Temperature management in stroke - an unsolved, but important topic

Clinical data clearly show that elevated body temperature contributes to an unfavorable outcome after ischemic and hemorrhagic stroke. Two promising therapeutic strategies arise from this observation: (1) treatment of fever aiming to sustain normothermia and (2) induced hypothermia, targeting core body temperatures below 36.5°C. A limited number of studies investigated antipyretic strategies after acute stroke and their results were rather disappointing in terms of clinical efficacy. For that reason, it remains unproven, whether sufficient fever treatment improves functional outcome. On the other hand, strong experimental evidence supports neuroprotective effects of induced hypothermia after stroke. Yet, clinical data on this topic remain preliminary and rely on a limited number of patients, mostly enrolled in nonrandomized trials. Therefore, induced hypothermia may be considered safe and feasible after ischemic stroke, but little can be said regarding efficacy. This review summarizes the data, both on fever treatment and induced hypothermia following stroke, starting with a synopsis of the most important experimental investigations, leading to the latest clinical trials. Given the promising data and the lack of successful acute neuroprotective therapies available thus far, suggestions are given for future investigation on both topics.     

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.     

Increased neuronal injury in transgenic mice with neuronal overexpression of human cyclooxygenase-2 is reversed by hypothermia and rofecoxib treatment

Cyclooxygenase-2 (COX-2) is up-regulated during ischemia. However, the role of COX-2 in neuronal injury is still unclear. In this study we tested whether neuronal overexpression of human COX-2 in a transgenic mouse model potentiates neuronal injury after global ischemic insult. Further, we tested whether the neuronal injury could be ameliorated by intra-ischemic mild hypothermia (33-34 degrees C) alone or in combination with diet treatment of rofecoxib, a COX-2 specific inhibitor. Global ischemia with intra-ischemic normothermia (36-37 degrees C) resulted in significantly higher neuronal damage in the CA1 region of hippocampus of transgenic mice than in wild type controls, confirming a deleterious role of COX-2 in ischemic neuronal damage. Hypothermia significantly reduced neuronal damage in both transgenic mice and wild type controls to the same extent, suggesting that the aggravating effect of COX-2 could be largely eliminated by hypothermia. When hypothermia was combined with rofecoxib treatment, neuronal damage was further reduced in response to global ischemia. The results suggest that COX-2 inhibition by prophylactic treatment with rofecoxib coupled with hypothermia at the time of acute stroke insult could be an effective therapeutic approach in early stages of stroke treatment in high risk patients.     

Delayed hypothermia in malignant ischaemic stroke

Moderate hypothermia may reduce mortality in malignant brain infarction. However, due to the extremely limited number of patients treated, it is still unknown whether it may be beneficial if undertaken several days after acute stroke, when the probability of a malignant oedema is higher. We report on a patient with malignant brain oedema after middle cerebral artery infarction, who was treated with moderate hypothermia on the third day after stroke when he became comatose. Hypothermia was induced at a rate of 1.25°C/h by an intravascular cooling catheter. The target temperature of 32°C was reached in about 6 h. After 36 h of hypothermia, the patient was actively re-warmed at a rate of 0.2°C/h. The patient survived and showed a progressive reduction of mass effect on CT scan. This single case study suggests a beneficial effect of hypothermia in the treatment of severe space-occupying ischemic infarction even on the third day after stroke onset.     

Therapeutic hypothermia for acute stroke

Experimental evidence and clinical experience show that hypothermia protects the brain from damage during ischaemia. There is a growing hope that the prevention of fever in stroke will improve outcome and that hypothermia may be a therapeutic option for the treatment of stroke. Body temperature is directly related to stroke severity and outcome, and fever after stroke is associated with substantial increases in morbidity and mortality. Normalisation of temperature in acute stroke by antipyretics is generally recommended, although there is no direct evidence to support this treatment. Despite its obvious therapeutic potential, hypothermia as a form of neuroprotection for stroke has been investigated in only a few very small studies. Therapeutic hypothermia is feasible in acute stroke but owing to serious side-effects--such as hypotension, cardiac arrhythmia, and pneumonia--it is still thought of as experimental, and evidence of efficacy from clinical trials is needed.     

RETRACTED: Feasibility and safety of moderate hypothermia after acute ischemic stroke

BACKGROUND AND PURPOSE: Moderate hypothermia decreases ischemic damage in experimental stroke models. This multicenter study was performed to evaluate (1) the safety and feasibility of moderate hypothermia and (2) its potential to reduce intracranial hypertension in acute stroke patients. METHODS: Fifty prospective patients with cerebral infarction involving at least the complete middle cerebral artery (MCA) territory treated with moderate hypothermia were evaluated. Hypothermia was induced with the use of cooling blankets as well as alcohol and ice bags within 22+/-9h after stroke onset and maintained for 24-72 h; subsequently, patients passively rewarmed over a mean duration of 17 h. Outcome was assessed at 4 weeks and at 3 months. RESULTS: Time required for cooling to <33 degrees C varied from 3.5 to 11h. The most frequent complications of hypothermic therapy were thrombocytopenia (70%), bradycardia (62%), and pneumonia (48%). Four patients (8%) died during hypothermia as a result of severe coagulopathy, cardiac failure, or uncontrollable intracranial hypertension. An additional 15 patients (30%) died during or after rewarming because of rebound increase in intracranial pressure (ICP) and fatal herniation. A shorter (<16 h) rewarming period was associated with a more pronounced rise of ICP. Elevated ICP values were significantly reduced under hypothermia. CONCLUSIONS: Moderate hypothermia is feasible in patients with acute stroke, although it is associated with several side effects. Most deaths occur during rewarming as a result of excessive ICP rise. Our preliminary observation that a longer duration of the rewarming period limits the ICP increase remains to be confirmed in future studies.     

Neuroprotection in acute ischemic stroke

Neuroprotection of patients with acute ischemic stroke should start at the scene and continue in the ambulance with the assessment and treatment of the airway, breathing, circulation, body temperature, and blood glucose. The key goal in eligible patients should be fast vessel recanalization with intravenous recombinant tissue-type plasminogen activator Results from a meta-analysis suggest that systemic thrombolysis is effective when given within 4.5 hours after stroke onset. The time window extends to 6 hours for patients undergoing intravascular thrombolysis. Acute stroke patients should be admitted to stroke care units. A crucial component of neuroprotection is the prevention of secondary brain damage, which can be caused by hypoxemia, hypotension, hyperthermia and hyperglycemia. This can be achieved by avoiding complications, e.g. aspiration, and intensive control of oxygenation, hydration and blood pressure, body temperature, blood glucose, and cardiac monitoring. Neuroprotective agents are designed to try to salvage brain tissue within the penumbra. Thus far, despite promising preclinical studies, clinical trials with neuroprotective drugs in acute ischemic stroke have been disappointing. However, we have been able to identify many of the factors that were responsible for these failures, and better-designed clinical trials with neuroprotective drugs should look more promising. Mild induced hypothermia is another form of neuroprotective treatment that is currently being investigated in acute stroke.     

Thermoregulatory vasococonstriction and shivering impede therapeutic hypothermia in acute ischemic stroke patients.

Objectives. We tested the hypothesis that vasoconstriction and shivering thresholds are sufficiently reduced by acute stroke to permit induction of therapeutic hypothermia without additional pharmacological inhibition of thermoregulatory control. Methods. We studied eight patients 2 +/- 1 days after ischemic stroke. Forced-air cutaneous cooling was administered until the patients shivered continuously or reached a tympanic membrane (ie, core) temperature of 34 degrees C. The tympanic membrane temperatures triggering vasoconstriction and shivering identified the thresholds for each response. Results. Patients had a mean age of 68 +/- 8 years and a mean National Institutes of Health Stroke Scale (NIHSS) score of 5. No patient reached the target core temperature of 34 degrees C. Vasoconstriction and shivering thresholds were 37.1 +/- 0.4 degrees C and 36.6 +/- 0.4 degrees C, respectively. Conclusions. Vasoconstriction and shivering were initiated at roughly normal temperatures in ischemic stroke patients, and these thermoregulatory responses prevented induction of therapeutic hypothermia. Pharmacological reduction of the vasoconstriction and shivering thresholds will be required if therapeutic hypothermia for stroke patients is to be induced easily by surface cooling.     

Temperature management in acute neurologic disorders

Temperature management in acute neurologic disorders has received considerable attention in the last 2 decades. Numerous trials of hypothermia have been performed in patients with head injury, stroke, and cardiac arrest. This article reviews the physiology of thermoregulation and mechanisms responsible for hyperpyrexia. Detrimental effects of fever and benefits of normalizing elevated temperature in experimental models are discussed. This article presents a detailed analysis of trials of induced hypothermia in patients with acute neurologic insults and describes methods of fever control.     

早期局部亚低温治疗急性脑血管病的临床研究

目的观察早期应用局部亚低温治疗急性脑血管病的临床疗效方法将90例急性脑血管病患者随机分为两组:治疗组46例在常规药物治疗的基础上早期加用局部亚低温治疗,对照组44例仅予常规药物治疗。在治疗前及治疗后不同时间点对两组进行NIH神经功能评分和Barthel指数评分对比。结果治疗组第2、4、8周NIHSS评分较对照组降低(P<0.05),第4、8、12周Barthel指数评分较对照组提高(P<0.05)。结论早期局部亚低温治疗可促进急性脑血管病患者神经功能的恢复,明显改善预后。     

急性脑梗死局部亚低温治疗的时间窗研究

目的 探讨局部亚低温治疗急性脑梗死的疗效和最佳治疗时间窗. 方法 将114例急性脑梗死患者按开始接受亚低温治疗时间的不同分为3组,即A组(≤6 h)、B组(6～24 h)和C组(≥24 h),每组再按随机数字表法分为治疗组(A1组、B1组、C1组)和对照组(A2组、B2组、C2组).对照组给予常规抗血小板等治疗,治疗组在常规治疗基础上给予病灶侧局部亚低温治疗48 h.各组患者均在人院时、治疗第7天、治疗第14天、治疗第30天进行美国国立卫生研究院卒中量表(NIHSS)评分,并在入院时及治疗第7天、治疗第14天动态监测血清中一氧化氮(NO)含量、超氧化物歧化酶(SOD)活力. 结果 与A2组、B2组相比,A1组、B1组治疗第7天、治疗第14天、治疗第30天NIHSS评分明显降低,治疗第7天、治疗第14天血清中NO含量明显降低,SOD活力明显升高,差异均有统计学意义(P＜0.05);而C1组在各时间点的NIHSS评分、NO含量、SOD活力与C2组比较差异均无统计学意义(P＞0.05).A1组、B1组在治疗第7天、治疗第14天、治疗第30天NIHSS评分较C1组明显下降,在治疗第7天、治疗第14天NO含量较C1组明显下降,SOD活力较C1组明显提高,差异均有统计学意义(P＜0.05),尤以A1组突出. 结论 早期局部亚低温治疗急性脑梗死临床有效,理想的治疗时间窗为6 h,6～24 h开始亚低温治疗仍有效,但24 h后开始亚低温治疗则无效.

Abstract：

Objective To determine the effect of local mild hypothermia on patients with acute cerebral infarction and ascertain its optimal therapeutic window. Methods According to the time receiving treatment, 114 patients with acute cerebral infarction were divided into group A (≤6 h), group B (6-24 h) and group C (≥ 24 h). Then, each group was subdivided into 2 groups at random: treatment group (A1, B1, C1) and control group (A2, B2, C2). Patients in the control group were subjected to such conventional therapy as anti-platelet aggregation. Patients in the treatment group were treated with local mild hypothermia (33-35 ℃ body-core temperature) for 48 h besides conventional therapy. Clinical outcomes were assessed by the National institutes of health stroke scale (NIHSS) on admission and 7, 14,30 d after treatment. Furthermore, we detected the serum level of nitrogen monoxidum (NO) and superoxide dismutasc (SOD) on admission, and 7 and 14 d after treatment. Results Compared with the control group, treatment group enjoyed significantly decreased scores of NIHSS 7, 14 and 30 d after treatment and significantly decreased level of NO 7 and 14 d after treatment (P＜0.05), but obviously increased SOD vitality 7 and 14 d after treatment (P＜0.05). No significant differences in terms of NIHSS scores, level of NO and SOD vitality were noted between group C1 and group C2 at each time point (P＞0.05). Group Al and group B1 had obviously lower scores of NIHSS than group C1 on the 7th, 14th and 30th d of treatment, and had significantly lower level of NO and obviously increased SOD vitality as compared with group C1 on the 7th and 14th d of treatment (P＜ 0.05), and group A1 enjoyed its advantage.Conclusion Early local mild hypothermia therapy can improve neurological function in patients with acute cerebral infarction. The mild hypothermia induced within 6 h may be optimal therapeutic window;mild hypothermia induced at 6-24 h is less effective and that above 24 h is non-effective.     

Therapy of severe ischemic stroke: breaking the conventional thinking

Large hemispheric infarcts must be recognized in the emergency department as a life-threatening condition that requires prompt and massive intervention. After stabilization of the airway, breathing, and circulation, the initial diagnostic work-up and transfer to a neurointensive care unit should not be delayed. Today several new therapeutic options can be offered. Surgical decompression seems to be effective in lowering increased intracranial pressure, preventing transtentorial herniation and reducing mortality in patients with malignant middle cerebral artery infarction. Another option may be therapeutic hypothermia, which has been found to be neuroprotective in animal models, as well as in clinical studies after cardiac arrest. Experience in stroke patients suggest that hypothermia may offer a new approach for the treatment of acute cerebral ischemia.     

Neuroprotection for ischemic stroke using hypothermia

The development of animal models of acute stroke has allowed the evaluation of mild and moderate hypothermia as a therapeutic modality in this clinical setting. Studies have demonstrated that animals subjected to hypothermia up to 3 hours after the primary central nervous system insult have reduced mortality and neuronal injury, and improved neurological outcome. These results warranted the evaluation of hypothermia in clinical trials. Even though hypothermia has potent neuroprotective effects in animal models of ischemic stroke, there are only a few clinical studies of therapeutic hypothermia in humans. Because of the small number of patients in the studies and the absence of matched controls, clinical studies are considered pilot studies for feasibility and safety. Thus, therapeutic hypothermia for ischemic stroke remains a promising but fiercely debated therapeutic modality.     

Mild hypothermia protects against oxygen glucose deprivation (OGD)-induced cell death in brain slices from adult mice

Most of neuroprotective strategies in stroke have failed to move from bench to bedside. One explanation might be the use of excessive uniform and smooth experimental models. Therefore, we have employed a more stringent in vitro model based on cultured brain slices from adult mice submitted to OGD. Using this acute model, we have confirmed that mild hypothermia protects against OGD-induced cell death when cooling the tissue during and after OGD, but not when hypothermia is induced only during reoxygenation.     

脑微出血急性卒中患者溶栓治疗的研究进展

脑微出血患者发生急性卒中事件时,在时间窗内给予溶栓治疗是十分具有挑战的临床决 策。如果给予溶栓治疗,出血的风险较高;不给予溶栓治疗,可能使时间窗内的卒中患者错过最佳治 疗的时机。研究发现,并不是所有的脑微出血急性卒中患者在接受溶栓治疗后都会发生出血,如果 可以明确导致出血的危险因素,就能识别出适合溶栓的脑微出血患者,从而采取有针对性的治疗措 施使患者受益。     

Therapeutic hypothermia in acute ischemic stroke

Increased body temperatures are common in the acute phase of stroke. Experimental and clinical studies have suggested that increased body temperatures are related to poor outcome. In animal studies of focal cerebral ischemia, early hypothermia consistently reduced infarct volume. Based on these findings, several Phase II clinical trials have been performed to study physical methods to reduce body temperature in patients with acute stroke. The feasibility and safety of these methods have not yet been established with sufficient certainty. Pharmacological lowering of body temperature may be an attractive alternative approach. In guidelines for the treatment of acute stroke, antipyretics are generally recommended to reduce fever, although their effect on functional outcome is unknown. There is currently no evidence from randomized trials to support routine use of physical or pharmacological cooling in acute stroke. Large randomized clinical trials are needed to study the effect of both physical and medical cooling on functional outcome after stroke.     

脑预适应保护研究进展

卒中是第3位常见的致死原因,给社会和经济带来沉重的负担。针对卒中的治疗多集中在 急性期,而卒中恢复期的治疗尚无有效方法。有关药物治疗或无效或存在不良影响,相应的神经保 护和大脑修复仍然是主要的尚未实现的医疗需求。近年来,大脑保护自身免受伤害性刺激以及修复 内源性修复损伤越来越受关注。其中,对预适应的研究（也被称为诱导耐受性）已产生多种有希望治 疗急性颅脑损伤的方法。一方面,预适应可以识别那些被诱导出的内源性保护或再生机制;另一方面, 对于那些预期会发生缺血性事件的人群（如接受过脑部手术、短暂性脑缺血发作或蛛网膜下腔出血 的患者）,预适应可以作为一种治疗手段来诱导出耐受性。     

Therapeutic hypothermia in experimental models of focal and global cerebral ischemia and intracerebral hemorrhage

Experimental evidence shows that therapeutic hypothermia (TH) protects the brain from cerebral injury in multiple ways. In different models of focal and global cerebral ischemia, mild-to-moderate hypothermia reduces mortality and neuronal injury and improves neurological outcome. In models of experimental intracerebral hemorrhage (ICH), TH reduces edema formation but does not show consistent benefi cial effects on functional outcome parameters. However, the number of studies of hypothermia on ICH is still limited. TH is most effective when applied before or during the ischemic event, and its neuroprotective properties vary according to species, strains and the model of ischemia used. Intrinsic changes in body and brain temperature frequently occur in experimental models of focal and global cerebral ischemia, and may have infl uenced studies on other neuroprotectants. This might be one explanation for the failure of a large amount of translational clinical neuroprotective trials. Hypothermia is the only neuroprotective therapeutic agent for cerebral ischemia that has successfully managed the transfer from bench to bedside, and it is an approved therapy for patients after cardiac arrest and children with hypoxic-ischemic encephalopathy. However, the implementation of hypothermia in the treatment of stroke patients is still far from routine clinical practice. In this article, the authors describe the development of TH in different models of focal and global cerebral ischemia, point out why hypothermia is so efficient in experimental cerebral ischemia, explain why temperature regulation is essential for further neuroprotective studies and discuss why TH for acute ischemic stroke still remains a promising but controversial therapeutic option.     

The effects of selective brain hypothermia on intracerebral hemorrhage in rats

Prolonged hypothermia effectively treats global cerebral ischemic injury in animal models as well as in cardiac arrest victims. Furthermore, clinical trials, based upon encouraging animal findings, are underway to assess efficacy in ischemic stroke. Intracerebral hemorrhage (ICH) is a more devastating stroke, but one that shares mechanisms of injury with ischemia. Accordingly, ICH may be amenable to hypothermia treatment. In this study we tested whether selective brain hypothermia improves outcome after an ICH in rats created by infusing 100 microL of autologous whole blood into the striatum. Striatal hypothermia ( approximately 32 degrees C) was induced with a novel method (implanted cooling coil) that does not cause systemic cooling, thereby providing a safer and potentially more effective treatment for stroke than systemic hypothermia. Edema occurred for 4 days after ICH, but it peaked at 3 days ( approximately 5%). At this time it was significantly reduced (to approximately 2%) by cooling starting 1 h after ICH (3 day duration). Next, we determined whether 1 and 12 h delayed cooling treatments (4 day duration) would lessen functional impairment and lesion size. Untreated (normothermic) ICH resulted in significant forelimb use asymmetry, as well as deficits in walking and skilled reaching. These deficits were unaffected by hypothermia, as was the volume of tissue lost ( approximately 20 mm(3)) at 1 month. Thus, attenuated edema did not result in behavioral or histological benefit. In conclusion, while additional research with alternative cooling protocols and ICH models are required, these findings suggest that while hypothermia lessens edema, it will not be directly neuroprotective after ICH.     

Hypertension and experimental stroke therapies

Hypertension is an established target for long-term stroke prevention but procedures for management of hypertension in acute stroke are less certain. Here, we analyze basic science data to examine the impact of hypertension on candidate stroke therapies and of anti-hypertensive treatments on stroke outcome. Methods: Data were pooled from 3,288 acute ischemic stroke experiments (47,899 animals) testing the effect of therapies on infarct size (published 1978–2010). Data were combined using meta-analysis and meta-regression, partitioned on the basis of hypertension, stroke model, and therapy. Results: Hypertensive animals were used in 10% of experiments testing 502 therapies. Hypertension was associated with lower treatment efficacy, especially in larger infarcts. Overall, anti-hypertensives did not provide greater benefit than other drugs, although benefits were evident in hypertensive animals even when given after stroke onset. Fifty-eight therapies were tested in both normotensive and hypertensive animals: some demonstrated superior efficacy in hypertensive animals (hypothermia) while others worked better in normotensive animals (tissue plasminogen activator, anesthetic agents). Discussion: Hypertension has a significant effect on the efficacy of candidate stroke drugs: standard basic science testing may overestimate the efficacy which could be reasonably expected from certain therapies and for hypertensive patients with large or temporary occlusions.