EVALUATING NEUROPROTECTIVE AGENTS FOR CLINICAL ANTIISCHEMIC BENEFIT USING NEUROLOGICAL AND NEUROPSYCHOLOGICAL CHANGES AFTER CARDIAC-SURGERYUNDER 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 effectiv e in acute experimental cerebral ischemia in animals. None have proven effective in human stroke trials. Even short treatment delays cause s ubstantial 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 d ysfunction from CS-CPB in a double-blind trial of the NPA GM, ganglios ide. Methods Eighteen GM(1) and 11 Control patients received GM(1) 300 mg or placebo, two doses intravenously, before nonemergency CS-CPB. I ndependent examiners administered structured neurological examinations and neuropsychological test batteries at Baseline and 1 day (Acute Po stop; neurological only), 1 week (Early F/U), and greater than or equa l to 6 months (Long-term F/U) postoperatively; using defined procedure s they employed ordinal Clinical Change Scores (CCSs) to quantify neur ological cerebral, neurological noncerebral, and neuropsychological pe rformance changes. Several methods to analyze CCSs and neuropsychologi cal test score changes were evaluated. Results The most sensitive indi cators were the mean Acute Postop Neurologist's CCS-Cerebral (P<10(-5) ) and the mean Early F/U Neuropsychologist's CCS (P<.01), with statist ically nonsignificant differences favoring GM(1). No significant mean changes in Neurologist's CCS-Noncerebral or any Long-term F/U CCSs occ urred. CCS distributions and neuropsychological test score mean change s showed similar temporal patterns, with less sensitivity to change. W hen, as usual in prior CS-CPB studies, impairment was defined by neuro psychological test score declines (increases ignored), results were sp urious. Conclusions The strokelike cerebral dysfunction (maximal acute ly, with eventual recovery) that occurs after CS-CPB is useful to scre en NPAs for clinical efficacy. CCSs based on detailed neurological exa mination and neuropsychological testing are sensitive measures: refine ment of this approach should enhance the efficiency of the CS-CPB mode l. Further testing of GM(1) is warranted.