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Targeted temperature management, or therapeutic hypothermia, is a potent neuroprotective approach after ischemic brain injury. Hypothermia should be induced as soon as possible after the onset of acute stroke to assure better outcomes. Accordingly, drugs with a fast-acting hypothermic effect sustainable through the period of emergency transportation to hospital would have clinical advantages. Activation of the transient receptor potential vanilloid-1 (TRPV1) can induce hypothermia. Our immunohistochemical investigations confirmed that TRPV1 was distributed to perivascular and periventricular regions of the rat brain, where TRPV1 can be easily detected by TRPV1 agonists. An endogenous TRPV1 selective agonist, N -oleoyldopamine (OLDA), and a synthetic antagonist, AMG 9810, were injected intraperitoneally into healthy adult male Wister rats, and brain and core temperatures and gross motor activities were monitored. Comparison with baseline temperatures showed that TRPV1 injection immediately induced mild hypothermia ( p  < 0.05 in brain and p  < 0.01 in body), and AMG 9810 induced immediate mild hyperthermia (not significant). However, the OLDA-induced hypothermia did not decrease lesion volume after middle carotid artery occlusion in rats. Relative to vehicle, OLDA yielded poorer outcomes and AMG 9810 yielded better outcomes in neurological scores and lesion size. Our study showed that, as an agonist of TRPV1, OLDA has suitable hypothermia-inducing properties, but did not decrease lesion volume. Therefore, the search for novel TRPV1 agonists and/or antagonists providing hypothermia and neuroprotection should continue. Further investigations should also target OLDA-induced transient hypothermia combined with long-term hypothermia maintenance with surface cooling, which mimics the anticipated clinical use of this class of drug.

Rationale: Cooling reduced infarct size and improved neurological outcomes in animal studies modeling ischemic stroke, and also improved outcome in randomized clinical trials in patients with hypoxic-ischemic brain injury after cardiac arrest. Cooling awake patients with ischemic stroke has been shown feasible in phase II clinical trials., Primary Aim: To determine whether systemic cooling to a target body temperature between 34·0 and 35·0°C, started within six-hours of symptom onset and maintained for 24 h, improves functional outcome at three-months in patients with acute ischemic stroke., Design: International, multicenter, phase III, randomized, open-label clinical trial with blinded outcome assessment in 1500 patients aged 18 years or older with acute ischemic stroke and a National Institutes of Health Stroke Scale score of 6 up to and including 18. In patients randomized to hypothermia, cooling to a target body temperature of 34-35°C will be started within six-hours after symptom onset with rapid intravenous infusion of refrigerated normal saline or a surface cooling technique and maintained for 24 h with a surface or endovascular technique. Patients randomized to hypothermia will receive pethidine and buspirone to prevent shivering and discomfort., Primary Outcome: Score on the modified Rankin Scale at 91 days, as analyzed with ordinal logistic regression and expressed as a common odds ratio., Discussion: With 750 patients per intervention group, this trial has 90% power to detect 7% absolute improvement at the 5% significance level. The full trial protocol is available at http://www.eurohyp1.eu. ClinicalTrials.gov Identifier: NCT01833312., (© 2014 World Stroke Organization.)

Background: Cerebral ischemia is associated with infectious complications due to immunosuppression and decreased T lymphocyte activity. G-CSF, which has neuroprotective properties, is known to modulate inflammatory processes after induced stroke. The aim of our study was to investigate the impact of G-CSF in experimental stroke and to compare two different modes of treatment, focusing on circulating T lymphocytes., Methods: Cerebral ischemia was induced in Wistar rats by occlusion of the middle cerebral artery, followed by reperfusion after 1h. G-CSF was applied either as a single dose 30 min after occlusion, or daily for seven days. Silver staining was used to determine infarct size. T lymphocytes in the peripheral blood were measured before and 7 days after induced cerebral ischemia by flow cytometry. In addition, migration of CD3-expressing T lymphocytes into the brain was investigated by immunohistochemistry., Results: Both single dose and daily treatment with G-CSF significantly reduced infarct size. A significant improvement of neurological outcome was only observed after single application of G-CSF. While a decrease in peripheral T lymphocytes was detected seven days after induced stroke, no reduction was observed in the G-CSF-treated groups. Apart from that, G-CSF significantly reduced the number of brain migrated T lymphocytes in both treatment settings as compared to vehicle., Conclusion: A single dose of G-CSF exerted neuroprotective effects in ischemic stroke, which were less pronounced after daily G-CSF application. Both treatment strategies inhibited stroke-induced reduction of T lymphocytes in peripheral blood, which may have contributed to the reduction of infarct size., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background and Purpose: Anticoagulation is a highly effective secondary prevention in patients with cardioembolic stroke and atrial fibrillation/flutter (AF). However, the condition remains underdiagnosed, because paroxysmal AF may be missed by diagnostic tests in the acute phase. In this study, the sensitivity of AF detection was assessed for serial electrocardiographic recordings and continuous stroke unit telemetric monitoring with or without a structured algorithm to analyze telemetric data (SEA-AF)., Methods: Three hundred forty-six consecutive patients with acute ischemic stroke were prospectively included and subjected to standard telemetric monitoring. In addition, telemetric data were separately analyzed following SEA-AF, consisting of a structured evaluation of episodes with high risk for AF and a chronological beat-to-beat screening of the full registration. Serial electrocardiograms were conducted in 24-hour intervals., Results: Median effective telemetry monitoring time was 75.5 hours (interquartile range 64-86 hours). Overall, AF was diagnosed in 119 of 346 patients (34.4%). The structured reading algorithm was the most sensitive method to detected AF. Conventional telemetry and serial electrocardiographic assessments were less effective. However, only 35% of patients with previously documented paroxysmal AF and negative baseline electrocardiogram demonstrated AF episodes during monitoring., Conclusions: Continuous stroke unit telemetry using SEA-AF shows a significantly higher detection rate for AF compared with daily electrocardiographic assessments and standard telemetry without structured reading. The low overall probability to detect paroxysmal AF with either method during the first days after stroke demonstrates the urgent need for complementary diagnostic strategies such as long-term monitoring and frequent follow-up assessments. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT01177748.

Therapeutic hypothermia is a means of neuroprotection well established in the management of acute ischemic brain injuries such as anoxic encephalopathy after cardiac arrest and perinatal asphyxia. As such, it is the only neuroprotective strategy for which there is robust evidence for efficacy. Although there is overwhelming evidence from animal studies that cooling also improves outcome after focal cerebral ischemia, this has not been adequately tested in patients with acute ischemic stroke. There are still some uncertainties about crucial factors relating to the delivery of hypothermia, and the resolution of these would allow improvements in the design of phase III studies in these patients and improvements in the prospects for successful translation. In this study, we discuss critical issues relating first to the targets for therapy including the optimal depth and duration of cooling, second to practical issues including the methods of cooling and the management of shivering, and finally, of factors relating to the design of clinical trials. Consideration of these factors should inform the development of strategies to establish beyond doubt the place of hypothermia in the management of acute ischemic stroke.

Background and Purpose: Neuroprotective effects of induced hypothermia depend on its time point of initiation after acute brain injury. Preliminary studies in cardiac arrest patients indicate that rapid infusion of ice cold saline (ICS) is safe and effective for induction of hypothermia. We investigated its use in patients with acute ischemic stroke (AIS)., Methods: Patients (n=10) with AIS were included within 3 hours after symptom onset. After cranial CT, they were treated-if indicated-with rt-PA. ICS of 4 degrees C (25 mL/kg body weight) was administered via peripheral intravenous lines. Patients received buspirone/pethidine to prevent and treat shivering. After infusion of the target volume of ICS, no further efforts were made to maintain hypothermia by other methods., Results: Ten patients with a median National Institutes of Health Stroke Scale (NIHSS) score of 5.5 (range 4 to 12) on admission were included into the study. Nine patients were treated with thrombolysis within a time window of 104+/-25 minutes. A mean amount of 2163+/-256 mL ICS was infused 17+/-11 minutes after rt-PA infusion had started. Tympanic temperature dropped significantly by a maximum of 1.6+/-0.3 degrees C (P<0.005) at 52+/-16 minutes after ICS was started. The procedure was well tolerated. The NIHSS score improved significantly to a median of 1 (range 1 to 15) at discharge compared to admission (P<0.02)., Conclusions: This pilot study suggests that rapid ICS infusions in combination with pethidine and buspirone lower the body temperature significantly without major side effects.

Beside aspirin administration and stroke unit care, thrombolysis is the only approved and effective therapy in acute ischemic stroke. Thrombolysis is essentially limited by the short therapeutic window and its potential side effects. Although there is a robust body of evidence on the neuroprotective characteristics of hypothermia in animal models of focal ischemia, the clinical data on hypothermia in stroke are inconclusive in terms of effectiveness. Previous trials suggest that hypothermia is safe and feasible in stroke, and may decrease intracranial pressure (ICP) in patients suffering from space-occupying infarcts. However, neuroprotection by hypothermia has never been shown previously in stroke patients. This lack of efficacy might be explained by the fact that hypothermia is not appropriately used in patients and animal data are not correctly interpreted. This review summarizes the major conclusions of animal studies and presents results of clinical stroke trials to date. Methods of delivery and maintenance of hypothermia are discussed, as well as a variety of open questions in the relevant animal and clinical research.

Background: Moderate hypothermia (MH) is a therapeutic approach for ischemic stroke as well as cardiac arrest. Two different technical strategies of ventilation during MH called alpha- and pH-stat dramatically influence cerebral blood flow (CBF). In turn this might influence neuronal damage and intracranial pressure (ICP). Therefore, effects of ventilation on CBF and ICP were measured in patients undergoing MH because of large ischemic stroke to address optimal ventilation management., Methods: Eight patients (n = 8) with large ischemic stroke in the territory of the middle cerebral artery (MCA) were treated by MH of 33 degrees C within 24 h after symptom onset. MH was applied at least for 72 h. Each day, patients were ventilated repetitively with either alpha-stat or pH-stat for 60 min periods. Alpha-stat was applied between the measurements. ICP, CBF, and mean arterial blood pressure (MABP) were measured. The xenon clearance method was used to assess CBF at the bedside., Results: There were no significant differences between ICP values for alpha-stat or pH-stat during days 1 and 2 after induction of hypothermia. However, ICP was higher in the pH- as compared to the alpha-stat group (P < 0.05) and exceeded a mean of 20 mmHg on day 3. pH-stat led to a significant increase of CBF in all measures (P < 0.05), while MABP was unaffected., Conclusions: pH-stat implies a better CBF to the injured brain, while it might be dangerous by elevating ICP in more subacute stages.

Background and Purpose: The neuroprotective role of mild therapeutic hypothermia was established in animal models of cerebral ischemia. Still, several issues, including optimal target temperature, remain unclear. The optimal depth of hypothermia in a rat model of focal cerebral ischemia was investigated., Methods: Eighty-four male Wistar rats (n=84) were subjected to filament occlusion of the middle cerebral artery for 90 minutes. Sixty animals were equally split into 6 groups kept at core temperatures of 37 degrees C, 36 degrees C, 35 degrees C, 34 degrees C, 33 degrees C, and 32 degrees C over a period of 4 hours starting 90 minutes after middle cerebral artery occlusion. Twenty-four hours later, after performing a neuroscore, animals were killed and brains examined for infarct size, edema, and invasion of leukocytes. In the second part, 24 animals (8 per group) were kept at 33 degrees C, 34 degrees C, and 37 degrees C for 4 hours, allowed to survive for 5 days, and underwent additional investigation of transferase dUTP nick-end labeling., Results: In the first part, one animal in each treatment group and 2 animals in group 37 degrees C died. The infarct size and edema were smaller for 34 degrees C and 33 degrees C compared with all other groups (P<0.05) over 24 hours. These animals also had better functional outcome (P<0.05) with an advantage for 34 degrees C versus 33 degrees C (P<0.05). Leukocyte count was lower for 34 degrees C and 33 degrees C as compared with the 37 degrees C group. Similar results were obtained in the second part of the study with an advantage for 34 degrees C versus 33 degrees C., Conclusions: Our results suggest that the optimal depth of therapeutic hypothermia in temporary middle cerebral artery occlusion is 34 degrees C.

Background: Hyperbaric oxygenation (HBO) after focal cerebral ischemia reduces infarct size and improves outcome when applied early after stroke. Here, we evaluated effects of HBO on permanent focal cerebral ischemia and applied magnetic resonance imaging (MRI) monitoring to study lesion evolution., Methods: Rats underwent permanent middle cerebral artery occlusion (MCAO). Two hours later, animals were treated with HBO (100% O(2)/2 atm; n=17) for 1 hour or treated with room air (n=17). Animals underwent serial MRI studies (DWI, PI, T2) beginning 90 minutes after MCAO. Neuroscore was assessed (5-point rating scale). Animals were euthanized and brains were 2,3,5-triphenyltetrazolium chloride (TTC)-stained for infarct volume calculation 120 hours after MCAO. Immunohistochemistry was performed with antibodies against c-FOS and 4-hydroxy-2-nonenal-modified proteins (HNE) to check for effects of oxidative stress caused by HBO treatment., Results: HBO reduced infarct volume by 38% (P<0.001). As shown by MRI, neuroprotection began 5 hours after ischemia and remained effective for 5 days. The relative regional cerebral blood flow was not different between groups at 3.5 and 5 hours after occlusion. There was less neurological deficit in HBO-treated animals compared with controls (P<0.05). Lipid peroxidation of cerebral vessels after HBO treatment as measured by HNE staining and pattern of c-FOS induction were not significantly different between groups at 3.5 and 8 hours after ischemia., Conclusions: As monitored by MRI HBO treatment reversed ischemic lesion size between 3 and 5 hours after ischemia and achieved a long-lasting neuroprotective effect without significant oxidative damage.

Objective: To determine total energy expenditure (TEE) in patients with acute ischemic stroke in the territory of the middle cerebral artery (MCA), treated with moderate hypothermia (33 degrees C)., Design and Setting: Prospective study in a neurological ICU., Patients: Ten consecutive patients with severe MCA infarction undergoing moderate hypothermia., Measurements and Results: Indirect calorimetry was performed continuously over the first 6 days after admission. Mean daily TEE decreased significantly from 1549 before initiation of hypothermia to 1099, 1129, and 1157 on the first, second, and third days of hypothermia, respectively and returned to baseline values after hypothermia was terminated. The ratio of TEE to predicted basal energy expenditure declined from 1.01 before induction of hypothermia to an average of 0.74 during steady state of hypothermia and increased to 1.16 after rewarming., Conclusions: We found a significant fall in TEE in sedated, curarized, and ventilated ischemic stroke patients during moderate hypothermia. Indirect calorimetry appears to be a useful tool for measuring energy expenditure in these patients, as predicted basal energy expenditure overestimates the caloric requirements during hypothermia.

We have previously shown that exogenous application of brain-derived neurotrophic factor (BDNF) reduces infarct volume in the cortical ischemic penumbra after experimental focal ischemia [Stroke 31 (2000) 2212-2217]. Since BDNF is known to modulate the expression and function of various neurotransmitter receptors, we addressed the question whether BDNF may act via modification of postischemic ligand binding to excitatory NMDA and AMPA and/or inhibitory GABA(A) receptors, respectively. Transient focal cerebral ischemia was induced in male Wistar rats for 2 h using the suture occlusion technique. A period of 30 min after occlusion of the middle cerebral artery, BDNF (300 microg/kg per hour in vehicle; n=5) or vehicle alone (n=5) was continuously infused intravenously for 3 h. Using quantitative receptor autoradiography, postischemic ligand binding of [(3)H]MK-801, [(3)H]AMPA and [(3)H]muscimol was analyzed in the ischemic core, the ischemic cortical penumbra and corresponding regions of the contralateral hemisphere. Transient focal ischemia caused a significant reduction of [(3)H]muscimol binding to GABA(A) receptors within the ischemic cortical penumbra of placebo-treated rats. This was largely prevented by exogenous application of BDNF. [(3)H]MK-801 and [(3)H]AMPA binding values were also reduced in the cortical penumbra and the corresponding area of the contralateral hemisphere. Our data suggest that the neuroprotective effect of BDNF against ischemic damage in the cortical penumbra may be mediated in part by maintained activity of the inhibitory GABAergic system which likely counteracts glutamate induced excitotoxicity.

Background: Although the frequency for the use of moderate hypothermia in acute ischemic stroke is increasing, the optimal acid-base management during hypothermia remains unclear. This study investigates the effect of pH- and alpha-stat acid-base management on cerebral blood flow (CBF), infarct volume, and cerebral edema in a model of transient focal cerebral ischemia in rats., Methods: Twenty Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (MCAO) for 2 h during normothermic conditions followed by 5 h of reperfusion during hypothermia (33 degrees C). Animals were artificially ventilated with either alpha- (n = 10) or pH-stat management (n = 10). CBF was analyzed 7 h after induction of MCAO by iodo[(14)C]antipyrine autoradiography. Cerebral infarct volume and cerebral edema were measured by high-contrast silver infarct staining (SIS)., Results: Compared with the alpha-stat regimen, pH-stat management reduced cerebral infarct volume (98.3 +/- 33.2 mm(3) vs. 53.6 +/- 21.6 mm(3); P > or = 0.05 mean +/- SD) and cerebral edema (10.6 +/- 4.0% vs. 3.1 +/- 2.4%; P > or = 0.05). Global CBF during pH-stat management exceeded that of alpha-stat animals (69.5 +/- 12.3 ml x 100 g(-1) x min(-1) vs. 54.7 +/- 13.3 ml x 100 g(-1) x min; P > or = 0.05). The regional CBF of the ischemic hemisphere was 62.1 +/- 11.2 ml x 100 g(-1) x min(-1) in the pH-stat group versus 48.2 +/- 7.2 ml x 100 g(-1) x min(-1) in the alpha-stat group ( P> or = 0.05)., Conclusions: In the very early reperfusion period (5 h), pH-stat management significantly decreases cerebral infarct volume and edema as compared with alpha-stat during moderate hypothermia, probably by increasing CBF.