Biomedical subjects
Publications and source records attributed to J R Marler.
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BACKGROUND AND PURPOSE: As part of the recruitment efforts for the National Institutes of Health Tissue Plasminogen Activator Pilot Study, public education and awareness campaigns were conducted to encourage early hospital arrival. We evaluated the change in arrival times during the course of the study for all stroke patients, including those who were not entered into study. METHODS: Data were gathered on all patients presenting within 24 hours of stroke onset to all of the study hospitals. Coincident with the start of the study, educational and promotional programs, which stressed signs and symptoms of stroke and the need to call 911, were presented to physicians, paramedical personnel, and the public. The study was divided into four quartiles to analyze differences in time to hospital arrival and use of 911. RESULTS: Of 2099 patients screened, time data were available on 1116. During the course of the study, the mean time from symptom onset to hospital arrival declined significantly (3.2 hours versus 1.5 hours). Patients arrived for treatment sooner at community hospitals than at university/teaching hospitals. The use of 911 increased from 39% in the first quartile of the study to 60% in the fourth quartile. This was a consistent finding in all study sites. Increased use of 911 was seen almost exclusively in patients with nonhemorrhagic stroke. CONCLUSIONS: Times from stroke onset to hospital arrival decreased significantly during the course of the National Institutes of Health Tissue Plasminogen Activator Pilot Study. Significantly increased use of 911 was the likely major explanation for the shortened arrival times. The decrease in arrival times may be a consequence of the public and professional education programs conducted at all study sites.
BACKGROUND AND PURPOSE: Several studies are currently evaluating tissue-type plasminogen activator (TPA) as a potential therapy in acute ischemic stroke. The possibility of inducing intracranial hematomas, however, introduces an important concern into ultimate evaluation of risk and benefit. This retrospective analysis sought to identify factors associated with intracranial hematoma formation in a pilot phase 1 study of TPA for stroke. METHODS: Ninety-four patients received TPA within 3 hours of the onset of an acute ischemic stroke. Five of these patients developed a symptomatic intracerebral hematoma: 3 of 74 (4%) among patients treated within 90 minutes of stroke onset and 2 of 20 (10%) among those treated at 91 to 180 minutes. Three of the 5 died within 2 weeks. The analysis investigated associations between clinical factors and intracerebral hematomas. RESULTS: Factors significantly related to the development of an intracerebral hematoma were TPA dose and diastolic hypertension. Intracerebral hematomas developed in 4 (18%) of 22 patients given a TPA dose of at least 0.90 mg/kg versus only 1 hematoma in the remaining 72 patients (1%; P < .02, Fisher's exact test). Four (18%) of 22 patients who had initial diastolic blood pressures of at least 100 mm Hg suffered an intracerebral hematoma versus only 1 (1%) of 72 patients (P < .02) with lower initial diastolic pressures. CONCLUSIONS: Since the study was not designed to test specific safety hypotheses, results must not be overinterpreted. Nonetheless, these data emphasize the need for caution in both patient and dose selection for further studies of thrombolytic agents in stroke.
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BACKGROUND: Stroke is a leading cause of death and disability in the United States. Although new treatments are being studied, most must be given early in the course of stroke to be effective. This study was performed to identify factors associated with early hospital arrival in patients with stroke. METHODS: As part of the National Institute of Neurologic Disorders and Stroke Tissue-Type Plasminogen Activator Pilot Study, information from patients, patients' families, or, most commonly, the medical record was gathered on all patients presenting to the hospital within 24 hours of the onset of stroke. A total of 14 hospitals participated. Three were university hospitals, and 11 were community hospitals with and without university affiliation. The main outcome measure was the time from stroke onset to hospital arrival. RESULTS: Of 2099 patients screened, adequate time data were available in 1159. Thirty-nine percent presented to the hospital 90 minutes or less after symptom onset and 59% within 3 hours. Early hospital arrival after stroke was greatly influenced by the type of first medical contact and, to a lesser degree, by the patient's location at the time of the stroke and the time of the day at which the stroke occurred. Hospital arrival was fastest in patients using 911 as their first medical contact (mean, 155 minutes; median, 84 minutes) vs their personal physician (mean, 379 minutes; median, 270 minutes; P < .0001) or a study hospital (mean, 333 minutes; median, 212 minutes; P < .0001). Time from symptom onset to arrival was longer for patients having the stroke at night compared with patients having a stroke in the morning (P < .05), in the afternoon (P < .01), or in the evening (P < .0001). Time to hospital arrival was significantly longer for patients having the stroke at home than for patients having the stroke at work (P < .01) or in an unknown place (P < .05). Gender, age, race, and presence of brain hemorrhage had no significant effect. CONCLUSIONS: As many as 50% of patients with stroke arrive at the hospital within 3 hours of symptom onset. Our data indicate that strategies to increase the use of 911 systems may have a high yield with regard to recruitment into urgent treatment protocols for stroke.
BACKGROUND AND PURPOSE: Early thrombolytic therapy with recombinant tissue-type plasminogen activator is a theoretically attractive approach to the treatment of acute focal cerebral ischemia. In preparation for a larger multicenter trial, three centers piloted a protocol for a randomized, double-blind, placebo-controlled trial of intravenous recombinant tissue-type plasminogen activator begun within 3 hours of the onset of symptoms of acute stroke to test its feasibility and to explore trends. METHODS: Eligible patients had pretreatment computed tomographic scanning, gave informed consent, and began treatment with either 0.85 mg/kg recombinant tissue-type plasminogen activator or placebo as soon as possible, but no later than 180 minutes after stroke onset. Patients were stratified by whether treatment was begun within 90 minutes or 91 to 180 minutes from onset. The primary end point was the proportion of patients in each group who improved by 4 or more points on the National Institutes of Health Stroke Scale at 24 hours, as determined by a separate blinded evaluator. RESULTS: Twenty-seven patients were randomized: 20 (10 recombinant tissue-type plasminogen activator, 10 placebo) within 90 minutes, and 7 (4 recombinant tissue-type plasminogen activator, 3 placebo) from 91 to 180 minutes. Median baseline Stroke Scale scores were 16 (minimum = 5, maximum = 26) for the recombinant tissue-type plasminogen activator-treated group and 11 (minimum = 3, maximum = 21) for the control subjects in the group treated within 90 minutes. Six patients treated with recombinant tissue-type plasminogen activator within 90 minutes improved by 4 or more points at 24 hours compared with 1 patient in the placebo group (P < .05, Fisher's Exact Test). Two patients in each group in the 91- to 180-minute arm improved. One fatal intracerebral hemorrhage occurred in the placebo group. CONCLUSIONS: A randomized, double-blind, placebo-controlled trial of recombinant tissue-type plasminogen activator very early in acute stroke is feasible. Preliminary observations suggest that recombinant tissue-type plasminogen activator treatment within 90 minutes may be associated with early neurological improvement. Larger studies are needed so that the potentially serious short-term risks of this treatment can be assessed in relation to meaningful long-term benefit.
BACKGROUND AND PURPOSE: Our purpose was to describe and further understand the determinants of the time of onset of parenchymatous intracerebral hemorrhage and subarachnoid hemorrhage in patients enrolled in the Stroke Data Bank. METHODS: We analyzed the observed times of onset of intracerebral hemorrhage (n = 237 patients) and subarachnoid hemorrhage (n = 243 patients) compared with expected times of onset if the probability of onset was constant across all time intervals. We also analyzed the role of clinical features (if any) in explaining the findings. RESULTS: For intracerebral hemorrhage, 52.5% of patients reported onset times between 0600 hours and 1400 hours, with peak onset between 1000 and 1200 hours (chi 2 = 62.94, df = 11, p less than 0.001). Patients with subarachnoid hemorrhage were more likely to lack a history of hypertension compared with patients who had intracerebral hemorrhage (chi 2 = 23.3, df = 1, p less than 0.001). Patients with subarachnoid hemorrhage were more likely to have more uniform onset time throughout the day (chi 2 = 12.92, df = 7, p = 0.074). However, subarachnoid hemorrhage patients with a history of hypertension were more likely to have peak onset times in mid-to-late morning compared with patients without such a history (chi 2 = 35.25, df = 10, p less than 0.001). The nonuniformity of onset times for intracerebral hemorrhage persisted even if patients with unknown onset times were treated as through their onset times were randomly distributed between 0000 and 0800 hours. Seasonal periodicity and the relation between initial systolic or diastolic blood pressure and time of onset for either type of hemorrhage were not observed. CONCLUSIONS: Our data suggest that the time of onset for both intracerebral hemorrhage and subarachnoid hemorrhage patients with a history of hypertension is similar to the diurnal variation in blood pressure.
BACKGROUND AND PURPOSE: Renewed interest in thrombolytic therapy as potential treatment for patients with acute ischemic stroke prompted a dose-escalation safety study of tissue plasminogen activator in patients with very early (less than or equal to 90 minutes; see Part I) neurological symptoms. To test whether this stringent entry window might be safely lengthened, a second study was organized to test tissue plasminogen activator in patients with symptoms of 91-180 minutes' duration before treatment. METHODS: An open-label, dose-escalation design was chosen. Eligible patients had pretreatment head computerized tomographic scanning and treatment begun 91-180 minutes from stroke onset. End points examined included the incidence of symptomatic and asymptomatic intracranial hemorrhage, other bleeding, and clinical outcome at 2 hours, 24 hours, and 3 months after treatment. RESULTS: Twenty patients were treated at three hospitals in 13 months. Three doses were tested: 0.6 mg/kg (n = 8), 0.85 mg/kg (n = 6), and 0.95 mg/kg (n = 6). Two patients, one each at the two highest doses, sustained fatal intracerebral hemorrhages. Three patients (15%) improved by greater than or equal to 4 points on the National Institutes of Health Stroke Scale by 24 hours. CONCLUSIONS: These observations suggest that tissue plasminogen activator treatment of acute ischemic stroke 91-180 minutes from onset in doses of greater than or equal to 0.85 mg/kg is attended by a risk of intracerebral hemorrhage approximating 17% (range 3-44%, 95% confidence interval). The rate of early neurological improvement observed in this study was small but does not exclude an improvement over the natural history. Future study with placebo control subjects and stratification by time to treatment is indicated.
A circadian pattern for the onset of myocardial and cerebral infarction has been identified. To evaluate this phenomenon further, we analyzed prospectively collected data from 151 patients with acute ischemic stroke. The number of strokes per 6-hour period were the following: midnight to 6 AM, 20 (13%); 6 AM to noon, 86 (57%); noon to 6 PM, 21 (14%); and 6 PM to midnight, 24 (16%). This pattern was not affected by previous use of aspirin. The most frequent time of onset was 6 AM to noon for all subgroups of ischemic stroke: small artery, 71%; cardioembolic, 62%; large artery atherothrombotic, 57%; large artery atheroembolic, 46%; and "other" or unknown cause, 40%. We also investigated the time between awakening and stroke onset in 145 patients and found that 24% of ischemic strokes occurred within the first hour after awakening. Our data demonstrate that an early morning peak exists for all subtypes of stroke. Our data also suggest that the most critical period is the first hour after awakening.
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.
We evaluated the safety and possible efficacy of large doses of the heparinoid ORG 10172 in 57 patients with acute or progressing ischemic stroke. Patients received a loading bolus of the drug followed by a maintenance intravenous infusion for 7 days. The plasma level of ORG 10172 was monitored by the degree of inhibition of coagulation factor Xa. In general, the drug was well tolerated and few hemorrhagic complications occurred. Two patients with large cardioembolic hemispheric strokes had intracranial hemorrhagic complications. Most patients improved during treatment. By 3 months after the stroke, 37 patients (65%) had a favorable outcome (minimal or no residual disability). This study suggests that high-dose intravenous infusions of ORG 10172 can be safely given to patients with acute ischemic stroke.
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The time of onset of ischemic stroke was determined for 1,167 of 1,273 patients during the collection of data by four academic hospital centers between June 30, 1983, and June 30, 1986. More strokes occurred in awake patients from 10:00 AM to noon than during any other 2-hour interval. The incidence of stroke onset declined steadily during the remainder of the day and early evening. The onset of stroke is least likely to occur in the late evening, before midnight.
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.
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).
An intravenous infusion of a low molecular weight heparinoid, with a reduced risk of hemorrhage, may be an alternative to heparin in the management of acute ischemic stroke. To evaluate this hypothesis, we studied the safety of the heparinoid, ORG 10172, in a dose-escalation study in 26 patients. The drug was administered as a loading bolus followed by a 7-day infusion in five rates with target anti-factor Xa levels from 0.2 to 1.0 U/ml. The drug was well tolerated; no major bleeding complications or thrombocytopenia occurred. There were no deaths or hemorrhagic transformation of cerebral infarctions. The results indicate that ORG 10172 at doses to achieve a level of 1.0 U/ml or less may be used safely in management of acute cerebral infarction.