Physical Hypothermia Research Articles

An Assessment of Physical and N6-Cyclohexyladenosine-Induced Hypothermia in Rodent Distal Focal Ischemic Stroke.

Therapeutic hypothermia (TH) mitigates damage in ischemic stroke models. However, safer and easier TH methods (e.g., pharmacological) are needed to circumvent physical cooling complications. This study evaluated systemic and pharmacologically induced TH using the adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA), with control groups in male Sprague-Dawley rats. CHA was administered intraperitoneally 10 minutes following a 2-hour intraluminal middle cerebral artery occlusion. We used a 1.5 mg/kg induction dose, followed by three 1.0 mg/kg doses every 6 hours for a total of 4 doses, causing 20-24 hours of hypothermia. Animals assigned to physical hypothermia and CHA-hypothermia had similar induction rates and nadir temperatures, but forced cooling lasted ∼6 hours longer compared with CHA-treated animals. The divergence is likely attributable to individual differences in CHA metabolism, which led to varied durations at nadir, whereas physical hypothermia was better regulated. Physical hypothermia significantly reduced infarction (primary endpoint) on day 7 (mean reduction of 36.8 mm3 or 39% reduction; p = 0.021 vs. normothermic animals; Cohen's d = 0.75), whereas CHA-induced hypothermia did not (p = 0.33). Similarly, physical cooling improved neurological function (physical hypothermia median = 0, physical normothermia median = 2; p = 0.008) and CHA-induced cooling did not (p > 0.99). Our findings demonstrate that forced cooling was neuroprotective compared with controls, but prolonged CHA-induced cooling was not neuroprotective.

A Direct Comparison of Physical Versus Dihydrocapsaicin-Induced Hypothermia in a Rat Model of Traumatic Spinal Cord Injury.

Spinal cord injury (SCI) is a devastating neurological condition with no effective treatment. Hypothermia induced by physical means (cold fluid) is established as an effective therapy in animal models of SCI, but its clinical translation to humans is hampered by several constraints. Hypothermia induced pharmacologically may be noninferior or superior to physically induced hypothermia for rapid, convenient systemic temperature reduction, but it has not been investigated previously in animal models of SCI. We used a rat model of SCI to compare outcomes in three groups: (1) normothermic controls; (2) hypothermia induced by conventional physical means; (3) hypothermia induced by intravenous (IV) dihydrocapsaicin (DHC). Male rats underwent unilateral lower cervical SCI and were treated after a 4-hour delay with physical cooling or IV DHC (∼0.60 mg/kg total) cooling (both 33.0 ± 1.0°C) lasting 4 hours; controls were kept normothermic. Telemetry was used to monitor temperature and heart rate during and after treatments. In two separate experiments, one ending at 48 hours, the other at 6 weeks, “blinded” investigators evaluated rats in the three groups for neurological function followed by histopathological evaluation of spinal cord tissues. DHC reliably induced systemic cooling to 32–33°C. At both the time points examined, the two modes of hypothermia yielded similar improvements in neurological function and lesion size compared with normothermic controls. Our results indicate that DHC-induced hypothermia may be comparable with physical hypothermia in efficacy, but more clinically feasible to administer than physical hypothermia.

Incidence of enteral feeding intolerance and its risk factors in patients with oral and maxillofacial malignancies

To explore the incidence of enteral feeding intolerance and its risk factors in patients with malignant oral and maxillofacial tumors. We conducted a retrospective analysis of 122 patients with malignant oral and maxillofacial tumor admitted in a general hospital for enteral nutrition between March, 2018 and March, 2021. The incidence of intolerance to enteral nutrition was analyzed, and the two groups of patients with and without intolerance were compared for age, gender, height, weight, pathological staging, types of enteral nutrition preparations, clinical treatment (physical hypothermia and nasal delivery), drug usage (sedatives, vasoactive drugs, acid suppressant, potassium preparation, antibiotics and hormones) and biochemical parameters (serum total protein, serum albumin, blood glucose and serum potassium concentration). Logistic regression analysis was used to analyze the influencing factors of enteral nutritional feeding intolerance in patients. Of the 122 patients, 52 had enteral feeding intolerance with an incidence rate of 42.6%. Logistic regression analysis showed that potassium preparation (OR=4.125, P=0.027, 95%CI: 1.178-14.444), sedatives (OR=4.125, P=0.000, 95%CI: 2.007-11.765) and hypoproteinemia (OR=3.557, P=0.010, 95%CI: 1.351-9.366) were independent risk factors of feeding intolerance in patients with malignant oral and maxillofacial tumors, while adding dietary fiber was a protective factor (OR= 0.108, P=0.015, 95%CI: 0.018-0.643). The incidence of enteral feeding intolerance is high in patients with malignant oral and maxillofacial tumors. Enteral nutrition preparations with dietary fiber are recommended for these patients. The patients with potassium preparations, sedatives and hypoproteinemia should be closely monitored for enteral feeding intolerance, and timely intervention should be administered to reduce its incidence.

Cannabinoid Receptor Agonist WIN55, 212-2 Adjusts Lipid Metabolism in a Rat Model of Cardiac Arrest.

The objective of this study was to investigate the effects of pharmacologically induced hypothermia with WIN55, 212-2 (WIN)on postresuscitation myocardial function, microcirculation, and metabolism-specific lipids in a rat cardiac arrest (CA) model. Ventricular fibrillation was electrically induced and untreated for 6 minutes in 24 Sprague-Dawley rats weighing 450-550 g. Cardiopulmonary resuscitation including chest compression and mechanical ventilation was then initiated and continued for 8 minutes, followed by defibrillation. At 5 minutes after restoration of spontaneous circulation (ROSC), animals were randomized into four groups: (1) normothermia with vehicle (NT); (2) physical hypothermia with vehicle (PH); (3) WIN55, 212-2 with normothermia (WN); and (4) WIN55, 212-2 with hypothermia (WH). For groups of WN and WH, WIN was administered by continuous intravenous infusion with a syringe pump for 4 hours. PH started at 5 minutes after resuscitation. NT maintained core temperature at 37°C ± 0.2°C with the aid of a heating blanket. Hypothermia groups maintained temperature at 33°C ± 0.5°C for 4 hours after ROSC. There was a significant improvement in myocardial function as measured by ejection fraction, cardiac output, and myocardial performance index in animals treated with WH and PH beginning at 1 hour after start of infusion. In the WH and PH groups, buccal microcirculation was significantly improved compared with NT and WN. Plasma at pre-CA and ROSC 4 hours was harvested for lipid metabolism. The WH group appeared to be closer to baseline than the other groups in lipid metabolism. lysophosphatidylcholine (LPC) 18:2, free fatty acid (FFA) 22:6, and ceramide (CER) (24:0) changed significantly among the lipidomic data compared with NT (p < 0.05). Postresuscitation hypothermia improved myocardial function and microcirculation. WH-mediated lipid metabolism had the best metabolic outcome to bring back the animals to normal metabolism, which may be protective to improve outcomes of CA. LPC 18:2, FFA 22:6, and CER (24:0) may be important predictors of outcomes of CA.

Case analysis of physical hypothermia combined with bromocriptine in the treatment of central hyperthermia

Case analysis of physical hypothermia combined with bromocriptine in the treatment of central hyperthermia

Abstract WP146: DHC Enhances the Hypothermia-induced Neuroprotection Following Ischemic Stroke in Rat Over a Long-term Period

Introduction: The combination of pharmacological hypothermia and intra-arterial selective cold infusions (SCI) was found to enhance the efficiency of hypothermia and efficacy of hypothermia-induced neuroprotection in acute ischemic stroke of rats. The aim of this study was to explore whether the combination could induce a long-term neuroprotective effects, as well as the underlying mechanism. Methods: Sprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 h using intraluminal hollow filament. The ischemic rats were randomized to receive: 1) pharmacological hypothermia by intraperitoneal (i.p.) injection of dihydrocapsaicin (DHC); 2) physical hypothermia by SCI for 10 min; or 3) the combined treatments. Extent of brain injury was determined by neurological deficit, infarct volume over a 21-day observation period. BBB permeability was assessed by detecting EB contents in ischemic hemispheric tissue at 2 h. Cytokine factors were determined in both infarct and penumbra areas in a quantitative way at 24 h after the onset of ischemia. Results: MRI-based infarct size analysis indicated that the combination of DHC and SCI resulted in a further reduction in infarct volume at both 48 h and 21 day following the onset of ischemia than either alone (P&lt;0.05). Furthermore, the combination treatment favorably improved neurologic deficit scores over the 21-day observation period (P&lt;0.01 or 0.05). This neuroprotective effects could partially be ascribed to decreased blood brain barrier injury, reduced pro-inflammatory cytokines (TNF-α, IL-2, and IFN-γ) in the infarct areas and/or penumbra areas, and increased protective cytokines (IL-4 and IL-10) in the infarct and/or penumbra regions. Conclusions: The combination approach was able to enhance the efficacy of hypothermia-induced neuroprotection following ischemic stroke in a long-term. The findings here provide a hint to translate the combination method from bench to bedside.

Inflammatory cytokines are involved in dihydrocapsaicin (DHC) and regional cooling infusion (RCI)-induced neuroprotection in ischemic rat

ObjectiveThe combination of pharmacological hypothermia – dihydrocapsaicin (DHC) and intra-arterial regional cooling infusions (RCI) was found to enhance the efficiency of hypothermia and efficacy of hypothermia-induced neuroprotection in acute ischemic stroke. The aim of this study was to explore whether the combination could induce a long-term neuroprotective effects, as well as the underlying mechanism. MethodsSprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h using intraluminal hollow filament. The ischemic rats were randomized to receive pharmacological hypothermia by intraperitoneal (i.p.) injection of DHC, physical hypothermia by RCI of 6 ml cold saline (4 °C), the combination, and no treatment. Over a 21-day period, brain damage was determined by infarct volume with MRI, and neurological deficit with grid-walking and beam balance tests. Blood brain barrier (BBB) was assessed by Evans-Blue (EB) contents. Inflammatory cytokines were determined in peri-infarct area by antibody array and ELISA. ResultsThe combination of DHC and RCI reduced (p < 0.05) infarct volume and neurologic deficit after stroke. BBB leakage and pro-inflammatory cytokines (IFN-γ, IL-2, and TNF-α) were significantly decreased (p < 0.05) because of the combination, while protective cytokines (IL-4 and IL-10) were increased (p < 0.05) in the peri-infarct area. ConclusionsThe combination approach enhanced the efficacy of hypothermia-induced neuroprotection following ischemic stroke. Our findings provide a hint to translate the combination method from bench to bedside.

Synergistically Induced Hypothermia and Enhanced Neuroprotection by Pharmacological and Physical Approaches in Stroke.

Hypothermia is considered as a promising neuroprotective treatment for ischemic stroke but with many limitations. To expand its clinical relevance, this study evaluated the combination of physical (ice pad) and pharmacological [transient receptor potential vanilloid channel 1 (TRPV1) receptor agonist, dihydrocapsaicin (DHC)] approaches for faster cooling and stronger neuroprotection. A total of 144 male Sprague Dawley rats were randomized to 7 groups: sham (n=16), stroke only (n=24), stroke with physical hypothermia at 31ºC for 3 h after the onset of reperfusion (n=24), high-dose DHC (H-DHC)(1.5 mg/kg, n=24), low-dose DHC (L-DHC)(0.5 mg/kg, n=32) with (n=8) or without (n=24) external body temperature control at ~38 ºC (L-DHC, 38 ºC), and combination therapy (L-DHC+ ice pad, n=24). Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Infarct volume, neurological deficits and apoptotic cell death were determined at 24 h after reperfusion. Expression of pro- and anti-apoptotic proteins was evaluated by Western blot. ATP and reactive oxygen species (ROS) were detected by biochemical assays at 6 and 24 h after reperfusion. Combination therapy of L-DHC and ice pad significantly improved every measured outcome compared to monotherapies. Combination therapy achieved hypothermia faster by 28.6% than ice pad, 350% than L-DHC and 200% than H-DHC alone. Combination therapy reduced (p<0.05) neurological deficits by 63% vs. 26% with L-DHC. No effect was observed when using ice pad or H-DHC alone. L-DHC and ice pad combination improved brain oxidative metabolism by reducing (p<0.05) ROS at 6 and 24 h after reperfusion and increasing ATP levels by 42.9% compared to 25% elevation with L-DHC alone. Finally, combination therapy decreased apoptotic cell death by 48.5% vs. 24.9% with L-DHC, associated with increased anti-apoptotic protein and reduced pro-apoptotic protein levels (p<0.001). Our study has demonstrated that combining physical and pharmacological hypothermia is a promising therapeutic approach in ischemic stroke, and warrants further translational investigations.

5-HT1a activation in PO/AH area induces therapeutic hypothermia in a rat model of intracerebral hemorrhage.

Therapeutic hypothermia is widely applied as a neuroprotective measure on intracerebral hemorrhage (ICH). However, several clinical trials regarding physical hypothermia encountered successive failures because of its side-effects in recent years. Increasing evidences indicate that chemical hypothermia that targets hypothalamic 5-HT1a has potential to down-regulate temperature set point without major side-effects. Thus, this study examined the efficacy and safety of 5-HT1a stimulation in PO/AH area for treating ICH rats. First, the relationship between head temperature and clinical outcomes was investigated in ICH patients and rat models, respectively. Second, the expression and distribution of 5-HT1a receptor in PO/AH area was explored by using whole-cell patch and confocal microscopy. In the meantime, the whole-cell patch was subsequently applied to investigate the involvement of 5-HT1a receptors in temperature regulation. Third, we compared the efficacy between traditional PH and 5-HT1a activation-induced hypothermia for ICH rats. Our data showed that more severe perihematomal edema (PHE) and neurological deficits was associated with increased head temperature following ICH. 5-HT1a receptor was located on warm-sensitive neurons in PO/AH area and 8-OH-DPAT (5-HT1a receptor agonist) significantly enhanced the firing rate of warm-sensitive neurons. 8-OH-DPAT treatment provided a steadier reduction in brain temperature without a withdrawal rebound, which also exhibited a superior neuroprotective effect on ICH-induced neurological dysfunction, white matter injury and BBB damage compared with physical hypothermia. These findings suggest that chemical hypothermia targeting 5-HT1a receptor in PO/AH area could act as a novel therapeutic manner against ICH, which may provide a breakthrough for therapeutic hypothermia.

Phenothiazines Enhance Mild Hypothermia-induced Neuroprotection via PI3K/Akt Regulation in Experimental Stroke

Physical hypothermia has long been considered a promising neuroprotective treatment of ischemic stroke, but the treatment’s various complications along with the impractical duration and depth of therapy significantly narrow its clinical scope. In the present study, the model of reversible right middle cerebral artery occlusion (MCAO) for 2 h was used. We combined hypothermia (33–35 °C for 1 h) with phenothiazine neuroleptics (chlorpromazine & promethazine) as additive neuroprotectants, with the aim of augmenting its efficacy while only using mild temperatures. We also investigated its therapeutic effects on the Phosphatidylinositol 3 kinase/Protein kinase B (PI3K/Akt) apoptotic pathway. The combination treatment achieved reduction in ischemic rat temperatures in the rectum, cortex and striatum significantly (P < 0.01) faster than hypothermia alone, accompanied by more obvious (P < 0.01) reduction of brain infarct volume and neurological deficits. The combination treatment remarkably (P < 0.05) increased expression of p-Akt and anti-apoptotic proteins (Bcl-2 and Bcl-xL), while reduced expression of pro-apoptotic proteins (AIF and Bax). Finally, the treatment’s neuroprotective effects were blocked by a p-Akt inhibitor. By combining hypothermia with phenothiazines, we significantly enhanced the neuroprotective effects of mild hypothermia. This study also sheds light on the possible molecular mechanism for these effects which involves the PI3K/Akt signaling and apoptotic pathway.

Dihydrocapsaicin (DHC) enhances the hypothermia-induced neuroprotection following ischemic stroke via PI3K/Akt regulation in rat

ObjectiveHypothermia has demonstrated neuroprotection following ischemia in preclinical studies while its clinical application is still very limited. The aim of this study was to explore whether combining local hypothermia in ischemic territory achieved by intra-arterial cold infusions (IACIs) with pharmacologically induced hypothermia enhances therapeutic outcomes, as well as the underlying mechanism. MethodsSprague-Dawley rats were subjected to right middle cerebral artery occlusion (MCAO) for 2h using intraluminal hollow filament. The ischemic rats were randomized to receive: 1) pharmacological hypothermia by intraperitoneal (i.p.) injection of dihydrocapsaicin (DHC); 2) physical hypothermia by IACIs for 10min; or 3) the combined treatments. Extent of brain injury was determined by neurological deficit, infarct volume, and apoptotic cell death at 24h and/or 7d following reperfusion. ATP and ROS levels were measured. Expression of p-Akt, cleaved Caspase-3, pro-apoptotic (AIF, Bax) and anti-apoptotic proteins (Bcl-2, Bcl-xL) was evaluated at 24h. Finally, PI3K inhibitor was used to determine the effect of p-Akt. ResultsDHC or IACIs each exhibited hypothermic effect and neuroprotection in rat MCAO models. The combination of pharmacological and physical approaches led to a faster and sustained reduction in brain temperatures and improved ischemia-induced injury than either alone (P<0.01). Furthermore, the combination treatment favorably increased the expression of anti-apoptotic proteins and decreased pro-apoptotic protein levels (P<0.01 or 0.05). This neuroprotective effect was largely blocked by p-Akt inhibition, indicating a potential role of Akt pathway in this mechanism (P<0.01 or 0.05). ConclusionsThe combination approach is able to enhance the efficiency of hypothermia and efficacy of hypothermia-induced neuroprotection following ischemic stroke. The findings here move us a step closer towards translating this long recognized TH from bench to bedside.

Abstract 142: Enhanced Neuroprotection by Synergistically Induced Hypothermia with Pharmacological and Physical Approach in Experimental Stroke

Background and Purpose: This study combined Transient Receptor Potential Vanilloid channel 1 (TRPV1) receptor agonist, dihydrocapsaicin (DHC), with physical hypothermia (PH) (ice pad) to achieve faster cooling to enhance its neuroprotective effects, thus potentially avoiding side effects brought on by monotherapies of high dose DHC and physical hypothermia. Methods: Middle cerebral artery (MCA) occlusion (2 h) was achieved using an intraluminal filament. Rats (n=8) were randomized to 7 groups: sham surgery, stroke only, PH, low DHC (0.5 mg/kg), low DHC/active rewarming (AR), high DHC (1.5 mg/kg) or combination (low DHC plus PH). The treatments were maintained for 3 h at the onset of reperfusion, which was 24 h. Rate to target hypothermia (31 °C) onset was measured. Extent of brain injury was determined by infarct volume, neurological deficit, and apoptotic cell death. Expressions of pro- and anti-apoptotic proteins were evaluated through Western blotting. Metabolic changes and oxidative injury were determined by ATP and ROS productions. Results: Combination had 28.6% faster cooling than PH, 350% faster than low DHC group and 200% faster than high DHC group. Combination had 63.2% reduction in infarct volume and low DHC had 25.9% reduction in infarct volume compared to stroke only. High DHC, DHC (AR) and PH and did not induce significant neuroprotection. Combination therapy significantly decreased apoptotic cell death by 48.5%, as compared to 24.9% with low DHC, in association with significantly increased anti-apoptotic and reduced pro-apoptotic protein expression. Combination therapy largely increased ATP levels by 42.9%, as compared to 25% increase with low DHC. Only combination therapy and PH had significant reductions in ROS at 6 and 24 h post-reperfusion. Neurological testing showed that combination therapy had the best outcomes at 24 h of reperfusion. Discussion: Combination of DHC and PH enhanced the neuroprotective effect produced by each alone. This synergistic protection is associated with faster cooling and more dramatic reduction in apoptotic cell death and more favorable cellular metabolism. The combination therapy is promising in clinical settings for its non-invasive, quick and effective outcomes.

Abstract TP113: Beneficial Effect of Faster Cooling Elicited by Combination of TRPV1 Agonist (Dihydrocapsaicin) and Mild Physical Hypothermia in Ischemia/Reperfusion Injury

Introduction: Pharmacologically induced hypothermia (PH) in stroke has been investigated. Achieving faster cooling after stroke would be important in the successful rescue of neurons and improve outcomes. However, drawbacks of PH and physical cooling are the time and large doses required to achieve neuroprotective hypothermia. The induced toxicity and possible drug complications largely limited PH translation in the clinics. Transient Receptor Potential Vanilloid (TRPV) 1 receptor and its agonist dihydrocapsaicin (DHC) have been reported to exert neuroprotective effects in animal stroke models by inducing hypothermia. It is proposed that TRPV1 agonism plays a central thermoregulatory role in possibly reducing thermoregulatory set-point. The combination therapy of physical cooling and PH may achieve faster cooling rates by increasing heat loss and decreasing heat generation. To this end, we assessed the hypothesis that combination of DHC and physical cooling leads to faster cooling and better neuroprotection. Methods: Sprague Dawley rats were subjected to 2 h middle cerebral artery occlusion (MCAO) and followed by 24 h of reperfusion. Ischemic rats in each group (n=8) received either: no treatment, mild hypothermia, low DHC (0.5 mg/kg), high DHC (1.5 mg/kg) or combination (low DHC plus hypothermia). Treatments lasted for 3 h. Rate to target hypothermia (31 °C) onset was measured. Infarct volume was determined using triphenyl tetrazolium chloride (TTC) staining. Results: Temperature decrease rate at which groups was determined as 0.1°C/min for hypothermia, 0.06°C/min for low DHC, 0.07°C/min for high DHC and 0.2°C/min for combination. The combination treatment was 3 times faster (p&lt;0.05) than low and high DHC groups, while 2 times faster (p&lt;0.05) than mild hypothermia. Infarct volume was largely and significantly reduced by combination therapy (19.2%), as compared to no treatment (49.5%), mild hypothermia only (50.0%), low DHC (36.6%), and high DHC (39.9%) groups. Conclusion: Combination of physical hypothermia and DHC elicited a faster reduction of body temperature and strong neuroprotection as compared to single treatments. This novel therapy may provide better opportunity for ischemic brain to reach therapeutic hypothermia temperature.

Effect of a pharmacologically induced decrease in core temperature in rats resuscitated from cardiac arrest

AimHypothermia is recommended by international guidelines for treatment of unconscious survivors of cardiac arrest to improve neurologic outcomes. However, temperature management is often underutilized because it may be difficult to implement. The present study evaluated the efficacy of pharmacologically induced hypothermia on survival and neurological outcome in rats resuscitated from cardiac arrest. MethodsCardiac arrest was induced for 10min in 120 rats. Sixty-one rats were resuscitated and randomized to normothermia, physical cooling or pharmacological hypothermia 5min after resuscitation. Pharmacological hypothermia rats received a combination of ethanol, vasopressin and lidocaine (HBN-1). Physical hypothermia rats were cooled with intravenous iced saline and cooling pads. Rats in the pharmacological hypothermia group received HBN-1 at ambient temperature (20°C). Normothermic rats were maintained at 37.3±0.2°C. ResultsHBN-1 (p<0.0001) shortened the time (85±71min) to target temperature (33.5°C) versus physical hypothermia (247±142min). The duration of hypothermia was 17.0±6.8h in the HBN-1 group and 17.3±7.5h in the physical hypothermia group (p=0.918). Survival (p=0.034), neurological deficit scores (p<0.0001) and Morris Water Maze performance after resuscitation (p=0.041) was improved in the HBN-1 versus the normothermic group. HBN-1 improved survival and early neurological outcome compared to the physical hypothermia group while there was no significant difference in performance in the Morris water maze. ConclusionHBN-1 induced rapid and prolonged hypothermia improved survival with good neurological outcomes after cardiac arrest suggesting that pharmacologically induced regulated hypothermia may provide a practical alternative to physical cooling.

Abstract 292: Comparison of Pharmacological and Physical Hypothermia in Cerebral and Myocardial Function in a Porcine Model of Cardiac Arrest and Resuscitation

Objective: Non-selective cannabinoid (CB) 1/2 receptor agonist, WIN 55,212-2, has been demonstrated to produce pharmacological hypothermia and improved outcomes of CPR in a rat model. In this study, we compared the effects of pharmacological hypothermia induced by WIN 55,212-2 and physical hypothermia by surface cooling in myocardial and neurological function in a porcine model of CPR. Hypothesis: Pharmacological hypothermia by WIN 55,212-2 produced the similar or better cerebral and myocardial function as surface cooling. Methods and results:Ventricular fibrillation (VF) was induced in 14 male domestic pigs weighing between 35 ± 2 kg. CPR was initiated after 7 min of untreated VF. Defibrillation was attempted after 5 min of CPR. If ROSC was not achieved, two mins of CPR was continued and sequenced with defibrillation attempt until ROSC or for a total of 15 mins. At 5 min post resuscitation, animals are randomized to receive intravenous infusion with WIN 55,212-2 at a dose of 1.0 mg/kg/h or surface cooling until blood temperature cooled down to 34 celcius degree and maintained for 4 hrs. When compared to the animals treated with surface cooling, significantly improvement in neurological alertness score (NAS) was observed in the WIN 55,212-2 treated animals at 24 and 48 hrs, but not at 72 hrs (WIN 55,212-2 vs surface cooling: 24 hrs, 93 ± 5 vs 77 ± 12, p&lt;0.01; 48 hrs, 100 ± 0 vs 93 ± 6, p=0.01) (Figure 1A). As to the post resuscitation myocardial function, there was no significant difference in ejection fraction (EF) between these two groups (Figure 1B). Conclusions: Pharmacological hypothermia induced by WIN 55,212-2 exerted better post resuscitation short-term neurological function than physical hypothermia with the similar post resuscitation myocardial function.