Role of circulating cytokines and chemokines in exertional heatstroke

OBJECTIVE: The interplay between inflammatory and anti-inflammatory cytokines, as well as chemokines, has not been well explored in exertional heatstroke. DESIGN: Prospective, observational study. PATIENTS: Seventeen military recruits who developed exertional heatstroke and 17 exertional controls who did not develop exertional heatstroke during the same training exercises. SETTING: University teaching hospital. MEASUREMENTS AND MAIN RESULTS: The severity of exertional heatstroke was evaluated using a Simplified Acute Physiology Score. Plasma cytokines and chemokines were determined using enzyme-linked immunosorbent assay kits. Body temperatures were 41.2 +/- 1.2 degrees C and 37.6 +/- 0.8 degrees C in exertional heatstroke and exertional controls, respectively. Significantly, plasma cytokines including interleukin (IL)-1beta (3.1 +/- 1.6 vs. 1.2 +/- 0.8 pg/mL; p <.05), tumor necrosis factor alpha (4.9 +/- 4.1 vs. 1.2 +/- 2.4 pg/mL; p <.05), IL-6 (15.8 +/- 3.2 vs. 1.2 +/- 1.2 pg/mL; p <.01), interferon gamma (7.3 +/- 4.9 vs. 2.4 +/- 4.1 pg/mL; p <.01), IL-2 receptor (1568 +/- 643 vs. 610 +/- 214 pg/mL; p <.01), IL-4 (2.5 +/- 1.2 vs. 1.2 +/- 0.8 pg/mL; p <.05), and IL-10 (12.9 +/- 9.4 vs. 2.5 +/- 4.9 pg/mL; p <.01) and serum chemokines IL-8 (84.2 +/- 79.9 vs. 10.4 +/- 3.2 pg/mL; p <.01), monocyte chemoattractant protein 1 (959 +/- 589 vs. 158 +/- 217 pg/mL; p <.01), and RANTES (12464 +/- 10505 vs. 5570 +/- 2894 pg/mL; p <.01) were elevated in exertional heatstroke compared with exertional controls. Among cytokines, IL-6, interferon gamma, and IL-2 receptor were positively correlated with Simplified Acute Physiology Score (r =.573, p <.01; r =.625, p <.01; and r =.56, p <.05, respectively). Among chemokines, only serum monocyte chemoattractant protein 1 was positively correlated with Simplified Acute Physiology Score (r =.78, p <.001). There was no correlation between either cytokines or chemokines and body temperature. CONCLUSIONS: Proinflammatory cytokines IL-1beta, tumor necrosis factor alpha, IL-6; T helper 1 cytokines INF-gamma and IL-2 receptor; and chemokines IL-8, monocyte chemoattractant protein 1, and RANTES are increased in patients with exertional heatstroke. T helper 2 cytokines may play a role as anti-inflammatory cytokines. IL-6, interferon gamma, IL-2 receptor, and monocyte chemoattractant protein 1 may serve as prognostic indicators of disease severity in exertional heatstroke.     

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.     

Heat stress and/or endotoxin effects on cytokine expression by human whole blood

Immune system cytokines induce vascular shock. Tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta), and bacterial endotoxin (E) circulate in human heatstroke to suggest that E release from a heat-damaged gut may stimulate cytokines that contribute to hypovolemia. However, immune activation by heat-induced tissue necrosis might stimulate cytokine generation in the absence of E. To evaluate this potential and heat stress effects on the anti-inflammatory cytokines, IL-1 receptor antagonist (IL-1ra) and IL-1 soluble receptor II (IL-1srII), a human whole blood (HWB) model was employed in which the presence or absence of E could be controlled. Using thermoelectric technology to regulate the HWB heat exposures, the temperature modulations of lethal heatstroke were precisely replicated (maximum temperature = 42.4 degrees C +/- 0.04 degrees C; thermal area = 52.3 degrees C +/- 1.5 degrees C per min). Cytokine and mRNA measurements employed enzyme-linked immunosorbant-based assay systems. Significant elevations in TNF-alpha, IL-1beta, interleukin 6 (IL-6), and IL-1ra resulted when HWB was exposed to E concentrations (10 ng/ml) reported to circulate in heatstroke. While E-stimulated IL-1ra was significantly decreased by the presence of prior heat stress (PPHS), E-stimulated IL-1beta, TNF-alpha, and IL-6 were not significantly altered by PPHS, but tended to be elevated. IL-1srII expression was unchanged by PPHS and/or E. PPHS in the absence of E did not induce cytokine responses, nor were there elevations in TNF-alpha or IL-1beta mRNA. Thus, some factor normally absent under in vitro conditions, like endotoxin, was required to provoke HWB cytokine expressions and the heat stress and E conditions that characterize heatstroke affected HWB cytokine metabolism to favor a proinflammatory environment.     

L-arginine causes amelioration of cerebrovascular dysfunction and brain inflammation during experimental heatstroke

Cerebrovascular dysfunction ensuing from severe heatstroke includes intracranial hypertension, cerebral hypoperfusion, and brain inflammation. We attempted to assess whether L-arginine improves survival during experimental heatstroke by attenuating these reactions. Anesthetized rats, 70 min after the start of heat stress (43 degrees C), were divided into two major groups and given the following: vehicle solution (1 mL/kg body weight) or L-arginine (50-250 mg/kg body weight) intravenously. Another group of rats was exposed to room temperature (24 degrees C) and used as normothermic controls. Their physiological and biochemical parameters were continuously monitored. When the vehicle-treated rats underwent heat stress, their survival time values were found to be 20 to 26 min. Treatment with i.v. doses of L-arginine significantly improved the survival rate during heatstroke (54-245 min). As compared with those of normothermic controls, all vehicle-treated heatstroke animals displayed higher levels of core temperature, intracranial pressure, and NO metabolite, glutamate, glycerol, lactate-pyruvate ratio, and dihydroxybenzoic acid in hypothalamus. In addition, hypothalamic levels of IL-1beta and TNF-alpha were elevated after heatstroke onset. In contrast, all vehicle-treated heatstroke animals had lower levels of MAP, cerebral perfusion pressure, cerebral blood flow, and brain partial pressure of oxygen. Administration of L-arginine immediately after the onset of heatstroke significantly reduced the intracranial hypertension and the increased levels of NO metabolite, glutamate, glycerol, lactate-pyruvate ratio, and dihydroxybenzoic acid in the hypothalamus that occurred during heatstroke. The heatstroke-induced increased levels of IL-1beta and TNF-alpha in the hypothalamus were suppressed by L-arginine treatment. In contrast, the hypothalamic levels of IL-10 were significantly elevated by L-arginine during heatstroke. The results suggest that L-arginine may cause attenuation of heatstroke by reducing cerebrovascular dysfunction and brain inflammation.     

Differential effects of in vitro and in vivo hyperthermia on the production of interleukin-10

OBJECTIVE: To determine whether hyperthermia activates an anti-inflammatory response. DESIGN: A prospective study. SETTING: Heatstroke Center, Makkah, and King Faisal Specialist Hospital, Riyadh, Saudi Arabia. PATIENTS: Twenty-five heatstroke patients pre-cooling (rectal temperature 42.4 +/- 0.8 degrees C) (group 1) and 13 normothermic heat-stressed subjects were studied (group 2). Twelve of the 25 heatstroke patients were also studied post-cooling (group 3). Mononuclear cells from six healthy blood donors resting at 24 degrees C were used for in vitro study. INTERVENTIONS: Mononuclear cells were cultured at a concentration of 1 x 10(6)/ml without and with lipopolysaccharide (LPS) added at concentration of 10, 100, and 1000 ng/ml. The cells were incubated for 24 h at 37, 39, 41, and 43 degrees C. ELISA was used to measure IL-10 in the supernatant and plasma from heatstroke and heat-stressed subjects. RESULTS: All patients in group 1, 40% of group 2, and 37% of group 3, showed elevation of IL-10 (1289 +/- 2519, 248 +/- 393, and 172 +/- 226 pg/ml, respectively) compared with normal control levels, (< 100 pg/ml) P < 0.05. IL-10 level on admission did not correlate with degree of hyperthermia. During 24 h incubation at 37 degrees C without LPS, no IL-10 was detected, whereas with 10 ng/ml LPS, monocytes released 658 +/- 291 pg IL-10/10(6) cells. At 39 degrees C and 41 degrees C IL-10 release was decreased to 225 +/- 114, and 245 +/- 90 pg/10(6) cells, respectively; and was completely inhibited at 43 degrees C (67 +/- 10 pg/10(6) cells), P < 0.0001. CONCLUSION: Heat-stress with and without hyperthermia is associated with anti-inflammatory response in vivo. However, it does not seem to be the direct effect of heat on monocytes, suggesting that other environmental or genetic factors may be involved.     

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.     

Brain cooling causes attenuation of cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heatstroke

The purpose of the present study was to assess the therapeutic effect of hypothermic retrograde jugular vein flush (HRJVF) on heatstroke. HRJVF was accomplished by infusion of 4 degrees C isotonic sodium chloride solution via the external jugular vein (1.7 mL/100 g of body weight over 5 min). Immediately after the onset of heatstroke, anesthetized rats were divided into 2 major groups and given the following: 36 degrees C or 4 degrees C isotonic sodium chloride solution, i.v. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats was exposed to room temperature (24 degrees C) and used as normothermic controls. When the 36 degrees C saline-treated rats underwent heat exposure, their survival time values were found to be 23 to 28 min. Immediately after the onset of heatstroke, resuscitation with an i.v. dose of 4 degrees C saline significantly improved survival during heatstroke (208-252 min). 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 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 glycerol, glutamate, and lactate/pyruvate; dihydroxy benzoic acid, lipid peroxidation, oxidized-form glutathione reduced-form glutathione, dopamine, and serotonin were all elevated during heatstroke. Core and brain temperatures and intracranial pressure were also increased during heatstroke. In contrast, the values of mean arterial pressure, cerebral perfusion pressure, and striatal levels of local blood flow, partial pressure of oxygen, superoxide dismutase, catalase, glutathione peroxidase, and glutathions reductase activities were all significantly lower during heatstroke. The circulatory dysfunction, systemic inflammation, hypercoagulable state, and cerebral oxidative stress, ischemia, and damage during heatstroke were all significantly suppressed by HRJVF. These findings demonstrate that brain cooling caused by HRJVF therapy may resuscitate persons who had a stroke by attenuating cerebral oxidative stress, systemic inflammation, activated coagulation, and tissue ischemia/injury during heatstroke.     

Platonin, a cyanine photosensitizing dye, is effective for attenuation of heatstroke in rats

The present study was performed to assess the prophylactic effect of platonin, a cyanine photosensitizing dye and an inhibitor of proinflammatory cytokines, in an animal model of heatstroke. Anesthetized rats were immediately divided into 2 major groups after the start of heat stress and administered either isotonic sodium chloride solution (dose, 1 mL/kg of body weight i.v.) or platonin (dose, 12.5-50 microg/mL per kilogram of 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. Their physiological and biochemical parameters were continuously monitored. When the isotonic sodium chloride solution-pretreated rats underwent heat stress, their survival time values were found to be from 20 to 24 min. Pretreatment with intravenous doses of platonin (12.5-50 microg/mL per kilogram of body weight) immediately after the start of heat exposure significantly improved survival time during heatstroke (duration, 63-185 min). As compared with normothermic controls, all vehicle-pretreated heatstroke animals displayed higher levels of creatinine, serum urea nitrogen, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor alpha, prothrombin time, activated partial thromboplastin time and D-dimer in the plasma, cellular ischemia and injury markers in striatum, and intracranial pressure. In contrast, all vehicle-pretreated heatstroke animals had lower levels of mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, brain Po2, and platelet count and protein C in the plasma. Immediately after the start of heat exposure, the previous administration of platonin significantly improved survival time by reducing the systemic inflammation, hypercoagulable state, and tissue ischemia and damage during heatstroke. The results demonstrate that platonin is effective for attenuation of heatstroke reactions.     

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.     

Acid-base alterations in heatstroke

OBJECTIVE: To analyze the acid-base balance during heatstroke. DESIGN: Retrospective study. SETTING: Heatstroke Center, Makkah, Saudi Arabia. PATIENTS: Hundred nine consecutive heatstroke patients (mean age 55 +/- 12 years) with rectal temperature from 40 to 43.4 degrees C following exposure to hot weather. INTERVENTION: Arterial blood gases collected prospectively and analyzed using 95% confidence limits established by controlled experimental studies. Severity of heatstroke on admission assessed by Simplified Acute Physiology Score and Organ System Failure score. RESULTS: Metabolic acidosis was the predominant acid-base change followed by respiratory alkalosis (81 and 55% of the patients, respectively). The prevalence of metabolic acidosis (but not respiratory alkalosis) was significantly associated with the degree of hyperthermia: 63, 95 and 100% at 41, 42 and 43 degrees C, respectively (p < 0.0001). Patients with metabolic acidosis had a large anion gap (24 +/- 5). Arterial partial pressure of oxygen (PaO2), systolic blood pressure and Organ System Failure score were similar with or without metabolic acidosis. Although the acute physiology score was higher in patients with, than without, metabolic acidosis (15.7 +/- 3.7 vs 9.8 +/- 4.4, p < 0.001), there was no significant difference in neurologic morbidity and mortality (7.9 vs 1.1%, 5.6 vs 0%, p = 0.776 and 0.581, respectively). CONCLUSION: We conclude that metabolic acidosis is the predominant response in heatstroke.     

Cerebral temperature and epidural pressure during whole body hyperthermia in dogs

Whole body hyperthermia was performed on 13 anaesthetized and intubated dogs. Cerebral temperature and epidural pressure were measured and related to rectal and oesophageal temperatures. The brain temperature was significantly higher than that of the rectum at normotemperature. The temperature gradients lessened during heating. At maximum rectal temperature (plateau) small differences between the left and right hand sides of the brain were seen, the temperatures being 0.4 degrees C and 0.3 degrees C higher than the rectal temperature, respectively. During the 2-h plateau period the difference between brain and oesophageal temperature became progressively smaller. The mean epidural pressure decreased slightly during the course of the treatment, but remained within the normal range of 1.2 +/- 0.4 KPa (8.7 +/- 2.5 mm Hg). From this investigation may be concluded that (1) the cerebral temperature is reflected better by the oesophageal than by the rectal temperature and (2) the epidural pressure does not increase during whole body hyperthermia for 2 h at a rectal temperature of up to 42.5 degrees C.     

Dantrolene sodium for treatment of heatstroke victims: Lack of efficacy in a canine model

Dantrolene sodium, a skeletal-muscle relaxant known to be effective for treatment of malignant hyperthermia, was evaluated for efficacy in treatment of heatstroke. Non-exertional heatstroke was induced in 11 dogs by external heating following barbiturate anesthesia. When core temperature reached 43 degrees C (109.4 degrees F) heating was discontinued and control animals (n = 6) were allowed to cool passively in room air. Treatment animals (n = 5) received 5 mg/kg dantrolene sodium intravenously at the start of room-air cooling. Serial temperatures (pulmonary arterial, rectal, cerebral, and subcutaneous), blood chemistry tests (including electrolytes, liver enzymes, and complete blood count), and hemodynamic parameters (including cardiac output, arterial pressure, and urinary output) were followed for 12 hours after induction of heatstroke. Autopsies, including gross and microscopic examination, were performed on all animals. Dantrolene administration did not significantly affect cooling rates, hemodynamic parameters, pathological changes, or clinical outcome. Statistically significant changes in urinary output and serum creatinine observed in the first hours after dantrolene administration can be attributed to the mannitol vehicle in which the drug was delivered. There were no statistically significant differences in these values at 12 hours. Dantrolene sodium does not appear to enhance passive cooling in treatment of non-exertional canine heatstroke.     

Hypothermic retrograde jugular perfusion reduces brain damage in rats with heatstroke

OBJECTIVE: To determine whether direct retrograde ice saline infusion in the jugular vein without cardiopulmonary bypass protects rat brains after heatstroke. DESIGN: Randomized, controlled, prospective study. SETTING: University physiology research laboratory. SUBJECTS: Sprague-Dawley rats (270-320 g, males). INTERVENTIONS: Rats were randomized into three groups and given a) no resuscitation after onset of heat stroke (HS, n = 8); b) ice saline infusion in the femoral vein after onset of heat stroke (HS + F, n = 8); or c) retrograde ice saline infusion in the external jugular vein after onset of heat stroke (HS + J, n = 8). Rats were exposed to an ambient temperature of 43 degrees C after vessel cannulation. Their mean arterial pressure, heart rate, colonic temperature, and brain temperature were continuously recorded. Survival time and brain pathology were checked. MEASUREMENTS AND MAIN RESULTS: Although colonic temperature decreased 0.8-1.0 degrees C 15 mins after heatstroke in all groups, no treatment-related changes in colonic temperature were noted in any group. However, significant changes were observed in brain temperature. Fifteen minutes after heatstroke, brain temperature was 37.6 +/- 0.4 degrees C, 36.1 +/- 0.4 degrees C, and 33.6 +/- 0.8 degrees C in HS, HS + F, and HS + J, respectively. Survival time was 16.1 +/- 2.1, 33.0 +/- 3.8, and >120 mins in these groups, respectively. Neuron damage score was significantly lower in HS + J and without lateralization. CONCLUSIONS: We successfully demonstrated that direct retrograde hypothermic perfusion via the jugular vein without cardiopulmonary bypass protected the brain after heat stroke. This technique cooled the brain but did not significantly interfere with body temperature.     

Evaporation versus iced gastric lavage treatment of heatstroke: comparative efficacy in a canine model

We compared the speed of cooling and treatment efficacy for evaporative cooling vs. iced gastric lavage in a canine heatstroke model. Nine random-source, mongrel dogs were anesthetized, shaved, and internally heated until the core temperature reached 43.0 degrees C. The animals were then randomly assigned to be cooled to 37 degrees C either by iced (1 degree C) tap water gastric lavage (n = 5200 ml/min) through a large (32-Fr) orogastric tube, or by spraying with tap water (n = 4, 15 degrees C, 12 L/min) before a large fan blowing room temperature air (23 degrees C) across the dog at 0.5 m/sec from a height of 50 cm. Temperatures were monitored by thermocouples in both tympanic membranes and the pulmonary artery. BP, pulse, and cardiac output were measured every 5 min. Evaporative cooling was twice as fast as iced gastric lavage (0.16 +/- .05 degree vs. 0.08 +/- .01 degree C/min X m2, p less than .01). Animals in the evaporatively cooled group also experienced a quicker and more complete return to baseline cardiac indices than the lavage-treated group. Moreover, all animals treated with evaporation survived and were neurologically intact 48 h later, while only one lavage-treated dog was neurologically intact over the same period. The others in the lavage group died one hour after cooling (n = 1), were grossly ataxic (n = 1), or were persistently comatose (n = 2). A simple evaporative cooling technique, readily available in the emergency department, appears to be the most rapid and effective means for cooling and treating heatstroke in the dog.     

低温对肠缺血-再灌注所致急性肺损伤早期炎症反应的影响

目的 研究低温对肠缺血-再灌注所致急性肺损伤早期炎症反应的影响,探讨低温治疗急性肺损伤的应用前景.方法 北京协和医院动物实验中心提供新西兰大白兔72只,随机分为4组(18只/组):(1)空白对照组(肛温37.0～38.0C,假手术组),(2)缺血对照组(肛温37.0-38.0)、(3)浅低温组(肛温32.0～35.0C)、(4)中低温组(肛温28.0～31.9℃).实验组采用完全夹闭肠系膜上动脉1 h,开放后再灌注的方法 制备肠缺血一再灌注(intestine isehemia repeffusion,IIR)致急性肺损伤(acutelung irjury,ALI)模型.模型成功的标准参照Koike等的标准.空白对照组行假手术,不夹闭肠系膜上动脉.采用体表降温控制实验动物体温.分别于再灌注开始前、再灌注后第2,4,6 h共4个时点抽取静脉血样,采用酶联免疫吸附法集中检测血清TNF-α,IL-1β,IL-6,IL-10水平;再灌注6 h后处死动物.取左肺上叶烤至恒重后计算肺组织湿/干比值,取左肺下叶行HE染色,观察光镜下病理变化.对各组数据采用完全随机的方差分析.如果检验结果 为有统计学意义,则采用tukey法进一步在组间作两两比较.以P<0.05为差异具有统计学意义.结果 实验组动物出现IIR所致ALI.和空白对照组比较,缺血对照组血清炎症介质水平升高,再灌注后第6 h后分别为TNF-α(6.96 4-1.93)ug/L,IL-1β(26.1±2.11)t,g/L,IL-6(13.12 4-1.84)ug/L,IL-10(9.97 -3.00)ug/tc/L,P<0.05;肺组织湿/干比值增加,W/D=(5.37 4±0.156),P<0.05;光镜下观察可见弥漫性肺泡和间质水肿,大量中性粒细胞浸润.在低温干预后,同缺血对照组比较,血清炎症介质水平降低,浅低温组再灌注第6 h后分别为TNF-α(4.90 4±1.58)μg/L,IL-1β(9.90±1.35)μg/L,IL-6(5.81 4-1.28)μg/L,IL-1O(3.90 4-1.58)μg/L,P<0.05;中低温组再灌注第6 h后分别为TNF-α(4.13 4-1.67)μg/L,IL-Iβ(6.93±1.07)t,.g/L,IL-6(4.09±0.81)ug/L,IL-10(3.63±1.57)ug/L,P<0.05;肺组织湿/干比值减小,浅低温组W/D=(4.60±0.152),P<0.05;中低温组W/D:(4.57 4-0.200),P<0.05;光镜下观察2组肺泡内有少量中性粒细胞渗出,肺问质水肿也减轻.同时发现浅低温同中低温的治疗效果类似.结论 浅低温和中低温可以有效改善IIR导致Au动物模型的早期炎症反应,减轻肺组织损伤的程度;浅低温效果同中低温类似.     

Le coup de chaleur

Heatstroke is a potentially fatal disorder caused by an extreme increase in body temperature. It can result in widespread damage to the cardiovascular system, liver, kidney and blood clotting function. Classical heatstroke can occur during heat waves or as a result of intense environmental heat in persons in whom the thermoregulatory functions fail to adapt to a sudden increase in temperature, as during a heat wave, or to a high regional temperature. Exertional heatstroke can occur as a result of strenuous exercise, especially in hot, humid conditions, and may affect young, healthy individuals such as athletes during severe physical exertion and military recruits during training. A significant number of the histopathological and clinical characteristics described in persons with heatstroke indicate that these changes are a consequence of hyperthermia per se. A new hypothesis is that splanchnic vasoconstriction following heat stress leads to an increase in epithelial permeability and endotoxic translocation. The inflammatory factors involved could be similar to those observed in sepsis. Classical heatstroke is characterized by the following triad: rectal temperature 0≥40.6°C (> 105° F); neurological dysfunction with coma; and anhydrosis. Exertional heatstroke is characterized by a sudden collapse and loss of consciousness during exercise. The internal body temperature often exceeds 40.6 °C at the time of collapse, but hyperthermia is not indispensable to the diagnosis. Following heatstroke, rhabdomyolysis, renal damage, hepatic disorders and blood clotting dysfunction rapidly occur. An early diagnosis, the prompt institution of body cooling, and the rapid transportation of patients to an intensive care unit are essential for a favorable outcome. The mortality rate in these patients can be as low as 5% or less in centers where appropriate facilities for whole body cooling and emergency treatment are available.     

Effect of hypervolaemic haemodilution on cerebral glutamate, glycerol, lactate and free radicals in heatstroke rats

In the present study, we attempted to assess the mechanisms underlying the neuroprotective effect of hypervolaemic haemodilution in rat heatstroke. In anaesthetized rats treated with normal saline (NS) immediately after the onset of heatstroke induced by T (a) (ambient temperature) of 42 degrees C for 88 min, followed by T (a) of 24 degrees C for 12 min, the values for MAP (mean arterial pressure), ICP (intracranial pressure), CPP (cerebral perfusion pressure), CBF (cerebral blood blow), brain P O(2) (partial pressure of O(2)) and striatal glutamate, glycerol, lactate/pyruvate ratio, hydroxyl radicals and neuronal damage score were 42+/-3 mmHg, 33+/-3 mmHg, 9+/-3 mmHg, 109+/-20 BPU (blood perfusion units), 6+/-1 mmHg, 51+/-7 micromol/l, 24+/-3 micromol/l, 124+/-32, 694+/-22% of baseline and 2.25+/-0.05 respectively. In animals treated with 10% albumin immediately after the onset of heatstroke ( T (a) of 42 degrees C for 88 min), the values for MAP, ICP, CPP, CBF, brain P O(2) and striatal glutamate, glycerol, lactate/pyruvate ratio, hydroxyl radicals and neuronal damage score were 64+/-6 mmHg, 10+/-2 mmHg, 54+/-5 mmHg, 452+/-75 BPU, 15+/-2 mmHg, 3+/-2 micromol/l, 4+/-2 micromol/l, 7+/-3, 119+/-7% of baseline and 0.38+/-0.05 respectively. Apparently, the heatstroke-induced arterial hypotension, intracranial hypertension, cerebral hypoperfusion, cerebral ischaemia, brain hypoxia, increased levels of striatal glutamate, glycerol, lactate/pyruvate ratio and hydroxyl radicals, and increased striatal neuronal damage score values were all attenuated significantly by the induction of hypervolaemic haemodilution in rats immediately at the onset of heatstroke. These results demonstrate that the neuroprotective effect of hypervolaemic haemodilution is associated with a decrease in the elevation of glutamate, glycerol, lactate and free radicals in brain exposed to experimental heatstroke-induced cerebral ischaemia/hypoxia injury.     

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.     

Hydroxyethyl starch produces attenuation of circulatory shock and cerebral ischemia during heatstroke

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.     

Premarin can act via estrogen receptors to rescue mice from heatstroke-induced lethality

The present study was conducted to assess whether Premarin, a water-soluble estrogen sulfate, can act via estrogen receptors (ERs) to rescue mice from heat-induced lethality. Unanesthetized, unrestrained mice were exposed to ambient temperature of 42.4 degrees C to induce heatstroke (HS). Another group of mice was exposed to room temperature (24 degrees C) and used as normothermic controls. They were given isotonic sodium chloride solution, Premarin (0.1 - 1.0 mg/kg of body weight, i.p.), or Premarin (1 mg/kg of body weight, i.p.) plus the nonselective ER antagonist ICI 182, 780 (0.25 mg/kg of body weight, i.p.) 1 h after the termination of heat stress. Their physiologic and biochemical parameters were continuously monitored. Mice that survived on day 4 of heat treatment were considered survivors. When the vehicle-treated mice underwent heat, the fraction survival and core temperature at +4 h of body heating were found to be 0 of 12 and 34.4 degrees C +/- 3 degrees C, respectively. Administration of Premarin (1 mg/kg) 1 h after the cessation of heat stress rescued the mice from heat-induced death (fraction survival, 12/12) and reduced the hypothermia (core temperature, 37.3 degrees C). The beneficial effects of Premarin in ameliorating lethality and hypothermia can be abolished by simultaneous administration of ICI 182, 780. Both IL-10 (an anti-inflammatory cytokine) and estradiol in the serum were increased significantly in heat-stressed mice administered Premarin compared with vehicle-treated HS group. Heat-induced apoptosis, as indicated by terminal deoxynucleotidyl-transferase-mediated alpha UDP-biotin nick end-labeling staining, in the spleen, liver, and kidney were significantly reduced by Premarin. The increased levels of cellular ischemia (e.g., glutamate, lactate-to-pyruvate ratio, and nitrite) and damage (e.g., glycerol) markers and iNOS expression in the hypothalamus during HS were decreased significantly by Premarin therapy. The levels of proinflammatory cytokines (e.g., IL-1 beta and TNF-alpha) and renal and hepatic dysfunction markers in plasma that are up-regulated in heat stressed mice were significantly lower in Premarin-administered mice. The data indicate that Premarin may act via ERs to rescue mice form HS-induced lethality.