Faculty Bibliography

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 predeterminable time point and should permit efficient screening of NPAs for stroke benefit. We sought to develop sensitive methods to assess dysfunction from CS-CPB in a double-blind trial of the NPA GM1 ganglioside. METHODS: Eighteen GM1 and 11 Control patients received GM1 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 > or = 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 GM1. 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 GM1 is warranted

GM1 ganglioside, a normal constituent of plasma membranes, has demonstrated neuroprotective benefit when given prior to the induction of experimental cerebral ischaemia. GM1 has also shown beneficial effects in in vivo and in vitro studies on CNS tissue injured by prior ischaemia. Ischaemic mechanisms have been implicated in alteration of neuropsychological functioning reported after open-heart surgery. In this placebo-controlled double-blind study, 28 cognitively and neurologically normal adults undergoing nonemergency coronary artery bypass graft and/or heart valve replace- ment surgery were pre-operatively given two doses of GM1 or placebo (on the day before and the day of surgery). A neuropsychological test battery (13 tests yielding 22 scores) was administered prior to any study medication, approximately one week after surgery and after six months. Pre- operative and one-week testing have been completed; six-months testing continues (no treatment codes broken). As a measure of change in neuropsychological functioning, a 'net change' score was calculated for each patient for the one-week postoperative versus baseline comparison. The net change score equals the number of individual test scores improved by at least one SD minus the number of test scores worsened by at least one SD. The average net change score was -2.36. The average numbers of test scores improved and worsened by at least one SD were, respectively, 2.46 and 4.82 per patient. Seven patients (25%) had a positive net change score, 18 (64%) a negative net change score, and three ( 11 % ) a net change score of zero