Cerebral neurons can probably tolerate at least 20 min of normothermic anoxia. After cardiac arrest (CA) of more than 5 min and cardiopulmonary resuscitation (CPR), however, the """"""""post- resuscitation syndrome"""""""" of multiple organ systems normally precludes cerebral recovery. Our overall goals are: to help determine the biologic limits to and potentials for resuscitation from CA; and to identify measurements for reliable prediction of outcome. We hypothesize that post-CA, inadequate cerebral reperfusion and prolonged global hypoperfusion are key factors in permanent brain damage; that blood brain barrier leakage and cerebral edema may be factors in reduced blood flow; and that control of post-CA perfusion failure and edema can improve outcome.
The specific aims of this project are to use an established dog model with CA of 10-15 min and long-term intensive care, to determine changes in cerebral and extracerebral variables and outcome, after: 1) uncontrollable reperfusion with CPR advanced life support (ALS) vs. controlled reperfusion and assisted circulation with cardiopulmonary bypass (CPB); 2) various reperfusion pressure patterns controlled by CPB; and 3) cerebral edema reducing hyperosmolar therapy. In an invasive, short-term 24-h model, global cerebral blood flow and metabolism will be monitored. In a noninvasive, long-term 6-d model, cerebral recovery will be determined by brain enzyme leakage into the CSF, overall performance categorization, neurologic deficit scoring, and histopathologic damage scoring. Cerebral edema and blood brain leakage will be monitored by NMR imaging. EEG spectrum, evoked potentials, and extracerebral variables will be monitored. In years 1 and 2 we propose to compare CPR-ALS with CPB (veno-arterial pumping via oxygenator, without thoracotomy, with heparinization and hemodilution), and study three different reperfusion pressure patterns controlled by CPB (normotenison, moderate hypertension, severe hypertension). In years 3 and 4 we propose to test a cerebral edema reducing therapy (e.g., mannitol i.v.) designed according to the results of years 1 and 2. Other related projects (not funded by this grant) will focus on post-CA multifocal hypoperfusion (1CBF by Xe enhanced CT), reoxygenation injury necrotizing cascades, intoxication from extracerebral organs, and blood-tissue interaction. Results will influence the protocols of future clinical trials of cardiac arrest and cardiopulmonary-cerebral resuscitation (our ongoing trial NS15295), and perhaps also the management of stroke, brain trauma and transplantation medicine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024446-03
Application #
3409083
Study Section
Neurology A Study Section (NEUA)
Project Start
1987-09-01
Project End
1991-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Safar, P; Xiao, F; Radovsky, A et al. (1996) Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 27:105-13
Radovsky, A; Safar, P; Sterz, F et al. (1995) Regional prevalence and distribution of ischemic neurons in dog brains 96 hours after cardiac arrest of 0 to 20 minutes. Stroke 26:2127-33;discussion 2133-4
Cerchiari, E L; Safar, P; Klein, E et al. (1993) Visceral, hematologic and bacteriologic changes and neurologic outcome after cardiac arrest in dogs. The visceral post-resuscitation syndrome. Resuscitation 25:119-36
Safar, P; Sterz, F; Leonov, Y et al. (1993) Systematic development of cerebral resuscitation after cardiac arrest. Three promising treatments: cardiopulmonary bypass, hypertensive hemodilution, and mild hypothermia. Acta Neurochir Suppl (Wien) 57:110-21
Sterz, F; Safar, P; Diven, W et al. (1993) Detoxification with hemabsorption after cardiac arrest does not improve neurologic recovery. Review and outcome study in dogs. Resuscitation 25:137-60
Cerchiari, E L; Safar, P; Klein, E et al. (1993) Cardiovascular function and neurologic outcome after cardiac arrest in dogs. The cardiovascular post-resuscitation syndrome. Resuscitation 25:9-33
Pomeranz, S; Safar, P; Radovsky, A et al. (1993) The effect of resuscitative moderate hypothermia following epidural brain compression on cerebral damage in a canine outcome model. J Neurosurg 79:241-51
Oku, K; Sterz, F; Safar, P et al. (1993) Mild hypothermia after cardiac arrest in dogs does not affect postarrest multifocal cerebral hypoperfusion. Stroke 24:1590-7;discussion 1598
Wolfson Jr, S K; Safar, P; Reich, H et al. (1992) Dynamic heterogeneity of cerebral hypoperfusion after prolonged cardiac arrest in dogs measured by the stable xenon/CT technique: a preliminary study. Resuscitation 23:1-20
Sterz, F; Leonov, Y; Safar, P et al. (1992) Multifocal cerebral blood flow by Xe-CT and global cerebral metabolism after prolonged cardiac arrest in dogs. Reperfusion with open-chest CPR or cardiopulmonary bypass. Resuscitation 24:27-47

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