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.     

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.     

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.     

The protective effect of hypervolemic hemodilution in experimental heatstroke

The authors tested the hypothesis in a rat model that hypervolemic hemodilution during heatstroke affected the mean arterial pressure (MAP), striatal dopamine (DA) release, and local cerebral blood flow and neuronal damage score in different brain structures. The heatstroke was induced by exposing the urethane-anesthetized rats to an ambient temperature of 42 degrees C. Hypervolemic hemodilution was produced by intravenous administration of 10% human albumin. Relative and absolute blood flow in the corpus striatum were determined using the laser Doppler flowmetry and the autoradiography diffusible tracer technique, respectively. The DA release in the striatum was estimated using the in vivo microdialysis technique. After onset of heatstroke, animals with hypervolemic state alone, produced by saline or heparinized blood injection, displayed higher values of DA release, as well as neuronal damage score in the striatum, hypothalamus, or cortex, but lower values of MAP and blood flow in the striatum, hypothalamus, or cortex compared to normothermic controls. However, the heatstroke-induced arterial hypotension, cerebral ischemia, increased striatal DA overload, and increased neuronal damage score were attenuated by induction of both hypervolemic and hemodilution state with 10% albumin either before or after the onset of heatstroke. In addition, constant infusions of a vasopressor agent phenylephrine (2 microg kg(-1) min(-1)) after the onset of heatstroke failed to maintain appropriate levels of MAP and resulted in no protection against heatstroke. Thus, it appears that the observed benefit of the 10% albumin is secondary to hemodilution and/or maintenance of MAP.     

Ipsapirone and ketanserin protects against circulatory shock, intracranial hypertension, and cerebral ischemia during heatstroke

We assess the effects of ipsapirone (a 5-HT1A receptor agonist), ketanserin (a 5-HT2A receptor antagonist), (-)-pindolol (a 5-HT1A receptor antagonist), and DOI (a 5-HT2A receptor agonist) on heatstroke in a rat model. Animals, under urethane anesthesia, were exposed to high ambient temperature of 42 degrees C until mean arterial pressure and local cerebral blood flow in the striatum began to decrease, which was arbitrarily defined as the onset of heatstroke. Normothermic controls were exposed to room temperature of 24 degrees C. In rats treated with normal saline immediately before the initiation of heat stress, the values for survival time were found to be 21 to 25 min. Systemic administration of ipsapirone (10 mg/kg) or ketanserin (2 mg/kg) immediately before the initiation of heat stress significantly increased the survival time to new values of 92 to 104 min. Combined treatment with ipsapirone and ketanserin had additive effects (survival time of 156-194 min). In contrast, systemic administration of (-)-pindolol (2 mg/kg) or DOI (2 mg/kg) significantly decreased the survival time to new values of 2 to 3 min. In vehicle-treated heatstroke rats, the values for core temperature, intracranial pressure, and the extracellular levels of cellular ischemia (e.g., glutamate and lactate/pyruvate ratio) or damage (e.g., glycerol) markers and neuronal damage scores in striatum were significantly higher than those of normothermic controls. On the other hand, the values for mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, and brain partial pressure of O2 were significantly lower than those of normothermic controls. The heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, cerebral hypoperfusion and hypoxia, and increased levels of cellular ischemia and damage markers in striatum were all significantly attenuated by prior administration of ipsapirone or ketanserin. The present results strongly suggest that previous activation of 5-HT1A receptors or antagonism of 5-HT2A receptors protects against heatstroke by reducing circulatory shock and cerebral ischemia, whereas prior antagonism of 5-HT1A receptors or activation of 5-HT2A receptors exacerbates heatstroke.     

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 ()     

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.     

Protective effects of low tidal volume ventilation in a rabbit model of Pseudomonas aeruginosa-induced acute lung injury

OBJECTIVE: To determine whether low "stretch" mechanical ventilation protects animals from clinical sepsis after direct acute lung injury with Pseudomonas aeruginosa as compared with high "stretch" ventilation. DESIGN: Prospective study. SETTING: Experimental animal laboratory. SUBJECTS: Twenty-seven anesthetized and paralyzed rabbits. INTERVENTIONS: P. aeruginosa (109 colony forming units) was instilled into the right lungs of rabbits that were then ventilated at a tidal volume of either 15 mL/kg (n = 11) or 6 mL/kg (n = 7) for 8 hrs. Control animals were ventilated at a tidal volume of either 15 mL/kg (n = 4) or 6 mL/kg (n = 5) for 8 hrs, but an instillate without bacteria was used. A positive end-expiratory pressure of 3-5 cm H2O was used for all experiments. Radiolabeled albumin was used as a marker of alveolar epithelial permeability. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, arterial blood gas determination, alveolar permeability, wet-to-dry ratios on lungs, and time course of bacteremia were determined. When final values were compared with the values at the beginning of the experiment, there were significant decreases in mean arterial pressure (from 104 +/- 15 to 57 +/- 20 mm Hg), pH (from 7.46 +/- 0.04 to 7.24 +/- 15), Pao2 (from 528 +/- 35 to 129 +/- 104 torr [70.4 +/- 4.7 to 17.2 +/- 13.9 kPa]), and temperature (from 38.2 +/- 1 to 36.2 +/- 1.2 degrees C) in the high tidal volume group, whereas no significant differences were found in the low tidal volume group. Decreased alveolar permeability was shown in the low tidal volume group, as was decreased extravascular lung water in the uninstilled lung in the low tidal volume group (12.7 +/- 2.5 vs. 4.3 +/- 0.45 g H2O/g dry lung). No noteworthy difference was noted in the time course of bacteremia, although there was a trend toward earlier bacteremia in the high tidal volume group. CONCLUSIONS: In our animal model of P. aeruginosa-induced acute lung injury, low tidal volume ventilation was correlated with improved oxygenation, hemodynamic status, and acid-base status as well as decreased alveolar permeability and contralateral extravascular lung water.     

Survival in a rat model of lethal hemorrhagic shock is prolonged following resuscitation with a small volume of a solution containing a drag-reducing polymer derived from aloe vera

Drag-reducing polymers (DRP) increase tissue perfusion at constant driving pressure. We sought to evaluate the effects of small-volume resuscitation with a solution containing a DRP in a rat model of hemorrhage. Anesthetized rats were hemorrhaged at a constant rate over 25 min. In protocol A, total blood loss was 2.45 mL/100 g, whereas in protocol B, total blood loss was 3.15 mL/100 g. Five minutes after hemorrhage, the animals were resuscitated with 7 mL/kg of either normal saline (NS) or NS containing 50 microg/mL of an aloe vera-derived DRP. In protocol B, a third group (CON) was not resuscitated. Whole-body O2 consumption (Vo2) and CO2 production (Vco2) were measured using indirect calorimetry. In protocol A, 5/10 rats in the NS group and 8/10 rats in the DRP group survived for 4 h (P = 0.14). Mean arterial pressure was higher in the DRP-treated group than in the NS-treated group 45 min after resuscitation (89 +/- 8 vs. 68 +/- 5 mmHg, respectively; P < 0.05). In protocol B, survival rates over 2 h in the DRP, NS, and CON groups were 5/15, 1/14, and 0/7, respectively (P < 0.05). Compared with NS-treated rats, those resuscitated with DRP achieved a higher peak Vo2 (9.0 +/- 1.0 vs. 6,3+/- 1.0 mL/kg/min) and Vco2 (9.0 +/- 1.1 vs. 6.0 +/- 1.0 mL/kg/min) after resuscitation. We conclude that resuscitation with a small volume of DRP prolongs survival in rats with lethal hemorrhagic shock.     

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.     

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.     

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.     

Factors influencing the estimation of extravascular lung water by transpulmonary thermodilution in critically ill patients

OBJECTIVE: To investigate factors that may influence the estimation of extravascular lung water (EVLW) with a single (cold) indicator compared with assessment using two indicators (thermo-dye dilution). DESIGN: Post hoc analysis of an electronic hemodynamic database. SETTING: Surgical intensive care unit of a university hospital. PATIENTS: Forty-eight critically ill patients monitored by the thermo-dye dilution technique in the postoperative period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The EVLW was simultaneously assessed by the thermo-dye dilution technique (EVLWref) and estimated by transpulmonary thermodilution (EVLWest). EVLWref index ranged between 1 and 40 mL/kg (mean 10 +/- 7 mL/kg) and EVLWest between 2 and 39 mL/kg (mean 9 +/- 6 mL/kg). EVLWref was closely correlated (r = .96) with EVLWest. The mean difference (bias) between EVLWref and EVLWest was -0.5 +/- 1.9 mL/kg. The bias was not influenced by the weight, height, body surface area, body mass index, Pao2, intrathoracic blood volume, cardiac output, or dosage of vasoactive agents. In contrast, the bias was slightly but significantly influenced by EVLWref, Pao2/Fio2 ratio, tidal volume, and level of positive end-expiratory pressure. CONCLUSIONS: In our surgical intensive care unit population, the estimation of EVLW by transpulmonary thermodilution was influenced by the amount of EVLW, the Pao2/Fio2 ratio, the tidal volume, and the level of positive end-expiratory pressure. However, compared with the double indicator method, transpulmonary thermodilution estimation remained clinically acceptable even in patients with severe lung disease.     

Continuous fluid resuscitation for treatment of uncontrolled hemorrhagic shock following massive splenic injury in rats

We have previously observed that bolus fluid resuscitation in uncontrolled hemorrhagic shock induced by solid organ injury leads to increased blood loss and mortality. In the present investigation, we studied the effect of continuous fluid resuscitation on the hemodynamic response and survival following massive splenic injury (MSI) in rats. The animals were randomized into 11 groups: group 1, sham-operated; group 2, MSI untreated; group 3, MSI treated with 17.5 mL/kg/h of Ringers lactate (RL) solution (RL-17.5); group 4, MSI treated with 35 mL/kg/h RL (RL-35); group 5, MSI treated with 70 mL/kg/h RL (RL-70); group 6, MSI treated with 7.5 mL/kg/h of 7.5% NaCl (HTS-7.5); group 7, MSI treated with 15 mL/kg/h of 7.5% NaCl (HTS-15); group S, MSI treated with 30 mL/kg/h of 7.5% NaCl (HTS-30); group 9, MSI treated with 7.5 mL/kg/h 6% hydroxyethyl starch (HES-7.5); group 10, MSI treated with 15 mL/kg/h 6% hydroxyethyl starch (HES-15); and group 11, MSI treated with 30 mL/kg/h 6% hydroxyethyl starch (HES-30). MSI in untreated group 2 was followed by a fall of mean arterial pressure (MAP) to 50.1 +/- 6.7 mmHg (P < 0.001) in 15 min. Mean survival time (MST) was 99.5 +/- 16.6 min, and total blood loss (TBL) was 37.8% +/- 2.6% of blood volume. Fluid treatment with increasing volumes of RL in groups 3, 4, and 5 was followed by a gradual increase in TBL compared with untreated animals, and MST remained unchanged. Increasing volumes of HTS infusion in groups 6, 7, and 8 was also followed by incease in TBL, but MST remained unchanged except for an increase to 123.0 +/- 20.5 min (P < 0.05) in group 6. Increasing volumes of HES in groups 9, 10, and 11 was also followed by increase in TBL, but MST remained unchanged. In conclusion, continuous infusion of LR, HTS, and HES following massive splenic injury resulted in a significant increase in intra-abdominal bleeding, but survival time in the first hour following injury remained unchanged in contrast to bolus fluid infusion, which increases early mortality.     

Crystalloid and colloid resuscitation of uncontrolled hemorrhagic shock following massive splenic injury.

Using a standardized massive splenic injury (MSI) model of uncontrolled hemorrhagic shock we studied the effect of vigorous crystalloid or colloid fluid resuscitation on the hemodynamic response, and survival in rats. The value of massive fluid infusion in uncontrolled hemorrhagic shock following intra-abdominal solid organ injury is still controversial. The effect of crystalloid and colloid infusion was studied following massive splenic injury. The animals were randomized into six groups: group 1 (n = 8) sham-operated, group 2 (n = 12) MSI untreated, group 3 (n = 10) MSI treated with 41.5 mL/kg Ringer's lactate (large-volume Ringer's lactate, LVRL), group 4 (n = 14) MSI treated with 5 mL/kg 7.5% NaCl (hypertonic saline, HTS), group 5 (n = 10) MSI treated with 7.5 mL/kg hydroxyethyl starch (HES-7.5), and group 6 (n = 11) MSI treated with 15 mL/kg hydroxyethyl starch (HES-15). Following MSI mean arterial pressure (MAP) in untreated group 2 decreased from 109.1 +/- 4.5 to 49.8 +/- 9.6 mmHg (P < 0.001) in 60 min. Mean survival time was 132.1 +/- 18.7 min, and total blood loss was 30.2 +/- 4.1% of blood volume. LVRL infusion resulted in an early rise in MAP from 59.7 +/- 7.3 to 90.0 +/- 11.3 mmHg (P < 0.01), which then rapidly dropped to 11.7 +/- 4.5 mmHg (P < 0.001) after 60 min. The mean survival time was 82.5 +/- 18.2 min (P < 0.01), and total blood loss was 53.7 +/- 2.9% (P < 0.01). Total blood loss following HTS infusion was 32.2 +/- 4.0% and survival time was 127.9 +/- 19.7 min. HES-7.5 infusion only moderately increased bleeding to 44.2 +/- 3.9% (P < 0.05), but mortality remained unchanged. HES-15 infusion resulted in an increase in blood loss to 47.8 +/- 7.1% (0.01), survival time dropped to 100.7 +/- 12.3 min (P < 0.05). Vigorous large volume infusion of Ringer's lactate or HES following MSI resulted in a significant increase in intra-abdominal bleeding and shortened survival time compared to untreated, small volume HTS, or HES-7.5-treated animals. The hemodynamic response to crystalloid or colloid infusion in blunt abdominal trauma is primarily dependent on the severity of injury and the rate of fluid resuscitation.     

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.     

Resuscitation with polyethylene glycol-modified human hemoglobin improves microcirculatory blood flow and tissue oxygenation after hemorrhagic shock in awake hamsters

OBJECTIVE: To determine whether resuscitation with polyethylene glycol-modified human hemoglobin (MalPEG-Hb), an oxygen-carrying blood replacement fluid with 4 g/dL Hb, viscosity of 2.5 cP, colloid osmotic pressure of 49 mm Hg, and p50 of 5.5 mm Hg, improves systemic and microvascular variables after hemorrhage compared with shed blood (SB) and 5% hydroxyethyl starch (HES). SETTING: Laboratory. SUBJECTS: Golden Syrian hamsters. DESIGN: Prospective study. INTERVENTIONS: Hamsters implemented with a skin fold chamber were hemorrhaged 50% of blood volume and resuscitated with 50% shed blood volume (SB, HES, or MalPEG-Hb). MEASUREMENTS AND MAIN RESULTS: Shock and resuscitation were monitored for 1 hr each. Microvascular events were characterized in terms of vessel diameter, flow velocity, functional capillary density, and Po(2) in arterioles, venules, and extravascular tissue. Systemic variables include mean arterial pressure, heart rate, Po(2), Pco(2), pH, and base excess. MalPEG-Hb resuscitation increased functional capillary density to 64% vs. 44% for SB and 32% for HES relative to baseline before shock. Microvascular flow increased 16% for MalPEG-Hb relative to baseline and remained decreased by 44% for SB and 80% for HES. Hemoglobin concentration was 10.4 g/dL with SB, 7.5 (6.8 g/dL in red blood cells and 0.9 g/dL in plasma) with MalPEG-Hb, and 7.5 g/dL with HES, leading to tissue Po(2) of 19, 8, and 5 mm Hg respectively. Calculations of oxygen extraction show that 0.9 g/dL of MalPEG-Hb increased oxygen extraction per gram of red cell hemoglobin in the tissue analyzed compared with SB. These measurements correlate well with a systemic indicator of recovery, base excess, 5.4 +/- 4.7 (MalPEG-Hb), 1.7 +/- 3.8 (SB), and -0.3 +/- 5.7 (HES). CONCLUSION: The presence of 0.9 g/dL of high oxygen affinity MalPEG-Hb improves microvascular blood flow and oxygen transport during shock to a significantly greater extent than that attainable with blood or HES.     

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.     

Volume expansion of albumin, gelatin, hydroxyethyl starch, saline and erythrocytes after haemorrhage in the rat

Objective To compare the colloids 5% albumin, 4% gelatin and 6% hydroxyethyl starch (HES) 130/0.4 with each other and with saline, regarding their plasma-expanding effects after haemorrhage; these were also compared with the intravascular volume-expanding effect of re-transfusion with erythrocytes.Design Controlled, prospective, randomised laboratory study.Setting University research laboratory.Subjects Thirty-five adult rats.Interventions Plasma volume was determined (I¹²⁵ albumin tracer technique) after haemorrhage of 20 ml/kg and 3 h after a bolus infusion of 20 ml/kg of each of the colloids or 80 ml/kg of saline, or 6.7 ml/kg of erythrocytes diluted in 9 ml/kg of saline. Blood pressure, haematocrit (Hct), blood gases and physiological parameters were measured.Measurements and results Plasma volume after haemorrhage was 29.6±2.6 ml/kg (n=35). With the bolus infusion, plasma volume increased by 21.1±3.6 ml/kg in the albumin group (n=7), by 13.1±2.9 ml/kg in the gelatin group (n=7), by 13.8±2.2 ml/kg in the HES group (n=7), by 16.0±2.4 ml/kg in the saline group (n=7) and by 6.9±2.3 ml/kg in the erythrocyte group (n=7) 3 h after the infusion. In the latter group, there was a total increase in intravascular volume of 13.6±2.5 ml/kg including the erythrocyte volume. Arterial pressure was better preserved in the albumin and erythrocyte groups than in the other groups.Conclusion Albumin 5% was a more effective plasma volume expander than gelatin and HES. Saline, with a four times larger volume, and erythrocytes in about 1/3 of the volume had a similar volume-expanding effect to gelatin and HES.