We prospectively evaluated the safety and recanalization efficacy of intra-arterially administere... more We prospectively evaluated the safety and recanalization efficacy of intra-arterially administered reteplase, a third-generation recombinant tissue plasminogen activator, for treating ischemic stroke in patients considered poor candidates for intravenously administered alteplase therapy. Patients were considered poor candidates for intravenously administered therapy because of severity of neurological deficits, interval from onset of symptoms to presentation of 3 hours or more, or recent major surgery. We administered a maximum total dose of 8 U of reteplase intra-arterially in 1-U increments via superselective catheterization. Adjunctive angioplasty of the occluded artery was performed in seven patients. Angiographic evidence of perfusion and thrombus was graded by use of modified Thrombolysis in Myocardial Infarction (TIMI) criteria. Neurological examinations were performed before and 24 hours and 7 to 10 days after treatment. Sixteen consecutive patients were treated (mean age, 64.1 +/- 16.4 yr; seven were men). Initial National Institutes of Health Stroke Scale scores ranged from 10 to 26. Time from onset of symptoms to treatment ranged from 2 to 9 hours. Occlusion sites were the cervical internal carotid artery (n = 4), intracranial internal carotid artery (n = 4), middle cerebral artery (n = 6), and vertebrobasilar artery (n = 2). Complete or near-complete perfusion (TIMI Grade 3 or 4) was achieved in the arteries in 14 patients (88%), with partial recanalization (TIMI Grade 2) or minimal response (TIMI Grade 1) in the arteries in one patient each. Neurological improvement (defined as decrease of four or more points in National Institutes of Health Stroke Scale score) was observed in 7 (44%) of the 16 patients at 24 hours. Symptomatic intracerebral hemorrhage occurred in one patient; three other patients experienced intracerebral hemorrhages that did not result in neurological worsening. The overall mortality during hospitalization was 56%, related to massive ischemic stroke (n = 7), withdrawal of care at the family's request after the development of aspiration pneumonia and renal failure (n = 1), and a combination of intracerebral hemorrhage and massive ischemic stroke (n = 1). In this study, intra-arterially administered reteplase in doses up to 8 U with or without angioplasty resulted in a high rate of recanalization. This strategy should be considered in treating patients considered poor candidates for intravenous thrombolysis.
We prospectively evaluated the safety and effectiveness of aggressive mechanical disruption of cl... more We prospectively evaluated the safety and effectiveness of aggressive mechanical disruption of clot in conjunction with intra-arterial administration of a low-dose third-generation thrombolytic agent (reteplase) to treat ischemic stroke in patients who were considered poor candidates for intravenous alteplase therapy or who failed to improve after intravenous thrombolysis. Mechanical clot disruption was used if low-dose pharmacological thrombolysis was ineffective. This strategy was adopted to increase the recanalization rate without increasing the risk of intracerebral hemorrhage. Patients were considered poor candidates for intravenous therapy because of severity of neurological deficits, interval from symptom onset to presentation of at least 3 hours, or recent major surgery. We administered a maximum total dose of 4 U of reteplase intra-arterially in 1-U increments via superselective catheterization. After the initial doses were administered, we performed mechanical angioplasty (for proximal occlusion) or snare manipulation (for distal occlusion) at the occlusion site if recanalization had not occurred. The remaining doses of thrombolytics were subsequently administered if required for further recanalization. Angiographic responses were graded using modified Thrombolysis in Myocardial Infarction (TIMI) criteria. Clinical evaluations were performed before and 24 hours, 7 to 10 days, and 1 to 3 months after treatment. Nineteen consecutive patients were treated (mean age, 64.3 +/- 16.2 yr; 10 were men). Initial National Institutes of Health Stroke Scale scores ranged from 11 to 42. Time from onset to treatment ranged from 1 to 9 hours. Occlusion sites were in the following arteries: cervical internal carotid (n = 7), intracranial internal carotid (n = 1), middle cerebral (n = 9), and basilar (n = 2). Of the 19 patients, thrombolysis alone was used in 5 patients, angioplasty was performed in 11 patients, and snare maneuvers were used in 5 patients. Complete restoration of blood flow (modified TIMI Grade 4) was observed in 12 patients, near-complete restoration of flow (modified TIMI Grade 3) in 4 patients, minimal response (modified TIMI Grade 1) in 1 patient, and no response in 2 patients (modified TIMI Grade 0). Neurological improvement at 24 hours (decline of at least 4 points in National Institutes of Health Stroke Scale score) was observed in seven patients. Five other patients experienced further improvement in National Institutes of Health Stroke Scale score at 7 to 10 days. No vessel rupture, dissection, or symptomatic intracranial hemorrhages were observed. At the time of follow-up evaluation, 7 of 19 patients were functionally independent. A high rate of recanalization and clinical improvement can be observed in patients with ischemic stroke using low-dose thrombolytic agents with adjunctive mechanical disruption of clot. Moreover, this strategy may reduce the risk of intracerebral hemorrhage observed with thrombolytics.
To determine the frequency of perioperative complications since the introduction of abciximab, we... more To determine the frequency of perioperative complications since the introduction of abciximab, we prospectively evaluated our experience in a consecutive series of patients undergoing carotid angioplasty and stent placement (CAS). CAS has been introduced recently for treatment of carotid artery stenosis. A major limitation to this modality is the risk of perioperative thromboembolic and ischemic events. To reduce the risk of ischemic complications, abciximab, a platelet glycoprotein IIb/IIIa receptor inhibitor, has been introduced as adjunctive treatment for high-risk patients. Each patient was evaluated by a neurologist before, immediately after, and 24 hours after CAS for identification and classification of new neurological deficits. Bleeding events or other complications during hospitalization were recorded. Bleeding complications were classified as major (hemoglobin decrease,g5 g/dl), minor (hemoglobin decrease, 3-5 g/dl), or insignificant. Abciximab was administered intravenously as a single bolus (0.25 mg/kg) and then via infusion (10 microg/min) for 12 hours as an adjunct to CAS in patients considered to be at high risk for thromboembolic events owing to recent ischemic symptoms and/or complex lesion morphology. Intravenously administered abciximab was used in 37 patients (mean age, 70 yr; 21 patients were men) as an adjunct to high-risk CAS. Thirty-three other patients underwent CAS performed with standard intraprocedural heparinization (mean age, 69 yr; 17 patients were men). Minor ischemic strokes were observed in 1 of 37 abciximab-treated patients and in 4 of 33 heparin-treated patients. No major ischemic strokes were observed in either group. Transient neurological deficits were observed in nine patients in the abciximab-treated group and in one patient in the heparin-treated group. Transient neurological deficits in abciximab-treated patients were mainly related to hemodynamic factors (associated with balloon inflation in two patients and with hypotension in another two patients) or occurred after completion of infusion (in three patients). Minor bleeding complications were observed in three patients who received abciximab and in four patients who received standard heparinization. Major bleeding complications were observed in four patients from each group. Two patients who received abciximab developed intracerebral hemorrhages; one hemorrhage was fatal. The frequency of ischemic stroke in high-risk patients (3%) with the use of intravenously administered abciximab was lower, but not significantly so, than rates observed in lower-risk patients (12%), although the benefit was lost because of the high rate of intracranial hemorrhages (5%). Further efforts are required to determine appropriate selection criteria for use of intravenously administered abciximab and the effect of other strategies that involve distal protection devices.
To determine the time interval between symptom onset and neurologic deterioration related to cere... more To determine the time interval between symptom onset and neurologic deterioration related to cerebral edema in patients with massive middle cerebral artery infarction. The time period between onset and neurologic deterioration represents the window for surgical intervention. Multicenter retrospective chart review. Five university-affiliated medical centers. Fifty-three patients with massive middle cerebral artery infarction who experienced neurologic deterioration defined by a decrease in the Glasgow Coma Scale score of two or more points attributable to mass effect. A total of 53 patients (mean age, 62 +/- 18 yrs; 25 [47%] were men) with neurologic deterioration were identified by using International Classification of Diseases (9th revision) codes and local registries. Medical records and neuroimaging studies were reviewed by a stroke neurologist or neurointensivist to identify the time of neurologic deterioration. Thrombolytics were used at presentation in 19 (35%) patients. A total of 19 (36%) patients had neurologic deterioration within 24 hrs of symptom onset. By 48 hrs, 36 (68%) patients had manifested clinical deterioration. A few patients had later neurologic deterioration on day 3 (n = 10), day 4 (n = 2), day 5 (n = 2), and day 6 or after (n = 3). A total of 25 (47%) of the 53 patients died during hospitalization. The highest frequency of deaths occurred on day 3. Neurologic deteriorations related to cerebral edema after massive middle cerebral artery infarction occur in most patients within 48 hrs of symptom onset.
The goals of this study were to identify and quantify the presence of programmed cell death (apop... more The goals of this study were to identify and quantify the presence of programmed cell death (apoptosis) in intracerebral hemorrhage (ICH) among human subjects. Recent evidence from laboratory models suggests that cell death in the perihematoma region may involve apoptosis. Retrospective clinical and histological analyses were performed for patients with spontaneous ICH who underwent surgical evacuation. Quantification of apoptotic cells was performed in sections obtained from the perihematoma region from 12 patients with ICH and stained with the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling method. Necrosis was identified on the basis of morphological criteria, using hematoxylin and eosin staining. Evidence of apoptosis was present in surgical specimens obtained from 10 of the 12 patients. The mean number of apoptotic cells in the perihematoma region in each patient specimen was 38% (range, 0-90%). For five patients, more than one-half of the total cells observed were apoptotic. Apoptosis was observed in specimens obtained within 1 day, 2 days, and 5 days after the onset of symptoms. No terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling-positive cells were observed in specimens from the two patients with cerebellar hematomas. The mean proportion of necrotic cells in the perihematoma region in each patient specimen was 25% (range, 0-100%). There was a prominent excess of apoptotic cells, in comparison with necrotic cells, for 6 of the 12 patients who underwent hematoma evacuation. For five other patients, similar proportions of apoptotic and necrotic cells were observed. Necrosis was the predominant finding for only one patient, who underwent late surgical evacuation on Day 5. These observations suggest that apoptosis represents a prominent form of cell death associated with ICH in the perihematoma region. Further studies are required to define the mediators of apoptosis in ICH.
To determine whether extracellular concentrations of glutamate and other amino acids are signific... more To determine whether extracellular concentrations of glutamate and other amino acids are significantly elevated after intracerebral hemorrhage and, if so, the temporal characteristics of these changes. Although the role of excitotoxic amino acids, particularly that of glutamate, has been described in ischemic stroke and head trauma, no information exists regarding their possible contribution to the pathogenesis of neuronal injury in intracerebral hemorrhage. Prospective, controlled, laboratory trial. Animal research laboratory. Sixteen anesthetized New Zealand rabbits. We introduced intracerebral hemorrhage in each of eight anesthetized New Zealand rabbits by injecting 0.4 mL of autologous blood under arterial pressure into the deep gray matter of the cerebrum. Extracellular fluid samples were collected from the perihematoma region and contralateral (right) hemisphere by in vivo microdialysis at 30-min intervals for 6 hrs. Corresponding samples were similarly collected from both hemispheres in each of eight control animals that underwent needle placement without introduction of a hematoma. Concentrations of amino acids (glutamate, aspartate, asparagine, glycine, taurine, and gamma-aminobutyric acid) in the samples were measured by use of high-pressure liquid chromatography with fluorescence detection. Glutamate concentrations (mean +/- sem) were significantly higher in the hemisphere ipsilateral to the hematoma than in the contralateral hemisphere (92 +/- 22 pg/microL vs. 22 +/- 6 pg/microL) at 30 mins after hematoma creation. A significant increase was observed at 30 mins posthematoma creation in the hemisphere ipsilateral to the hematoma compared with the baseline value. A nonsignificant increase in glutamate concentration persisted in the hemisphere ipsilateral to the hematoma, ranging from 134% to 187% of baseline value between 1 and 5 hrs after hematoma creation. In the hemisphere ipsilateral to the hematoma, a three-fold increase in the concentration of glycine was observed at 30 mins after hematoma creation compared with the baseline level (890 +/- 251 pg/microL vs. 291 +/- 73 pg/microL). There was a significant difference between the hemisphere ipsilateral to the hematoma compared with the ipsilateral (corresponding) hemisphere of the control group at 30 mins posthematoma (890 +/- 251 pg/microL vs. 248 +/- 66 pg/microL). A similar transient increase was observed in taurine and asparagine concentrations at 30 mins after hematoma creation, compared with baseline measurements. Taurine concentrations in the hemisphere ipsilateral to the hematoma were significantly higher than the ipsilateral hemisphere of the control group (622 +/- 180 pg/microL vs. 202 +/- 64 pg/microL) at 30 mins after hematoma creation. The present study suggests that glutamate and other amino acids accumulate transiently in extracellular fluids in the perihematoma region during the early period of intracerebral hemorrhage. The exact role of these amino acids in the pathogenesis of neuronal injury observed in intracerebral hemorrhage needs to be defined.
Eptifibatide, a competitive platelet glycoprotein IIb-IIIa receptor inhibitor with high selectivi... more Eptifibatide, a competitive platelet glycoprotein IIb-IIIa receptor inhibitor with high selectivity and a short half-life, has been demonstrated to reduce the risk of ischemic events associated with coronary interventions. However, its role in neurointerventional procedures needs to be analyzed. We report the results of an open-label Phase I study to evaluate the safety of the use of eptifibatide during carotid angioplasty and stent placement. Each study patient received eptifibatide administered intravenously as a 135-microg/kg single-dose bolus, then a 0.5-microg/kg/min infusion for 20 to 24 hours during carotid angioplasty and stent placement. The primary efficacy end point was the 30-day composite occurrence of death, cerebral infarction, transient ischemic attack, and unplanned or urgent surgical intervention, thrombolysis, or subsequent percutaneous revascularization. The primary safety end point was bleeding. Bleeding complications were classified as major (hemoglobin decrease >5 g/dl), minor (hemoglobin decrease 3-5 g/dl), or insignificant. Ten patients (mean age, 73 yr; four men) were treated by use of the study protocol. One patient developed a minor stroke postprocedurally (National Institutes of Health Stroke Scale score of 21 at 24 h that improved to 1 at 7 d). Three patients underwent scheduled coronary artery bypass graft surgery 4 to 12 days after undergoing carotid angioplasty and stent placement. At 1-month follow-up, no new ischemic events were observed. Major or minor bleeding was not observed in any patient. Insignificant bleeding was observed in two patients. The use of eptifibatide as an adjunct to carotid angioplasty and stent placement seems to be safe. Further studies are required to analyze the effectiveness and role of eptifibatide in neurointerventional procedures.
We prospectively evaluated the safety and recanalization efficacy of intra-arterially administere... more We prospectively evaluated the safety and recanalization efficacy of intra-arterially administered reteplase, a third-generation recombinant tissue plasminogen activator, for treating ischemic stroke in patients considered poor candidates for intravenously administered alteplase therapy. Patients were considered poor candidates for intravenously administered therapy because of severity of neurological deficits, interval from onset of symptoms to presentation of 3 hours or more, or recent major surgery. We administered a maximum total dose of 8 U of reteplase intra-arterially in 1-U increments via superselective catheterization. Adjunctive angioplasty of the occluded artery was performed in seven patients. Angiographic evidence of perfusion and thrombus was graded by use of modified Thrombolysis in Myocardial Infarction (TIMI) criteria. Neurological examinations were performed before and 24 hours and 7 to 10 days after treatment. Sixteen consecutive patients were treated (mean age, 64.1 +/- 16.4 yr; seven were men). Initial National Institutes of Health Stroke Scale scores ranged from 10 to 26. Time from onset of symptoms to treatment ranged from 2 to 9 hours. Occlusion sites were the cervical internal carotid artery (n = 4), intracranial internal carotid artery (n = 4), middle cerebral artery (n = 6), and vertebrobasilar artery (n = 2). Complete or near-complete perfusion (TIMI Grade 3 or 4) was achieved in the arteries in 14 patients (88%), with partial recanalization (TIMI Grade 2) or minimal response (TIMI Grade 1) in the arteries in one patient each. Neurological improvement (defined as decrease of four or more points in National Institutes of Health Stroke Scale score) was observed in 7 (44%) of the 16 patients at 24 hours. Symptomatic intracerebral hemorrhage occurred in one patient; three other patients experienced intracerebral hemorrhages that did not result in neurological worsening. The overall mortality during hospitalization was 56%, related to massive ischemic stroke (n = 7), withdrawal of care at the family's request after the development of aspiration pneumonia and renal failure (n = 1), and a combination of intracerebral hemorrhage and massive ischemic stroke (n = 1). In this study, intra-arterially administered reteplase in doses up to 8 U with or without angioplasty resulted in a high rate of recanalization. This strategy should be considered in treating patients considered poor candidates for intravenous thrombolysis.
We prospectively evaluated the safety and effectiveness of aggressive mechanical disruption of cl... more We prospectively evaluated the safety and effectiveness of aggressive mechanical disruption of clot in conjunction with intra-arterial administration of a low-dose third-generation thrombolytic agent (reteplase) to treat ischemic stroke in patients who were considered poor candidates for intravenous alteplase therapy or who failed to improve after intravenous thrombolysis. Mechanical clot disruption was used if low-dose pharmacological thrombolysis was ineffective. This strategy was adopted to increase the recanalization rate without increasing the risk of intracerebral hemorrhage. Patients were considered poor candidates for intravenous therapy because of severity of neurological deficits, interval from symptom onset to presentation of at least 3 hours, or recent major surgery. We administered a maximum total dose of 4 U of reteplase intra-arterially in 1-U increments via superselective catheterization. After the initial doses were administered, we performed mechanical angioplasty (for proximal occlusion) or snare manipulation (for distal occlusion) at the occlusion site if recanalization had not occurred. The remaining doses of thrombolytics were subsequently administered if required for further recanalization. Angiographic responses were graded using modified Thrombolysis in Myocardial Infarction (TIMI) criteria. Clinical evaluations were performed before and 24 hours, 7 to 10 days, and 1 to 3 months after treatment. Nineteen consecutive patients were treated (mean age, 64.3 +/- 16.2 yr; 10 were men). Initial National Institutes of Health Stroke Scale scores ranged from 11 to 42. Time from onset to treatment ranged from 1 to 9 hours. Occlusion sites were in the following arteries: cervical internal carotid (n = 7), intracranial internal carotid (n = 1), middle cerebral (n = 9), and basilar (n = 2). Of the 19 patients, thrombolysis alone was used in 5 patients, angioplasty was performed in 11 patients, and snare maneuvers were used in 5 patients. Complete restoration of blood flow (modified TIMI Grade 4) was observed in 12 patients, near-complete restoration of flow (modified TIMI Grade 3) in 4 patients, minimal response (modified TIMI Grade 1) in 1 patient, and no response in 2 patients (modified TIMI Grade 0). Neurological improvement at 24 hours (decline of at least 4 points in National Institutes of Health Stroke Scale score) was observed in seven patients. Five other patients experienced further improvement in National Institutes of Health Stroke Scale score at 7 to 10 days. No vessel rupture, dissection, or symptomatic intracranial hemorrhages were observed. At the time of follow-up evaluation, 7 of 19 patients were functionally independent. A high rate of recanalization and clinical improvement can be observed in patients with ischemic stroke using low-dose thrombolytic agents with adjunctive mechanical disruption of clot. Moreover, this strategy may reduce the risk of intracerebral hemorrhage observed with thrombolytics.
To determine the frequency of perioperative complications since the introduction of abciximab, we... more To determine the frequency of perioperative complications since the introduction of abciximab, we prospectively evaluated our experience in a consecutive series of patients undergoing carotid angioplasty and stent placement (CAS). CAS has been introduced recently for treatment of carotid artery stenosis. A major limitation to this modality is the risk of perioperative thromboembolic and ischemic events. To reduce the risk of ischemic complications, abciximab, a platelet glycoprotein IIb/IIIa receptor inhibitor, has been introduced as adjunctive treatment for high-risk patients. Each patient was evaluated by a neurologist before, immediately after, and 24 hours after CAS for identification and classification of new neurological deficits. Bleeding events or other complications during hospitalization were recorded. Bleeding complications were classified as major (hemoglobin decrease,g5 g/dl), minor (hemoglobin decrease, 3-5 g/dl), or insignificant. Abciximab was administered intravenously as a single bolus (0.25 mg/kg) and then via infusion (10 microg/min) for 12 hours as an adjunct to CAS in patients considered to be at high risk for thromboembolic events owing to recent ischemic symptoms and/or complex lesion morphology. Intravenously administered abciximab was used in 37 patients (mean age, 70 yr; 21 patients were men) as an adjunct to high-risk CAS. Thirty-three other patients underwent CAS performed with standard intraprocedural heparinization (mean age, 69 yr; 17 patients were men). Minor ischemic strokes were observed in 1 of 37 abciximab-treated patients and in 4 of 33 heparin-treated patients. No major ischemic strokes were observed in either group. Transient neurological deficits were observed in nine patients in the abciximab-treated group and in one patient in the heparin-treated group. Transient neurological deficits in abciximab-treated patients were mainly related to hemodynamic factors (associated with balloon inflation in two patients and with hypotension in another two patients) or occurred after completion of infusion (in three patients). Minor bleeding complications were observed in three patients who received abciximab and in four patients who received standard heparinization. Major bleeding complications were observed in four patients from each group. Two patients who received abciximab developed intracerebral hemorrhages; one hemorrhage was fatal. The frequency of ischemic stroke in high-risk patients (3%) with the use of intravenously administered abciximab was lower, but not significantly so, than rates observed in lower-risk patients (12%), although the benefit was lost because of the high rate of intracranial hemorrhages (5%). Further efforts are required to determine appropriate selection criteria for use of intravenously administered abciximab and the effect of other strategies that involve distal protection devices.
To determine the time interval between symptom onset and neurologic deterioration related to cere... more To determine the time interval between symptom onset and neurologic deterioration related to cerebral edema in patients with massive middle cerebral artery infarction. The time period between onset and neurologic deterioration represents the window for surgical intervention. Multicenter retrospective chart review. Five university-affiliated medical centers. Fifty-three patients with massive middle cerebral artery infarction who experienced neurologic deterioration defined by a decrease in the Glasgow Coma Scale score of two or more points attributable to mass effect. A total of 53 patients (mean age, 62 +/- 18 yrs; 25 [47%] were men) with neurologic deterioration were identified by using International Classification of Diseases (9th revision) codes and local registries. Medical records and neuroimaging studies were reviewed by a stroke neurologist or neurointensivist to identify the time of neurologic deterioration. Thrombolytics were used at presentation in 19 (35%) patients. A total of 19 (36%) patients had neurologic deterioration within 24 hrs of symptom onset. By 48 hrs, 36 (68%) patients had manifested clinical deterioration. A few patients had later neurologic deterioration on day 3 (n = 10), day 4 (n = 2), day 5 (n = 2), and day 6 or after (n = 3). A total of 25 (47%) of the 53 patients died during hospitalization. The highest frequency of deaths occurred on day 3. Neurologic deteriorations related to cerebral edema after massive middle cerebral artery infarction occur in most patients within 48 hrs of symptom onset.
The goals of this study were to identify and quantify the presence of programmed cell death (apop... more The goals of this study were to identify and quantify the presence of programmed cell death (apoptosis) in intracerebral hemorrhage (ICH) among human subjects. Recent evidence from laboratory models suggests that cell death in the perihematoma region may involve apoptosis. Retrospective clinical and histological analyses were performed for patients with spontaneous ICH who underwent surgical evacuation. Quantification of apoptotic cells was performed in sections obtained from the perihematoma region from 12 patients with ICH and stained with the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling method. Necrosis was identified on the basis of morphological criteria, using hematoxylin and eosin staining. Evidence of apoptosis was present in surgical specimens obtained from 10 of the 12 patients. The mean number of apoptotic cells in the perihematoma region in each patient specimen was 38% (range, 0-90%). For five patients, more than one-half of the total cells observed were apoptotic. Apoptosis was observed in specimens obtained within 1 day, 2 days, and 5 days after the onset of symptoms. No terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling-positive cells were observed in specimens from the two patients with cerebellar hematomas. The mean proportion of necrotic cells in the perihematoma region in each patient specimen was 25% (range, 0-100%). There was a prominent excess of apoptotic cells, in comparison with necrotic cells, for 6 of the 12 patients who underwent hematoma evacuation. For five other patients, similar proportions of apoptotic and necrotic cells were observed. Necrosis was the predominant finding for only one patient, who underwent late surgical evacuation on Day 5. These observations suggest that apoptosis represents a prominent form of cell death associated with ICH in the perihematoma region. Further studies are required to define the mediators of apoptosis in ICH.
To determine whether extracellular concentrations of glutamate and other amino acids are signific... more To determine whether extracellular concentrations of glutamate and other amino acids are significantly elevated after intracerebral hemorrhage and, if so, the temporal characteristics of these changes. Although the role of excitotoxic amino acids, particularly that of glutamate, has been described in ischemic stroke and head trauma, no information exists regarding their possible contribution to the pathogenesis of neuronal injury in intracerebral hemorrhage. Prospective, controlled, laboratory trial. Animal research laboratory. Sixteen anesthetized New Zealand rabbits. We introduced intracerebral hemorrhage in each of eight anesthetized New Zealand rabbits by injecting 0.4 mL of autologous blood under arterial pressure into the deep gray matter of the cerebrum. Extracellular fluid samples were collected from the perihematoma region and contralateral (right) hemisphere by in vivo microdialysis at 30-min intervals for 6 hrs. Corresponding samples were similarly collected from both hemispheres in each of eight control animals that underwent needle placement without introduction of a hematoma. Concentrations of amino acids (glutamate, aspartate, asparagine, glycine, taurine, and gamma-aminobutyric acid) in the samples were measured by use of high-pressure liquid chromatography with fluorescence detection. Glutamate concentrations (mean +/- sem) were significantly higher in the hemisphere ipsilateral to the hematoma than in the contralateral hemisphere (92 +/- 22 pg/microL vs. 22 +/- 6 pg/microL) at 30 mins after hematoma creation. A significant increase was observed at 30 mins posthematoma creation in the hemisphere ipsilateral to the hematoma compared with the baseline value. A nonsignificant increase in glutamate concentration persisted in the hemisphere ipsilateral to the hematoma, ranging from 134% to 187% of baseline value between 1 and 5 hrs after hematoma creation. In the hemisphere ipsilateral to the hematoma, a three-fold increase in the concentration of glycine was observed at 30 mins after hematoma creation compared with the baseline level (890 +/- 251 pg/microL vs. 291 +/- 73 pg/microL). There was a significant difference between the hemisphere ipsilateral to the hematoma compared with the ipsilateral (corresponding) hemisphere of the control group at 30 mins posthematoma (890 +/- 251 pg/microL vs. 248 +/- 66 pg/microL). A similar transient increase was observed in taurine and asparagine concentrations at 30 mins after hematoma creation, compared with baseline measurements. Taurine concentrations in the hemisphere ipsilateral to the hematoma were significantly higher than the ipsilateral hemisphere of the control group (622 +/- 180 pg/microL vs. 202 +/- 64 pg/microL) at 30 mins after hematoma creation. The present study suggests that glutamate and other amino acids accumulate transiently in extracellular fluids in the perihematoma region during the early period of intracerebral hemorrhage. The exact role of these amino acids in the pathogenesis of neuronal injury observed in intracerebral hemorrhage needs to be defined.
Eptifibatide, a competitive platelet glycoprotein IIb-IIIa receptor inhibitor with high selectivi... more Eptifibatide, a competitive platelet glycoprotein IIb-IIIa receptor inhibitor with high selectivity and a short half-life, has been demonstrated to reduce the risk of ischemic events associated with coronary interventions. However, its role in neurointerventional procedures needs to be analyzed. We report the results of an open-label Phase I study to evaluate the safety of the use of eptifibatide during carotid angioplasty and stent placement. Each study patient received eptifibatide administered intravenously as a 135-microg/kg single-dose bolus, then a 0.5-microg/kg/min infusion for 20 to 24 hours during carotid angioplasty and stent placement. The primary efficacy end point was the 30-day composite occurrence of death, cerebral infarction, transient ischemic attack, and unplanned or urgent surgical intervention, thrombolysis, or subsequent percutaneous revascularization. The primary safety end point was bleeding. Bleeding complications were classified as major (hemoglobin decrease >5 g/dl), minor (hemoglobin decrease 3-5 g/dl), or insignificant. Ten patients (mean age, 73 yr; four men) were treated by use of the study protocol. One patient developed a minor stroke postprocedurally (National Institutes of Health Stroke Scale score of 21 at 24 h that improved to 1 at 7 d). Three patients underwent scheduled coronary artery bypass graft surgery 4 to 12 days after undergoing carotid angioplasty and stent placement. At 1-month follow-up, no new ischemic events were observed. Major or minor bleeding was not observed in any patient. Insignificant bleeding was observed in two patients. The use of eptifibatide as an adjunct to carotid angioplasty and stent placement seems to be safe. Further studies are required to analyze the effectiveness and role of eptifibatide in neurointerventional procedures.
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Papers by Zulfiqar Ali