Mild Brain Hypothermia Research Articles

Selective brain hypothermia attenuates focal cerebral ischemic injury and improves long-term neurological outcome in aged female mice.

This study aimed to investigate the effects of mild selective brain hypothermia on aged female ischemic mice. A distal middle cerebral artery occlusion (dMCAO) model was established in aged female mice, who were then subjected to mild selective brain hypothermia immediately after the dMCAO procedure. Neurological behavioral examinations were conducted prior to and up to 35 days post-ischemia. Infarct volume, brain atrophy, pro-inflammation, and anti-inflammation microglia/macrophages phenotype and white matter injury were evaluated by immunofluorescence staining. Correlations between neurological behaviors and histological parameters were evaluated by Pearson product linear regression analysis. Sensorimotor and cognitive function tests confirmed the protective effect of mild selective brain hypothermia in elderly female ischemic mice. In addition, hypothermia decreased the infarct volume and brain atrophy induced by focal cerebral ischemia. Furthermore, hypothermia alleviated ischemia-induced short-term and long-term white matter injury, which was correlated with behavioral deficits. Finally, hypothermia suppressed the harmful immunological response by promoting the transformation of pro-inflammatory microglia/macrophages to anti-inflammatory phenotype. This polarization was negatively correlated with neuronal loss and white matter injury. Mild selective brain hypothermia promoted long-term functional recovery by alleviating white matter damage in an aged female mouse model of ischemia.

Successful mild brain hypothermia therapy followed by targeted temperature management for pediatric hemorrhagic shock and encephalopathy syndrome.

Hemorrhagic shock and encephalopathy syndrome (HSES) is the most severe form of acute encephalopathy that progresses rapidly, often resulting in death or severe neurological sequelae. We report the case of a 4-year-old girl with HSES with shock and impaired consciousness. Blood test results showed hypercytokinemia, and the 4-year-old patient was immediately admitted to the intensive care unit. Within 4 h of symptom onset, she received mild brain hypothermia therapy with a target body temperature of 35°C. Methylprednisolone pulse, high dose immunoglobulin, and large doses of circulatory drugs were administered. After 72 h of brain hypothermia therapy, targeted temperature management with a target body temperature between 36°C and 37°C was continued for 96 h. The patient was diagnosed with HSES based on acute encephalopathy with shock, hypercytokinemia, low platelet count, coagulation disorder, renal damage, and intestinal bleeding. Magnetic resonance imaging results revealed no signs of any specific acute encephalopathy. She was discharged without neurological sequelae 28 days after symptom onset. Mild brain hypothermia therapy initiated in the early stages followed by targeted temperature management may be an effective way to improve neurological outcomes in children suffering from HSES.

Cold Exposure After Exercise Impedes the Neuroprotective Effects of Exercise on Thermoregulation and UCP4 Expression in an MPTP-Induced Parkinsonian Mouse Model.

Moderate exercise and mild hypothermia have protective effects against brain injury and neurodegeneration. Running in a cold environment alters exercise-induced hyperthermia and outcomes; however, evaluations of post-exercise cold exposure related to exercise benefits for the brain are relatively rare. We investigated the effects of 4°C cold exposure after exercise on exercise-induced thermal responses and neuroprotection in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced Parkinsonian mouse model. Male C57BL/6J mice were pretreated with MPTP for five consecutive days and follow-up treadmill exercise for 4 weeks. After 1-h running at a 22°C temperature, the mice were exposed to a 4°C environment for 2 h. An MPTP injection induced a transient drop in body and brain temperatures, while mild brain hypothermia was found to last for 4 weeks after MPTP treatment. Preventing brain hypothermia by exercise or 4°C exposure was associated with an improvement in MPTP-induced striatal uncoupling protein 4 (UCP4) downregulation and nigrostriatal dopaminergic neurodegeneration. However, 4°C exposure after exercise abrogated the exercise-induced beneficial effects and thermal responses in MPTP-treated mice, including a low amplitude of exercise-induced brain hyperthermia and body temperature while at rest after exercise. Our findings elucidate that post-exercise thermoregulation and UCP4 expression are important in the neuroprotective effects of exercise against MPTP toxicity.

13C NMR Metabolomic Evaluation of Immediate and Delayed Mild Hypothermia in Cerebrocortical Slices after Oxygen–Glucose Deprivation

Mild brain hypothermia (32°-34°C) after human neonatal asphyxia improves neurodevelopmental outcomes. Astrocytes but not neurons have pyruvate carboxylase and an acetate uptake transporter. C nuclear magnetic resonance spectroscopy of rodent brain extracts after administering [1-C]glucose and [1,2-C]acetate can distinguish metabolic differences between glia and neurons, and tricarboxylic acid cycle entry via pyruvate dehydrogenase and pyruvate carboxylase. Neonatal rat cerebrocortical slices receiving a C-acetate/glucose mixture underwent a 45-min asphyxia simulation via oxygen-glucose-deprivation followed by 6 h of recovery. Protocols in three groups of N=3 experiments were identical except for temperature management. The three temperature groups were: normothermia (37°C), hypothermia (32°C for 3.75 h beginning at oxygen--glucose deprivation start), and delayed hypothermia (32°C for 3.75 h, beginning 15 min after oxygen-glucose deprivation start). Multivariate analysis of nuclear magnetic resonance metabolite quantifications included principal component analyses and the L1-penalized regularized regression algorithm known as the least absolute shrinkage and selection operator. The most significant metabolite difference (P<0.0056) was [2-C]glutamine's higher final/control ratio for the hypothermia group (1.75±0.12) compared with ratios for the delayed (1.12±0.12) and normothermia group (0.94±0.06), implying a higher pyruvate carboxylase/pyruvate dehydrogenase ratio for glutamine formation. Least Absolute Shrinkage and Selection Operator found the most important metabolites associated with adenosine triphosphate preservation: [3,4-C]glutamate-produced via pyruvate dehydrogenase entry, [2-C]taurine-an important osmolyte and antioxidant, and phosphocreatine. Final principal component analyses scores plots suggested separate cluster formation for the hypothermia group, but with insufficient data for statistical significance. Starting mild hypothermia simultaneously with oxygen-glucose deprivation, compared with delayed starting or no hypothermia, has higher pyruvate carboxylase throughput, suggesting that better glial integrity is one important neuroprotection mechanism of earlier hypothermia.

1H nuclear magnetic resonance brain metabolomics in neonatal mice after hypoxia–ischemia distinguished normothermic recovery from mild hypothermia recoveries

Background:Mild brain hypothermia (31–34 °C) after neonatal hypoxia–ischemia (HI) improves neurodevelopmental outcomes in human and animal neonates. Using an asphyxia model with neonatal mice treated with mild hypothermia after HI, we investigated whether 1H nuclear magnetic resonance (NMR) metabolomics of brain extracts could suggest biomarkers and distinguish different treatments and outcome groups.Methods:At postnatal day 7 (P7), CD1 mice underwent right carotid artery occlusion, 30 min of HI (8% oxygen), and 3.5 h of either hypothermia (31 °C) or normothermia (37 °C). Whole brains were frozen immediately after HI, immediately after 3.5 h of hypothermia or normothermia treatments, and 24 h later. Perchloric acid extractions of 36 metabolites were quantified by 900 MHz 1H NMR spectroscopy. Multivariate analyses included principal component analyses (PCA) and a novel regression algorithm. Histological injury was quantified after HI at 5 d.Results:PCA scores plots separated normothermia/HI animals from hypothermia/HI and control animals, but more data are required for multivariate models to be predictive. Loadings plots identified 11 significant metabolites, whereas the regression algorithm identified 6. Histological injury scores were significantly reduced by hypothermia.Conclusion:Different treatment and outcome groups are identifiable by 1H NMR metabolomics in a neonatal mouse model of mild hypothermia treatment of HI.

Regional cooling for reducing brain temperature and intracranial pressure

To evaluate the effectiveness of regional cooling for reducing brain temperature (BrTe) and intracranial pressure (ICP) in patients where conventional clinical treatment has failed. Regional cooling was carried out using ice bags covering the area of the craniectomy (regional method) in 23 patients. The BrTe and ICP were determined using a fiber optic sensor. Thirteen patients (56.52%) were female. The ages ranged from 16 to 83 years (mean of 48.9). The mean APACHE II score was 25 points (11-35). The patients were submitted, on mean, to 61.7 hours (20-96) of regional cooling. There was a significant reduction in mean BrTe (p<0.0001--from 37.1 degrees C to 35.2 degrees C) and mean ICP (p=0.0001--from 28 mmHg to 13 mmHg). Our results suggest that mild brain hypothermia induced by regional cooling was effective in the control of ICP in patients who had previously undergone decompressive craniectomy.

Initiation time of post-ischemic hypothermia on the therapeutic effect in cerebral ischemic injury

Objective: To study the efficacy of mild brain hypothermia beginning at different time intervals on cerebral ischemic injury.Methods: Male Sprague–Dawley rats were divided into sham-operated group, normothermia (37–38°C) and mild hypothermia (31–32°C) ischemia groups. The last group was subdivided into four groups: 240 minute hypothermia, 30 minute normothermia plus 210 minute hypothermia, 60 minute normothermia plus 180 minute hypothermia, and 90 minute normothermia plus 150 minute hypothermia (n=8). Global cerebral ischemia was established using the Pulsinelli four-vessel occlusion model for 20 minutes and mild hypothermia was applied after 20 minutes of ischemia. Brain tissue was collected following 20 minute cerebral ischemia and 240 minute reperfusion, and used to measure the levels of malondialdehyde (MDA), lactate, water content and the amounts of electrolytes, such as sodium (Na+), potassium (K+) and calcium (Ca++).Results: Mild hypothermia beginning at 0–60 minutes decreased the levels of malondialdehyde and lactate (p<0.05 or p<0.01), decreased water content, Na+ and Ca++, and increased the amount of K+ (p<0.05 or p<0.01) in ischemic tissue, except the amounts of Na+, K+ and Ca++ in mild hypothermia beginning at 60 minute ischemia group (p>0.05). Mild hypothermia beginning at 90 minutes had little effect on the levels of targeted molecules, water content and amounts of electrolytes of Na+, K+ and Ca++ in ischemic tissue (p>0.05).Discussion: Post-ischemic mild brain hypothermia can decrease the accumulation of lactate and lipid peroxidation in ischemic tissue, and delay the development of brain edema following ischemic reperfusion. The best neuroprotection of mild hypothermia to attenuate ischemic injury was begun within 60 minutes.

Neuroprotection of mild brain hypothermia against cerebral ischemic injury

Objective To study the effect of mild brain hyothermia on cerebral ischemic injury. Methods Global cerebral ischemia was established by modified Pulsinelli 4-vessel occlusion model. Forty-eight Sprague-Dawley rats were divided into 4 group: a sham-operated group, a normothermia (37～38℃) ischemic group and a mild is-chemic hypothermia (31～32℃) group; the mild ischemic hypothermia was subdivided into 4 groups with the hypo-thermia lasting for 30 min, 60 min, 120 min and 240 min, respectively. After 240 rain of reperfusion following 20 min cerebral ischemia, the levels of nitric oxide products nitrite (NO2) ,endothelin-1 (ET1) , tumor necrosis fac-tor alpha (TNFα) and interleukin-1 beta (IL-1β) in brain tissue and the lactate dehydrogenase (LDH), aspartate aminotransferase(AST) , creatine kinase(CK) and its brain band isoenzyme (CK-BB) in plasma were measured. Results The levels of IL-1β,TNFα, ET1 and NO2. in brain tissue, and the amounts of LDH, AST, CK and CK-BB in serum were higher in normothermia ischemic group than those in sham-operated group (P 0.05). Con-clusion Mild brain hypothermia post-ischemia can significantly suppress the inflammation response in ischemic brain tissue and stabilize the function of cell membrane. The best neuroprotection of mild brain hypothermia must be carried out immediately and last for more than 60 minutes. Key words: Mild hypotherrnia ; Cerebral ischemia ; Rats ; Therapeutic window ;

Effect of Delayed Mild Brain Hypothermia on Edema Formation After Intracerebral Hemorrhage in Rats

Secondary consequences of intracerebral hemorrhage (ICH) including inflammation, edema, and oxidative damage all contribute to cell death after ICH. Brain hypothermia (BH) has been used as an effective neuroprotective treatment in experimental brain ischemia and traumatic brain injury. In this study, we first attempted to evaluate the effect of delayed mild BH (35 degrees C) on brain edema formation 48 hours after ICH. BH was started 3, 6, 12, and 24 hours after the induction of 100 muL of autologous blood into the basal ganglia (hypothermic [HT]; HT3: n = 4, HT6: n = 6, HT12: n = 11, HT24: n = 6) in rats. To examine the protective mechanism of BH, blood-brain barrier (BBB) permeability to Evans blue, accumulation of polymorphonuclear leukocyte, and oxidative DNA damage in the lesion were compared between normothermic (NT) (37 degrees C) and HT6 rats 48 hours after ICH. Finally, neurologic recovery was assessed using behavioral tests in NT and HT6 rats 48 hours after ICH. Brain water content in the ispilateral basal ganglia was significantly reduced with delayed BT compared with NT (n = 7, 81.8 +/- 0.7% v HT3: 78.9 +/- 0.8%, P < .01; HT6: 78.7 +/- 0.6%, P < .01; HT12: 79.4 +/- 1.1%, P < .01; HT24: 80.3 +/- 0.6%, P < .01). The BBB disruption to Evans blue was significantly reduced with BH (HT6: n = 6) compared with NT (n = 6) rats in the ipsilateral basal ganglia (23.0 +/- 5.2 v 42.3 +/- 4.0 ng/g wet tissue, P < .05). HT6 treatment (n = 6) significantly inhibited the accumulation of polymorphonuclear leukocyte compared with NT treatment (n = 6) (0.43 +/- 0.22 v 1.49 +/- 0.61 DeltaAbs/mg tissue, P < .05). HT6 treatment (n = 3) also significantly reduced oxidative DNA damage determined with 8-hydroxyl-2'-deoxyguanosine compared with NT treatment (n = 3) (92 +/- 18 v 40 +/- 7 pg 8-hydroxyl-2'-deoxyguanosine/mug DNA, P < .05). Furthermore, HT6 treatment (n = 5) significantly improved neurologic recovery assessed with forelimb placing score compared with NT treatment (42.0 +/- 5.8 v 12.0 +/- 3.7, P < .05). In conclusion, mild BH significantly reduces the brain edema formation after ICH, even when the BH is applied 24 hours after hematoma induction in rats. Several neuroprotective mechanisms, including reduced BBB disruption, inflammation and oxidative damage, are suggested in this study.

Therapeutic effect of post-ischemic hypothermia duration on cerebral ischemic injury

Objective: To study the efficacy of post-ischemic mild brain hypothermia lasting for different time intervals on cerebral ischemic reperfusion injury.Method: Male Sprague–Dawley rats were divided into a sham-operated group, normothermia (37–38° C) ischemia group and mild hypothermia (31–32° C) group. The last group was subdivided into four groups: 30 minute hypothermia plus 210 minute normothermia, 60 minute hypothermia plus 180 minute nomothermia,120 minute hypothermia plus 120 minute normothermia, and 240 minute hypothermia (n=8). Global cerebral ischemia was established using the Pulsinelli four-vessel occlusion model. Brain tissue was collected following a 20 minute cerebral ischemia and 240 minute reperfusion, and was used to measure the levels of glutamate (Glu), aspartate (Asp), glycine (Gly), gamma-aminobutyric acid (GABA), dopamine (DA), norepinephrine (NE), serotonin(5-HT) and hydroxyindoleacetic acid (5-HIAA), nitrite (NO2), endothelin-1 (ET1), tumor necrosis factor alpha(TNFα) and interleukin-1beta (IL-1β). Serum was collected to measure the levels of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), creatine kinase (CK) and its brain band isoenzyme (CK-BB).Results: Hypothermia lasting for 60–240 minutes delayed the decrease in these amino acids, postponed the decrease in DA, NE and 5-HT and increase in hydroxyindoleacetic acid (5-HIAA), and decreased the levels of IL-1β, TNFα, ET1 and NO2 in brain tissue. Hypothermia also decreased the levels of LDH, AST, CK and CK-BB in serum as compared to normothermia group (p<0.05 or p<0.01). Hypothermia lasting for 30 minutes delayed the decreases in these amino acids and 5-HT and increase in 5-HIAA in brain tissue (p<0.05), but failed to influence the levels of IL-1β, TNFα, ET1 and NO2 in brain tissue and the amounts of LDH, AST, CK and CK-BB in serum as compared to normothermia ischemia group (p>0.05).Conclusions: Post-ischemic mild brain hypothermia can significantly suppress the excessive release of amino acids, monoamine neurotransmitters and inflammation response in ischemic tissue. It can also stabilize the function of the cell membrane, which is associated with the mechanism of cerebral protection by mild hypothermia. These results suggest that mild hypothermia should be applied immediately after ischemia and last for more than 60 minutes in order to obtain neuroprotective effects.

Revascularization of the Posterior Circulation

The primary objective of revascularization procedures in the posterior circulation is the prevention of vertebrobasilar ischemic stroke. Specific anatomical and neurophysiologic characteristics such as posterior communicating artery size affect the susceptibility to ischemia. Current indications for revascularization include symptomatic vertebrobasilar ischemia refractory to medical therapy and ischemia caused by parent vessel occlusion as treatment for complex aneurysms. Treatment options include endovascular angioplasty and stenting, surgical endarterectomy, arterial reimplantation, extracranial-to-intracranial anastomosis, and indirect bypasses. Pretreatment studies including cerebral blood flow measurements with assessment of hemodynamic reserve can affect treatment decisions. Careful blood pressure regulation, neurophysiologic monitoring, and neuroprotective measures such as mild brain hypothermia can help minimize the risks of intervention. Microscope, microinstruments and intraoperative Doppler are routinely used. The superficial temporal artery, occipital artery, and external carotid artery can be used to augment blood flow to the superior cerebellar artery, posterior cerebral artery, posterior inferior cerebellar artery, or anterior inferior cerebellar artery. Interposition venous or arterial grafts can be used to increase length. Several published series report improvement or relief of symptoms in 60 to 100% of patients with a reduction of risk of future stroke and low complication rates.

A case of influenza-associated acute encephalopathy with congenital hypothyroidism treated by mild brain hypothermia and other specific therapy

A case of influenza-associated acute encephalopathy with congenital hypothyroidism treated by mild brain hypothermia and other specific therapy

Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture.

The pathophysiology of cerebral ischemia is well studied in small-animal models, which offer reproducibility and control of confounding variables-factors essential to hypothesis-testing. This presentation first highlights insights into the ischemic penumbra enabled by a multimodal experimental approach; second, discusses gene expression in ischemia; and third, confronts the challenges of neuroprotectant therapy. The ischemic penumbra: Transient (2-hour) middle cerebral artery suture-occlusion in anesthetized rats gives rise to highly consistent neurological and histopathological sequelae. Autoradiographic local cerebral blood flow (LCBF) studies at 2 hours of occlusion define the penumbra as a region of intermediate CBF depression (20% to 40% of control) surrounding the densely ischemic core (5% to 20% of control) and constituting one half of the entire lesion. Local glucose metabolic rate in the acute penumbra is not reduced despite the critical CBF reduction, so that the penumbral metabolism/blood flow ratio is markedly elevated. In contrast, following 1 hour of recirculation, glucose metabolism throughout the previously ischemic hemisphere has become markedly depressed, and the metabolism/flow ratio has pseudonormalized. By correlating these data with histopathology using multimodal image analysis, the probability of infarction is shown to be highly determined by the degree of antecedent CBF reduction. These animal data agree strikingly with published results in patients with acute stroke studied by positron emission tomography. This remarkable correspondence belies the assertion that data from lower species may not be relevant to human stroke. Gene expression: Perfusion gradients also determine differential patterns of gene expression in ischemia. This can be demonstrated by correlating in situ hybridization autoradiographs for gene expression with autoradiographic LCBF data and histological infarct maps derived from replicate series. In other studies, DNA microarray technology is used to screen for thousands of expressed genes. In the 2-hour middle cerebral artery occlusion model with 3-hour recirculation, we have identified 28 known ischemia-hypoxia response genes that are upregulated and 6 that are downregulated, together with 35 upregulated and 41 downregulated genes newly connected with ischemia. These findings underscore the enormous complexity of ischemic biology and suggest possible novel mechanisms for future exploration. NEUROPROTECTION: A desirable neuroprotectant would, in theory, antagonize multiple injury mechanisms. We have explored 2 such therapies of particular promise. Mild brain hypothermia (32 degrees C target temperature, for 5 hours) is highly neuroprotective even when initiated at the onset of recirculation. Another highly protective agent is human albumin, administered in doses of 1.25 to 2.5 g/kg--a therapy that reduces infarct volume in this ischemia model by 60% to 65%, markedly diminishes brain swelling, and has a therapeutic window extending to 4 hours. The careful study of rodent ischemia models can yield valuable, clinically relevant insights into the pathophysiology of ischemic stroke.

Neuroprotection of mild hypothermia beginning at different time intervals on cerebral ischemia/reperfusion injury

The effects of mild hypothermia beginning at different time intervals on cerebral ischemia was studied in SD rats which were divided into sham‐operated, normothermia (37–38°C) ischemia and mild hypothermia (31–32°C) group. The latter was subdivided into: 240 min hypothermia, 30 min normothermia plus 210 min hypothermia, 60 min normothermia plus 180 min hypothermia and 90 min normothermia plus 150 min hypothermia. Global cerebral ischemia was induced by modified 4‐vessel occlusion model. 240 min reperfusion following 20 min cerebral ischemia. Results showed that in normothermia group, the amount of SOD, GSH‐Px, GSH, ATP, K+ were lower and MDA, lactate, water content, Ca++ were higher than those in sham‐operated group. Mild hypothermia beginning immediately within 60 min delayed the consumption of SOD, GSH‐Px, GSH, ATP and decreased the accumulation of MDA, lactate, water content and Ca++ as compared with normothermia group. Mild hypothermia beginning immediately within 30 min significantly decreased the elevation of Na+, Ca++ and increased K+ in brain tissue when compared with normothermia. Mild hypothermia beginning immediately at 90 min has little effect on the content of SOD, GSH‐Px, GSH, MDA, lactate, ATP, water content and Na+, K+, Ca++ as compared with the normothermia group. Mild brain hypothermia beginning immediately after ischemia delay consumption of endogenous antioxidant enzyme and energy metabolism, decrease accumulation of lactate and lipid peroxidation and the development of brain edema, which is involved in the mechanism of cerebral protection by mild hypothermia. Mild hypothermia limits ischemia injury beginning immediately within 30 or 60 min, but lost its function when beginning at 90 min following ischemia.

Perinatal asphyxia: a clinical review, including research with brain hypothermia.

Perinatal asphyxia may occur in utero, during labor and delivery, or in the postnatal period. There are numerous causes, and the clinical manifestations vary. Infants who experience mild asphyxia may show no neurologic injury. Severe asphyxia may be fatal in utero, or immediately after birth, with survivors showing extensive neurologic sequelae, with or without cognitive deficits. Mild brain hypothermia appears promising in the prevention of further neurologic damage in encephalopathic infants following asphyxia. Recent research on newborn animal models has focused on the timing, duration, and depth of hypothermia. Promising new research is now under way in nurseries in the U.S. in an attempt to establish clinical protocols for use of hypothermia in human neonates.

重症くも膜下出血に対する可及的早期手術の有用性

We retrospectively analyzed and compared overall outcome of poor-grade patients (WFNS Grade IV, V, and cardiopulmonary arrest on arrival |CPAOA|) with subarachnoid hemorrhage (SAH) in 2 study periods. The first was from July 1993 to June 1994 and the second from July 1998 to June 1999. A total of 20 patients, 7 with Grade IV, 5 with Grade V, and 8 with CPAOA were included in the first period; and a total of 36 patients, 6 with Grade IV, 21 with Grade V, and 9 with CPAOA, in the second period. The major recent changes in the treatment protocol were 1) deep sedation, intensive control of blood pressure, and endotracheal intubation in the emergency room in the resuscitative phase; 2) immediate cerebral angiography under general anesthesia after diagnosis of SAH; 3) aneurysm obliteration by Guglielmi detachable coil (GDC) as an option; and 4) early enteric feeding and tracheostomy for patients in a prolonged comatose state. Therapeutic mild brain hypothermia was conducted in 3 Grade V patients in the second-period study. Aneurysm was obliterated by clipping in 7 and 18 patients in each period and by GDC in 4 patients in the second period. The median time from onset to admission, to angiography, and to surgery was 29, 440, and 797.5 minutes, respectively, in the first period, and 32, 99, and 210 minutes, respectively, in the second period. Overall outcome assessed at 3 months by the Glasgow Outcome Scale was; GR: 2 (10%), MD: 0 (0%), SD: 1 (5%), VS: 2 (10%), D: 15 (75%) for the first period and GR: 5 (13.9%), MD: 3 (8.3%), SD: 7 (19.4%), VS: 1 (2.8%), D: 20 (55.6%) for the second period. A favorable outcome (GR+MD) increased from 10% to 22.2%, and deaths were reduced from 75% to 55.6% (P=0.02, chi-square test). Angiography and surgical intervention immediately after resuscitation produce a more favorable outcome for severe SAH patients without increasing the risk of rerupture.

Mild hypothermia improves recovery of cortical extracellular potassium ion activity and excitability after middle cerebral artery occlusion in the rat.

Mild brain hypothermia significantly alleviates damage after focal ischemia, although the mechanism of this protection remains poorly defined. In the present study, we tested the hypothesis that mild hypothermia would protect cortex from early deterioration of ion homeostasis and loss of excitability associated with reperfusion after focal ischemia. Cortical extracellular potassium ion activity ([K+]o) and the response of [K+]o to direct cortical stimulation was measured both in the ischemic core and in the ischemic penumbra of normothermic and mildly hypothermic (31.5 degrees C to 32 degrees C) rats after distal middle cerebral artery occlusion (MCAO) and reperfusion. The response of [K+]o during MCAO was similar in normothermic and hypothermic animals. However, within 1 hour of reperfusion, [K+]o in the ischemic core region of normothermic animals showed incomplete recovery and was refractory to direct cortical stimulation. [K+]o in hypothermic animals returned to preischemic levels on reperfusion and continued to respond to direct cortical stimulation. Mild hypothermia prevented extensive infarction 24 hours after transient MCAO. The data suggest that transient focal ischemia is accompanied by early disturbances of potassium ion homeostasis during reperfusion, which are accompanied by loss of excitability and which may contribute ultimately to cortical infarction.

Mild brain hypothermia: potential for neuronal protection and resuscitation against ischemic damage

Although hypothermia as a means of neuronal protection and resuscitation after ischemic damage has a history of approximately four decades, extensive studies on the mechanisms, effects and methods of mild hypothermia at no less than 32°C have been started only in the last decade, both in basic and clinical fields. In experiments on rodents, postischemically introduced hypothermia, even as late as several hours after reperfusion, which was maintained for one day followed by a slow rewarming, definitely rescued hippocampal neurons against damage. Hypothermia appears to have a much greater potential for cerebral resuscitation than any chemical proposed so far for this purpose. The mode of action of hypothermia is apparently nonspecific and multifocal in widely progressing cascade reactions in ischemic cells, including (i) suppressing glutamate surge followed by (ii) intraneuronal calcium mobilization, (iii) postischemic sustained activation of glutamate receptors, (iv) dysfunction of blood-brain barrier, (v) proliferation of microglial cells, and (vi) production of superoxide unions and nitric oxide in microglial cells, and of activator protein-1 in ischemically vulnerable regions like hippocampal CA1. Recent clinical trials of mild hypothermia have revealed significantly beneficial outcomes along with an accumulation of knowhows on various techniques and treatments. Large scale randomized studies involving multiple institutions as well as exchanging ideas are needed for further development of hypothermia treatment. Biomedical Reviews 1997; 8: 23-36.

Intraischemic hypothermia during pretreatment with sublethal ischemia reduces the induction of ischemic tolerance in the gerbil hippocampus.

We examined whether mild brain hypothermia during pretreatment with sublethal 2-min ischemia affected the tolerance to subsequent lethal 5-min ischemia. The neuronal densities in the hippocampal CA1 sector of gerbils preconditioned at mild brain hypothermia (32% of normal) were significantly lower than those in gerbils preconditioned at brain normothermia (70% of normal). 72-kDa heat-shock protein immunoreactivity in the CA1 sector preconditioned at mild hypothermia was reduced. These results suggest that mild brain hypothermia during pretreatment with sublethal ischemia reduces the tolerance to subsequent lethal ischemia.

Intraischemic hypothermia during pretreatment with sublethal ischemia reduces the induction of ischemic tolerance in the gerbil hippocampus

We examined whether mild brain hypothermia during pretreatment with sublethal 2-min ischemia affected the tolerance to subsequent lethal 5-min ischemia. The neuronal densities in the hippocampal CA1 sector of gerbils preconditioned at mild brain hypothermia (32% of normal) were significantly lower than those in gerbils preconditioned at brain normothermia (70% of normal). 72-kDa heat-shock protein immunoreactivity in the CA1 sector preconditioned at mild hypothermia was reduced. These results suggest that mild brain hypothermia during pretreatment with sublethal ischemia reduces the tolerance to subsequent lethal ischemia.