Ensuring patient safety in clinical trials for treatment of acute stroke.
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Clinical Trials as Topic↗
Biomedical subjects
K J Becker
Publications and source records attributed to K J Becker.
Intra-arterial urokinase for acute ischemic stroke: factors associated with complications.
The authors abstracted the records of 43 patients treated with intra-arterial urokinase for acute ischemic stroke to identify predictors of serious complications. Sixteen (37%) had such a complication. Higher urokinase dose (>1.5 x 10(6) U), higher mean arterial blood pressure before treatment (>130 mm Hg), basilar occlusive strokes, and severe strokes were most predictive of these complications. Although urokinase is no longer manufactured, these findings identify patients at risk for complications from other intra-arterial thrombolytics.
Acute Disease↗
Withdrawal of support in intracerebral hemorrhage may lead to self-fulfilling prophecies.
BACKGROUND: Withdrawal of support in patients with severe brain injury invariably leads to death. Preconceived notions about futility of care in patients with intracerebral hemorrhage (ICH) may prompt withdrawal of support, and modeling outcome in patient populations in whom withdrawal of support occurs may lead to self-fulfilling prophecies. METHODS: Subjects included consecutive patients with supratentorial ICH. Radiographic characteristics of the hemorrhage, clinical variables, and neurologic outcome were assessed. Attitudes about futility of care were examined among members of the departments of neurology and neurologic surgery through a written survey and case presentations. RESULTS: There were 87 patients with supratentorial ICH; overall mortality was 34.5% (30/87). Mortality was 66.7% (18/27) in patients with Glasgow Coma Score < or = 8 and ICH volume > 60 cm(3). Medical support was withdrawn in 76.7% (23/30) of patients who died. Inclusion of a variable to account for the withdrawal of support in a model predicting outcome negated the predictive value of all other variables. Patients undergoing surgical decompression were unlikely to have support withdrawn, and surgery was less likely to be performed in older patients (p < 0.01) and patients with left hemispheric hemorrhage (p = 0.04). Survey results suggested that practitioners tend to be overly pessimistic in prognosticating outcome based upon data available at the time of presentation. CONCLUSIONS: The most important prognostic variable in determining outcome after ICH is the level of medical support provided. Withdrawal of support in patients felt likely to have a "poor outcome" biases predictive models and leads to self-fulfilling prophecies. Our data show that individual patients in traditionally "poor outcome" categories can have a reasonable neurologic outcome when treated aggressively.
Aged↗
Inflammation after stroke: is it harmful?
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Animals↗
Targeting the central nervous system inflammatory response in ischemic stroke.
In experimental models of stroke, inflammation appears to contribute to cerebral ischemic injury. Clinical trials that are aimed at limiting the postischemic inflammatory response, however, have thus far had disappointing results. These clinical failures probably reflect the fact that there has been insufficient preclinical data and inadequate trial design, rather than provide evidence against a role for inflammation in ischemic brain injury.
Animals↗
Effects of the AMPA receptor antagonist NBQX on outcome of newborn pigs after asphyxic cardiac arrest.
In neonates, asphyxia is a common cause of neuronal injury and often results in seizures. The authors evaluated whether blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors during asphyxia and early recovery with 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-(F)-quinoxaline (NBQX) ameliorates neurologic deficit and histopathology in 1-week-old piglets. Anesthetized piglets were exposed to a sequence of 30 minutes of hypoxia, 5 minutes of room air ventilation, 7 minutes of airway occlusion, and cardiopulmonary resuscitation. Vehicle or NBQX was administered intravenously before asphyxia (30 mg/kg) and during the first 4 hours of recovery (15 mg/kg/h). Neuropathologic findings were evaluated at 96 hours of recovery by light microscopic and cytochrome oxidase histochemical study. Cardiac arrest occurred at 5 to 6 minutes of airway occlusion, and cardiopulmonary resuscitation restored spontaneous circulation independent of treatment modalities in about 2 to 3 minutes. Neurologic deficit over the 96-hour recovery period was not ameliorated by NBQX. Seizure activity began after 24 to 48 hours in 7 of 10 animals with vehicle and in 9 of 10 of animals with NBQX. In each group, four animals died in status epilepticus. Neuropathologic outcomes were not improved by NBQX. The density of remaining viable neurons was decreased in parietal cortex and putamen by NBQX treatment. Metabolic defects in cytochrome oxidase activity were worsened by NBQX treatment. Seizure activity during recovery was associated with reduced neuronal viability in neocortex and striatum in piglets from both groups that survived for 96 hours. This neonatal model of asphyxic cardiac arrest and resuscitation generates neurologic deficits, clinical seizure activity, and selective damage in regions of basal ganglia and sensorimotor cortex. In contrast to other studies in mature brain, AMPA receptor blockade with NBQX failed to protect against neurologic damage in the immature piglet and worsened postasphyxic histopathologic outcome in neocortex and putamen.
Animals↗
Extravasation of radiographic contrast is an independent predictor of death in primary intracerebral hemorrhage.
BACKGROUND AND PURPOSE: Hematomas that enlarge following presentation with primary intracerebral hemorrhage (ICH) are associated with increased mortality, but the mechanisms of hematoma enlargement are poorly understood. We interpreted the presence of contrast extravasation into the hematoma after CT angiography (CTA) as evidence of ongoing hemorrhage and sought to identify the clinical significance of contrast extravasation as well as factors associated with the risk of extravasation. METHODS: We reviewed the clinical records and radiographic studies of all patients with intracranial hemorrhage undergoing CTA from 1994 to 1997. Only patients with primary ICH were included in this study. Univariate and multivariate logistic regression analyses were performed to determine the associations between clinical and radiological variables and the risk of hospital death or contrast extravasation. RESULTS: Data were available for 113 patients. Contrast extravasation was seen in 46% of patients at the time of CTA, and the presence of contrast extravasation was associated with increased fatality: 63.5% versus 16.4% in patients without extravasation (P=0.011). There was a trend toward a shorter time (median+/-SD) from symptom onset to CTA in patients with extravasation (4.6+/-19 hours) than in patients with no evidence of extravasation (6.6+/-28 hours; P=0.065). Multivariate analysis revealed that hematoma size (P=0.022), Glasgow Coma Scale (GCS) score (P=0.016), extravasation of contrast (P=0.006), infratentorial ICH (P=0.014), and lack of surgery (P<0.001) were independently associated with hospital death. Variables independently associated with contrast extravasation were hematoma size (P=0.024), MABP >120 mm Hg (P=0.012), and GCS score of </=8 (P<0.005). CONCLUSIONS: Contrast extravasation into the hematoma after ICH is associated with increased fatality. The risk of contrast extravasation is increased with extreme hypertension, depressed consciousness, and large hemorrhages. If contrast extravasation represents ongoing hemorrhage, the findings in this study may have implications for therapy of ICH, particularly with regard to blood pressure management.
Adolescent↗
Thrombolysis for acute ischemic stroke.
Data generated from randomized controlled trials in the last decade have shown that acute intervention can improve neurologic outcome in patients with ischemic stroke. This article reviews recent studies of systemic and intra-arterial thrombolysis for cerebrovascular disease in detail. Important considerations for treating patients with thrombolysis are explored, and theoretic and practical differences in the approach to patients with anterior and posterior circulation disease are highlighted.
Brain Ischemia↗
Inflammation and acute stroke.
There are now overwhelming data suggesting that inflammation contributes to cerebral ischemic injury. The mechanisms that lead to the inflammatory response which follows stroke, however, are not fully understood. This review will highlight the most recent advances in our knowledge as well as the early experience of using anti-inflammatory strategies to treat acute stroke.
Animals↗
Epidemiology and clinical presentation of aneurysmal subarachnoid hemorrhage.
This article provides an overview of the epidemiology and acquired risk factors associated with intracranial aneurysms and aneurysmal subarachnoid hemorrhage. The clinical presentation of subarachnoid hemorrhage is reviewed and compared to important conditions that can mimic aneurysm rupture, such as thunderclap headache and perimesencephalic nonaneurysmal subarachnoid hemorrhage.
Diagnosis, Differential↗
Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia.
Immune mechanisms contribute to cerebral ischemic injury. Therapeutic immunosuppressive options are limited due to systemic side effects. We attempted to achieve immunosuppression in the brain through oral tolerance to myelin basic protein (MBP). Lewis rats were fed low-dose bovine MBP or ovalbumin (1 mg, five times) before 3 h of middle cerebral artery occlusion (MCAO). A third group of animals was sensitized to MBP but did not survive the post-stroke period. Infarct size at 24 and 96 h after ischemia was significantly less in tolerized animals. Tolerance to MBP was confirmed in vivo by a decrease in delayed-type hypersensitivity to MBP. Systemic immune responses, characterized in vitro by spleen cell proliferation to Con A, lipopolysaccharide, and MBP, again confirmed antigen-specific immunologic tolerance. Immunohistochemistry revealed transforming growth factor beta1 production by T cells in the brains of tolerized but not control animals. Systemic transforming growth factor beta1 levels were equivalent in both groups. Corticosterone levels 24 h after surgery were elevated in all sham-operated animals and ischemic control animals but not in ischemic tolerized animals. These results demonstrate that antigen-specific modulation of the immune response decreases infarct size after focal cerebral ischemia and that sensitization to the same antigen may actually worsen outcome.
Animals↗
Arterial changes after thrombolysis and percutaneous transluminal angioplasty in vertebrobasilar thrombosis.
We present clinicopathologic findings in a patient treated with intraarterial thrombolysis and angioplasty for vertebrobasilar thrombosis. Autopsy revealed a marked inflammatory infiltrate within the vertebral artery at the site of catheter manipulation. This finding may have important implications for the use of interventional angiography in cerebrovascular disease.
Angioplasty, Balloon↗
Vertebrobasilar ischemia.
Advances in stroke treatment are discussed in the context of vertebrobasilar ischemia. The anatomy of the vertebral and basilar arteries and the pathophysiology of posterior circulation stroke are reviewed. The diagnosis and management of patients with vertebrobasilar occlusion is emphasized and the controversies surrounding the use of intra-arterial and intravenous thrombolytic therapy in posterior circulation disease are addressed.
Basilar Artery↗
Vertebrobasilar thrombosis: diagnosis, management, and the use of intra-arterial thrombolytics.
OBJECTIVES: To review the diagnosis and management of vertebrobasilar thrombosis and to discuss the use of thrombolytics in the treatment of this disease. DATA SOURCES: Selected references discussing epidemiology, anatomy, pathophysiology, diagnosis, therapy, and rehabilitation of vertebrobasilar occlusive disease. STUDY SELECTION: Studies addressing acute intervention and outcome in the therapy of vertebrobasilar thrombosis were reviewed. DATA EXTRACTION: Only those studies with angiographic documentation of arterial thrombosis and, in the case of thrombolysis, recanalization, were considered valid. DATA SYNTHESIS: Thrombosis of the vertebrobasilar system is a highly fatal disease and should be treated as a neurologic emergency. The key to effective management depends on early recognition of the symptom complex and a thorough understanding of the anatomy and pathophysiology of the disease process. CONCLUSIONS: A timely, integrated, multidisciplinary approach to the patient with vertebrobasilar thrombosis can improve outcome. The use of thrombolytics in the treatment of vertebrobasilar occlusion holds promise but the benefits have not yet been proven in a controlled, randomized study.
Humans↗
Intraarterial thrombolysis in vertebrobasilar occlusion.
PURPOSE: To report our experience using intraarterial thrombolysis in the treatment of vertebrobasilar occlusion. METHODS: Twelve patients with 13 angiographically proved thromboses of the vertebrobasilar system underwent local intraarterial thrombolysis with urokinase. Angiographic and clinical outcomes were analyzed with respect to clinical examination at presentation, arterial occlusion patterns, and time to recanalization. RESULTS: The overall mortality was 75%. Recanalization could not be achieved in 3 of 13 treatments; all patients in whom recanalization failed died. The mortality rate was 60% in those patients in whom recanalization was successful. Coma or quadriparesis at the time of therapy uniformly predicted death. There were two cases each of bilateral proximal vertebral occlusions and midbasilar occlusions and nine cases of bilateral distal vertebral occlusions. There were three cases of fatal rethrombosis after initial successful thrombolysis. The mortality rate in the recanalized group before rethrombosis was 30%. There were two fatal hemorrhages of the central nervous system. CONCLUSION: Recanalization of the vertebrobasilar system is necessary but not sufficient for effective treatment of vertebrobasilar occlusive disease. The site of occlusion may help predict angiographic and clinical outcome. Time to initiation of thrombolysis is not an invariable correlate of survival, although clinical condition at presentation may be. Rethrombosis and hemorrhage are significant problems affecting mortality after successful thrombolysis.
Aged↗
Intracerebroventricular infusion of interleukin 1 rapidly decreases peripheral cellular immune responses.
Low doses (50-200 pg or 3.1-12.4 fmol) of interleukin 1 (IL-1) infused into the brain of rats produced rapid suppression of various cellular immune responses in peripheral lymphocytes of rats. Fifteen minutes after infusion of purified IL-1 beta into the lateral ventricle, natural killer cell activity, response to phytohemagglutinin stimulation, and interleukin 2 production were markedly suppressed in lymphocytes isolated from blood and spleen. These effects were due to infusion of IL-1 into brain since they did not occur when IL-1 was infused into the cisterna magna (essentially posterior to brain) or was injected intraperitoneally. Effects of IL-1 in brain could be blocked by simultaneous infusion of alpha-melanocyte-stimulating hormone, which is known to block the biological actions of IL-1. To stimulate release of endogenous IL-1 in brain, lipopolysaccharide was infused; this produced similar effects as IL-1, and these effects also were blocked by alpha-melanocyte-stimulating hormone. At longer intervals after infusion of IL-1 and lipopolysaccharide (3, 6, and 24 hr), immune responses returned to baseline or remained suppressed; i.e., "rebound" immunopotentiation did not occur. Finally, IL-1 infusion suppressed cellular immune responses in adrenalectomized animals, thereby showing that the effects of central IL-1 on peripheral cellular immune responses were, at least in part, independent of the stimulatory effect of IL-1 on secretion of adrenal hormones. These results indicate a link from brain to peripheral immune responses by means of action of a cytokine acting in the brain.
Animals↗
Behavioral and neural influences on cellular immune responses: effects of stress and interleukin-1.
A series of experiments examined effects of stressful conditions on several cellular immune responses and attempted to elucidate the physiological mechanisms underlying these effects. Initial studies showed that stressful conditions can profoundly suppress immune responses of blood and splenic lymphocytes, including T-cell mitogenesis, natural killer cell activity, production of interleukin-2 (IL-2) and interferon and IL-2 receptor expression. Subsequent studies found that (1) multiple physiological pathways mediate stress-induced suppression of these responses; (2) stress-induced suppression of these responses is produced, at least in part, by a peptide with molecular weight greater than 10 kilodaltons, which stressed animals release into circulation; (3) whereas most stressful conditions suppress immune responses, stressful conditions of moderate intensity can enhance cellular immune responses; and (4) extremely small quantities of interleukin-1 (IL-1) acting in the brain (e.g., 3.1-12.4 X 10(-15) moles) bring about suppression of cellular immune responses very rapidly and for a prolonged period of time. The relationship between the newly-discovered immunosuppressive influence of IL-1 in the brain and immunosuppression produced by stressful conditions remains to be determined.
Animals↗
[Effect of single 60Co whole-body irradiation on the absolute count and degree-of-maturity distribution of reticulocytes in the rat].
Wistar-rats were exposed to a single 60Co-gamma-total body irradiation with 1.5 Gy, 3.0 Gy and 4.5 Gy. The trend of reticulocyte count and the reticulocyte maturation distribution were measured with an automatic analysis system over a period of 30 days. In all animals the reticulocyte count as well as the maturation distribution showed minima at the second and the twelfth day post irradiation. The duration of the minima were dose dependent. The changes of the reticulocyte count and the maturation distribution are equivalent.
Animals↗