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(Stroke. 1996;27:858-874.)
© 1996 American Heart Association, Inc.
Articles |
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 GM1 Ganglioside
From the Departments of Neurology and Surgery (A.T.C.), New York University Medical Center (NY).
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 
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.
Key Words: cardiopulmonary bypass • cerebrovascular disorders • clinical trials • cognition • gangliosides • neuroprotection
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