Combination Of Hypothermia Research Articles

The safety and efficacy of hypothermia combining mechanical thrombectomy or thrombolysis in the treatment of ischemic stroke: A systematic meta-analysis

BackgroundStroke is a major global public health problem, affecting 13.7 million people worldwide. Previous studies have found a neuroprotective effect of hypothermia therapy and the efficacy and safety of combined hypothermia and mechanical thrombectomy or thrombolysis in the treatment of ischemic stroke have also attracted attention. ObjectiveIn the present research, the authors conducted a meta-analysis to comprehensively assess the safety and efficacy of hypothermia combining mechanical thrombectomy or thrombolysis in the treatment of ischemic stroke. MethodsArticles published from January 2001 to May 2022 were searched from Google Scholar, Baidu Scholar and PubMed to evaluate the clinical significance of hypothermia treatment in ischemic stroke. Complications, short-term mortality, and the modified Rankin Scale (mRS) in the full text was extracted. Results89 publications were selected and 9 among them were included in this study with sample size of 643. All selected studies are in accordance with the inclusion criteria. Forest plot of clinical characteristics was as follows: complications (RR = 1.132, 95% CI 0.942‒1.361, p = 0.186, I2 = 37.2%), mortality within 3 months (RR = 1.076, 95% CI 0.694‒1.669, p = 0.744, I2 = 0.00%), mRS ≤ 1 at 3 months (RR = 1.138, 95% CI 0.829‒1.563, p = 0.423, I2 = 26.0%), mRS ≤ 2 at 3 months (RR = 1.672, 95% CI 1.236‒2.263, p = 0.001, I2=49.6%) and mRS ≤ 3 at 3 months (RR = 1.518, 95% CI 1.128‒2.043, p = 0.006, I2 = 0.00%). The funnel plot suggested that there was no significant publication bias in the meta-analysis on complications, mortality within 3 months, mRS ≤ 1 at 3 months and mRS ≤ 2 at 3 months. ConclusionIn summary, the results showed that hypothermia treatment was correlated with mRS ≤ 2 at 3 months, but not linked with complications and mortality within 3 months.

Is Selective Head Cooling Combined with Whole-Body Cooling the Most Effective Hypothermia Method for Neonatal Hypoxic-Ischemic Encephalopathy?

This study aimed to compare combined hypothermia (CH) to the 2 classical therapeutic hypothermia (TH) methods selective head cooling (SHC) and whole-body cooling (WBC). This retrospective cohort study included neonates who underwent CH, SHC, and WBC between 2012 and 2020. Mean rectal temperature was maintained at 33.5 ± 0.5°C by cooling the head and the body in the CH group, at 34.5 ± 0.5°C by cooling the head in the SHC group, and at 33.5 ± 0.5°C by cooling the body in the WBC group. The groups were compared in terms of side effects, magnetic resonance imaging (MRI) scores, and status at discharge. The study included 60 neonates in the CH group, 112 in the WBC group, and 27 in the SHC group. There was no significant difference in side effects between the groups (p > 0.05). There was no significant difference in brain MRI scores between the groups (p > 0.05); however, gray matter, white matter, and total MRI scores in the CH group were lower than in the WBC group. Duration of hospitalization was shorter in the CH group than in the other two groups (p = 0.022). CH was not associated with more side effects than the two classical TH methods. In addition, some of these findings suggest that CH might result in better clinical outcome than the two classical TH methods.

Accidental Hypothermia in a Swiss Alpine Trauma Centre-Not an Alpine Problem.

Background: Research in accidental hypothermia focuses on trauma patients, patients exposed to cold environments or patients after drowning but rarely on hypothermia in combination with intoxications or on medical or neurological issues. The aim of this retrospective single-centre cohort study was to define the aetiologies, severity and relative incidences of accidental hypothermia, methods of measuring temperature and in-hospital mortality. Methods: The study included patients ≥18 years with a documented body temperature ≤35 °C who were admitted to the emergency department (ED) of the University Hospital in Bern between 2000 and 2019. Results: 439 cases were included, corresponding to 0.32 per 1000 ED visits. Median age was 55 years (IQR 39–70). A total of 167 patients (38.0%) were female. Furthermore, 63.3% of the patients suffered from mild, 24.8% from moderate and 11.9% from severe hypothermia. Exposure as a single cause for accidental hypothermia accounted for 12 cases. The majority were combinations of hypothermia with trauma (32.6%), medical conditions (34.2%), neurological conditions (5.2%), intoxications (20.3%) or drowning (12.0%). Overall mortality was 22.3% and depended on the underlying causes, severity of hypothermia, age and sex.

Magnesium Sulfate as an Adjunct to Therapeutic Hypothermia in the Management of Term Infants with Hypoxic-Ischemic Encephalopathy: A Randomized, Parallel-Group, Controlled Trial.

To evaluate whether magnesium sulfate and therapeutic hypothermia in combination decreases mortality and/or major neurodevelopmental disability at 1 y of age among term neonates with hypoxic-ischemic encephalopathy. A total of 134 term neonates were randomized to receive intravenous magnesium sulfate at a dose of 250mg/kg (at 8mg/kg/min) once daily for 3 d starting within 6h after birth along with therapeutic hypothermia in the intervention group and therapeutic hypothermia alone in the comparator group. The primary outcome was the composite outcome of mortality and/or major neurodevelopmental disability (Developmental Assessment Scale for Indian Infants score < 70) at 1 y of age. A total of 115 infants were included in the primary analysis. The composite primary outcome occurred in 14 (24%) infants in the intervention group and 19 (33%) infants in the comparator group, and the difference was not statistically significant (p = 0.30; relative risk 0.72; 95% confidence interval 0.40-1.30). The secondary outcomes including neonatal mortality, major neurodevelopmental disability at 1 y of age, neurological status at discharge, level of oxidative stress markers, and adverse effects including hypotension and respiratory depression requiring support were also comparable between the groups. The combination of magnesium sulfate and therapeutic hypothermia did not improve the composite outcome of neonatal mortality and/or major neurodevelopmental disability at 1 y of age. Clinical Trials Registry of India (CTRI/2018/06/014594), prospectively registered.

Outcome Prediction in Neonatal Hypoxic-Ischaemic Encephalopathy Using Neurophysiology and Neuroimaging

Objective: The aim of the study was to determine the predictive power of the combined use of neurophysiological (amplitude-integrated electroencephalography [aEEG], near-infrared spectroscopy [NIRS]) methods and neuroimaging (magnetic resonance imaging [MRI]) for long-term outcome prediction in neonates with hypoxic-ischaemic encephalopathy (HIE). Study Design: Prospective cohort study of 56 patients with moderate to severe HIE and hypothermia treatment at the Medical University of Vienna between 2008 and 2020. aEEG and NIRS were recorded continuously over a period of >4 days (102 h) starting at the initiation of hypothermia treatment, MRI was performed at a median age of 8 days. Receiver operating characteristic curves and area under the curve were calculated to evaluate the prognostic ability of aEEG, NIRS, and MRI parameters for outcome assessed via Bayley Scales of Infant Development 3rd edition at 2 years of age. Results: Combined aEEG and MRI parameters showed highest predictive power regarding long-term outcome. The highest area under the curve values (0.96–0.99) were obtained for aEEG (combination of background pattern and sleep-wake cycling) between 66 and 102 h after initiation of hypothermia in combination with MRI findings. NIRS parameters did not differ significantly between infants with favourable and adverse outcome. Conclusions: Combined aEEG and MRI parameter scores were more predictive than single parameter scores. No further improvement was observed when combining aEEG/MRI with NIRS data.

Hypoxic Ischemic Encephalopathy (HIE) in Term and Preterm Infants.

Hypoxic-ischemic syndrome (HIS) and Hypoxic-ischemic encephalopathy (HIE) are conditions that affect term and premature babies, with different pathophysiology and different brain disorders. HIE appears in 1-6 / 1000 live births and 26/1000 live births in developing countries. 15-20% die in the early neonatal period, while surviving babies have severe neurological impairment, including cerebral palsy, epilepsy, visual and hearing impairment, cognitive impairment, intellectual, behavioural, and social disorders. The hypoxic-ischemic event occurs before, during or after birth. The reasons may be related to the mother, the way of birth, the placenta, and the newborn. The criteria for diagnosis of HIE include a combination of perinatal factors, the need for resuscitation, standard neurological examinations, neurophysiological monitoring, neuroimaging methods and biochemical markers. The most effective treatment for HIE is hypothermia in combination with pharmacological therapy. HIE and HIS are problem that still persist in developing countries due to inadequate obstetric care, neonatal resuscitation, and hypothermia. Current and emerging research for HIE examines new markers for early recognition, treatment, and appropriate neuroprotection of high-risk term and premature infants.

Значение волны Осборна в выборе своевременной тактики лечения пациентов с гипотермией на примере клинического случая

Гипотермия ассоциируется с рядом электрокардиографических изменений, которые варьируют в зависимости от степени гипотермии. В данной статье мы рассматриваем факторы риска развития гипотермии, клиническое значение волны Осборна, механизмы ее возникновения, критерии выявления волны Осборна на электрокардиограмме, а также представляем клинический случай, когда даже незначительная гипотермия в сочетании с неврологической патологией индуцирует появление волны Осборна. Также рассматривается прогностическое значение волны Осборна в возникновении желудочковых аритмий.

Passive antipyretic therapy is not as effective as invasive hypothermia for maintaining normothermia after cardiac arrest.

Targeted temperature management is a class I indication in comatose patients after a cardiac arrest. While the literature has primarily focused on innovative methods to achieve target temperatures, pharmacologic therapy has received little attention. We sought to examine whether pharmacologic therapy using antipyretics is effective in maintaining normothermia in post cardiac arrest patients. Patients ≥18 years who were resuscitated after an in-hospital or out-of-hospital cardiac arrest and admitted at our institution from January 2012 to September 2015 were retrospectively included. Patients were divided into groups based on the method of temperature control that was utilized. The primary outcome was temperature control <38 °C during the first 48 h after the cardiac arrest. 671 patients were identified in Group 1 (no hypothermia), 647 in Group 2 (antipyretics), 44 in Group 3 (invasive hypothermia), and 51 in Group 4 (invasive hypothermia and antipyretics). Mean patient age was 59 (SD ±15.7) years with 40.6% being female. Using Group 1 as the control arm, 57.7% of patients maintained target temperature with antipyretics alone (p < 0.001), compared to 69.3% in the control group and 82.1% in the combined hypothermia groups 3&4 (p = 0.01). Patients receiving both invasive hypothermia and antipyretics (Group 4), had the greatest mean temperature decrease of 5.2 °C. Among patients undergoing targeted temperature management, relying solely on as needed use of antipyretics is not sufficient to maintain temperatures <38 °C. However, antipyretics could be used as an initial strategy if given regularly and/or in conjunction with more aggressive cooling techniques.

Combined hypothermia and mesenchymal stem cells in animal models of neonatal hypoxic-ischaemic encephalopathy: a systematic review.

The objective of this study was to systematically review the literature to determine the effect of combined hypothermia (HTH) and mesenchymal stem cell (MSC) therapy (administered during or immediately before or after HTH) compared with HTH alone on brain injury and neurobehavioural outcomes in animal models of neonatal hypoxic-ischaemic encephalopathy. Primary outcomes assessed were neuropathological measures and neurobehavioural measures of brain outcome. Secondary outcomes were brain protein proinflammatory cytokine status. Risk of bias (ROB) was assessed with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) ROB assessment tool. Of 393 studies identified, 3 studies in postnatal day 7 (P7) male Sprague-Dawley rats met the inclusion criteria. Meta-analyses were undertaken for neuropathological measures (apoptotic cells, astrocytes, microglia), neurobehavioral measures (rotarod test and negative geotaxis), and proinflammatory cytokine levels. Two of the three studies scored low or unclear ROB across all measures. Treatment with HTH-MSCs together significantly improved astrocyte optical density by standardised mean difference (SMD) of 0.71 [95% confidence interval (CI) -1.14, -0.28]. No other measures showed significant differences. There is insufficient preclinical data to confirm the efficacy of combined HTH-MSC therapy over HTH alone. Future studies should utilise a reporting checklist such as in SYRCLE or Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines to improve reporting standards. Very few articles investigating the use of MSCs for the treatment of hypoxic-ischaemic encephalopathy are clinically relevant. Continuing to publish studies in models of hypoxic-ischaemic encephalopathy without the inclusion of HTH therapy does not progress the field towards improved clinical outcomes. This study shows that HTH and MSC therapy improves measures of astrogliosis. More studies are required to establish the efficacy of HTH and MSCs on measures of neuropathology and neurobehavior. The reporting of preclinical data in this space could be improved by using reporting checklists such as the SYRCLE or ARRIVE tools.

Melatonin for neuroprotection in neonatal encephalopathy: A systematic review & meta-analysis of clinical trials.

Melatonin has shown neuroprotective properties in pre-clinical studies of perinatal asphyxia through antioxidant, anti-apoptotic and anti-inflammatory actions. Studies have also demonstrated its safety and efficacy in neonatal encephalopathy (NE). However, its role in the current era of therapeutic hypothermia (HT) is unclear. The review aims to describe the currently available clinical evidence for Melatonin as a potential therapy for NE. Data Sources: We searched Medline, EMBASE, CINAHL, LILACS, and Cochrane central databases, published journals, and conference proceedings from inception to May 31, 2020. Randomized controlled trials (RCTs) of Melatonin for NE in term or late preterm infants reporting neurodevelopmental outcomes, death, or both. The evidence quality was evaluated using the GRADE system, while the recommendations were taken according to the quality. We included five RCTs involving 215 neonates. Long-term development outcome data is lacking in all except in one small study, reporting significantly higher composite cognition scores at 18 months. One study reported intermediate 6-month favorable development on follow-up. Meta-analysis of mortality in combined HT+Melatonin group vs HT alone (Studies=2, participants=54) demonstrated no significant reduction with relative risk (RR) 0.42; 95%CI, 0.99-1.12). The overall GRADE evidence quality was very low for a very small sample size. We did not meta-analyze the data for Melatonin alone therapy without HT, as the included studies were of very low quality. Despite strong experimental data supporting the role of Melatonin as a neuroprotective agent in NE (both alone and as an adjunct with therapeutic hypothermia), the clinical data supporting the neuroprotective effects in neonates is limited. Larger well designed, adequately powered multicentre clinical trials are urgently needed to define the neuroprotective role of Melatonin in optimizing outcomes of NE.

Bilateral antegrade cerebral perfusion may be the winner as an adjunct for brain protection.

Brain protection during open distal aortic arch replacement surgery is of utmost importance. Hypothermia in combination with cerebral perfusion offers optimal results by maintaining the brain's metabolic supply. Both retrograde cerebral perfusion and antegrade cerebral perfusion, used in combination with hypothermia, produce comparable results when the hypothermic circulatory arrest times are short; in contrast, for longer perfusion times, most aortic surgery centers are trending toward the use of antegrade rather than retrograde cerebral perfusion. Our own preference has been to use a bilateral mode of delivering antegrade cerebral perfusion instead of a unilateral approach, as bilateral perfusion appears to be more protective. We maintain that there is no harm in perfusing both brain hemispheres, so long as an appropriate balloon-tipped catheter is used carefully and manipulation of the head vessels is avoided.

Whole body hypothermia extends tissue plasminogen activator treatment window in the rat model of embolic stroke

Late treatment with tissue plasminogen activator (tPA) leads to reperfusion injury and poor outcome in ischemic stroke. We have recently shown the beneficial effects of local brain hypothermia after late thrombolysis. Herein, we investigated whether transient whole-body hypothermia was neuroprotective and could prevent the side effects of late tPA therapy at 5.5 h after embolic stroke. After induction of stroke, male rats were randomly assigned into four groups: Control, Hypothermia, tPA and Hypothermia+tPA. Hypothermia started at 5 h after embolic stroke and continued for 1 h. Thirty min after hypothermia, tPA was administrated. Infarct volume, brain edema, blood-brain barrier (BBB) and matrix metalloproteinase-9 (MMP-9) were assessed 48 h and neurological functions were assessed 24 and 48 hour post-stroke. Compared with the control or tPA groups, whole-body hypothermia decreased infarct volume (P < 0.01), BBB disruption (P < 0.05) and MMP-9 level (P < 0.05). However, compared with hypothermia alone a combination of hypothermia and tPA was more effective in reducing infarct volume. While hypothermia alone did not show any effect, its combination with tPA reduced brain edema (P < 0.05). Hypothermia alone or when combined with tPA decreased MMP-9 compared with control or tPA groups (P < 0.01). Although delayed tPA therapy exacerbated BBB integrity, general cooling hampered its leakage after late thrombolysis (P < 0.05). Moreover, only combination therapy significantly improved sensorimotor function as well as forelimb muscle strength at 24 or 48 h after stroke (P < 0.01). Transient whole-body hypothermia in combination with delayed thrombolysis therapy shows more neuroprotection and extends therapeutic time window of tPA up to 5.5 h.

Perfusion process combining low temperature and valeric acid for enhanced recombinant factor VIII production.

Perfusion operation mode remains the preferred platform for production of labile biopharmaceuticals (e.g., blood factors) and is also being increasingly adopted for production of stable products (e.g., monoclonal antibodies). Regardless of the product, process development typically aims at maximizing production capacity. In this work, we investigated the impact of perfusion cultivation conditions on process productivity for production of human factor VIII (FVIII). Recombinant CHO cells were cultivated in bioreactors coupled to inclined settlers and the effects of reducing the temperature to 31°C with or without valeric acid (VA) supplementation were evaluated. Increases in cell specific productivity (qp ) up to 2.4-fold (FVIII concentration) and up to 3.0-fold (FVIII biological activity) were obtained at 31°C with VA compared to the control at 37°C. Biological activity is the most important quality attribute for FVIII and was positively affected by mild hypothermia in combination with the chemical inducer. The low temperature conditions resulted in enhanced product transcript levels, suggesting that the higher qp is related to the increased mRNA levels. Furthermore, a high-producer subclone was evaluated under the perfusion conditions optimized for the parental clone (31°C with VA), yielding increases in qp of 6-fold and 15-fold compared to the parental clone cultivated under the same condition and at 37°C, respectively. The proposed perfusion strategy enables increased product formation without increasing production costs, being potentially applicable to perfusion production of other CHO-derived biopharmaceuticals. To the best of our knowledge, this is the first report showing the benefits of perfusion combining mild hypothermia with VA supplementation.

The cause of chronic prostatitis and prostate enlargement is a change in the vascular level and requires similar treatment: innovative Thermobalancing therapy

INTRODUCTION: The outcomes of clinical studies show Thermobalancing therapy (TT) with Dr Allen’s Therapeutic Device (DATD) successfully helps men treat chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS) and lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH). The purpose of this study is to compare the ratio of the causes of these diseases with their treatment.&#x0D; METHODS: Two clinical trials observed dynamics of urinary symptoms, pain score and prostate volume in men with BPH and CP/CPPS after using the device for six months. There were 124 men with BPH and 45 men with chronic prostatitis investigated in the treatment groups and the same number of men were in the control groups.&#x0D; RESULTS: These studies have shown that TT with DATD reduced prostate volume from 45 mL to 31 mL (P&lt;0.001) and, consequently, urinary symptoms from 14.2 to 4.9 (P&lt;0.001) in the treatment group of 124 patients with BPH. Pain score was reduced from 10.3 to 3.5 (P&lt;0.001) and prostate volume decreased from 31 mL to 27 mL (P&lt;0.001) in the treatment group of 45 men with CP/CPPS. In the control groups of 124 men with BPH and 45 men with CP/CPPS no difference in the symptoms and parameters was observed.&#x0D; CONCLUSION: The clinical studies indicated that the cause of these chronic diseases lies at the vascular level, namely the pathological activity of capillaries. The focus of hypothermia in combination with the spontaneous expansion of capillaries creates pressure in the tissue of the prostate gland, causing inflammation in it as well as symptoms in men with CP/CPPS and prostate growth in men with BPH. TT with DATD proved to be effective in treating LUTS related to BPH and CP/CPPS. Therefore, the same therapy can be used for the treatment of both chronic prostatic diseases: BPH and CP/CPPS.

Role of scalp hypothermia in patients undergoing minimally invasive evacuation of hypertensive cerebral hemorrhage.

Objective:Hypertensive intracerebral hemorrhage (HICH) is one of the common multiple diseases in neurology. Patients with severe HICH have high risk of disability and poor prognosis.Methods:In order to explore the clinical effect of mild hypothermia combined with micro-traumatic evacuation of cerebral hemorrhage in the treatment of severe HICH, 136 patients with severe HICH were selected and divided into control group and study group using random number table method, 68 each group. The control group was treated with micro-traumatic evacuation of cerebral hemorrhage on the basis of conventional symptomatic treatment, while the study group was treated with mild hypothermia combined with micro-traumatic evacuation of cerebral hemorrhage on the basis of conventional symptomatic treatment. After treatment, the two groups were followed up for eight weeks.Results:The overall effective rate, residual hematoma volume, rebleeding rate, National Institute of Health stroke scale (NIHSS) score, Barthel index score and incidence of adverse reactions after treatment were observed and compared. The overall effective rate of the study group was 89.7%, which was significantly higher than that of the control group (67.6%). The mortality rate of the study group was 3.0%, which was significantly lower than that of the control group (14.7%, P<0.05). The residual hematoma volume and rebleeding rate of the study group were significantly lower than those of the control group (P<0.05). Before treatment, the NIHSS score and Barthel index score of the two groups had no significant differences (P>0.05). After treatment, they were improved, and the improvement of the study group was more significant (P<0.05). The incidence of adverse reactions in the study group was 10.0%, which was significantly lower than that in the control group (36.0%, P<0.05).Conclusion:Mild hypothermia in combination with micro-traumatic evacuation of cerebral hemorrhage has significant clinical effect in the treatment of severe HICH. It can significantly improve neurological function and quality of life, causing few adverse reactions. Its clinical application value is high.

ГИПОКСИЧЕСКИ-ИШЕМИЧЕСКАЯ ЭНЦЕФАЛОПАТИЯ У НОВОРОЖДЁННЫХ, РОЖДЁННЫХ В ТЯЖЁЛОЙ АСФИКСИИ

This article provides a literature review on the topic of hypoxic-ischemic encephalopathy (HIE). Hypoxic-ischemic brain damage of newborn belongs to one of the most important problems of anesthesiology and resuscitation of newborn babies. Despite progress, perinatal hypoxic-ischemic encephalopathy remains an important cause of child mortality and damage to the central nervous system resulting in a disability of children. HIE clinical signs are nonspecific, so the diagnosis is based on the combination of medical history, physical and neurological examination, laboratory data and neuroimaging techniques. Pathological stage runs when after undergoing asphyxia is the main purpose neuroprotective therapy. The first 6 hours of life of the child, born in asphyxia, is a therapeutic window for the stabilization of the vital functions of the body, during which therapeutic measures are most effective in reducing apoptosis of brain cells. The only method, relatively widely used and effective in infants with severe birth asphyxia, is controlled hypothermia. Published clinical studies show a statistically significant reduction in mortality and severe neuropsychiatric disability at 18 months of life in infants treated with hypothermia. The use of stem cells, the use of hypothermia in combination with xenon or erythropoietin improves neurological outcome: fewer deaths and serious damage to the nervous system. However, these techniques to date are in the experimental stage. Currently, the main task of neonatologists, anesthesiologists and intensive care specialists is not only saving newborn lives, but also creating conditions for proper growth and development of the child.

Protective roles of intra-arterial mild hypothermia and arterial thrombolysis in acute cerebral infarction.

Objective Herein, we evaluated the efficacy and safety of intra-arterial mild hypothermia in combination with arterial thrombolysis to treat acute cerebral infarction due to middle cerebral artery occlusion.MethodsA total of 26 patients with acute middle cerebral artery occlusion were divided into a normothermia group (n = 15) and a mild hypothermia group (n = 11). The infarct volumes at 24 h and 7 days after the operation were compared between the normothermia group and the mild hypothermia group. Additionally, we compared neurological deficit scores between the two groups at 24 h, 7 days, and 1 mo after the operation.ResultsThe infarct volumes and neurological deficit scores of the mild hypothermia group were significantly reduced compared to those in the normothermia group (p < 0.05). Furthermore, no adverse reactions or complications occurred in the mild hypothermia group.ConclusionIntra-arterial mild hypothermia reduced infarct volume after ischemia–reperfusion injury in the arterial thrombolysis of an acute cerebral infarction. Additionally, it improved the prognosis of patients with an acute middle cerebral artery occlusion, suggesting that this procedure is safe and effective for treating acute cerebral infarction.

Combining Normobaric Oxygen with Ethanol or Hypothermia Prevents Brain Damage from Thromboembolic Stroke via PKC-Akt-NOX Modulation.

In a thromboembolic stroke model after reperfusion by recombinant tissue plasminogen activator (rt-PA), we aimed to determine whether therapeutic hypothermia (TH) and ethanol (EtOH) in combination with low concentration (60%) of normobaric oxygen (NBO) enhanced neuroprotection, as compared to using each of these agents alone. We further aimed to elucidate a potential role of the NADPH oxidase (NOX), phosphorylated protein kinase B (Akt), and protein kinase C-δ (PKC-δ) pathway in oxidative stress and neuroprotection. In Sprague-Dawley rats, a focal middle cerebral artery (MCA) occlusion was induced by an autologous embolus in the following experimental groups: rt-PA treatment alone, rt-PA + NBO treatment, rt-PA + TH at 33°C, rt-PA + EtOH, rt-PA + NBO + EtOH, rt-PA + NBO + TH, rt-PA + NOX inhibitor, rt-PA + EtOH + NOX inhibitor, or rt-PA + EtOH + Akt inhibitor. Control groups included sham-operated without stroke or stroke without treatment. Infarct volume and neurological deficit were assessed at 24h after rt-PA-induced reperfusion with or without treatments. ROS levels, NOX activity, and the protein expression of NOX subunits p22phox, p47phox, p67phox, gp91phox, as well as PKC-δ and phosphorylated Akt were measured at 3 and 24h after rt-PA-induced reperfusion. Following rt-PA in thromboembolic stroke rats, NBO combined with TH or EtOH more effectively decreased infarct volume and neurological deficit, as well as reactive oxygen species (ROS) production than with any of the used monotherapies. NOX activity and subunit expressions were downregulated and temporally associated with reduced PKC-δ and increased p-Akt expression. The present study demonstrated that combining NBO with either TH or EtOH conferred similar neuroprotection via modulation of NOX activation. The results suggest a role of Akt in NOX activation and implicate an upstream PKC-δ pathway in the Akt regulation of NOX. It is possible to substitute EtOH for TH, thus circumventing the difficulties in clinical application of TH through the comparatively easier usage of EtOH as a potential stroke management.

Therapeutic effect of tPA in ischemic stroke is enhanced by its combination with normobaric oxygen and hypothermia or ethanol

Background and Purpose: Our lab has previously elucidated the neuroprotective effects of normobaric oxygen (NBO) and ethanol (EtOH) in ischemic stroke. The present study further evaluated the effect of EtOH or hypothermia (Hypo) in the presence of low concentration of NBO and determined whether EtOH can substitute hypothermia in a more clinically relevant autologous embolus rat stroke model in which reperfusion was established by tissue-type plasminogen activator (t-PA). Methods: At 1h of middle cerebral artery occlusion (MCAO) by an autologous embolus, rats received t-PA. In addition, at the same time, ischemic animals were treated with either EtOH (1.0g/kg) or hypothermia (33°C for 3h) in combination with NBO (60% for 3h). Extent of neuroprotection was assessed by apoptotic cell death measured by ELISA and Western immunoblotting analysis for pro- (AIF, activated Caspase-3, Bax) and anti-apoptotic (Bcl-2) protein expression at 3 and 24h of reperfusion induced by t-PA administration. Results: Compared to ischemic rats treated only with t-PA, animals with NBO, hypothermia or EtOH had significantly reduced apoptotic cell death by 32.5%, 43.1% and 36.0% respectively. Furthermore, combination therapy that included NBO+EtOH or NBO+Hypo with t-PA exhibited a much larger decline (p<0.01) in the cell death by 71.1% and 73.6%, respectively. Similarly, NBO+EtOH or NBO+Hypo treatment in addition to t-PA enhanced beneficial effects on both pro- and anti-apoptotic protein expressions as compared to other options. Conclusions: Neuroprotection after stroke can be enhanced by combination treatment with either EtOH or hypothermia in the presence of t-PA and 60% NBO. Because the effects produced by EtOH and hypothermia are comparable, their mechanism of action may be not only similar but also could be interchangeable in future clinical trials.

Non-additive effects of delayed connexin hemichannel blockade and hypothermia after cerebral ischemia in near-term fetal sheep.

Hypothermia is partially neuroprotective after neonatal hypoxic-ischemic encephalopathy. Blockade of connexin hemichannels can improve recovery of brain activity and cell survival after ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed hypothermia with connexin hemichannel blockade with intracerebroventricular infusion of a mimetic peptide can further improve outcomes after cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia (n=8), hypothermia for 3 days (n=8), connexin hemichannel blockade (50 μmol/L intracerebroventricular over 1 hour followed by 50 μmol/L over 24 hours, n=8) or hypothermia plus hemichannel blockade (n=7). After 7 days recovery, hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology (P<0.05). There was no further improvement in outcomes with combined hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined hypothermia and hemichannel blockade after cerebral ischemia in near-term fetal sheep.