Hypothermic retrograde jugular vein flush in heatstroke rats provides brain protection by maintaining cerebral blood flow but not by hemodilution

OBJECTIVE: To determine the fundamental mechanism of brain protection by hypothermic retrograde jugular vein flush (HRJVF) in heatstroke rats. DESIGN: Randomized, controlled, and prospective study. SETTING: University physiology research laboratory. SUBJECTS: Sprague-Dawley rats (270-320 g, males). INTERVENTIONS: Rats were randomized into four groups as follows: a) normothermic control (NC, n = 8); b) heatstroke rats without cold saline delivery (HS, n = 8); c) heatstroke rats treated with cold saline via femoral vein (HS+F, n = 8); and d) heatstroke rats treated with HRJVF (HS+J, n = 8). Right external jugular vein and right femoral vein were cannulated in each rat. The cannulation in the jugular vein was with cranial direction. To produce heatstroke, rats were placed in a chamber with an ambient temperature of 43 degrees C. The cold saline (4 degrees C, 1.7 mL/100 g) was delivered via the cannula in either the femoral vein or jugular vein immediately after the onset of heatstroke. Glutamate release in the brain, cerebral blood flow (CBF), and hematocrit of arterial blood were determined. MEASUREMENTS AND MAIN RESULTS: After onset of heatstroke, HRJVF significantly decreased the glutamate release. In contrast, cold saline delivery via femoral vein could only delay the elevation of glutamate release in the brain. The CBF of HS and HS+F rats decreased rapidly after the onset of heatstroke, but the CBF of HS+J rats was initially elevated by HRJVF and was maintained at baseline 30 mins after onset of heatstroke. Hematocrit in all the rats did not change after testing. CONCLUSIONS: HRJVF protects the brain by maintaining cerebral blood flow in rats after heatstroke. To preserve brain function and prolong survival after severe heatstroke, maintenance of cerebral blood flow is important in the management of heatstroke.     

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.     

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.     

Resuscitation from experimental heatstroke by transplantation of human umbilical cord blood cells

OBJECTIVE: Human umbilical cord blood cells (HUCBCs) are effective in the treatment of conventional stroke in experimental models. In the study described herein, we administered HUCBCs into the femoral vein or directly into the cerebral ventricular system and assessed their effects on circulatory shock, cerebral ischemia, and damage during heatstroke. DESIGN: Controlled, prospective study. SETTING: Hospital medical research laboratory. SUBJECTS: Sprague-Dawley rats (287 +/- 16 g body weight, males). INTERVENTIONS: Anesthetized rats, immediately after the onset of heatstroke, were divided into four major groups and given the following: a) normal saline or AIM-V medium intravenously (0.3 mL) or intracerebroventricularly (10 microL); b) peripheral blood mononuclear cells (5 x 10 in 0.3 mL AIM-V medium, intravenously, or 5 x 10 in 10 microL AIM-V medium, intracerebroventricularly); or c) HUCBCs (5 x 10 in 0.3 mL AIM-V medium, intravenously, or 5 x 10 in 10 microL AIM-V medium, intracerebroventricularly). Another group of rats, under urethane anesthesia, were exposed to room temperature (26 degrees C) and used as normothermic controls. Urethane-anesthetized animals were exposed to an ambient temperature of 43 degrees C to induce heatstroke. Their physiologic and biochemical parameters were continuously monitored. MEASUREMENTS AND MAIN RESULTS: When the vehicle-treated rats underwent heat exposure, their survival time values were found to be 21-23 mins. Resuscitation with intravenous or intracerebroventricular doses of HUCBCs, but not peripheral blood mononuclear cells, immediately at the onset of heatstroke significantly improved survival during heatstroke (61-148 mins). As compared with values for normothermic controls, the vehicle-treated heatstroke rats had lower mean arterial pressure, cerebral blood flow, and brain PO2 values but higher intracranial pressure and cerebral ischemia values and more injury markers. The circulatory shock, intracranial hypertension, cerebral hypoperfusion and hypoxia, increment of cerebral ischemia, and damage markers during heatstroke were all significantly attenuated by intravenous or intracerebroventricular delivery of HUCBCs but not peripheral blood mononuclear cells. CONCLUSIONS: We successfully demonstrate that HUCBC therapy may resuscitate heatstroke victims by reducing circulatory shock and cerebral ischemic injury; central delivery of HUCBCs seems superior to systemic delivery of HUCBCs in resuscitating patients with heatstroke.     

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.     

Jugular vein temperature reflects brain temperature during hypothermia

PURPOSE: The neuroprotective properties of mild to moderate hypothermia are well recognized but may not be employed correctly because brain temperature cannot usually be measured directly. This study investigated the jugular vein as a more accessible site that accurately reflects the actual brain temperature during mild, induced hypothermia. METHODS: We selected ten mongrel dogs (mean weight 12 +/- 2 kg) and measured temperatures of the brain, jugular vein, cisterna magna, pulmonary artery and rectum during hypothermia, including cooling and rewarming. The brain temperature needle probe was inserted 2.0 cm into the parenchyma. A temperature probe was placed in the cisterna magna with an epidural needle. Swan-Ganz thermistor probes measured the jugular venous and pulmonary artery blood temperatures. RESULT: The brain temperature decreased from 37.5 +/- 0.3 to 33.0 +/- 0.3 degrees C over an average 150 +/- 45 min cooling period. Stable cool was maintained for 245 +/- 32 min, followed by 165 +/- 50 min for rewarming from 33.5 +/- 0.3 to 37.5 +/- 0.3 degrees C. Jugular, cisterna magna and pulmonary arterial blood (PAB), but not rectal temperature, were close to brain temperature during stable cool. The mean jugular and cisterna magna temperatures were near the brain temperature at 0.1 degrees C higher and 0.1 degrees C lower, respectively. No significant effects of hypothermia were noted on hemodynamics in any phase. CONCLUSION: Jugular vein temperature, along with cisterna magna and pulmonary artery blood and rectal temperature, reflected brain temperature during hypothermia. The jugular vein and cisterna magna sites more sensitively reflected brain temperature than other sites.     

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.     

Resuscitation from experimental heatstroke by hyperbaric oxygen therapy

OBJECTIVE: Heatstroke is characterized by hyperthermia, vasoplegic shock, and cerebral ischemia and hypoxia. Hyperbaric oxygen (HBO) has been shown to reduce brain ischemia and behavioral dysfunction during cerebral artery occlusion. The efficacy of HBO therapy for resuscitation from heatstroke remains to be determined in the laboratory. DESIGN: Anesthetized rats were randomized to several groups and administered: 1) no resuscitation (normobaric air) after onset of heatstroke, 2) HBO for 1 hr (100% oxygen at 253 kPa for 1 hr), 3) cyclic HBO intermitted by a 5-min air break for 1 hr of treatment (100% oxygen at 253 kPa), 4) hyperbaric air (air at 253 kPa for 1 hr), 5) normobaric hyperoxia (100% oxygen at 101 kPa for 1 hr), or 6) 8% HBO (hyperbaric 8% oxygen at 253 kPa for 1 hr). SETTING: Laboratory investigation. SUBJECTS: Sprague-Dawley rats (300- to 400-g males). INTERVENTIONS: Rats were exposed to an ambient temperature of 43 degrees C to induce heatstroke. Their colonic temperature; mean arterial pressure; heart rate; arterial blood levels of pH, Paco2, Pao2, So2%, and tumor necrosis factor-alpha; the cortical levels of ischemic and damage markers, and cortical neuronal damage scores were determined. The moment at which mean arterial pressure began to decrease from peak levels was arbitrarily taken as the onset of heatstroke. MAIN RESULTS: Survival time (interval between onset of heatstroke and animal death) was 19 +/- 1 (n = 10), 131 +/- 18 (n = 14), 159 +/- 28 (n = 13), 72 +/- 14 (n = 10), 68 +/- 12 (n = 10), and 45 +/- 11 (n = 10) mins, respectively, for normobaric air, HBO for 1 hr, cyclic HBO, hyperbaric air, normobaric hyperoxia, and 8% HBO groups. The heatstroke induced arterial hypotension and bradycardia, decreased arterial levels of pH, Pao2, and So2%, increased arterial levels of tumor necrosis factor-alpha, and increased values of cellular ischemia and damage markers. In addition, neuronal damage scores in the cortex were significantly reduced by HBO for 1 hr and cyclic HBO resuscitation. CONCLUSION: We successfully demonstrated that HBO and, to some extent, hyperbaric air, normobaric hyperoxia, or HBO 8% was found beneficial in resuscitating rats with experimental heatstroke. HBO effectively reduced heatstroke-induced arterial hypotension, hypoxia, plasma tumor necrosis factor-alpha overproduction, and cerebral ischemia and damage and improved survival.     

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.     

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.     

Induction of hypothermia in patients with various types of neurologic injury with use of large volumes of ice-cold intravenous fluid

OBJECTIVE: Mounting evidence suggests that mild to moderate hypothermia can mitigate neurologic and myocardial injury. The speed of induction appears to be a key factor in determining its efficacy. However, even when the fastest currently available cooling techniques are used, reaching target temperatures takes at least 2 hrs and usually longer. We hypothesized that infusion of refrigerated fluids could be a safe accessory method to increase cooling speed. DESIGN: Prospective intervention study. SETTING: University teaching hospital. PATIENTS: One hundred thirty-four patients with various types of neurologic injury (postanoxic encephalopathy, subarachnoid hemorrhage, or traumatic brain injury). MEASUREMENTS AND MAIN RESULTS: Hypothermia was induced in 134 patients with various types of neurologic injury, by means ice-water cooling blankets and infusion of refrigerated (4 degrees C) saline (110 patients) or saline and colloids (24 patients). An average volume of 2340 +/- 890 mL of refrigerated fluids was infused in 50 mins. Core temperatures decreased from 36.9 +/- 1.9 degrees C to 34.6 +/- 1.5 degrees C at t = 30 mins and to 32.9 +/- 0.9 degrees C at t = 60 mins (target temperature: 32 degrees C-33 degrees C). Monitoring of blood pressure, heart rhythm, central venous pressure, blood gasses, electrolyte and glucose levels, and platelet and white blood cell count revealed no additional adverse effects. Mean arterial pressure increased by 15 mm Hg, with larger increases in blood pressure occurring in hemodynamically unstable patients. No patient developed pulmonary edema. CONCLUSIONS: Induction of hypothermia by means of cold-fluid infusion combined with ice-water cooling blankets is safe, efficacious, and quick. Because the speed of cooling is important to increase its protective effects, we recommend that cold-fluid infusion be used in all patients treated with induced hypothermia. This should be combined with another method to safely and accurately maintain hypothermia once target temperatures have been reached.     

Effects of hypertonic (3%) saline in rats with circulatory shock and cerebral ischemia after heatstroke

Objective To evaluate the effects of hypertonic (3%) saline in heatstroke rats with circulatory shock, intracranial hypertension, and cerebral ischemia.Design and setting Urethane-anesthetized rats were exposed to a high ambient temperature of 42°C until mean arterial pressure and local cerebral blood flow (CBF) in the corpus striatum began to decrease from their peak levels, which was arbitrarily defined as the onset of heatstroke. Control rats were exposed to 24°C.Measurements and results Extracellular concentrations of glutamate and lactate/pyruvate ratio (cellular ischemia markers), and glycerol (a cellular injury marker) in the corpus striatum of rat brain were assessed by intracerebral microdialysis methods. Striatal PO₂, temperature, and local CBF were measured with a combined OxyLite PO₂, thermocouple, and OxyFlo LDF, respectively. The values of mean arterial pressure, cerebral perfusion pressure, and striatal CBF and PO₂ in rats treated with 0.9% NaCl solution after the onset of heatstroke were all significantly lower than those in normothermic controls. In contrast, the values of intracranial pressure, brain temperature, and extracellular concentrations of glutamate, glycerol, and lactate/pyruvate in the corpus striatum were greater. Intravenous infusion of hypertonic (3%) saline solution either "0" time before the start of heat exposure or right after the onset of heatstroke significantly attenuated the heatstroke-induced arterial hypotension, intracranial hypertension, decreased cerebral perfusion, and cerebral ischemia and damage and resulted in prolongation of survival time.Conclusions Our results strongly suggest that the experimental heatstroke syndromes can be effectively prevented and treated by hypertonic saline.An editorial regarding this article can be found in the same issue ()     

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.     

Nasopharyngeal cooling selectively and rapidly decreases brain temperature and attenuates neuronal damage, even if initiated at the onset of cardiopulmonary resuscitation in rats

OBJECTIVE: To determine the effectiveness of nasopharyngeal cooling for selective brain cooling and neuroprotection from ischemia. DESIGN: Prospective animal study. SETTING: Experimental laboratory in a university hospital. SUBJECTS: Male Wistar rats (n = 28). INTERVENTIONS: In study 1, hippocampal temperature was decreased to 31 degrees C under spontaneous circulation. In the nasopharyngeal cooling group, physiologic saline (5 degrees C) was infused to the bilateral nasal cavities at the rate of 100 mL.min-1.kg weight-1. In the whole body cooling group, a fan and a water blanket (5 degrees C) were used. In study 2, ischemia and resuscitation were performed in normothermic and nasopharyngeal cooling (initiated with resuscitation after 5 mins of ischemia and continued for 20 mins) groups. MEASUREMENTS AND MAIN RESULTS: The hippocampal temperature was decreased to 31 degrees C in 7 +/- 2 mins without any change in the rectal temperature in the nasopharyngeal cooling group, whereas a decrease in hippocampal temperature to 31 degrees C took 33 +/- 1 mins in the whole body cooling group. Although skull base region was cooled by nasopharyngeal cooling, the epidural temperature of the parietal region was lower than the hippocampal temperature, indicating that brain temperature was hematogenously lowered. There was no difference between changes in cerebral blood flow or between the ratios of oxygen extraction from arterial blood in the head region in the nasopharyngeal cooling and whole body cooling groups. In the second study, all animals were successfully resuscitated, and the times required for recovery of mean arterial blood pressure (60 mm Hg) after resuscitation in the nasopharyngeal cooling and normothermic groups were the same. The histologic damage was significantly attenuated in the nasopharyngeal cooling group (33 +/- 21% cell death in the hippocampus) compared with that in the normothermic group (73 +/- 11%). CONCLUSIONS: Nasopharyngeal cooling enables rapid and selective reductions in cortical and subcortical temperatures without disturbing the recovery of systemic circulation after resuscitation.     

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.     

Hypothermia attenuates circulatory shock and cerebral ischemia in experimental heatstroke

We tested the hypothesis in a rat model that body cooling suppresses circulatory shock and cerebral ischemia in heatstroke. Animals under urethane anesthesia were exposed to water blanket temperature (Tblanket) of 42 degrees C until mean arterial pressure (MAP) and local cerebral blood flow (CBF) in the hippocampus began to decrease from their peak levels, which was arbitrarily defined as the onset of heatstroke. Control rats were exposed to 26 degrees C. Extracellular concentrations of glutamate, glycerol, lactate, and lactate/pyruvate in the hippocampus were assessed by microdialysis methods. Cooling was accomplished by decreasing Tblanket from 42 degrees C to 16 degrees C. The values of MAP and CBF after the onset of heat stroke in heatstroke rats received no cooling were all significantly lower than those in control rats. However, the neuronal damage score and extracellular levels of ischemia and damage markers in the hippocampus were greater. Cooling immediately after the onset of heatstroke reduced the heatstroke-induced circulatory shock, cerebral ischemia, neuronal damage, and surge of tissue ischemia and damage markers in the hippocampus, and resulted in prolongation of survival time. Delaying the onset of cooling reduced the therapeutic efficiency. The results suggest that body cooling attenuates circulatory shock and cerebral ischemia insults in heatstroke.     

Heat shock pretreatment may protect against heatstroke-induced circulatory shock and cerebral ischemia by reducing oxidative stress and energy depletion

The mechanisms underlying the protective effects of heat shock pretreatment on heatstroke remain unclear. Here we attempted to ascertain whether the possible occurrence of oxidative stress and energy depletion exhibited during heatstroke can be reduced by heat shock preconditioning. In the present study, colonic temperature, mean arterial pressure, heart rate, striatal levels of heat shock protein 72 (HSP72), local Po2, brain temperature, cerebral blood flow, cellular ischemia and damage markers, dihydroxybenzoic acid (DHBA), lipid peroxidation, glutathione, glutathione peroxidase and reductase activities, and ATP were assayed in normothermic control rats and in heatstroke rats with or without preconditioning 16 or 96 h before initiation of heatstroke. Heatstroke was induced by exposing the anesthetized rats to a high ambient temperature (Ta = 43 degrees C) until the moment at which MAP decreased from its peak level. Sublethal heat shock pretreatment 16 h before initiation of heatstroke, in addition to increasing striatal HSP72 levels, conferred significant protection against heatstroke-induced arterial hypotension, striatal ischemia and damage, increment of hydroxyl radical formation, lipid peroxidation, glutathione oxidation, and decrement of glutathione peroxidase activity and ATP. However, at 96 h after heat shock, when striatal HSP72 expression returned to basal levels, the above responses that occurred during onset of heatstroke were indistinguishable between the two groups. These results suggest that heat shock pretreatment induces HSP72 overexpression in striatum and confers protection against heatstroke-induced striatal ischemia and damage by reducing oxidative stress and energy depletion.     

Quantitative evaluation of the neuroprotective effects of hypothermia ranging from 34 degrees C to 31 degrees C on brain ischemia in gerbils and determination of the mechanism of neuroprotection

OBJECTIVE: The present study was designed to determine whether the predominant factor responsible for neuroprotection of hypothermia ranging from 31 to 34 degrees C is prolongation of onset of ischemic depolarization or suppression of neuronal injury during ischemic depolarization and to quantitatively determine the neuroprotective effects of hypothermia of 34 degrees C and 31 degrees C. DESIGN: Prospective animal study. SETTING: A university research laboratory. SUBJECTS: Eighty-nine gerbils. INTERVENTIONS: Bilateral common carotid arteries were occluded for 3-20 mins. The brain temperature was set at 37 degrees C, 34 degrees C, or 31 degrees C before and during ischemic depolarization. MEASUREMENTS AND MAIN RESULTS: DC potentials were measured in the CA1 region, where histologic evaluation was performed 7 days later. Onset times of ischemic depolarization were 1.3 +/- 0.2, 1.6 +/- 0.4, and 2.4 +/- 0.7 mins at 37 degrees C, 34 degrees C, and 31 degrees C, respectively. The logistic regression curve demonstrated a close relationship between duration of ischemic depolarization and neuronal damage and showed a rightward shift by lowering the brain temperature. In the 37 degrees C, 34 degrees C, and 31 degrees C groups, the durations of ischemic depolarization causing 50% neuronal damage were estimated to be 8.0, 14.2, and 26.0 mins, respectively, and the ischemia times causing 50% neuronal damage were estimated to be 4.9, 8.1, and 14.2 mins, respectively. CONCLUSIONS: The onset of ischemic depolarization was prolonged in the 34 degrees C and 31 degrees C groups by only 0.3 and 1.1 mins, respectively, compared with that in the 37 degrees C group. Most of the neuroprotection by hypothermia was attributed to the suppression of neuronal injury during ischemic depolarization, suggesting that hypothermia has neuroprotective effects if it is initiated during the ischemic depolarization period. The results also indicate that the neuroprotective effect at 31 degrees C is about three times greater than that at 34 degrees C and that neuronal cells can withstand 2.9 times longer duration of ischemia at 31 degrees C than at 37 degrees C.     

Survival without brain damage after clinical death of 60-120 mins in dogs using suspended animation by profound hypothermia

OBJECTIVES: This study explored the limits of good outcome of brain and organism achievable after cardiac arrest (no blood flow) of 60-120 mins, with preservation (suspended animation) induced immediately after the start of exsanguination cardiac arrest. DESIGN: Prospective experimental comparison of three arrest times, without randomization. SETTING: University research laboratory. SUBJECTS: Twenty-seven custom-bred hunting dogs (17-25 kg). INTERVENTIONS: Dogs were exsanguinated over 5 mins to cardiac arrest no-flow of 60 mins, 90 mins, or 120 mins. At 2 mins of cardiac arrest, the dogs received, via a balloon-tipped catheter, an aortic flush of isotonic saline at 2 degrees C (at a rate of 1 L/min), until tympanic temperature reached 20 degrees C (for 60 mins of cardiac arrest), 15 degrees C (for 60 mins of cardiac arrest), or 10 degrees C (for 60, 90, or 120 mins of cardiac arrest). Resuscitation was by closed-chest cardiopulmonary bypass, postcardiac arrest mild hypothermia (tympanic temperature 34 degrees C) to 12 hrs, controlled ventilation to 20 hrs, and intensive care to 72 hrs. MEASUREMENTS AND MAIN RESULTS: We assessed overall performance categories (OPC 1, normal; 2, moderate disability; 3, severe disability; 4, coma; 5, death), neurologic deficit scores (NDS 0-10%, normal; 100%, brain death), regional and total brain histologic damage scores at 72 hrs (total HDS >0-40, mild; 40-100, moderate; >100, severe damage), and morphologic damage of extracerebral organs. For 60 mins of cardiac arrest (n = 14), tympanic temperature 20 degrees C (n = 6) was achieved after flush of 3 mins and resulted in two dogs with OPC 1 and four dogs with OPC 2: median NDS, 13% (range 0-27%); and median total HDS, 28 (range, 4-36). Tympanic temperature of 15 degrees C (n = 5) was achieved after flush of 7 mins and resulted in all five dogs with OPC 1, NDS 0% (0-3%), and HDS 8 (0-48). Tympanic temperature 10 degrees C (n = 3) was achieved after flush of 11 mins and resulted in all three dogs with OPC 1, NDS 0%, and HDS 16 (2-18). For 90 mins of cardiac arrest (n = 6), tympanic temperature 10 degrees C was achieved after flush of 15 mins and resulted in all six dogs with OPC 1, NDS 0%, and HDS 8 (0-37). For 120 mins of cardiac arrest (n = 7), three dogs had to be excluded. In the four dogs within protocol, tympanic temperature 10 degrees C was achieved after flush of 15 mins. This resulted in one dog with OPC 1, NDS 0%, and total HDS 14; one with OPC 1, NDS 6%, and total HDS 20; one with OPC 2, NDS 13%, and total HDS 10; and one with OPC 3, NDS 39%, and total HDS 22. CONCLUSIONS: In a systematic series of studies in dogs, the rapid induction of profound cerebral hypothermia (tympanic temperature 10 degrees C) by aortic flush of cold saline immediately after the start of exsanguination cardiac arrest-which rarely can be resuscitated effectively with current methods-can achieve survival without functional or histologic brain damage, after cardiac arrest no-flow of 60 or 90 mins and possibly 120 mins. The use of additional preservation strategies should be pursued in the 120-min arrest model.     

Vasopressin improves survival in a pig model of hypothermic cardiopulmonary resuscitation

OBJECTIVE: During hypothermic cardiopulmonary resuscitation with a body core temperature <30 degrees C administration of a vasopressor to support coronary perfusion pressure is controversial. The purpose of the current study was to assess the effects of a single 0.4-unit/kg dose of vasopressin on coronary perfusion pressure, defibrillation success, and 1-hr survival in a pig model of hypothermic closed-chest cardiopulmonary resuscitation combined with rewarming. DESIGN: Prospective, randomized study in an established pig model. SETTING: University hospital research laboratory. SUBJECTS: Fifteen 12- to 16-wk-old domestic pigs. INTERVENTIONS: Pigs were surface cooled to a body core temperature of 26 degrees C and ventricular fibrillation was induced. After 15 mins of untreated cardiac arrest, manual closed-chest cardiopulmonary resuscitation and thoracic lavage with 40 degrees C warmed tap water were started. After 3 mins of external chest compression, animals were assigned randomly to receive vasopressin (0.4 units/kg, n = 8; or saline placebo, n = 7). Defibrillation was attempted 10 mins after drug administration. MEASUREMENTS AND MAIN RESULTS: Compared with saline placebo treated-animals, coronary perfusion pressure in vasopressin-treated pigs was significantly higher 90 secs (36 +/- 5 mm Hg vs. 7 +/- 4 mm Hg, p =.000) to 10 mins (24 +/- 4 mm Hg vs. 8 +/- 4 mm Hg, p =.000) after drug administration. Restoration of spontaneous circulation and 1 hr survival were significantly higher in vasopressin animals compared with saline placebo (8 of 8 vasopressin pigs vs. 0 of 7 placebo pigs, p <.001). CONCLUSIONS: A single 0.4-unit/kg dose of vasopressin administered at a body core temperature <30 degrees C significantly improved defibrillation success and 1-hr survival in a pig model of hypothermic cardiopulmonary resuscitation.