nitric oxide synthase immunoreactivity occurred during heatstroke were significantly suppressed by brain cooling. Although the serum and hypothalamic interleukin-10 maintained at a negligible level before stress, they were significantly elevated by brain cooling during heatstroke. These findings suggest that brain cooling may resuscitate persons who had heatstroke by decreasing overproduction of reactive nitrogen species, tumor necrosis factor-alpha, reactive oxygen species and cerebrovascular dysfunction, but increasing production of interleukin-10.

Activated protein C therapy in a rat heat stroke model.

OBJECTIVE: To evaluate the therapeutic effects of activated protein C in an animal model of heat stroke. DESIGN: Laboratory investigation. SETTING: Chi-Mei Medical Center research laboratory. SUBJECTS: Male Sprague-Dawley rats weighing 252-304 g. INTERVENTIONS: Anesthetized animals were subjected to heat stress (40 degrees C) to induce heat stroke. A bolus injection of normal saline or recombinant human activated protein C (drotrecogin alfa, activated) was conducted via femoral catheters immediately after the onset of heat stroke. Blood sampling was done before initiation of heat stress and 0 and 40 mins after the onset of heat stroke. MEASUREMENTS AND MAIN RESULTS: When the vehicle-treated rats underwent heat exposure, their survival time values were found to be 56-64 mins (n = 16). Resuscitation with activated protein C significantly and dose-dependently improved survival during heat stroke (108-246 mins for doses of 0.5-20 mg of activated protein C per kilogram of body weight) (n = 32). All heat-stressed animals displayed systemic inflammation and activated coagulation, evidenced by increased tumor necrosis factor-alpha, prothrombin time, activated partial thromboplastin time, and D-dimer and decreased platelet count and protein C. Biochemical markers evidenced by cellular ischemia and injury/dysfunction included increased plasma levels of blood urea nitrogen, creatinine, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase; increased striatal levels of glutamate, glycerol, and lactate/pyruvate ratio; and decreased striatal levels of partial pressure of oxygen and local cerebral blood flow, which were all observed during heat stroke. These heat stroke reactions were all significantly suppressed by resuscitation with activated protein C but not vehicle solution. CONCLUSIONS: The results indicate that systemic delivery of human recombinant activated protein C at the time point of onset of heat stroke may improve survival by ameliorating systemic inflammation, hypercoagulable state, and tissue ischemia and injury in multiple organs.

Resuscitation from experimental heatstroke by estrogen therapy.

OBJECTIVE: We investigated the effect of estrogen therapy on inflammatory responses, cardiovascular functions, and survival in a rat model of heatstroke. DESIGN: Controlled, prospective study. SETTING: Hospital medical research laboratory. SUBJECTS: Sprague-Dawley rats (280-312 g of body weight, males and females). INTERVENTIONS: Four major groups of anesthetized rats were designated for experiments: a) vehicle-treated male rats; b) vehicle- or premarin-treated estrus female rats; c) vehicle- or premarin-treated ovariectomized rats; and d) vehicle- or premarin-treated leuprolide-treated rats. All animals were exposed to heat stress (ambient temperature 43 degrees C for 70 mins) and then allowed to recover at room temperature (24 degrees C). Their survival time (interval between the onset of heatstroke and animal death) and physiologic and biochemical variables were monitored. Vehicle (normal saline 1 mL/kg of body weight, intravenously) or premarin (1 mg/mL/kg of body weight, intravenously) was administered 70 mins after initiation of heat stress. Ovariectomy or leuprolide (100 mug/kg/day, subcutaneously) injection was conducted 4 wks before the start of heat stress experiments. Another group of rats were exposed to 24 degrees C and used as normothermic controls. MEASUREMENTS AND MAIN RESULTS: Compared with the estrus female rats, the ovariectomized rats, the leuprolide-treated rats, and male rats all had lower levels of plasma estradiol and lower survival time values. However, after an intravenous dose of premarin, both the plasma estradiol and survival time values were significantly increased. Compared with the normothermic controls, the vehicle-treated male and ovariectomized rats all displayed higher levels of serum tumor necrosis factor-alpha, which could be suppressed by premarin therapy. In contrast, the serum levels of IL-10 in these groups were significantly elevated by premarin during heatstroke. Furthermore, the heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, and cerebral hypoperfusion, hypoxia, and ischemia were significantly attenuated by premarin therapy in ovariectomized rats. CONCLUSIONS: We successfully demonstrated that estrogen replacement may improve survival during heatstroke by ameliorating inflammatory responses and cardiovascular dysfunction.

Platonin, a cyanine photosensitizing dye, causes attenuation of circulatory shock, hypercoagulable state, and tissue ischemia during heat stroke.

The aim of this study was to investigate the therapeutic effect of platonin, a cyanine photosensitizing dye as well as an inhibitor of proinflammatory cytokines, in an animal model of heat stroke. Anesthetized rats, immediately after the onset of heat stroke, were divided into two major groups and given the following: normal saline (1 mL per kg body weight) intravenously, or platonin (12.5-50 microg/mL per kg body weight) intravenously. They were exposed to ambient temperature of 43 degrees C to induce heat stroke. Another group of rats was exposed to room temperature (26 degrees C) and used as normothermic controls. Their physiologic and biochemical parameters were continuously monitored. When the vehicle-treated rats underwent heat exposure, their survival time values were found to be 18 to 22 min. Resuscitation with intravenous doses of platonin, but not normal saline, immediately at the onset of heat stroke, significantly improved survival during heat stroke (41-147 min). All heat-stressed animals displayed systemic inflammation and activated coagulation, evidenced by increased tumor necrosis factor-alpha, prothrombin time, activated partial thromboplastin time, fibrinogen degradation products, and D-dimer, and decreased platelet count and protein C. Biochemical markers evidenced cellular ischemia and injury/dysfunction: plasma levels of blood urea nitrogen, creatinine, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase, and striatal levels of partial pressure of oxygen, local cerebral blood flow, glycerol, glutamate, and lactate/pyruvate were all elevated during heat stroke. The systemic inflammation, hypercoagulable state, and cerebral ischemia and injury during heat stroke were all significantly suppressed by platonin. The data demonstrate that platonin therapy may resuscitate heat stroke victims by reducing circulatory shock, systemic inflammation, hypercoagulable state, and tissue ischemia and injury.