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Clot lysis is desirable in patients with thrombi in arteries and arterioles by a safe rapidly-acting thrombolytic agent. Ancrod cleaves fibrinogen; the resulting circulating ancrod-fibrin stimulates fibrinolysis. Ancrod action and effect were studied in 20 patients with acute developing stroke in a double-blind, placebo-controlled study. Patients were randomly assigned to one of two treatment groups, and received either normal saline or ancrod 0.5 mu/kg in normal saline administered as a constant-rate intravenous infusion over 6 hours. Subsequent doses of ancrod (or saline placebo) were determined daily thereafter for a total treatment period of 7 days. Neither bleeding nor re-thrombosis occurred within the 90 day follow-up period. That ancrod acted rapidly was shown by a significant decrease in functional plasminogen activator inhibitor (PA-I) within 60 minutes, and by significant elevations of fibrin(ogen) degradation products (FDP) and D-dimer within 3 and 4 hours. The biological effect of fibrinolysis in ancrod infused patients was demonstrated by a greater improvement in stroke score when compared to those infused with saline.

To evaluate the safety and possible efficacy of high-dose naloxone for the treatment of acute cerebral ischemia, 38 patients received a loading dose of 160 mg/m2 over 15 minutes followed by a 24-hour infusion at the rate of 80 mg/m2/hr. Nausea and/or vomiting were common side effects. Naloxone was discontinued in seven patients (because of hypotension in one, bradycardia and hypotension in two, myoclonus in one, focal seizures in two, and hypertension in one); all seven patients responded to treatment and no permanent sequelae to naloxone were noted. Twelve of the 38 patients showed early neurologic improvement (by completion of the naloxone loading dose). However, there was no correlation between such a loading dose response and clinical outcome at 3 months. Our experience suggests that naloxone is safe at the dose used, but data for efficacy are inconclusive.

Four patients with symptoms and signs of brain stem ischemia due to occlusive disease of the vertebrobasilar system and one patient with similar cerebrovascular disease who was thought to be prone to brain stem stroke underwent a microvascular anastomosis between the occipital artery and the caudal loop of the posterior inferior cerebellar artery. There was no morbidity of mortality and neurologically all patients improved. Post-operative angiograms showed patent anastomosis in all the patients and improved circulation in three. This new operation may prove beneficial in a selected group of stroke patients who suffer from vertebrobasilar insufficiency and cannot be treated with gross surgical techniques.

The standard of care for acute thromboembolic stroke is changing rapidly with the advent of new pharmacologic therapies. The deterioration of focal cerebral ischemia to infarction can be lessened with timely restoration of cerebral blood flow. As pharmacologic therapy of acute stroke evolves, emergency physicians will increasingly facilitate its implementation. The purpose of this study was to elucidate those factors significantly affecting the acute stroke patient's emergency department (ED) evaluation time. The pretreatment ED evaluations of 20 patients entered in an ongoing trial of a fibrinolytic agent (ancrod) for acute ischemic stroke were reviewed. Pretreatment screening factors included the assessment of hematologic status, concurrent illness, and potential neoplastic disease or cerebral hemorrhage as the etiology for the neurological deficit. The following factors had a statistically significant effect on pretreatment evaluation time (range, 2.6 to 11.4 hours) by multiple linear regression analysis: time from arrival until bleeding time completed (P less than .005), time from arrangement of computed head tomography until its completion (P less than .05), chosen site of treatment (ED v neurological step-down unit; P less than .005), order of patient entry (P less than .01), and time from arrival until completion of fibrinogen level assay (P less than .05). These results emphasize the need to coordinate and streamline the clinical evaluation process. The use of the ED as the site of treatment, abbreviating the time until pharmacologic therapy, has not been previously documented. Expedient completion of an evaluation compatible with safe pharmacologic therapy of acute ischemic stroke will dictate the time of definitive therapy. These results should assist other institutions considering rapid pharmacologic therapy for acute ischemic stroke.

The hyperdense middle cerebral artery sign (HMCAS) is recognized as a CT finding that indicates thrombus or embolus within the middle cerebral artery. The incidence and significance of this sign are quantitatively evaluated in 50 patients entered into experimental drug studies for treatment of cerebral infarction.

We designed a 15-item neurologic examination stroke scale for use in acute stroke therapy trials. In a study of 24 stroke patients, interrater reliability for the scale was found to be high (mean kappa = 0.69), and test-retest reliability was also high (mean kappa = 0.66-0.77). Test-retest reliability did not differ significantly among a neurologist, a neurology house officer, a neurology nurse, or an emergency department nurse. The stroke scale validity was assessed by comparing the scale scores obtained prospectively on 65 acute stroke patients to the patients' infarction size as measured by computed tomography scan at 1 week and to the patients' clinical outcome as determined at 3 months. These correlations (scale-lesion size r = 0.68, scale-outcome r = 0.79) suggested acceptable examination and scale validity. Of the 15 test items, the most interrater reliable item (pupillary response) had low validity. Less reliable items such as upper or lower extremity motor function were more valid. We discuss methods for improving the reliability and validity of brief examination scales to be used in stroke therapy trials.

Intra-arterial endoscopy of the common carotid artery and its bifurcation was accomplished in 100 random autopsy cases. Resulting still photographs and movies reveal fatty dots and streaks, elevated gelatinous plaques, mural thrombi, thrombosis, ulcerations and ulcers with or without organizing thrombi, boulder and stalagmite-shaped lesions, bridging and elevated plaques in the carotid artery. These findings suggest possible explanations for some surgical and angiographic complications, bruits, transient ischemic attacks or strokes following reportedly normal carotid angiograms. Endoscopy aids in understanding the theories of inception, progression and sequelae of atherosclerosis,the role of risk factors, trauma and hemodynamics.

We studied the ability of serum glucose concentration and neurologic deficits at admission in predicting the outcome of acute cerebral ischemia in 65 patients given naloxone. Among our patients, the volume of infarction on computed tomograms and outcome were strongly related to the severity of neurologic deficits found at admission. Neither a history of diabetes nor hyperglycemia when added to the results of the initial neurologic assessment improved prediction of outcome after acute cerebral infarction.

Although time has been recognized as a critical factor in the treatment of other arterial occlusive disorders, it has been an underemphasized variable in the treatment of acute stroke. Animal models of cerebral arterial occlusion have demonstrated that neurologic recovery is more likely the shorter the duration of occlusion. Complete recovery does not occur if the occlusion persists more than six hours. Prior trials have only rarely begun treatment within six hours of stroke onset. Over the past five years, we have participated in three stroke trials and have tried to identify factors that lead to delays in treatment. Factors that affect the time from stroke onset to arrival at the hospital include recognition of acute stroke by the patient, prehospital care personnel, and physicians. After arrival at the hospital, factors that can significantly delay treatment include the time to obtain computed tomography and the site of treatment (emergency department vs ICU). With proper attention, the time from patient arrival until treatment should be less than one hour. Future efforts should be directed toward reducing the time from stroke onset until arrival at the hospital. Education of the public, high-risk patients, prehospital care providers, and physicians may aid in these efforts.

Stroke therapy trials have historically allowed for late patient entry (ie, within 24 to 48 hours from stroke onset) despite evidence suggesting the importance of early intervention. Experimental studies of cerebral infarction suggest treatment may be most effective when begun within three hours and may be only marginally effective when begun after 12 hours. Lysis of an acute intra-arterial thrombus in the setting of thrombolytic therapy is also time dependent. We describe an ongoing dose-escalation study of tissue plasminogen activator (tPA) as ultra-early therapy for cerebral infarction. The protocol requires that hemorrhage be ruled out by computed tomography scan of the brain prior to tPA infusion, and the infusion must begin within 90 minutes of symptom onset. The two primary goals of the study are to assess safety and potential efficacy. Preliminary results from the study and the future of ultra-early stroke intervention are discussed.

As part of a prospective therapy study of 65 patients with acute, nonhemorrhagic, cerebral infarction, computed tomographic scans of the head were obtained at admission, 7-10 days, and 3 months. The scans were analyzed for the presence, site, size, and volume measurement of the infarction. At 7-10 days, the mean infarction volume as measured by computed tomography was 55 cm3 or about 4 x 4 x 3.5 cm (range = 0-507 cm3). At 3 months, the mean infarction volume decreased by 25% to 41 cm3. For the 26 scans showing infarction at the time of admission, the mean lesion volume was 33 cm3 at admission, 51 cm3 at 7-10 days, and 49 cm3 at 3 months. With lesion size at 7-10 days expressed as percentage of total brain volume, the mean infarction size was only 5%. Of the 49 patients with lesions revealed by computed tomography at 7-10 days, 20 had an infarction of 1% or less of total brain volume, while only six had an infarction of 20% or more of total brain volume. The lesion volumes as measured by the 7-10-day computed tomography correlated with the neurologic examination scores on admission (Spearman's rank-order correlation = 0.78) and with the scores at 1 week (Spearman's rank-order correlation = 0.79).

Ultrasonic echoarteriography is a noninvasive method of visualizing extracranial arteries in health and disease. The real-time echoscanning device developed at the University of Cincinnatti utilizes a 5-MHz (center frequency) pulse-echoimaging system. B-mode pictures of the tissues studied are obtained and displayed on a video screen, real-time operation being provided by the scanning mechanism operating at 30 frames per second. In our experiments internal arterial damage produced by surgically scraping the intima induced experimental thrombosis in nine carotid in nine carotid and three femoral arteries in dogs. Where pathologically demonstrated, the thrombi were demonstrated by ultrasonic echoarteriography in every instance. Echoarteriography seemed more sensitive than contrast arteriography in the detection of a partially occlusive thrombus.

Ancrod has been used in Europe for over 15 years for peripheral vascular disease, deep vein thrombosis, and central retinal venous thrombosis, and in patients at risk for thromboembolism. In a double-blind, randomized, placebo-controlled study at University Hospitals in Cincinnati, 20 acute cerebral infarction patients received a series of IV infusions of ancrod (ten) or placebo (ten) for seven days. Early fibrinolysis with a small decrease in fibrinogen was observed, and d-dimers were elevated at four hours, indicating early clot lysis. At three months, patients with moderate to severe strokes (less than 40 on the Scandinavian Stroke Scale) in the ancrod group showed average improvement by a factor of 3 over the placebo group. No bleeding, abnormal laboratory results, or deaths occurred, but ancrod was discontinued in one patient who had seizures. As a result of this study, a double-blind multicenter international clinical trial to further assess the safety and effectiveness of ancrod is being planned.

The effects of high dose naloxone in humans have not been studied extensively. We treated 36 patients who had acute ischemic cerebral infarction with high doses of naloxone to evaluate potential efficacy and toxicity. All patients were treated with a 160-mg/m2 (4-mg/kg) loading dose followed by 80 mg/m2.h (2 mg/kg.h) x 24 h. There were no statistically significant changes in group mean arterial pressure, respiratory rate, or heart rate in response to the loading dose or infusion, although clinically significant changes did occur in four patients. Twenty-three patients had adverse reactions possibly related to naloxone, the most common of which were nausea (n = 20), bradycardia and/or hypotension (n = 3), myoclonus (n = 1), and hypertension (n = 1). Seven patients had naloxone discontinued for possible adverse reactions. All adverse reactions abated with discontinuation of naloxone and/or pharmacologic therapy when indicated. No deaths were attributable to naloxone treatment. High dose naloxone appears to be well tolerated in the majority of elderly patients with acute cerebral infarction.

A specially designed acoustic stethoscope electronic-computer-analysis system has repeatedly detected and identified angiographically demonstrated anteriorly located intracranial aneurysms by their characteristic signals. The system has detected and measured clinically significant disease in the carotid siphon and bifurcation, even in cases with normal angiograms, and has recorded the onset and disappearance of cerebral vasospasm. Our data suggests that an aneurysm may act as a flexible Helmholtz resonator, possibly being driven by vortex shed or turbulence. Our goal is the development of a safe, non-invasive method by which the physician could investigate warning symptoms of aneurysms, cerebral vasospasm, and arterial disease in order to recommend preventive surgery or medical treatment early before the patient's condition might deteriorate. Individual cases, falsely positive and negative results are discussed.

A dose-escalation study was performed in 27 patients to determine the highest safe and potentially optimal dose of naloxone for treatment of acute cerebral ischemia. All patients received a bolus of naloxone followed by a continuous 24 hour infusion at an hourly rate 50% of the bolus. Loading doses ranged from 2.5 to 200 mg/m2. Total patient doses ranged from 52.3 to 4978 mg. No major dose-related side effects occurred. This study was not designed to determine naloxone's efficacy in stroke, but transient or sustained improvement was observed in 13 patients. Three patients' neurological condition worsened within three hours after the naloxone was discontinued. Our experience suggests that further therapeutic trials of naloxone are worthwhile.