This project is designed to study the cardiopulmonary sequelae of CNS injury, with a particular emphasis on pulmonary edema. Sheep will be used as the experimental model since this animal allows continual monitoring of the variables (hydrostatic and oncotic) associated with changes in pulmonary fluid movement. Several varieties of CNS trauma have been chosen: seizure, intracranial hypertension, cerebral ischemia, and cerebral intraventricular endotoxin. Each of these lesions is diffuse, involving the brain in toto, and is known to result in pulmonary edema. In our previous studies we have had experience with two of these: seizures and intracranial hypertension. Seizures produce transient marked systemic and pulmonary vascular hypertension, with a resultant prolonged doubling of pulmonary transcapillary fluid and protein flux. Raising intracranial pressure elicits the Cushing response of systemic hypertension; associated is an increase in pulmonary artery pressure and pulmonary transcapillary fluid flux, but no change in left atrial pressure. In our proposed experiments we will separate out the ischemic component from mechanical pressure effects by transiently occluding the cerebral circulation and comparing any consequent alterations in cardiopulmonary parameters with those we have observed following elevated CSF pressure. Endotoxemia reults in still another cardiovascular pattern: elevated pulmonary artery pressure in the face of systemic hypotension. The role of the CNS in the genesis of and control of endotoxin shock has been documented in studies of the brain stem, cerebellum, and endorphin systems. Such information has so far been largely limited to the consequences of endotoxin on the systemic circulation. The intracerebroventricular administration of endotoxin, by eliminating direct systemic consequences of this agent, will provide a clear tool for studying CNS control. The effects of naloxone which have recently been described in regard to the systemic circulation during sepsis will be examined in respect to the pulmonary circulation as well. Each of thes models results in diffuse damage to the CNS. Once the cardiopulmonary consequences of each manipulation have been established, future studies will attempt to localize the effector sites by prior brain transection at different levels or locations.
| Johnston, S C; Darragh, T M; Simon, R P (1996) Postictal pulmonary edema requires pulmonary vascular pressure increases. Epilepsia 37:428-32 |
| Johnston, S C; Horn, J K; Valente, J et al. (1995) The role of hypoventilation in a sheep model of epileptic sudden death. Ann Neurol 37:531-7 |
| Shiraishi, K; Sharp, F R; Simon, R P (1989) Sequential metabolic changes in rat brain following middle cerebral artery occlusion: a 2-deoxyglucose study. J Cereb Blood Flow Metab 9:765-73 |
| Simon, R P; Copeland, J R; Benowitz, N L et al. (1987) Brain phenobarbital uptake during prolonged status epilepticus. J Cereb Blood Flow Metab 7:783-8 |
