Selective brain hypothermia-induced neuroprotection against focal cerebral ischemia/reperfusion injury is associated with Fis1 inhibition

Selective brain hypothermia is considered an effective treatment for neuronal injury after stroke,and avoids the complications of general hypothermia.However,the mechanisms by which selective brain hypothermia affects mitochondrial fission remain unknown.In this study,we investigated the effect of selective brain hypothermia on the expression of fission 1 (Fis1) protein,a key factor in the mitochondrial fission system,during focal cerebral ischemia/reperfusion injury.Sprague-Dawley rats were divided into four groups.In the sham group,the carotid arteries were exposed only.In the other three groups,middle cerebral artery occlusion was performed using the intraluminal filament technique.After 2 hours of occlusion,the filament was slowly removed to allow blood reperfusion in the ischemia/reperfusion group.Saline,at 4℃ and 37℃,were perfused through the carotid artery in the hypothermia and normothermia groups,respectively,followed by restoration of blood flow.Neurological function was assessed with the Zea Longa 5-point scoring method.Cerebral infarct volume was assessed by 2,3,5-triphenyltetrazolium chloride staining,and apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining.Fis1 and cytosolic cytochrome c levels were assessed by western blot assay.Fis1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction.Mitochondrial ultrastructure was evaluated by transmission electron microscopy.Compared with the sham group,apoptosis,Fis1 protein and mRNA expression and cytosolic cytochrome c levels in the cortical ischemic penumbra and cerebral infarct volume were increased after reperfusion in the other three groups.These changes caused by cerebral ischemia/reperfusion were inhibited in the hypothermia group compared with the normothermia group.These findings show that selective brain hypothermia inhibits Fis1 expression and reduces apoptosis,thereby ameliorating focal cerebral ischemia/reperfusion injury in rats.Experiments were authorized by the Ethics Committee of Qingdao Municipal Hospital of China (approval No.2019008).

A safety evaluation of profound hypothermia-induced suspended animation for delayed resuscitation at 90 or 120min

Background: The successful treatment of military combat casualties with penetrating injuries is significantly dependent on the time needed to get the patient to an adequate treatment facility. Profound hypothermia induced suspended animation for delayed resuscitation(SADR) is a novel approach for inducing cardiac arrest and buying additional time for such injuries. However, the time used to safely administer circulatory arrest(CA) is controversial. The goal of this study was to evaluate the safety of hypothermia-induced SADR over 90 and 120 min time intervals.Methods: Sixteen male BAMA minipigs were randomized into two groups: CA90 group(90 min, n =8) and CA120 group(120 min, n =8). Cannulation of the right common carotid arteries and internal jugular veins was performed to establish cardiopulmonary bypass for each animal. Through the perfusion of cold organ preservation solution(OPS), cardioplegia and profound hypothermia(15℃) were induced. After CA, cardiopumonary bypass(CPB) was restarted, and the animals were gradually re-warmed and resuscitated. The animals were assisted with ventilators until spontaneous breathing was achieved. The index of hemodynamic perioperative serum chemistry values [alanine transaminase(ALT), aspartate aminotransferase(AST), creatinine(CR), lactic dehydrogenase(LDH) and troponin T(TnT)] and survival were observed from pre-operation to 7 days post-operation.Results: Fifteen animals were enrolled in the experiment, while 1 animal in CA120 group died from surgical error. All 8 animals in CA90 group recovered, with only 1 animal displaying mild disability. However, in CA120 group, only 2 animals survived with severe disability, and the other 5 animals died after 2 days post-operation. In CA90 group, the perioperative serum chemistry values increased at 1 day post-operation(ALT 84.43±18.65 U/L; AST 88.99±23.19 U/L; Cr 87.90±24.49μmol/L; LDH 1894.13±322.26 U/L; TnT 0.849±0.135 ng/ml) but decreased to normal or almost normal levels at 7 days post-operation(ALT 52.48±9.04 U/L; AST 75.23±21.46 U/L; Cr 82.69±18.41μmol/L; LDH 944.67±834.32 U/L; TnT 0.336±0.076 ng/ml).Conclusion: Profound hypothermia-induced SADR is an effective method for inducing cardiac arrest. Our results indicate that inducing CA for 90 min(at 15℃) is safer than doing so for 120 min. Our results indicate that 120 min of CA at 15℃ is dangerous and can result in high mortality and severe neurological complications. Further experimentation is needed to determine whether 120 min of CA at temperatures lower than 15℃ can lead to safe recovery.

Electrocardiographic changes during induced therapeutic hypothermia in comatose survivors after cardiac arrest

AIM: To assess the safety of therapeutic hypothermia(TH) concerning arrhythmias we analyzed serial electrocardiograms(ECG) during TH.METHODS: All patients recovered from a cardiac arrest with Glasgow < 9 at admission were treated with induced mild TH to 32-34℃. TH was obtained with cool fluid infusion or a specific intravascular device. Twelvelead ECG before,during,and after TH,as well as ECG telemetry data was recorded in all patients. From a total of 54 patients admitted with cardiac arrest during the study period,47 patients had the 3 ECG and telemetry data available. ECG analysis was blinded and performed with manual caliper by two independent cardiologists from blinded copies of original ECG,recorded at 25 mm/s and 10 mm/m V. Coronary care unit staff analyzed ECG telemetry for rhythm disturbances. Variables measured in ECG were rhythm,RR,PR,QT and corrected QT(QTc by Bazett formula,measured in lead v2) intervals,QRS duration,presence of Osborn's J wave and U wave,as well as ST segment displacement and T wave amplitude in leads Ⅱ,v2 and v5.RESULTS: Heart rate went down an average of 19 bpm during hypothermia and increased again 16 bpm with rewarming(P < 0.0005,both). There was a nonsignificant prolongation of the PR interval during TH and a significant decrease with rewarming(P = 0.041). QRS duration significantly prolonged(P = 0.041) with TH and shortened back(P < 0.005) with rewarming. QTc interval presented a mean prolongation of 58 ms(P < 0.005) during TH and a significant shortening with rewarming of 22.2 ms(P = 0.017). Osborn or J wave was found in 21.3% of the patients. New arrhythmias occurred in 38.3% of the patients. Most frequent arrhythmia was non-sustained ventricular tachycardia(19.1%),followed by severe bradycardia or paced rhythm(10.6%),accelerated nodal rhythm(8.5%) and atrial fibrillation(6.4%). No life threatening arrhythmias(sustained ventricular tachycardia,polymorphic ventricular tachycardia or ventricular fibrillation) occurred during TH. CONCLUSION: A 38.3% of patients had cardiac arrhythmias during TH but without life-threatening arrhythmias. A concern may rise when inducing TH to patients with long QT syndrome.

Ondansetron and Hypothermia Induced Cardiac Arrest in a 97-Year-Old Woman: A Case Report

Background:Ondansetron and hypothermia are both known to induce bradycardia or QT interval prolongation,thus placing affected patients at risk of cardiac arrest.Case Report:Herein,we report the case of a 97-year-old woman who initially presented with confusion and hypothermia,and experienced severe bradycardia and asystolic cardiac arrest after a 4 mg intravenous ondansetron bolus injection.Conclusion:Ondansetron is associated with bradycardia and QTc prolongation,both of which might be further exacerbated by hypothermia.Clinicians should be aware that administering ondansetron in patients with hypothermia might further increase the risk of adverse cardiac events and eventual cardiac arrest.

Duration of Hypothermia is Associated with Postoperative Complications in Patients Undergoing Gynecological Surgery:A Prospective Cohort Study

Objective To investigate the relationship between hypothermia duration and postoperative complications in patients undergoing gynecological surgery.Methods Patients who underwent elective gynecological surgery at our hospital were consecutively enrolled between October 2020 and January 2022.Core temperature was continuously monitored intraoperatively,and early postoperative complications were collected.By adjusting the logistic regression model for potential confounding factors,the association of postoperative complications with the duration of hypothermia,the lowest body temperature below 36°C,and the hypothermia upon admission to postanesthesia care unit(PACU)or intensive care unit(ICU)were analyzed.Additionally,the potential inflection point in the relationship between the duration of hypothermia and the risk of postoperative complications was explored by using cumulative probability scatter plots and moving average sequences.Results The study included 370 patients,with 193(52.2%)experiencing hypothermia and 177(47.8%)not.Among them,92(24.9%)developed complications.The duration of hypothermia(adjusted odds ratio[OR]for each one-minute increase:1.003;95%confidence interval[CI]:1.000-1.006,P=0.047)and hypothermia upon admission to PACU or ICU(adjusted OR:1.980;95%CI:1.135-3.454,P=0.016)were associated with early postoperative complications.Notably,the cumulative incidence of postoperative complications tended to rise as the duration of hypothermia increased,with a potential inflection point observed at 120 minutes.Conclusions In gynecological surgery,the duration of hypothermia as well as hypothermia upon admission to PACU or ICU are associated with postoperative complications.Minimizing the duration of hypothermia may be clinically beneficial.

Inadvertent perioperative hypothermia and surgical site infections after liver resection

Background:In the overall surgical population,inadvertent perioperative hypothermia has been associated with an increased incidence of surgical site infection(SSI).However,recent clinical trials did not validate this notion.This study aimed to investigate the potential correlation between inadvertent perioperative hypothermia and SSIs following liver resection.Methods:This retrospective cohort study included all consecutive patients who underwent liver resection between January 2019 and December 2021 at the First Affiliated Hospital,Zhejiang University School of Medicine.Perioperative temperature managements were implemented for all patients included in the analysis.Estimated propensity score matching(PSM)was performed to reduce the baseline imbalances between the normothermia and hypothermia groups.Before and after PSM,univariate analyses were performed to evaluate the correlation between hypothermia and SSI.Multivariate regression analysis was performed to determine whether hypothermia was an independent risk factor for postoperative transfusion and major complications.Subgroup analyses were performed for diabetes mellitus,age>65 years,and major liver resection.Results:Among 4000 patients,2206 had hypothermia(55.2%),of which 150 developed SSI(6.8%).PSM yielded 1434 individuals in each group.After PSM,the hypothermia and normothermia groups demonstrated similar incidence rates of SSI(7.0%vs.6.3%,P=0.453),postoperative transfusion(13.7%vs.13.3%,P=0.743),and major complications(10.1%vs.9.0%,P=0.309).Univariate regression analysis revealed no significant effects of hypothermia on the incidence of SSI in the group with the highest hypothermia exposure[odds ratio(OR)=1.25,95%confidence interval(CI):0.84-1.87,P=0.266],the group with moderate exposure(OR=1.00,95%CI:0.65-1.53,P=0.999),or the group with the lowest exposure(OR=1.11,95%CI:0.73-1.65,P=0.628).The subgroup analysis revealed similar results.Regarding liver function,patients in the hypothermia group demonstrated lowerγ-glutamyl transpeptidase(37 vs.43 U/L,P<0.001)and alkaline phosphatase(69 vs.72 U/L,P=0.016).However,patients in the hypothermia group exhibited prolonged activated partial thromboplastin time(29.2 vs.28.6 s,P<0.001).Conclusions:In our study of patients undergoing liver resection,we found no significant association between mild perioperative hypothermia and SSI.It might be due to the perioperative temperature managements,especially active warming measures,which limited the impact of perioperative hypothermia on the occurrence of SSI.

Application value of machine learning models in predicting intraoperative hypothermia in laparoscopic surgery for polytrauma patients

BACKGROUND Hypothermia during laparoscopic surgery in patients with multiple trauma is a significant concern owing to its potential complications.Machine learning models offer a promising approach to predict the occurrence of intraoperative hypothermia.AIM To investigate the value of machine learning model to predict hypothermia during laparoscopic surgery in patients with multiple trauma.METHODS This retrospective study enrolled 220 patients who were admitted with multiple injuries between June 2018 and December 2023.Of these,154 patients were allocated to a training set and the remaining 66 were allocated to a validation set in a 7:3 ratio.In the training set,53 cases experienced intraoperative hypothermia and 101 did not.Logistic regression analysis was used to construct a predictive model of intraoperative hypothermia in patients with polytrauma undergoing laparoscopic surgery.The area under the curve(AUC),sensitivity,and specificity were calculated.RESULTS Comparison of the hypothermia and non-hypothermia groups found significant differences in sex,age,baseline temperature,intraoperative temperature,duration of anesthesia,duration of surgery,intraoperative fluid infusion,crystalloid infusion,colloid infusion,and pneumoperitoneum volume(P<0.05).Differences between other characteristics were not significant(P>0.05).The results of the logistic regression analysis showed that age,baseline temperature,intraoperative temperature,duration of anesthesia,and duration of surgery were independent influencing factors for intraoperative hypothermia during laparoscopic surgery(P<0.05).Calibration curve analysis showed good consistency between the predicted occurrence of intraoperative hypothermia and the actual occurrence(P>0.05).The predictive model had AUCs of 0.850 and 0.829 for the training and validation sets,respectively.CONCLUSION Machine learning effectively predicted intraoperative hypothermia in polytrauma patients undergoing laparoscopic surgery,which improved surgical safety and patient recovery.

Moderate hypothermia attenuates lung in flammation inlipopolysaccharide- induced acute lung injury in rats

Objective To investigate the role of moderate h.vpothennia in the lung inflammation of rat acute lung injury induced by lipopolysaccharide(LPS). Methods A rat model of acute lung injury (ALl) was established by in-tin-tracheal instillation of lipopolysaccharide ( 1.5 mg/kg, 0.5 ml) at 16 h after LPS ( 1.0 mg/kg) intraperitoneal adrninis-tmtion. Thirty-four male Sprague Dawley rats were randomly divided into four groups: control group, receiving saline only;LPS group, receiving LPS; hypothennia group, treated with hypothennia without LPS; LPS + hypothennia group, treated with LPS and cooled to 32.5℃-33.0℃ as PaO2/FiO2. was below 300 mmHg. Hemodynamics and blood gases were record-ed every hour throughout the study. Rats were killed 4 h after ALl, and lung lavage was performed to measure the tumor ne-crosis factor α(TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) concentrations in bronchoalveolar lavage fluid (BALF) by using enzyme-linked immunosorbent assay (ELISA). Results PaO2/FiO2 was significantly decreased and PaCO2 was increased in the LPS group as compared to their baseline values( P＜0.01). Treatment with hypothermia inhib-ited the increase in PaCO2( P＜0.05) but had no effect on PaO2/FiO2 in the presence of LPS. The administration of LPS significantly increased the concentrations of TNF-α, IL-6 and IL-10 in BALF as compared to the control experiment( P＜0.05, P＜0.01 ). Moderate hypothermia reduced the expressions of TNF-α and IL-6 ( P＜0.01 ) but had no effect on the production of IL-10 ( P＞0.05). Conclusion Moderate hypothermia significantly inhibits proinflammatory cytokine ex-pressions in lipopolysaccharide-induced acute lung injury.

Neuroprotective mechanisms and translational potential of therapeutic hypothermia in the treatment of ischemic stroke

Stroke is a leading cause of disability and death,yet effective treatments for acute stroke has been very limited.Thus far,tissue plasminogen activator has been the only FDA-approved drug for thrombolytic treatment of ischemic stroke patients,yet its application is only applicable to less than 4–5% of stroke patients due to the narrow therapeutic window（〈 4.5 hours after the onset of stroke） and the high risk of hemorrhagic transformation.Emerging evidence from basic and clinical studies has shown that therapeutic hypothermia,also known as targeted temperature management,can be a promising therapy for patients with different types of stroke.Moreover,the success in animal models using pharmacologically induced hypothermia（PIH） has gained increasing momentum for clinical translation of hypothermic therapy.This review provides an updated overview of the mechanisms and protective effects of therapeutic hypothermia,as well as the recent development and findings behind PIH treatment.It is expected that a safe and effective hypothermic therapy has a high translational potential for clinical treatment of patients with stroke and other CNS injuries.

Mild hypothermia as a treatment for central nervous system injuries Positive or negative effects?

Besides local neuronal damage caused by the primary insult, central nervous system injuries may secondarily cause a progressive cascade of related events including brain edema, ischemia, oxida- tive stress, excitotoxicity, and dysregulation of calcium homeostasis. Hypothermia is a beneficial strategy in a variety of acute central nervous system injuries. Mild hypothermia can treat high in- tracranial pressure following traumatic brain injuries in adults. It is a new treatment that increases survival and quality of life for patients suffering from ischemic insults such as cardiac arrest, stroke, and neurogenic fever following brain trauma. Therapeutic hypothermia decreases free radical pro- duction, inflammation, excitotoxicity and intracranial pressure, and improves cerebral metabolism after traumatic brain injury and cerebral ischemia, thus protecting against central nervous system damage. Although a series of pathological and physiological changes as well as potential side ef- fects are observed during hypothermia treatment, it remains a potential therapeutic strategy for central nervous system injuries and deserves further study.

Can we further optimize therapeutic hypothermia for hypoxic-ischemic encephalopathy?

Perinatal hypoxic-ischemic encephalopathy is a leading cause of neonatal death and disability.Therapeutic hypothermia significantly reduces death and major disability associated with hypoxic-ischemic encephalopathy;however,many infants still experience lifelong disabilities to movement,sensation and cognition.Clinical guidelines,based on strong clinical and preclinical evidence,recommend therapeutic hypothermia should be started within 6 hours of birth and continued for a period of 72 hours,with a target brain temperature of 33.5 ±0.5℃ for infants with moderate to severe hypoxic-ischemic encephalopathy.The clinical guidelines also recommend that infants be re warmed at a rate of 0.5℃ per hour,but this is not based on strong evidence.There are no randomized controlled trials investigating the optimal rate of rewarming after therapeutic hypothermia for infants with hypoxic-ischemic encephalopathy.Preclinical studies of rewarming are conflicting and results were confounded by treatment with sub-optimal durations of hypothermia.In this review,we evaluate the evidence for the optimal start time,duration and depth of hypothermia,and whether the rate of rewarming after treatment affects brain injury and neurological outcomes.

Neuroprotective effects of cold-inducible RNA-binding protein during mild hypothermia on traumatic brain injury

Cold-inducible RNA-binding protein（CIRP）, a key regulatory protein, could be facilitated by mild hypothermia in the brain, heart and liver. This study observed the effects of mild hypothermia at 31 ± 0.5℃ on traumatic brain injury in rats. Results demonstrated that mild hypothermia suppressed apoptosis in the cortex, hippocampus and hypothalamus, facilitated CIRP m RNA and protein expression in these regions, especially in the hypothalamus. The anti-apoptotic effect of mild hypothermia disappeared after CIRP silencing. There was no correlation between mitogen-activated extracellular signal-regulated kinase activation and CIRP silencing. CIRP silencing inhibited extracellular signal-regulated kinase-1/2 activation. These indicate that CIRP inhibits apoptosis by affecting extracellular signal-regulated kinase-1/2 activation, and exerts a neuroprotective effect during mild hypothermia for traumatic brain injury.

Electrophysiological functional recovery in a rat model of spinal cord hemisection injury following bone marrow-derived mesenchymal stem cell transplantation under hypothermia

Following successful establishment of a rat model of spinal cord hemisection injury by resecting right spinal cord tissues, bone marrow stem cells were transplanted into the spinal cord lesions via the caudal vein while maintaining rectal temperature at 34 ± 0.5°C for 6 hours （mild hypothermia）. Hematoxylin-eosin staining showed that astrocytes gathered around the injury site and formed scars at 4 weeks post-transplantation. Compared with rats transplanted with bone marrow stem cells under normal temperature, rats transplanted with bone marrow stem cells under hypothermia showed increased numbers of proliferating cells （bromodeoxyuridine-positive cells）, better recovery of somatosensory-evoked and motor-evoked potentials, greater Basso, Beattie, and Bresnahan locomotor rating scores, and an increased degree of angle in the incline plate test. These findings suggested that hypothermia combined with bone marrow mesenchymal stem cells transplantation effectively promoted electrical conduction and nerve functional repair in a rat model of spinal cord hemisection injury.

Moderate hypothermia prevents neural cell apoptosis following spinal cord ischemia in rabbits

Paraplegia is a disastrous complication after operations of descending and thoracoabdominal aortic aneurysm. Re- gional hypothermia protects against spinal cord ischemia although the protective mechanism is not well know. The objective of this study is to examine whether hypothermia protects the spinal cord by preventing apoptosis of nerve cell and also investigate a possible mechanism involved in hypothermia neuroprotection. Cell apoptosis with necrosis was evident in the spinal cord 24 h after 30 min of ischemia. Moderate hypothermia decreased the incidence of apoptotic nerve cells. Both cell apoptosis and necrosis were attenuated by hypothermia. p53 expression increased and bcl-2 expression declined after ischemia, while hypothermia mitigated these changes. This study suggests that apoptosis contributes to cell death after spinal cord ischemia, and that moderate hypothermia can prevent nerve cell apoptosis by a mechanism associated with bcl-2 and p53 genes.

Mild hypothermia combined with neural stem cell transplantation for hypoxic-ischemic encephalopathy: neuroprotective effects of combined therapy

Neural stem cell transplantation is a useful treatment for ischemic stroke, but apoptosis often occurs in the hypoxic-ischemic environment of the brain after cell transplantation. In this study, we determined if mild hypothermia （27-28~C） can increase the survival rate of neural stem cells （1.0 x 105/~tL） transplanted into neonatal mice with hypoxic-ischemic encephalopathy. Long-term effects on neurological functioning of the mice were also examined. After mild hy- pothermia combined with neural stem cell transplantation, we observed decreased expression levels of inflammatory factor nuclear factor-kappa B and apoptotic factor caspase-3, reduced cerebral infarct volumes, increased survival rate of transplanted cells, and marked improvements in neurological function. Thus, the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation are superior to those of monotherapy. Moreover, our findings suggest that the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation on hypoxic-ischemic encephalopathy are achieved by anti-inflammatory and an- ti-apoptotic mechanisms.

Mild hypothermia combined with a scaffold of Ng Rsilenced neural stem cells/Schwann cells to treat spinal cord injury

Because the inhibition of Nogo proteins can promote neurite growth and nerve cell differentiation, a cell-scaffold complex seeded with Nogo receptor （NgR）-silenced neural stem cells and Schwann cells may be able to improve the microenvironment for spinal cord injury repair. Previous studies have found that mild hypothermia helps to attenuate secondary damage in the spinal cord and exerts a neuroprotective effect. Here, we constructed a cell-scaffold complex consisting of a poly（D,L-lactide-co-glycolic acid） （PLGA） scaffold seeded with NgR-silenced neural stem cells and Schwann cells, and determined the effects of mild hypothermia combined with the cell-scaffold complexes on the spinal cord hemi-transection injury in the T9 segment in rats. Compared with the PLGA group and the NgR-silencing cells ＋ PLGA group, hindlimb motor function and nerve electrophysiological function were dearly improved, pathological changes in the injured spinal cord were attenuated, and the number of surviving cells and nerve fibers were increased in the group treated with the NgR-silenced cell scaffold ＋ mild hypothermia at 34℃ for 6 hours. Furthermore, fewer pathological changes to the injured spinal cord and more surviving cells and nerve fibers were found after mild hypothermia therapy than in injuries not treated with mild hypothermia. These experimental results indicate that mild hypothermia combined with NgR gene-silenced cells in a PLGA scaffold may be an effective therapy for treating spinal cord injury.

Mild hypothermia effects on matrix metalloproteinase-9 expression in the perihematomal region of rats following experimental intracerebral hemorrhage

BACKGROUND： Matrix metalloproteinase-9 （MMP-9） expression increases with intracerebral hemorrhage, and participates in the pathophysiological processes of secondary brain injury after intracerebral hemorrhage. OBJECTIVE： To investigate the effects of mild hypothermia on MMP-9 expression and brain edema in the perihematomal region of experimental intracerebral hemorrhage rats. DESIGN, TIME AND SETTING： The randomized, controlled experiment was performed at the Central Laboratory of Shandong Provincial Hospital between May and September 2007. MATERIALS： Seventy-two, Wistar, male rats, 12-weeks old, were used for this study. Rabbit anti-MMP-9 primary antibody was purchased from Boster, China. METHODS： Wistar rats were equally and randomly divided into normothermia and mild hypothermia groups. The two groups each comprised control, 6-hour intracerebral hemorrhage, 24-hour intracerebral hemorrhage, 48-hour intracerebral hemorrhage, 72-hour intracerebral hemorrhage, and l-week intracerebral hemorrhage subgroups, with six rats in each subgroup. Rat models of intracerebral hemorrhage were established by injecting 100 μL of autologous blood into the rat caudate nucleus. Rats in the mild hypothermia group received four hours of local mild hypothermia immediately following the injection. lntracerebral temperature was maintained at （33 ± 0.5） ℃. Subsequently, intracerebral temperature was spontaneously recovered at 25 ℃. Rats in the control subgroup were not injected with autologous blood and received only with intracerebral hemorrhage. MAIN OUTCOME MEASURES： Brain water content and MMP-9 expression surrounding the hematoma region. RESULTS： MMP-9 expression increased at 6 hours, and brain edema reached a peak at 48 hours after intracerebral hemorrhage. MMP-9 expression was significantly decreased in the mild hypothermia group compared with the normothermia group at each time point （P 〈 0.05）. CONCLUSION： Mild hypothermia can significantly inhibit MMP-9 overexpression and relieve brain edema following intracerebral hemorrhage.

The pathways by which mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury

Several studies have demonstrated that mild hypothermia exhibits a neuroprotective role and it can inhibit endothelial cell apoptosis following ischemia/reperfusion injury by decreasing casp- ase-3 expression, It is hypothesized that mild hypothermia exhibits neuroprotective effects on neurons exposed to ischemia/reperfusion condition produced by oxygen-glucose deprivation. Mild hypothermia significantly reduced the number of apoptotic neurons, decreased the expres- sion of pro-apoptotic protein Bax and increased mitochondrial membrane potential, with the peak of anti-apoptotic effect appearing between 6 and 12 hours after the injury. These findings indicate that mild hypothermia inhibits neuronal apoptosis following ischemia/reperfusion injury by protecting the mitochondria and that the effective time window is 6-12 hours after ischemia/reperfusion injury.

Effects of environmental hypothermia on hemodynamics and oxygen dynamics in a conscious swine model of hemorrhagic shock

BACKGROUND:Hypothermia is associated with poor outcome in trauma patients;however,hemorrhagic shock(HS)model with anesthetized swine was different from that of clinical reality.To identify the effects of environmental hypothermia on HS,we investigated hemodynamics and oxygen dynamics in an unanesthetized swine model of HS under simulating hypothermia environment.METHODS:Totally 16 Bama pigs were randomly divided into ambient temperature group(group A)and low temperature group(group B),8 pigs in each group.Venous blood(30 mL/kg)was continuously withdrawn for more than 15 minutes in conscious swine to establish a hemorrhagic shock model.Pulmonary arterial temperature(Tp),heart rate(HR),mean arterial pressure(MAP),pulmonary arterial pressure(PAP),pulmonary arterial wedge pressure(PAWP),central venous pressure(CVP),cardiac output(CO),hemoglobin(Hb),saturation of mixed venous blood(SvO_2)and blood gas analysis were recorded at the baseline and different hemorrhagic shock time(HST).The whole body oxygen delivery indices,DO_2l and VO_2l,and the O_2 extraction ratio(O_2ER)were calculated.RESULTS:Core body temperature in group A decreased slightly after the hemorrhagic shock model was established,and environmental hypothermia decreased in core body temperature.The mortality rate was significantly higher in group B(50%)than in group A(0%).DO_2l and VO_2l decreased significantly after hemorrhage.No difference was found in hemodynamics,DO_2l and VO_2l between group A and group B,but the difference in pH,lactic acid and O_2ER was significant between the two groups.CONCLUSION:Environmental hypothermia aggravated the disorder of oxygen metabolism after hemorrhagic shock,which was associated with poor prognosis.

Induction of therapeutic hypothermia via the esophagus:a proof of concept study

BACKGROUND:Induction of hypothermia(a 4℃decrease from baseline)improves outcomes in adult cardiac arrest and neonatal hypoxic ischemic encephalopathy,and may benefit other conditions as well.Methods used to implement or prevent hypothermia typically require skin contact with blankets or pads or intravascular access with catheter devices.The study was to evaluate the potential to induce mild therapeutic hypothermia via an esophageal route in a porcine model.METHODS:Single-animal proof-of-concept study of a prototype esophageal device in a 70 kg Yorkshire swine.We measured the rate of temperature change after placement of a prototype device to induce hypothermia via the esophagus,and compared this rate to known temperature changes that occur under similar laboratory conditions without a hypothermic device.RESULTS:Swine temperature decreased from a starting temperature of 37.8℃to 33.8℃(achieving the goal of a 4℃decrease)in 175 minutes,resulting in a cooling rate of 1.37℃/h.Histopathology of the esophagus showed normal tissue without evidence of injury.CONCLUSION:A prototype of an esophageal cooling device induced hypothermia effectively in a large single-swine model.