The neuroprotective effect of the novel AMPA receptor antagonist PD152247 (PNQX) in temporary focal ischemia in the rat.
(9/1261)
BACKGROUND AND PURPOSE: Evidence suggests that glutamate contributes to ischemic brain damage through activation of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor. We tested the novel, selective AMPA receptor antagonist PD152247 (PNQX) in a model of temporary focal ischemia to determine the dose-response relationship and to investigate the contribution of drug-induced hypothermia to the neuroprotective action of AMPA receptor antagonists. METHODS: Temporary focal cerebral ischemia was induced in Sprague-Dawley rats by occluding the middle cerebral artery and both carotid arteries for 3 hours. Body temperature was monitored by telemetry. PNQX was administered intraperitoneally or by intravenous infusion with various doses for 6 hours. Lesion volume was determined after 3 days by stereological methods. RESULTS: PNQX reduced the lesion volume by 51% after intraperitoneal administration. The intravenous dose-response study demonstrated that the lowest effective dose of PNQX was 1.0 mg/kg per hour, which corresponded to a steady state plasma level of 685 ng/mL. Neuroprotection was demonstrated at PNQX plasma concentrations that did not lower body temperature over the entire course of the experiment. CONCLUSIONS: AMPA receptor activation plays an important role in the development of ischemic brain damage. Thus, novel AMPA receptor antagonists may be useful for the treatment of stroke in humans. (+info)
Hypothermia bed system for stroke patients. Technical note.
(10/1261)
A new hypothermia bed system was used to induce mild hypothermia (33-35 degrees C) in six patients with stroke due to subarachnoid hemorrhage, hypertensive intracerebral hemorrhage, or embolic internal carotid artery occlusion. The system bed contained all necessary equipment including a respirator, a cooling unit, physiological monitors, and a storage battery. Surface cooling of the patients was performed using water-circulating blankets, and core temperature was maintained based on bladder temperature and a feedback computer program. During hypothermic therapy, patient transfer and radiological examination including computed tomography and positron emission tomography could be easily and safely performed. Differences between the measured bladder temperature and the target temperature were approximately +/- 0.1 degree C. The proposed hypothermia system bed may be useful for serial radiological examination of patients with stroke. (+info)
Selective hypothermia in repair of aneurysms of the descending aorta.
(11/1261)
Since 1991, we have used a simple, single-clamp technique with open distal anastomosis to repair aneurysms of the descending aorta. To enhance the results of the single-clamp technique in a recent high-risk patient, we used selective hypothermia, cooling primarily the tissues and organs supplied by the aorta and tributaries distal to the left subclavian artery. This preliminary report describes the technique and gives the rationale for its use. (+info)
Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass.
(12/1261)
BACKGROUND: It is not known whether developmental and neurological outcomes in the preschool period differ depending on whether the predominant vital organ support strategy used in infant heart surgery was total circulatory arrest (CA) or low-flow cardiopulmonary bypass. METHODS AND RESULTS: Infants with D-transposition of the great arteries who underwent an arterial-switch operation were randomly assigned to a support method consisting predominantly of CA or low-flow cardiopulmonary bypass. Developmental and neurological status were evaluated blindly at 4 years of age in 158 of 163 eligible children (97%). Neither IQ scores nor overall neurological status were significantly associated with either treatment group or duration of CA. The CA group scored lower on tests of motor function (gross motor, P=0.01; fine motor, P=0.03) and had more severe speech abnormalities (oromotor apraxia, P=0.007). Seizures in the perioperative period, detected either clinically or by continuous electroencephalographic monitoring, were associated with lower mean IQ scores (12.6 and 7.7 points, respectively) and increased risk of neurological abnormalities (odds ratios, 8.4 and 5.6, respectively). The performance of the full cohort was below expectations in several domains, including IQ, expressive language, visual-motor integration, motor function, and oromotor control. CONCLUSIONS: Use of CA to support vital organs during open heart surgery in infancy is associated, at the age of 4 years, with worse motor coordination and planning but not with lower IQ or with worse overall neurological status. (+info)
Effects of moderate hypothermia on leukocyte- endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion.
(13/1261)
Background and Purpose--It has been demonstrated that moderate hypothermia attenuates brain damage, but the mechanism whereby this is achieved has not been clearly shown. Recently, the role of leukocytes as mediators of secondary brain damage after brain ischemia has been discussed. The aim of this study is to examine the effects of moderate hypothermia on leukocyte-endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion (MCAO). Methods--Rhodamine 6G-labeled leukocytes in brain surface were visualized with intravital fluorescence videomicroscopy through a closed cranial window. We analyzed the number of leukocytes adhering to the venular and arteriolar endothelium before ischemic insult and up to 3 hours after reperfusion. Rats were divided into 4 experimental groups. Group I (n=6) consisted of sham-operated animals. Groups II (n=6) and III (n=6) received left MCAO for 1 hour under normothermia (36 degrees C to 37 degrees C, group II) and under moderate hypothermia (30 degrees C to 32 degrees C, group III). Group IV (n=4) received left common carotid artery occlusion for 1 hour under normothermia. Results--The number of adhering leukocytes in venules in groups II and IV increased significantly (P<0.001) after reperfusion compared with the group I, but that in group III did not increase significantly (P>0.05). The number of adhering leukocytes in arterioles in group II increased significantly (P<0.01) compared with the other groups, although the adhering leukocytes were not as numerous as those seen in venules. Conclusions--It is demonstrated that hypothermia attenuates adhering leukocytes in venules and arterioles after reperfusion of MCAO. The inhibition of the leukocyte function may be an important factor in the neuroprotective effect of hypothermia. (+info)
Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia.
(14/1261)
BACKGROUND AND PURPOSE: Hypothermia has been suggested to be the most potent therapeutic approach to reduce experimental ischemic brain injury identified to date, and mild hypothermia is increasingly used for neuroprotection during neurovascular surgery. We have recently demonstrated that combined administration of tirilazad mesylate and magnesium provides for an overall enhanced neuroprotective effect. The present study was designed to determine whether the efficacy of mild hypothermia (33 degrees C) can be increased by combination pharmacotherapy with tirilazad and magnesium (MgCl(2)). METHODS: Forty Sprague-Dawley rats were subjected to transient, middle cerebral artery occlusion and were randomly assigned to 1 of 4 treatment arms (n=10 each): (1) normothermia+vehicle, (2) normothermia+tirilazad+MgCl(2), (3) hypothermia+vehicle, or (4) hypothermia+tirilazad+MgCl(2). Cortical blood flow was monitored by a bilateral laser-Doppler flowmeter, and the electroencephalogram was continuously recorded. Functional deficits were quantified by daily neurological examinations. Infarct volume was assessed after 7 days. RESULTS: Tirilazad+MgCl(2), hypothermia, and hypothermia+tirilazad+MgCl(2) reduced total infarct volume by 56%, 63%, and 77%, respectively, relative to controls. In animals treated with both hypothermia and combination pharmacotherapy, cortical infarction was almost completely abolished (-99%), and infarct volume in the basal ganglia was significantly reduced by 55%. In addition, this treatment provided for the best electrophysiological recovery and functional outcome. CONCLUSIONS: The neuroprotective efficacy of hypothermia can be increased by pharmacological antagonism of excitatory amino acids and free radicals by using clinically available drugs. This treatment strategy could be of great benefit when applied during temporary artery occlusion in cerebrovascular surgery. (+info)
Hypothermia and the trauma patient.
(15/1261)
Hypothermia has profound effects on every system in the body, causing an overall slowing of enzymatic reactions and reduced metabolic requirements. Hypothermic, acutely injured patients with multisystem trauma have adverse outcomes when compared with normothermic control patients. Trauma patients are inherently predisposed to hypothermia from a variety of intrinsic and iatrogenic causes. Coagulation and cardiac sequelae are the most pertinent physiological concerns. Hypothermia and coagulopathy often mandate a simplified approach to complex surgical problems. A modification of traditional classification systems of hypothermia, applicable to trauma patients is suggested. There are few controlled investigations, but clinical opinion strongly supports the active prevention of hypothermia in the acutely traumatized patient. Preventive measures are simple and inexpensive, but the active reversal of hypothermia in much more complicated, often invasive and controversial. The ideal method of rewarming is unclear but must be individualized to the patient and institution specific. An algorithm reflecting newer approaches to traumatic injury and technical advances in equipment and techniques is suggested. Conversely, hypothermia has selected clinical benefits when appropriately used in cases of trauma. Severe hypothermia has allowed remarkable survivals in the course of accidental circulatory arrest. The selective application of mild hypothermia in severe traumatic brain injury is an area with promise. Deliberate circulatory arrest with hypothermic cerebral protection has also been used for seemingly unrepairable injuries and is the focus of ongoing research. (+info)
Mild hypothermia improves recovery of cortical extracellular potassium ion activity and excitability after middle cerebral artery occlusion in the rat.
(16/1261)
BACKGROUND AND PURPOSE: Mild brain hypothermia significantly alleviates damage after focal ischemia, although the mechanism of this protection remains poorly defined. In the present study, we tested the hypothesis that mild hypothermia would protect cortex from early deterioration of ion homeostasis and loss of excitability associated with reperfusion after focal ischemia. METHODS: Cortical extracellular potassium ion activity ([K+]o) and the response of [K+]o to direct cortical stimulation was measured both in the ischemic core and in the ischemic penumbra of normothermic and mildly hypothermic (31.5 degrees C to 32 degrees C) rats after distal middle cerebral artery occlusion (MCAO) and reperfusion. RESULTS: The response of [K+]o during MCAO was similar in normothermic and hypothermic animals. However, within 1 hour of reperfusion, [K+]o in the ischemic core region of normothermic animals showed incomplete recovery and was refractory to direct cortical stimulation. [K+]o in hypothermic animals returned to preischemic levels on reperfusion and continued to respond to direct cortical stimulation. Mild hypothermia prevented extensive infarction 24 hours after transient MCAO. CONCLUSIONS: The data suggest that transient focal ischemia is accompanied by early disturbances of potassium ion homeostasis during reperfusion, which are accompanied by loss of excitability and which may contribute ultimately to cortical infarction. (+info)