Evaluating neuroprotective agents for clinical anti-ischemic benefit using neurological and neuropsychological changes after cardiac surgery under cardiopulmonary bypass - Methodological strategies and results of a double-blind, placebo-controlled trial of GM(1) ganglioside

Background and Purpose Many neuroprotective agents (NPAs) are effective in acute experimental cerebral ischemia in animals. None have proven effective in human stroke trials. Even short treatment delays cause substantial efficacy loss. Cardiac surgery under cardiopulmonary bypass (CS-CPB) causes cerebral ischemia with cognitive impairment at a pre-determinable time point and should permit efficient screening of NPAs fur stroke benefit. We sought to develop sensitive methods to assess dysfunction from CS-CPB in a double-blind trial of the NPA GM, ganglioside. Methods Eighteen GM(1) and 11 Control patients received GM(1) 300 mg or placebo, two doses intravenously, before nonemergency CS-CPB. Independent examiners administered structured neurological examinations and neuropsychological test batteries at Baseline and 1 day (Acute Postop; neurological only), 1 week (Early F/U), and greater than or equal to 6 months (Long-term F/U) postoperatively; using defined procedures they employed ordinal Clinical Change Scores (CCSs) to quantify neurological cerebral, neurological noncerebral, and neuropsychological performance changes. Several methods to analyze CCSs and neuropsychological test score changes were evaluated. Results The most sensitive indicators were the mean Acute Postop Neurologist's CCS-Cerebral (P<10(-5)) and the mean Early F/U Neuropsychologist's CCS (P<.01), with statistically nonsignificant differences favoring GM(1). No significant mean changes in Neurologist's CCS-Noncerebral or any Long-term F/U CCSs occurred. CCS distributions and neuropsychological test score mean changes showed similar temporal patterns, with less sensitivity to change. When, as usual in prior CS-CPB studies, impairment was defined by neuropsychological test score declines (increases ignored), results were spurious. Conclusions The strokelike cerebral dysfunction (maximal acutely, with eventual recovery) that occurs after CS-CPB is useful to screen NPAs for clinical efficacy. CCSs based on detailed neurological examination and neuropsychological testing are sensitive measures: refinement of this approach should enhance the efficiency of the CS-CPB model. Further testing of GM(1) is warranted.