Jumat, 13 Juni 2008

BRAIN COOLING—A HOT TOPIC IN STROKE

http://www.neurologyreviews.com/apr01/nr_apr01_brain.html
BRAIN COOLING—A HOT TOPIC IN STROKE
FORT LAUDERDALE, Fla—Lowering body temperature has long been thought to lessen the damaging effects of stroke. Indeed, animal stroke models have successfully shown dramatic neuroprotection with moderate degrees of cooling. With recent improvements in technology and methodology, researchers are beginning to test the clinical potential of hypothermic therapy in patients with stroke.“If you step back and look at all of the stroke literature, probably the most consistent and most effective means to reduce the bad effects of stroke has been through lowering temperature. And one of most consistent ways to worsen the effects of stroke in animal models is to elevate temperature,” said Marc Mayberg, MD, Professor and Chair, Department of Neurosurgery, Cleveland Clinic Foundation, Ohio.At the 26th International Stroke Conference, experts reviewed the preclinical studies and the ongoing hypothermia trials.CHILLING RATS PROVIDES DRAMATIC RESULTSIn experimental models of cerebral ischemia, cooling the brain temperature by just a few degrees is capable of conferring dramatic neuroprotection, said Myron D. Ginsberg, MD, Director of Cerebral Vascular Disease Research Center and Co-Director of Neurotrauma Research Center at the University of Miami School of Medicine, Florida. Initial rat studies found that decreasing temperatures to 30°C to 34°C during global forebrain ischemia can preserve brain regions vulnerable to stroke damage. There was a “virtually complete preservation of pyramidal cell layer” in the CA1 hippocampus as well as neuroprotection in the central and dorsolateral striatum, he said. Significant reduction of infarct volume after focal ischemia in rats has also been demonstrated with hypothermia treatment, he added. These results have been reproduced in more than a dozen laboratories in the past decade. “There is absolutely no question as to the robustness of this observation,” Dr. Ginsberg said.Post-ischemic hypothermia can provide some degree of chronic protection if the duration and degree of hypothermia are sufficient, commented Ashfaq Shuaib, MD, FRCPC, Director of Neurology at the University of Alberta Hospital, in Edmonton. For example, prolonged hypothermia for 48 hours at 32°C to 34°C was capable of providing neuroprotection when initiated 2.5 hours after onset of middle cerebral artery occlusion in rats. Moreover, the treated rats maintained their ability to retrieve food pellets in a staircase test that measures independent forelimb reaching ability, he pointed out.IS STROKE PATHOLOGY TEMPERATURE SENSITIVE?In addition to the therapeutic potential, manipulating brain temperature has been useful in the study of stroke pathology. Temperature variations can improve a wide spectrum of processes associated with neuronal injury, including reduction in glutamate release, free radical mechanisms, ischemic depolarization, and kinase activities; preservation of the blood-brain barrier and cytoskeleton; and suppression of inflammatory mechanisms, Dr. Ginsberg said.Elevated levels of glutamate in plasma and cerebrospinal fluid have been found in patients with stroke progression, Dr. Shuaib added. “If hypothermia attenuates this glutamate increase, it may offer protection for the patients,” he suggested. Microdialysis studies in animals have shown that hypothermia can completely suppress intra-ischemic glutamate release.Hydroxyl radical production is also suppressed when ischemia is carried out under hypothermic conditions, according to a recent study in rats. On the other hand, ischemia at higher temperatures produced a 12-fold increase in hydroxyl radical production during the recirculation period, Dr. Ginsberg said. “When one subjects the brain to a global ischemic insult of short duration, but under hyperthermic conditions (39°C), things happen that would never occur under normothermia,” he said.Neuroimaging studies of stroke models have demonstrated the influence of temperature on brain metabolism, Dr. Ginsberg said. Also, there is an increasing number of ischemic depolarizations with increasing temperature during stroke, which impose a severe energy burden on the penumbra. The blood-brain barrier is also “exquisitely sensitive to temperature,” he added. Under hypothermic conditions during ischemia, he noted, there is complete protection of the barrier.“It’s high time now for a controlled, randomized, prospective study of hypothermia in ischemic stroke,” Dr. Ginsberg remarked. The experimental studies suggest that cooling to 32°C to 34°C is sufficient to confer neuroprotection, particularly if it’s prolonged for 24 to 48 hours. “There’s no excuse now for failing to control the body temperature” in patients with stroke and acute brain injury, he said.TECHNIQUES OF BRAIN COOLINGBrain temperature can be lowered by cooling the body surface or by cooling the inner body. Although the target temperature and duration of cooling is still under debate, preliminary trials have suggested that hypothermic therapy may be feasible and safe, said Thorsten Steiner, MD, from the University of Heidelberg, Germany.Surface cooling can be achieved by wiping the patient’s body with alcohol and by using cooling blankets, cooling mattresses, or cooling tents. This method can take 3.5 to 6.5 hours to bring the core temperature down to 32°C and it is very labor intensive, he said. In order to counteract the shivering response, the patient has to be paralyzed, intubated, and sedated.Surface cooling has been tested in two trials with stroke patients. In the first trial, hypothermia was induced in 25 patients with severe ischemic stroke in the middle cerebral artery territory for therapy of post-ischemic brain edema. Hypothermia began within 14 hours after stroke onset, and patients were maintained at 33°C for 48 to 72 hours. “The overall result was encouraging because intracranial pressure could be lowered significantly and the mortality rate could be decreased to 44% compared to 70% to 80% of patients who were conservatively treated,” Dr. Steiner said. However, there was a high rate of pneumonia and septic syndrome. Rewarming was done in a passive mode, he noted, and all the patients had some elevation of intracranial pressure. Five patients died because of transtentorial herniation. In the second hypothermia trial, 15 stroke patients were rewarmed in a controlled manner. This leads to significantly better control of intracranial pressure, Dr. Steiner said. However, prolonged hypothermia led to an increase of infectious complications.Inner-core cooling can be achieved by cooling the blood returning to the heart, Dr. Steiner explained. This method has been applied to eight patients with traumatic brain injury. The cooling speed was 3.5°C per hour and controlled rewarming was relatively easy since it was possible to control the temperature in intervals of 0.1°C. However, these patients required mechanical ventilation and four patients died due to uncontrollable intracranial pressure.PREEMPTIVE FEVER REDUCTIONIn addition to cooling below normal temperatures, researchers are looking for ways to prevent fever after stroke. Fever can exacerbate stroke damage and it is an independent predictor of poor outcome, said Mary A. Kalafut, MD, from the Scripps Clinic in La Jolla, California.Conventional stroke treatment calls for antipyretics in response to elevated temperature; however, Dr. Kalafut and colleagues have taken the first look at preemptive fever reduction. Prophylactic acetaminophen (650 mg) was given “around the clock, every four hours” to 16 consecutive patients who presented with acute ischemic stroke within 24 hours of onset.During the three-day study period, the control group had significantly increased temperatures when compared to baseline admission temperatures, Dr. Kalafut said. The temperatures of the acetaminophen-treated patients, in contrast, did not increase over baseline at four of the six eight-hour time points tested. A randomized trial is needed to determine whether this effect will result in reduced brain injury and improved outcomes, he said.INTRAOPERATIVE HYPOTHERMIAResults from a pilot trial found that cooling patients during aneurysm surgery is feasible and well tolerated, said Christopher M. Loftus, MD, FACS, from the University of Oklahoma, Oklahoma City. A total of 114 patients undergoing cerebral aneurysm clipping were randomized to normothermic (36.5°C) or hypothermic (33.5°C) conditions. Hypothermia was achieved with cooling blankets. Patients who were cooled had a lower frequency of neurologic deterioration at 24 and 72 hours after surgery and a greater incidence of good long-term outcome than did the noncooled patients, Dr. Loftus said. Currently, a multicenter, randomized trial is under way to test whether intraoperative hypothermia can improve long-term neurologic outcome in 920 patients with subarachnoid hemorrhage.According to a three-year prospective trial with 27 patients, mild resuscitative hypothermia after cardiac arrest was found to be feasible and well tolerated, said Fritz Sterz, MD, from the University Clinic of Emergency Medicine, Vienna, Austria. Temperature was lowered to 32°C to 34°C for at least 24 hours after cardiac arrest. The surface cooling method used was not associated with any major complications, he said. Currently, Dr. Sterz and his colleagues are in the process of enrolling patients in a larger multicenter trial to assess long-term neurologic outcomes.HYPOTHERMIA IN ACUTE ISCHEMIC STROKE—THE COOL AID TRIALHypothermic therapy has the potential to limit ischemic damage, reduce reperfusion injury, and dampen the risk of hemorrhage occurring after thrombolytic therapy, said Derk W. Krieger, MD, PhD, from the Cleveland Clinic Foundation, Ohio. The feasibility and safety of moderate hypothermia in stroke was recently tested in the Cooling for Acute Ischemic Brain Damage (COOL AID) trial.This pilot study included patients with severe strokes affecting the middle cerebral artery territory who failed to improve after thrombolysis. Ten patients were cooled to 32°C using a cooling blanket and an ice water-alcohol bath. It took 3.6 hours to reach target temperature and there were difficulties in maintaining temperature (average duration, 22 hours), Dr. Krieger noted.According to modified Rankin Scale scores at three months, 50% of the patients treated with hypothermia had a good outcome compared to only about 11% of the control patients. The percentage of good outcome in historic controls is 20%, “so we had kind of a net benefit of 30%,” Dr. Krieger said. Accordingly, there was a trend towards a reduction in stroke size in the cooled patients, he added. Complications included bradycardia in five patients, ventricular arrhythmia in two patients, and fever after rewarming in three patients. “Most of the complications occurred very late in the cooling process or at temperatures below target,” he pointed out.The Cleveland Clinic Foundation researchers have recently begun enrolling patients in the COOL AID phase II multicenter trial to examine the safety and feasibility of the catheter cooling method. A catheter will be placed in the vena cava to cool the blood circulating to the heart. The temperature can be set and precisely maintained using a feedback mechanism. In addition, warming blankets placed on the chest can allow patients to feel warm even though their core temperature is decreasing. The researchers hope to achieve hypothermia and neuroprotection in patients without the use of sedation and ventilation.There is great anticipation of the results from these ongoing trials, Dr. Mayberg said. “If hypothermia is effective—and that’s a big if—and if the technology allows it to be applied safely outside the intensive care unit setting, then it may become part of the standard equipment for emergency medical technicians in the ambulance to begin cooling the patients en route to the hospital before their thrombolysis.”NR—Shauna KuboseSuggested Reading1. Ginsberg MD, Busto R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke. 1998;29:529-534.2. Hindman BJ, Todd MM, Gelb AW, et al. Mild hypothermia as a protective therapy during intracranial aneurysm surgery: a randomized prospective pilot trial. Neurosurgery. 1999; 44:23-32.3. Schwab S, Schwarz S, Spranger M, et al. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke. 1998;29:2461-2466.4. Zeiner A, Holzer M, Sterz F, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group. Stroke. 2000;31:86-94. WHAT CAUSES FEVER AFTER STROKE?Stroke patients are prone to infections, but damage to the hypothalamus—the temperature regulation center—may also play a role in the rise of body temperature after stroke, according to Michael A. DeGeorgia, MD, Head of the Neurological Intensive Care Program at the Cleveland Clinic Foundation, Ohio.According to imaging studies of 61 patients with intracerebral hemorrhage, noninfectious fever was mildly correlated with enlarged hemorrhage volume and

Tidak ada komentar: