Evaluation of medical therapies of acute ischemic stroke

Abstract

The pharmacological approach to acute ischemic stroke has been characterized so far by negative results, thus generating a generalized pessimistic opinion on the possibihties of effective treatment. Indeed, drug efficacy would have been better assessed and generated more enthusiasm if clinical trials had been conducted in accordance with more adequate guidelines based on the pathophysiology of brain circulation The essential ingredients for correctly planning a study on acute stroke therapy are the following: (a) knowledge about the mechanisms of ischemic injury at brain tissue level; (b) availability of pharmacologic agents influencing those mechanisms based on experimental data; (c) possibilities of clinical application, within appropriate temporal limits and (d) organization of an adequate team, including multiple cooperating clinical services as required. Controversies on the reliability of animal models are reported in the literature. Some authors emphasize the unavailability of models reproducing human disease (1), whereas others, and we are among them, believe that experimental models are important, since they provide useful indications for clinical application (2). Relevance to new therapeutic approaches to ischemic stroke treatment should also be recognized because current epidemiological studies suggest an increase in stroke incidence in the 1980s (3). Experimental evidence reveals the existence of an ischemic penumbra around the infarcted area in which neurons, although functionally inhibited by cerebral blood flow reduction, are liable to complete recovery if blood flow is promptly restored (4). Hence, a time is available for short-lasting therapeutic window, whose temporal limits are as yet not completely defined. According to pathological evidence, after transient ligation of the middle cerebral artery (MCA) in the cat, cerebral infarction develops 0I11y when the occlusion lasts over 2 h, and reaches its maximum severity after 6 h (5). Obviously, a residual collateral flow allows such persistence of tissue viability. One can argue that young healthy cats are different from atherothrombotic stroke patients, and Caplan and Stein correctly remind us not to downgrade the etiopathogenic aspects of individual cases (6). Nevertheless, the time interval between onset and treatment remains fundamental, as good results of early thrombolysis in myocardial ischemia have demonstrated (7). This interval will depend, among other factors, on the residual (collateral) flow in the early period of cerebral ischemia. This issue has been analyzed in a consecutive series of 80 acute ischemic strokes in the territory of the MCA (8). Within 6 h from onset, each enrolled patient was submitted to transcranial Doppler sonography (TCD) and cerebral angiography. Intracranial occlusions at angiography probably related to embolic sources were found in 58 cases (66%). Of 40 occluded patients followed up by TCD, 11 showed spontaneous recanalization. None had clinical improvement. Patients with occlusion were considered to have good collateral circulation when the vessels distal to occlusion were fully visualized at angiography within 5 s of the end of contrast medium injection. Not surprisingly, those with poor or absent collateral filling had the worst clinical outcome.