From the Departments of Neurosurgery, Neurology (M.A.Y.), Anesthesiology
(J.E.L.), and Stanford Stroke Center, Stanford University, Stanford, Calif.
Correspondence to Gary K. Steinberg, MD, PhD, Professor and Chairman, SUMC, Department of Neurosurgery, 300 Pasteur Dr, Room R281, Stanford, CA 94305. E-mail mk.gks{at}forsythe.stanford.edu
Background and Purpose—Mild
hypothermia is possibly the single most effective method of
cerebroprotection developed to date. However, many questions regarding
mild hypothermia remain to be addressed before its potential
implementation in the treatment of human stroke. Here we report the
results of 2 studies designed to determine the optimal depth and
duration of mild hypothermia in focal stroke and its effects on infarct
size, neurological outcome, programmed cell death, and
inflammation.
Methods—Rats underwent a 2-hour occlusion of the left middle
cerebral artery. In the first study (I) animals were kept
(intraischemically) at either 37°C (n=8), 33°C (n=8), or
30°C (n=8). Study II consisted of 4 groups: (1) controls (37°C,
n=10), (2) 30 minutes of hypothermia started at ischemic onset
(33°C, n=9), (3)1 hour (33°C, n=8), and (4) 2 hours (33°C, n=8).
Brain temperature was measured by a thermocouple probe placed in the
contralateral cortex. After suture removal, all animals were rewarmed
and reperfused for 22 hours (I) or 70 hours (II).
Results—Mild hypothermia to 33°C or 30°C was neuroprotective
(17±7% and 27±6%, respectively) relative to controls (53±8%,
P<0.02), but 33°C was better tolerated and recovery
from anesthesia was faster. The neurological score of
hypothermic animals was significantly better than that of controls (I &
II) at both 24 and 72 hours postischemia except for the
30-minute group (II), which showed no improvement. In Study II, 2 hours
of hypothermia reduced injury by 59%, 1 hour reduced injury by 84%
whereas 30 minutes did not reduce injury. Normalized for infarct
size, 2 hours of mild hypothermia decreased neutrophil accumulation by
57% whereas both 1 hour and 30 minutes had no effect. At 72 hours, 1
and 2 hours of mild hypothermia decreased transferase dUTP nick-end
labeling (TUNEL) staining by 78% and 99%, respectively, and 30
minutes of hypothermia had no effect.
Conclusions—Intraischemic mild hypothermia must be
maintained for 1 to 2 hours to obtain optimal neuroprotection against
ischemic cell death due to necrosis and apoptosis.
Department
of Anesthesiology and Critical Care Medicine,
Johns Hopkins Medical Institutions,
Baltimore, Maryland
© 1998 American Heart Association, Inc.
Original Contributions
Optimal Depth and Duration of Mild Hypothermia in a Focal Model of Transient Cerebral Ischemia
Effects on Neurologic Outcome, Infarct Size, Apoptosis, and Inflammation
Editorial Comment
Effects on Neurologic Outcome, Infarct Size, Apoptosis, and Inflammation
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