Neurologic Preservation by Na+-H+ Exchange Inhibition Prior to 90 Minutes of Hypothermic Circulatory Arrest

Background: The effects of pretreatment with cariporide (HOE 642 Aventis Pharma, Strasbourg – Cedex, France), a Na⁺–H⁺ exchanger (NHE) blocker, were studied in a cerebral ischemia–reperfusion model of hypothermic arrest.

Methods: Fifteen Yorkshire-Duroc pigs (37.1 ± 4.2 kg) underwent femoral–jugular bypass and 90 minutes of deep hypothermic circulatory arrest at 19°C. Ten animals were untreated, whereas 5 received 5 mg/kg of intravenous cariporide before cooling. After rewarming and off cardiopulmonary bypass, the pigs were weaned from anesthesia and followed for 24 hours. A standardized neurologic scoring system assessed brain functional recovery. Biochemical markers were used to analyze cellular injury. Control studies without circulatory arrest were done in 2 animals that underwent similar cooling and rewarming.

Results: Neurologic recovery was rapid and complete in the nonischemic controls and in all pretreated animals. Conversely, at 24 hours, all untreated pigs exhibited a cloudy or stuporous level of consciousness, abnormal positioning, and with only one exception, could not sit or stand. The gradation of neurologic score (evaluating central nervous system, motor and sensory functions, respiration condition, level of consciousness, and behavior) was 0 ± 0 (0 = normal, 500 = brain death) in the treated group, compared with 124 ± 59 in the untreated animals. Biochemical analysis showed every variable of whole-body injury (including conjugated dienes (p < 0.05), serum aspartate amino transferase (p < 0.01), creatine kinase p < 0.001) and endothelin-1 (p < 0.001) to be higher in the untreated group.

Conclusions: NHE function alters experimental brain ischemia–reperfusion damage. These observations imply that NHE inhibition therapy before ischemia may improve neurologic protection in adult and infant patients undergoing cerebral ischemia during procedures that use hypothermic circulatory arrest.