Donald Prough - US grants

More than 2,500 patients per year suffer severe strokes following coronary artery bypass surgery. Twenty thousand (20,000) patients or more experience transient cerebral dysfunction. More than half of all patients undergoing heart surgery demonstrate enzymatic evidence of neurologic insult. Prevention of neurological deficits following coronary artery bypass graft surgery would increase the safety of this frequently-performed operation. The etiology of neurological deficits after cardiac surgery may be embolic in origin or may be related to cerebral hypoperfusion. Nevertheless, despite the fact that cerebral perfusion is impaired either in a global or a diffuse, multifocal fashion, there is very little data available regarding the functional characteristics of the human cerebral circulation during cardiopulmonary bypass. This proposal is intended to further characterize the physiologic responses of the cerebral circulation during cardiopulmonary bypass and to formulate hypotheses regarding potentially effective prophylactic or therapeutic strategy which may then be subjected to clinical testing. This proposal will study two questions. First, the changes in cerebral blood flow and cerebral metabolism produced by changes in carbon dioxide tension during cardiopulmonary bypass will be defined. Two strategies for the management of carbon dioxide tension and pH during cardiopulmonary bypass will be compared in terms of their effects on cerebral blood flow and metabolism. Second, the effects of a reduction in mean arterial pressure on cerebral blood flow and metabolism will be studied. Three different, commonly employed methods for avoiding high mean arterial pressure during cardiopulmonary bypass will be studied in relationship to their interaction with changes in acid-base management. The interventions to be studied include a reduction in blood flow through the pump-oxygenator, the effects of the vasodilator sodium nitroprusside, and the effects of the anesthetic isoflurane, a drug which reduces systemic blood pressure and also causes a reduction in the cerebral metabolic rate for oxygen.

Neurologic, neuro-ophthalmologic, and neuropsychologic complications constitute a primary source of morbidity and disability following cardiac surgery. As many as 12,500 patients suffer frank strokes and at least 100,000 manifest measurable deterioration in psychomotor performance after cardiac surgery. Neurologic complications occur more frequently after valvular surgery and in elderly individuals. This Program Project will utilize a multidisciplinary team of investigators to determine the influence of physiologic and pharmacologic factors on the combined prevalence of new postoperative neurologic, neuro-ophthalmologic, and neuropsychologic deficits. In patients undergoing myocardial revascularization, Project 1 will determine if careful avoidance of hyperglycemia, which worsens experimental ischemic neurologic injury, will improve neurologic outcome. That project will include patients with the important risk factor of cerebrovascular disease. Project 2 will evaluate, in patients undergoing cardiac valve surgery, if the calcium entry clocker nimodipine will reduce the prevalence of new postoperative deficits. Project 3 will determine the frequency, etiology, and clinical implications of newly observed diffuse microvascular lesions after cardiopulmonary bypass. Each of the projects will be supported by the Administrative Core (Core A) and the Biostatistical Core (Core D). In addition, the Clinical Projects (1 and 2) will utilize common physiologic measurements from the Neurologic and Neurobehavioral Assessment Core (Core C). The interaction between the laboratory and clinical components will enhance the productivity of both components and will maximize the likelihood of deriving clinically useful information from the Program Project. Demonstration of improved outcome in any of the clinical projects should immediately be applicable to thousands of patients.

DESCRIPTION (provided by applicant): After traumatic brain injury (TBI), systemic hypotension causes secondary ischemic brain injury that markedly worsens mortality and neurologic outcome. We will test the hypothesis that, as a consequence of TBI and posttraumatic hemorrhagic hypotension, neurotoxic concentrations of Zn2+ are released from presynaptic glutamatergic vesicles in association with glutamate, enter postsynaptic neurons through receptor-associated calcium channels (especially AMPA/kainite receptors) and voltage-operated calcium channels, and worsen outcome by accumulating in postsynaptic neurons. Specific aim 1: In rats subjected to TBI with our without hypotension, we will test the hypothesis that neuronal Zn2+ accumulation is related to Zn2+ release, which is proportional to the severity of TBI and hypotension and the interval between TBI and hypotension. Methodologies: microdialysis (Zn2+ and glutamate); staining with the Zn2+-specific dye TSQ (intracellular Zn2+ accumulation); vanadium acid fuchsin (VAF) staining (acute cell injury); staining for DNA fragmentation (TUNEL); ribonuclease protection assays (apoptosis); neuronal counts (histopathologic outcome), and beam walking, beam balance and the Morris water maze (neurobehavioral outcome). Specific aim 2: In rats subjected to moderate TBI with or without hypotension, we will address the hypothesis that after TBI, Zn2+ enters neurons through receptor-associated calcium channels and voltage-operated calcium channels (VOCCs) and that entry through (VOCCs) is enhanced by posttraumatic brain tissue acidosis. Interventions: the NMDA receptor antagonist MK-801, the AMPA/kainite receptor antagonist LY300164, the L-type calcium channel antagonist nimodipine, and increases and decreases in extracellular pH. Methodologies: microdialysis, TSQ staining, and VAF staining. Specific aim 3: In rats subjected to moderate TBI and hypotension, we will address the hypothesis that after, TBI and hypotension, modifying extracellular Zn2+ concentrations will modify neurobehavioral and histopathologic injury. We will test this hypothesis by using intracerebroventricular (icv) injection of Zn2+ and by icv injection of the specific Zn2+-binding apoenzyme of carbonic anhydrase. Methodologies: identical to specific aim 1 plus monitoring for signs of neurologic zinc deficiency.