Biomedical subjects
Warren R Selman
Publications and source records attributed to Warren R Selman.
Effect of human albumin administration on clinical outcome and hospital cost in patients with subarachnoid hemorrhage.
OBJECT: Human albumin is used to induce hypervolemia (central venous pressure [CVP] > 8 mm Hg) after subarachnoid hemorrhage (SAH). Unfortunately, human albumin may increase the mortality rate in critically ill patients; because of this, its use became restricted in the authors' hospital in May 1999. The goal of this study was to determine the effect of human albumin on outcome and cost in patients with SAH before and after this restriction was put into place. METHODS: All patients with aneurysmal SAH who were admitted to the authors' institution between May 1998 and May 2000 were studied. Basic demographic information, dosage of human albumin given, length of stay, and the incidence of in-hospital deaths and complications were collected. The authors obtained Glasgow Outcome Scale (GOS) scores at 3 months after SAH (good outcome, GOS > or = 4). Data were analyzed using t-test and chi-square analysis. Logistic regression was used to identify independent associations between use of human albumin and outcome. The authors studied 140 patients: 63 who were admitted between May 1998 and May 1999 (Group 1) and 77 treated between June 1999 and May 2000 (Group 2). Two subgroups of patients were further analyzed. Group 1 patients who received human albumin (albumin subgroup, 37 patients) and Group 2 patients who would have received albumin under the old protocol (that is, those who failed to achieve CVP > 8 mm Hg after normal saline administration; nonalbumin subgroup, 47 patients). Patients in the nonalbumin subgroup were more likely to be male (38% compared with 16%), to experience hypertension (55% compared with 30%), to suffer from hypomagnesemia (49% compared with 5.4%), and to have hydrocephalus (47% compared with 27%). There was a trend for these patients to have more vasospasm (28% compared with 19%, p = 0.2). Patients in the albumin subgroup were more likely to have a good outcome at 3 months. CONCLUSIONS: Administration of human albumin after SAH may improve clinical outcome and reduce hospital cost.
Activation of caspase-12, an endoplasmic reticulum resident caspase, after permanent focal ischemia in rat.
The endoplasmic reticulum (ER) is emerging as a contributory component of cell death after ischemia. Since caspase-12 has been localized to the ER and is a novel signal for apoptosis, we examined the message levels and protein expression of caspase-12 after cerebral ischemia in vivo. Animals underwent permanent middle cerebral artery occlusion (MCAO) and were sacrificed 24 h after ischemia. Protein analysis revealed a significant increase in caspase-12 and a corresponding up-regulation of caspase-12 mRNA in the ischemia group compared with that in the sham group. Immunohistochemical analysis revealed diffuse positive immunostaining of caspase-12 throughout the striatum and cerebral cortex in animals that underwent ischemia, with more intense caspase-12 immunostaining in the striatum than in the cortex after ischemia. These results demonstrate that cerebral ischemia initiates an ER-based stress response that results in the transcriptional up-regulation and corresponding increased expression of caspase-12 protein, and may provide a new area for therapeutic intervention to ameliorate outcomes following stroke.
Changing metabolic and energy profiles in fetal, neonatal, and adult rat brain.
The regional energy status and the availability of metabolic substrates during brain development are important, since a variety of fetal metabolic insults have been increasingly implicated in the evolution of neonatal brain disorders. The response of the brain to a metabolic insult is determined, in large part, by the ability to utilize the various substrates for intermediary metabolism in order to maintain energy stores within the tissue. To ascertain if metabolic conditions of the fetal brain make it more or less vulnerable to a stress, the high-energy phosphates and glucose-related compounds were examined in five regions of the embryonic day 18 (E-18) fetal brain. Glucose and glycogen levels in the E-18 fetal brain were generally higher in the cerebellum and its neuroepithelium than in the hippocampus, cerebral cortex, and its neuroepithelium. Regional lactate and high-energy phosphate concentrations were essentially the same in the five regions. Subsequently, the metabolic profile was examined in the cerebral cortex and striatum from E-18, postpartum day 7 (P-7) and adult rats. At the various stages of development, there were only minimal differences in the high-energy phosphate levels in the striatum and cortex. Glucose levels, the primary substrate in the adult brain, were essentially unchanged throughout development. In contrast, lactate was significantly elevated by 6- and 2-fold over those in the adult brain in the E-18 and P-7 striatum and cortex, respectively. Another alternative substrate, beta-hydroxybutyrate, was also significantly elevated at E-18 and increased more than 2-fold at P-7, but was barely detectable in the adult cortex and striatum. Finally, glucose and lactate levels were examined in cerebrospinal fluid, blood, and brain from the E-18 brain to determine if a gradient among the compartments exists. The levels of both lactate and glucose exhibited a concentration gradient in the E-18 fetus: blood > cerebrospinal fluid > brain parenchyma. The results indicate that energy state in the fetal brain is comparable to that in the neonates and the adults, but that the availability of alternative substrates for intermediary metabolism change markedly with development. The age-dependent substrate specificity for intermediary metabolism could affect the response of the fetal brain to a metabolic insult.
Integration of neurosurgical image guidance and an intraoperative magnetic resonance scanner. The University Hospitals of Cleveland experience.
BACKGROUND: Intraoperative magnetic resonance (MR) imaging has been employed as an alternative to image guidance using preoperative images. We integrated both systems to evaluate their clinical use. METHODS: The BrainLAB VectorVision system was integrated in an intraoperative Siemens Open Viva 0.2-tesla MR system. Clinical experience was assessed. RESULTS: Patterns of intraoperative imaging emerged, and benefit was seen in registering preoperative and intraoperative images. CONCLUSIONS: This integrated system has clinically observed effects on imaging, navigation, and surgery.
Ischemic cell death: dynamics of delayed secondary energy failure during reperfusion following focal ischemia.
Reperfusion injury is believed to contribute to the pathophysiology of ischemic cell death, but the precipitating factors have yet to be completely elucidated. The goal of this study was to examine if reflow-induced secondary energy failure is a component in the events that lead to cell death following increasing periods of middle cerebral artery (MCA) occlusion in Wistar rats. Discrete sections within the MCA distribution were dissected and analyzed for high-energy phosphates and glucose. Regional cerebral blood flow was determined by [14C]-iodoantipyrine technique in representative groups. The levels of ATP + P-creatine were initially depressed at the end of the focal ischemia and the concentrations in the penumbra were unchanged for up to 8 h after 2 h of ischemia which contrasts with response in the ischemic core, striatum, and penumbra where the HEP generally recovered to values near those of control only to decrease with increasing periods of reflow. The possibility of a rebound ischemia in secondary energy failure (SEF) was precluded by regional CBF values and concentrations of glucose that were significantly higher than the threshold for an ischemic effect. The depletion of cellular energy stores following SEF strongly indicates that the evolution of infarct during reflow results from loss of ATP and its synthesis.
Caspase-9 inhibition after focal cerebral ischemia improves outcome following reversible focal ischemia.
Cerebral ischemia initiates a program of cell death known as apoptosis. Early steps in these death promoting events are the release of cytochrome c from the mitochondria and activation of caspase-9. The purpose of this report is to determine if the administration of a specific caspase-9 inhibitor, Z-Leu-Glu(Ome)-His-Asp(Ome)-FMK x TFA (Z-LEHD-FMK) would attenuate apoptosis and the resultant brain injury after ischemia. Adult Wistar rats underwent 3 h of temporary middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. An intraventricular injection of 4.8 microg of Z-LEHD-FMK was given 15-min postreperfusion. Administration of the caspase-9 inhibitor, Z-LEHD-FMK, to the experimental group (n = 12) reduced total infarction volume by 49% (p < 0.05) and improved neurological outcome by 63% (p < 0.01) as compared to the control group (n = 12). Western blot analysis of animals that underwent ischemia-reperfusion showed the appearance of the active form of caspase-9. Inhibition of caspase-9, the apical caspase in cytochrome-c-dependent apoptosis, is an effective intervention to attenuate neurological injury after focal ischemia.
Delayed changes in regional brain energy metabolism following cerebral concussion in rats.
Traumatic brain injury (TBI) results in an acute altered metabolic profile of brain tissue which resolves within hours of initial insult and yet some of the functional deficits and cellular perturbations persist for days. It is hypothesized that a delayed change in energy status does occur and is a factor in the neural tissue's ability to survive and regain function. Regional metabolic profile and glucose consumption were determined at either 1 or 3 days following two different intensities of parasagittal fluid-percussion (F-P). A significant decrease in both 1CMRgluc and levels of ATP and P-creatine was evident in the hemisphere ipsilateral to the trauma at 1 day after the insult. The effect was greater in the cortical than the subcortical regions and was more pronounced at the higher trauma intensity. Normalization of glucose consumption and energy levels was essentially complete by 3 days. It would appear that the delayed metabolic changes at 1 day postinsult cannot be explained by a secondary ischemia since the changes in the metabolite profile do not elicit an increase in the consumption of glucose. These changes in energy metabolites may account for and contribute to the chronic neurological deficits following TBI.
Endovascular administration after intravenous infusion of thrombolytic agents for the treatment of patients with acute ischemic strokes.
OBJECTIVE: To determine the feasibility of combined intravenous and intra-arterial thrombolytic therapy for acute ischemic strokes and to evaluate its associated risks, using magnetic resonance imaging as a triage tool. Intravenous treatment followed by intra-arterial infusion may increase the rate of recanalization and lead to better clinical results, with reduced frequency of intracranial hemorrhage. METHODS: Our Brain Attack Team evaluated patients who presented within 3 hours after symptom onset. Patients who did not demonstrate improvement and exhibited no evidence of intracranial hemorrhage on head computed tomographic scans were treated with intravenously administered recombinant tissue plasminogen activator (0.6 mg/kg) and underwent emergency magnetic resonance imaging of the head. T2-weighted turbo-gradient and spin echo and echo-planar diffusion- and perfusion-weighted imaging scans were obtained. Patients with evidence of imaging abnormalities indicating acute cortical infarction underwent cerebral angiography. After determination of vessel occlusion, intra-arterially administered urokinase (up to 750,000 units) or intra-arterially administered recombinant tissue plasminogen activator (maximal dose, 0.3 mg/kg) was used to achieve recanalization. RESULTS: We treated 45 patients with this protocol. The mean age was 67 +/- 13 years, and 58% of the patients were women. There was a significant improvement in National Institutes of Health Stroke Scale scores after treatment. There was good correlation between abnormal perfusion-weighted imaging findings and cerebral angiographic findings (complete vessel occlusion). The incidence of symptomatic intracranial hemorrhage was 4.4% in this cohort. Seven patients died in the hospital, and the majority of survivors (77%) experienced good outcomes (Barthel index of >or=95) 3 months after treatment. CONCLUSION: Our data demonstrate that this protocol is feasible and that combined intravenous and intra-arterial thrombolysis to treat acute ischemic strokes is sufficiently safe to warrant further evaluation.
Steal affecting the central nervous system.
Steal is a pathophysiological process in which increased blood flow through a low-resistance vascular bed is sufficient to divert flow away from a region of the central nervous system. Three disease states in which steal may cause neurological deficits due to central nervous system ischemia are reviewed. Subclavian steal occurs when stenosis of the subclavian artery proximal to the vertebral origin causes retrograde flow in the left vertebral artery. Patients with anatomic subclavian steal usually do not develop neurological symptoms but may rarely present with posterior circulation ischemia. Arteriovenous malformations alter cerebral blood flow patterns and regional perfusion pressure. It has been hypothesized that cerebral arteriovenous malformations may cause neurological deficits due to steal and that these deficits may be cured with arteriovenous malformation treatment. Intra-arterial pressure measurements and transcranial velocity studies show regional hemodynamic alterations. However, these changes have not been correlated with presenting symptoms. Evidence from single-photon emission computed tomography does suggest a relationship between regional hypoperfusion and neurological deficits. Coarctation of the aorta may divert flow from the spinal cord circulation through intercostal arteries distal to the stenosis. This is a possible but unproven mechanism of myelopathology. Steal syndromes may be amenable to treatment by open surgical or endovascular approaches. Experimental studies of the pathophysiology of steal are strengthened by precise definitions of the measured parameters and innovative applications of technology.
Response to intra-arterial and combined intravenous and intra-arterial thrombolytic therapy in patients with distal internal carotid artery occlusion.
BACKGROUND AND PURPOSE: The objective of this study was to determine the clinical features, angiographic findings, and response to treatment with thrombolytic therapy in patients with ischemic stroke caused by acute occlusion of the distal internal carotid artery. METHODS: This is a retrospective case series from a prospectively collected stroke database for patients with acute internal carotid occlusion presenting within 6 hours of stroke onset to evaluate safety, feasibility, and response to thrombolytic therapy. The University Hospital-based brain attack database was reviewed over a 5-year period. Demographics, clinical features, stroke mechanisms, severity, imaging findings, type of thrombolysis, treatment responses, mortality, and long-term outcome using modified Rankin Scale and Barthel Index were determined. The short-term outcome was assessed using the National Institutes of Health Stroke Scale (NIHSS). Acute thrombolytic therapy was administered using recombinant tissue plasminogen activator or urokinase given intra-arterially or in combination with intravenous (IV) routes. RESULTS: Two hundred seven patients treated with thrombolysis between 1995 and 2000 were reviewed, and of these, 101 were studied with cerebral angiography. Eighteen patients were identified with acute ischemic stroke and ipsilateral occlusion of the distal internal carotid artery. Time to treatment was the most powerful predictor of response to thrombolytic therapy (P<0.001). The response to therapy also correlated well with the severity of the initial clinical deficit as judged by the NIHSS (P<0.001). There was no difference in recanalization rate, symptomatic hemorrhage, and NIHSS for IV/intra-arterial (IA) versus IA alone (P=NS). Complete angiographic recanalization was accomplished in 80% of those who received combined IV/IA thrombolysis and in 62% of those who received IA therapy (P=NS). Those with distal occlusions extending to the middle and anterior cerebral arteries were the least likely to respond to thrombolysis. Symptomatic intracerebral hemorrhage occurred in 20% of the patients receiving IV/IA therapy, and in 15% of the IA only (P=NS). At 24 hours, the NIHSS dropped by 3 points in the IA group and 4 points in the IV/IA group (P=NS). Mild disability with independence was found in 77% of the survivors at 3-month follow-up. The mortality rate was 50% in this group despite thrombolysis. CONCLUSIONS: Thrombolytic therapy using a combination of IV and IA routes and using the IA-only route may be effective in improving outcome for the patients suffering from occlusion of the distal internal carotid artery. Shorter intervals between onset and treatment seem to be correlated with higher rate of recanalization and improved outcome.
Training, competency, and credentialing standards for diagnostic cervicocerebral angiography, carotid stenting, and cerebrovascular intervention.
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