Pulse pressure variability is associated with unfavorable outcomes in acute ischaemic stroke patients treated with intravenous thrombolysis.

BACKGROUND AND PURPOSE: Blood pressure (BP) variability has been associated with worse neurological outcomes in acute ischaemic stroke (AIS) patients receiving treatment with intravenous thrombolysis (IVT). However, no study to date has investigated whether pulse pressure (PP) variability may be a superior indicator of the total cardiovascular risk, as measured by clinical outcomes. METHODS: Pulse pressure variability was calculated from 24-h PP measurements following tissue plasminogen activator bolus in AIS patients enrolled in the Combined Lysis of Thrombus using Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization (CLOTBUST-ER) trial. The outcomes of interest were the pre-specified efficacy and safety end-points of CLOTBUST-ER. All associations were adjusted for potential confounders in multivariable regression models. RESULTS: Data from 674 participants was analyzed. PP variability was identified as the BP parameter with the most parsimonious fit in multivariable models of all outcomes, and was independently associated (P < 0.001) with lower likelihood of both 24-h neurological improvement and 90-day independent functional outcome. PP variability was also independently related to increased odds of any intracranial bleeding (P = 0.011) and 90-day mortality (P < 0.001). Every 5-mmHg increase in the 24-h PP variability was independently associated with a 36% decrease in the likelihood of 90-day independent functional outcome (adjusted odds ratio 0.64, 95% confidence interval 0.52-0.80) and a 60% increase in the odds of 90-day mortality (adjusted odds ratio 1.60, 95% confidence interval 1.23-2.07). PP variability was not associated with symptomatic intracranial bleeding at either 24 or 36 h after IVT administration. CONCLUSIONS: Increased PP variability appears to be independently associated with adverse short-term and long-term functional outcomes of AIS patients treated with IVT.

Intra-arterial reteplase compared to urokinase for thrombolytic recanalization in acute ischemic stroke.

BACKGROUND AND PURPOSE: Reteplase (RP) and urokinase (UK) are being used "off-label" to treat acute ischemic stroke. The safety and efficacy of intra-arterial RP or UK in the treatment of acute ischemic stroke, however, has yet to be proved. We aim to evaluate the safety and efficacy of RP compared with UK in acute ischemic stroke patients with large vessel occlusion. METHODS: Retrospective analysis was conducted of cases from a prospectively collected stroke data base on consecutive acute ischemic stroke patients with large vessel occlusion by digital subtraction angiography treated with intra-arterial RP or UK. Thrombolytic dosage, recanalization rate, intracerebral hemorrhage (ICH), mortality, and outcome were determined. RESULTS: Thirty-three patients received RP and 22 received UK (mean doses, 2.5 +/- 1.4 mg and 690,000 +/- 562,000 U, respectively). Vascular occlusions included 9 basilar arteries (BAs), 7 internal carotid arteries (ICAs), and 17 middle cerebral arteries (MCAs) with RP and 9 BAs, 4 ICAs, and 9 MCAs with UK. Median baseline National Institutes of Health Stroke Scales were as follows: 16 (range, 5-25; 81% > or = 10) with RP and 17 (range, 6-38; 85% > or =10) with UK. Mean time from symptom onset to thrombolytic initiation: 333 +/- 230 minutes with RP and 343 +/- 169 minutes with UK. Recanalization rates were as follows: 82% with RP and 64% with UK (P = .13). Symptomatic ICH rates were as follows: 12% with RP and 4.5% with UK (P = .50). The mortality rate was 24% with RP and 27% with UK (P = .8). CONCLUSION: Although limited in statistical power, our study suggests that, although IA thrombolysis with RP shows a trend for higher recanalization rates and hemorrhage rates, IA thrombolysis with RP is not significantly different in recanalization, outcome, mortality, and ICH compared with that of UK or rates reported with IA pro-UK.

Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short-term improvement.

BACKGROUND: Arterial recanalization precedes clinical improvement or may lead to hemorrhage or reperfusion injury. Speed of clot lysis was not previously measured in human stroke. METHODS AND RESULTS: Transcranial Doppler (TCD) and the National Institutes of Health Stroke Scale (NIHSS) were used to monitor consecutive patients receiving intravenous tissue plasminogen activator (tPA), before tPA bolus and at 24 hours. Patients with complete or partial recanalization of the middle cerebral or basilar artery on TCD were studied. Recanalization was classified a priori as sudden (abrupt appearance of a normal or stenotic low-resistance signal), stepwise (flow improvement over 1 to 29 minutes), or slow (>/=30 minutes). Recanalization was documented in 43 tPA-treated patients (age 68+/-17 years; NIHSS score 16.8+/-6, median 15 points). tPA bolus was given at a mean of 135+/-61 minutes after symptom onset. Recanalization began at a median of 17 minutes and was completed at 35 minutes after tPA bolus, with mean duration of recanalization of 23+/-16 minutes. Recanalization was sudden in 5, stepwise in 23, and slow in 15 patients. Faster recanalization predicted better short-term improvement (P=0.03). At 24 hours, 80%, 30%, and 13% of patients in these respective recanalization groups had NIHSS scores of 0 to 3. Symptomatic hemorrhage occurred in only 1 patient, who had stepwise recanalization 5.5 hours after stroke onset. Slow or partial recanalization with dampened flow signal was found in 53% of patients with total NIHSS scores >10 points at 24 hours (P=0.01). Complete recanalization (n=25) occurred faster (median 10 minutes) than partial recanalization (n=18; median 30 minutes; P=0.0001). CONCLUSIONS: Rapid arterial recanalization is associated with better short-term improvement, mostly likely because of faster and more complete clot breakup with low resistance of the distal circulatory bed. Slow (>/=30 minutes) flow improvement and dampened flow signal are less favorable prognostic signs. These findings may be evaluated to assist with selection of patients for additional pharmacological or interventional treatment.

Hypothermia after cardiac arrest: feasibility and safety of an external cooling protocol.

BACKGROUND: No proven neuroprotective treatment exists for ischemic brain injury after cardiac arrest. Mild-to-moderate induced hypothermia (MIH) is effective in animal models. METHODS AND RESULTS: A safety and feasibility trial was designed to evaluate mild-to-moderate induced hypothermia by use of external cooling blankets after cardiac arrest. Inclusion criteria were return of spontaneous circulation within 60 minutes of advanced cardiac life support, hypothermia initiated within 90 minutes, persistent coma, and lack of acute myocardial infarction or unstable dysrhythmia. Hypothermia to 33 degrees C was maintained for 24 hours followed by passive rewarming. Nine patients were prospectively enrolled. Mean time from advanced cardiac life support to return of spontaneous circulation was 11 minutes (range 3 to 30); advanced cardiac life support to initiation of hypothermia was 78 minutes (range 40 to 109); achieving 33 degrees C took 301 minutes (range 90 to 690). Three patients completely recovered, and 1 had partial neurological recovery. One patient developed unstable cardiac dysrhythmia. No other unexpected complications occurred. CONCLUSIONS: Mild-to-moderate induced hypothermia after cardiac arrest is feasible and safe. However, external cooling is slow and imprecise. Efforts to speed the start of cooling and to improve the cooling process are needed.

Patient refusal of thrombolytic therapy for suspected acute ischemic stroke.

OBJECTIVE: To determine factors associated with patients refusing IV t-PA for suspected acute ischemic stroke (AIS), and to compare the outcomes of patients who refused t-PA (RT) with those treated with t-PA. METHODS: Patients who were treated with and refused t-PA at our stroke center were identified retrospectively. Demographics, clinical presentation, and outcome measures were collected and compared. Clinical outcome was defined as excellent (mRS: 0-1), good (mRS: 0-2), and poor (mRS: 3-6). RESULTS: Over 7·5 years, 30 (4·2%) patients refused t-PA. There were no demographic differences between the treated and RT groups. The rate of RT decreased over time (OR 0·63, 95% CI 0·50-0·79). Factors associated with refusal included a later symptom onset to emergency department presentation time (OR 1·02, 95% CI 1·01-1·03), lower NIHSS (OR 1·11, 95% CI 1·03-1·18), a higher proportion of stroke mimics (OR 17·61, 95% CI 6·20-50·02) and shorter hospital stay (OR 1·32, 95% CI 1·09-1·61). Among patients who were subsequently diagnosed with ischemic stroke, only length of stay was significantly shorter for refusal patients (OR 1·37, 95% CI 1·06-1·78). After controlling for mild strokes and stroke mimics, clinical outcome was not different between the groups (OR 1·61, 95% CI 0·69-3·73). CONCLUSION: The incidence of patients refusing t-PA has decreased over time, yet it may be a cause for t-PA under-utilization. Patients with milder symptoms were more likely to refuse t-PA. Refusal patients presented later to the hospital and had shorter hospital stays. One out of six refusal patients (16·6%) had a stroke mimic.

Should mild or moderate stroke patients be admitted to an intensive care unit?

BACKGROUND AND PURPOSE: Inhospital placement of patients with mild (National Institutes of Health Stroke Scale [NIHSS] score <8) or moderate (NIHSS 8 through 16) acute strokes is variable. We assessed the outcome of such patients based on intensive care unit (ICU) versus general ward placement. METHODS: We reviewed 138 consecutive patients admitted within 24 hours of stroke onset to 2 physically adjacent hospitals with different admitting practices. Outcome measures included complication rates, discharge Rankin scale score, hospital discharge placement, costs, and length of stay (LOS). RESULTS: Hospital A, a 626-bed university-affiliated hospital, admitted 43% of mild and moderate strokes (MMS) to an ICU (26% of mild, 74% of moderate), whereas hospital B, a 618-bed community facility, admitted 18% of MMS to an ICU (3% of mild, 45% of moderate; P<0.004). There were no significant differences in outcomes between the 2 hospitals. Analysis of only patients admitted to hospital A, and of all patients, demonstrated that mild stroke patients admitted to the general ward had fewer complications and more favorable discharge Rankin scale scores than similar patients admitted to an ICU. There was no statistically significant difference in LOS, but total room costs for a patient admitted first to the ICU averaged $15 270 versus $3638 for admission directly to the ward. CONCLUSIONS: While limited by the retrospective nature of our study, routinely admitting acute MMS patients to an ICU provides no cost or outcomes benefits.

Clinical deterioration following improvement in the NINDS rt-PA Stroke Trial.

BACKGROUND AND PURPOSE: Little is known in regard to cerebral arterial reocclusion after successful thrombolysis. In the absence of arteriographic information, the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial investigators prospectively identified clinical deterioration following improvement (DFI) as a possible surrogate marker of cerebral arterial reocclusion after rt-PA-induced recanalization. Also, we identified any significant clinical deterioration (CD) even if not preceded by improvement. This observational analysis was designed to determine the incidence of DFI and CD in each treatment group, to identify baseline or posttreatment variables predictive of DFI or CD, and to determine any relationship between DFI, CD, and clinical outcome. METHODS: DFI was defined as any 2-point deterioration on the NIH Stroke Scale after an initial 2-point improvement after treatment. CD was defined as any 4-point worsening after treatment compared with baseline. All data were collected prospectively by investigators blinded to treatment allocation. A noncontrast brain CT was mandated when a 2-point deterioration occurred. All cases were validated by a central review committee. RESULTS: DFI was identified in 81 of the 624 patients (13%); 44 were treated with rt-PA and 37 were treated with placebo (P:=0.48). DFI occurred more often in patients with a higher baseline NIH Stroke Scale score. CD within the first 24 hours occurred in 98 patients (16% of all patients); 43 were given rt-PA and 55 were given placebo (P:=0.19). Baseline variables associated with CD included a less frequent use of prestroke aspirin and a higher incidence of early CT changes of edema or mass effect or dense middle cerebral artery sign. Patients with CD had higher rates of increased serum glucose and fibrin degradation products, and they also had higher rates of symptomatic intracranial hemorrhage and death. Patients who experienced either DFI or CD were less likely to have a 3-month favorable outcome. CONCLUSIONS: We found no association between DFI, CD, and rt-PA treatment, and no clinical evidence to suggest reocclusion. Deterioration was strongly associated with stroke severity and poor outcome and was less frequent in patients whose stroke occurred while they were on aspirin.

Reperfusion injury: demonstration of brain damage produced by reperfusion after transient focal ischemia in rats.

During reperfusion after ischemia, deleterious biochemical processes can be triggered that may antagonize the beneficial effects of reperfusion. Research into the understanding and treatment of reperfusion injury (RI) is an important objective in the new era of reperfusion therapy for stroke. To investigate RI, permanent and reversible unilateral middle cerebral artery/common carotid artery (MCA/CCA) occlusion (monitored by laser Doppler) of variable duration in Long-Evans (LE) and spontaneously hypertensive (SH) rats and unilateral MCA and bilateral CCA occlusion in selected LE rats was induced. In LE rats, infarct volume after 24 hours of permanent unilateral MCA/CCA occlusion was 31.1 +/- 34.6 mm3 and was only 28% of the infarct volume after 120 to 300 minutes of reversible occlusion plus 24 hours of reperfusion, indicating that 72% of the damage of ischemia/reperfusion is produced by RI. When reversible ischemia was prolonged to 480 and 1080 minutes, infarct volume was 39.6 mm3 and 16.6 mm3, respectively, being indistinguishable from the damage produced by permanent ischemia and significantly smaller than damage after 120 to 300 minutes of ischemia. Reperfusion injury was not seen in SH rats or with bilateral CCA occlusion in LE rats, in which perfusion is reduced more profoundly. Reperfusion injury was ameliorated by the protein synthesis inhibitor cycloheximide or spin-trap agent N-tert-butyl-alpha-phenylnitrone pretreatment.

Neuronal protection and preservation of calcium/calmodulin-dependent protein kinase II and protein kinase C activity by dextrorphan treatment in global ischemia.

This study analyzed the ability of the N-methyl-D-aspartate receptor antagonist dextrorphan (DX) to prevent neuronal degeneration (analyzed by light microscopy), calmodulin (CaM) redistribution (analyzed by immunocytochemistry) and changes in activity of two major Ca(2+)-dependent protein kinases--calcium/calmodulin-dependent protein kinase II (CaM-KII) and protein kinase C (PKC) (analyzed by specific substrate phosphorylation) after 20 min of global ischemia (four-vessel occlusion model) in rats. DX treatment before and after ischemia significantly protected hippocampal and cortical neurons from neurodegeneration whereas DX posttreatment alone did not have any effect on preservation of neuronal morphology as compared with placebo treatment analyzed 72 h after 20 min of ischemia. Similarly to histological changes, DX exhibited protection against redistribution of CaM observed after ischemia. These changes were detected both in hippocampus as well as in cerebral cortex. Finally, DX administered before ligation of the carotid arteries reduced loss in both CaM-KII and PKC activity evoked by ischemia.

Neurofilament proteolysis after focal ischemia; when do cells die after experimental stroke?

To determine the occurrence and time-course of presumably irreversible subcellular damage after moderate focal ischemia, rats were subjected to 1, 3, 6, 9, or 24 hours of permanent unilateral middle cerebral and common carotid occlusion or 3 hours of reversible occlusion followed by 3, 6, or 21 hours of reperfusion. The topography and the extent of damage were analyzed with tetrazolium staining and immunoblot using an antibody capable of detecting breakdown of neurofilament. Neurofilament proteolysis began after 3 hours in the infarct core but was still incomplete in penumbral regions up to 9 hours. Similarly, tetrazolium-staining abnormalities were observed in the core of 50% of animals after 3 hours of ischemia. At 6 hours of permanent ischemia, infarct volume was maximal, and further prolongation of occlusion to 9 or 24 hours did not increase abnormal tetrazolium staining. In contrast to permanent ischemia and in agreement with the authors' previous demonstration of "reperfusion injury" in this model, prolongation of reperfusion from 3 hours to 6 and 21 hours after 3 hours of reversible occlusion gradually augmented infarct volume by 203% and 324%, respectively. Neurofilament proteolysis initiated approximately 3 hours after ischemia was quantitatively greatest in the core and extended during reperfusion to incorporate penumbra with a similar time course to that of tetrazolium abnormalities. These data demonstrate that, at least as measured by neurofilament breakdown and mitochondrial failure, extensive cellular damage is not present in penumbral regions for up to 9 hours, suggesting the potential for rescuing these regions by appropriate and timely neuroprotective strategies.

Motor performance, histologic damage, and calcium influx in rats treated with NBQX after focal ischemia.

2,3-Dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX), an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist, has been reported to provide neuronal protection after global ischemia. The objectives of this study were to evaluate the neuroprotective effects of NBQX initiated after focal cortical ischemia and to validate a method for measuring functional outcome in this model. Male spontaneously hypertensive rats (SHRs) were exposed to various durations of transient or permanent tandem middle cerebral artery (MCA) occlusion. Studies compared motor performance using balance beam and prehensile-traction tests, calcium-calmodulin (Ca-CaM) binding by immunohistochemistry, and infarct volume between NBQX-treated animals [intravenous (i.v.) 5 mg/kg/h x 6 h or intraperitoneal (i.p.) 30 mg/kg q 30 min x 3 begun postischemia] and controls. All ischemic groups performed less well than sham-operated controls on the motor performance tasks in proportion to the severity of ischemia. No significant improvement in motor performance was noted in the NBQX-treated versus the control animals after 1 h or permanent MCA/CCA occlusion. Treatment with NBQX (i.v. or i.p. dosing) did not reduce Ca-CaM binding after 1 h of occlusion with 1 h of reperfusion or after 2 h of occlusion. Similarly, there was no reduction in infarct size between NBQX-treated and control animals after 24 h of permanent MCA/CCA occlusion (74.6 +/- 7.1 vs. 80.1 +/- 6.0 ml; ns) or after 1 h of occlusion with 23 h of reperfusion (55.1 +/- 4.4 vs. 47.4 +/- 6.2 ml; ns).(ABSTRACT TRUNCATED AT 250 WORDS)

Interplay between the gamma isoform of PKC and calcineurin in regulation of vulnerability to focal cerebral ischemia.

Protein phosphorylation and dephosphorylation mediated by protein kinases and protein phosphatases, respectively, represent essential steps in a variety of vital neuronal processes that could affect susceptibility to ischemic stroke. In this study, the role of the neuron-specific gamma isoform of protein kinase C (gammaPKC) in reversible focal ischemia was examined using mutant mice in which the gene for gammaPKC was knocked-out (gammaPKC-KO). A period of 150 minutes of unilateral middle cerebral artery and common carotid artery (MCA/CCA) occlusion followed by 21.5 hours of reperfusion resulted in significantly larger (P < 0.005) infarct volumes (n = 10; 31.1+/-4.2 mm3) in gammaPKC-KO than in wild-type (WT) animals (n = 12; 22.6+/-7.4 mm3). To control for possible differences related to genetic background, the authors analyzed Balb/cJ, C57BL/6J, and 129SVJ WT in the MCA/CCA model of focal ischemia. No significant differences in stroke volume were detected between these WT strains. Impaired substrate phosphorylation as a consequence of gammaPKC-KO might be corrected by inhibition of protein dephosphorylation. To test this possibility, gammaPKC-KO mice were treated with the protein phosphatase 2B (calcineurin) inhibitor, FK-506, before ischemia. FK-506 reduced (P < 0.008) the infarct volume in gammaPKC-KO mice (n = 7; 24.6+/-4.6 mm3), but at this dose in this model, had no effect on the infarct volume in WT mice (n = 7; 20.5+/-10.7 mm3). These results indicate that gammaPKC plays some neuroprotective role in reversible focal ischemia.

Immunohistochemical determination of calcium-calmodulin binding predicts neuronal damage after global ischemia.

Since ionic Ca2+ binds with intracellular calmodulin (CaM) before activating proteases, kinases, and phospholipases, demonstration of persistent Ca2+-CaM binding in neurons destined to show ischemic cellular injury would support the concept that elevated intracellular Ca2+ plays a causative role in ischemic neuronal damage. In order to characterize Ca2+-CaM binding, we used a sheep anti-CaM antibody (CaM-Ab) which recognizes CaM that is not bound to Ca2+ or brain target proteins. Therefore, immunohistochemical staining of brain sections by labeled CaM-Ab represented only unbound CaM. Six normal rats were compared to 15 animals rendered ischemic for 30 min by a modification of the four-vessel occlusion model. Animals were killed immediately after ischemia, and after 2 and 24 h of reperfusion. Brain sections through hippocampus were incubated in CaM-Ab, and a diaminobenzadiene labeled anti-sheep secondary antibody was added to stain the CaM-Ab. Staining in the endal limb of dentate, dorsal CA1, lateral CA3, and parietal cortex was graded on a 4-point scale. All normal animals had grade 4 staining indicating the presence of unbound CaM in all four brain regions. Ischemic animals demonstrated reduced (grade 0 to 2) staining in the CA1 and CA3 regions immediately and 2 and 24 h after ischemia (p less than 0.01 for both regions at all three time intervals) indicating persistent binding of CaM with Ca2+ and target proteins in these regions. Staining decreased in dentate and cortex up to 2 h after ischemia (p = 0.02 for both regions) but returned toward normal by 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

An alternative method for the quantitation of neuronal damage after experimental middle cerebral artery occlusion in rats: analysis of behavioral deficit.

We tested the hypothesis that increasing durations of focal ischemia that have been shown to result in enlargement of cortical infarct will be associated with progression of behavioral dysfunction that can be measured by a battery of tests sufficiently sensitive and reproducible to detect a positive effect of pharmacotherapy. Untreated or N-methyl-D-aspartate receptor antagonist (CNS-1102)-treated spontaneously hypertensive rats underwent 45, 60, 90, or 120 min of tandem middle cerebral and common carotid artery occlusion followed by reperfusion. We then evaluated the extent of damage and its recovery for up to 21 days using nine behavioral tests aimed at analyzing strength, coordination, and bilateral asymmetry. Also using a graded bioassay that employs a curve-fitting computer program (ALLFIT) to correlate duration of ischemia with degree of behavioral dysfunction, we calculated the average of maximal behavioral dysfunction and duration of ischemia required to produce half-maximal behavioral dysfunction and compared these values in untreated controls with analogous values obtained from animals treated with CNS-1102. Three behavioral tests, forearm flex, tape (somatosensory neutralization), and foot-fault placing, were each separately and combined able to distinguish between the degrees of damage produced by increasing durations of ischemia. The behavioral abnormalities assessed using the tape test were reversible within a week, whereas those using forearm flex or foot-fault tests persisted for at least 21 days. CNS-1102 significantly reduced behavioral dysfunction measured by all three tests. This analysis of behavioral dysfunction represents a useful experimental model to grade efficacy of therapies aimed at protecting the brain from damage produced by acute stroke and might also be used to assess recovery from preexisting ischemic damage.

Ischemia-induced neuronal damage: a role for calcium/calmodulin-dependent protein kinase II.

Calcium/calmodulin-dependent protein kinase II (CaM-kinase) is a central enzyme in regulating neuronal processes. Imbalances in the activity and distribution of this enzyme have been reported following in vivo ischemia, and sustained decreases in activity correlate with subsequent neuronal death. In this report, mice that had been rendered deficient in the alpha subunit of CaM-kinase using gene knock-out technology were utilized to determine whether this enzyme is causally related to ischemic damage. Using a focal model of cerebral ischemia, we showed that homozygous knock-out mice lacking the alpha subunit exhibited an infarct volume almost twice that of wild-type litter mates. Heterozygous mice exhibited slightly less damage following ischemia than did homozygous mice, but infarct volumes remained significantly larger than those of wild-type litter mates. We conclude that reduced amounts of the alpha subunit of CaM-kinase predisposes neurons to increased damage following ischemia and that any perturbation that decreases the amount or activity of the enzyme will produce enhanced susceptibility to neuronal damage.

Cerebral mucormycosis: an unusual case.

A 36-year-old obese woman with hyperglycemia and immunosuppression died of bilateral internal carotid artery occlusion associated with mucormycosis. This report describes a rare case in which cerebral mucormycosis occurred without the usual preceding clinical evidence of nasal and orbital infection.

Positron imaging in ischemic stroke disease using compounds labeled with oxygen 15. Initial results of clinicophysiologic correlations.

Initial results in over 50 patients with stroke suggest that positron images made during continuous inhalation of carbon dioxide labeled with oxygen 15 and molecular oxygen labeled with oxygen 15 provide data on tissue function that may be relevant to acute stroke management. Five cases illustrate the following findings: 15O-activity patterns observed in areas of ischemic injury or infarction are what one would expect if the 15O distributions represented physiologic functions, such as cerebral blood flow and metabolism. Areas of abnormal 15O activity correlate with the clinical or computed tomographic (CT) localization of the deficit. In studies performed acutely, changes in 15O distributions anticipate alterations in CT scans and may be predictive of outcome. Data related to oxygen metabolism correlate better with tissue viability than do those reflecting cerebral blood flow.

Intravenous tissue-type plasminogen activator therapy for ischemic stroke: Houston experience 1996 to 2000.

CONTEXT: Intravenous tissue-type plasminogen activator (tPA) therapy using the National Institute of Neurological Disorders and Stroke criteria has been given with variable safety to less than 5% of the patients who have ischemic strokes nationwide. Our center is experienced in treating large numbers of stroke patients with intravenous tPA. OBJECTIVE: To report our total 4-year experience in the treatment of consecutive patients who had an ischemic stroke. DESIGN: Prospective inception cohort registry of all patients seen by our stroke team and an additional retrospective medical record review of all patients treated between January 1, 1996, and June 1, 2000. SETTING: A veteran stroke team composed of fellows and stroke-specialty faculty servicing 1 university and 3 community hospitals in a large urban setting. PATIENTS: Consecutive patients with ischemic stroke treated within the first 3 hours of symptom onset. INTERVENTION: According to the National Institute of Neurological Disorders and Stroke protocol, 0.9 mg/kg of intravenous tissue-type plasminogen activator was administered. MAIN OUTCOME MEASURES: Number and proportion treated, patient demographics, time to treatment, hemorrhage rates, and clinical outcome. RESULTS: A total of 269 patients were treated between January 1, 1996, and June 1, 2000. Their mean age was 68 years (age range, 24-93 years); 48% were women. This represented 9% of all patients admitted with symptoms of cerebral ischemia at our most active hospital (over the final 6 months, 13% of all patients with symptoms of cerebral ischemia and 15% of all acute ischemic stroke patients). Before treatment the mean +/- SD National Institutes of Health Stroke Scale (NIHSS) score was 14.4 +/- 6.1 points (median, 14 points; range, 4-33 points). A tPA bolus was given at 137 minutes (range, 30-180 minutes); 28% of the patients were treated within 2 hours. The mean door-to-needle time was 70 minutes (range, 10-129 minutes). The symptomatic intracerebral hemorrhage rate was 5.6% of those patients with a second set of brain scans (4.5% of all patients), with a declining trend from 1996 to 2000. Protocol violations were found in 13% of all patients; the symptomatic intracerebral hemorrhage rate in these patients was 15%. At 24 hours, the NIHSS score was 10 +/- 8 points (median, 8 points; range, 0-36 points). In-hospital mortality was 15% and the patients' discharge NIHSS scores were 7 +/- 7 points (median, 3 points; range, 0-35 points). CONCLUSIONS: Intravenous tPA therapy can be given to up to 15% of the patients with acute ischemic stroke with a low risk of symptomatic intracerebral hemorrhage. Successful experience with intravenous tPA therapy depends on the experience and organization of the treating team and adherence to published guidelines.

Should hypertension be treated after acute stroke? A randomized controlled trial using single photon emission computed tomography.

OBJECTIVE: To determine if previously hypertensive patients with acute ischemic stroke should be treated with antihypertensive medication in the immediate poststroke period. DESIGN: Randomized double-blind, placebo-controlled trial. SETTING: Sixteen consecutive hypertensive patients (four men and 12 women; mean age, 66 years [age range, 46 to 83 years]) with middle cerebral artery infarction within 72 hours of onset and blood pressure between 170 and 220 mm Hg(systolic) and 95 and 120 mm Hg (diastolic). INTERVENTION: Placebo (n = 6), nicardipine hydrochloride (20 mg [n = 5]), captopril (12.5 mg [n = 3]), or clonidine hydrochloride (0.1 mg [n = 2]) given every 8 hours for 3 days. MAIN OUTCOME MEASURES: Decline in blood pressure, change in cerebral blood flow as measured by single photon emission computed tomography, and clinical change as determined by the National Institutes of Health Stroke Scale. RESULTS: Blood pressure fell significantly in both the drug-treated group as a whole and in those patients receiving placebo (P < .001). There was no difference in blood pressure levels between these two groups throughout the study period. Patients receiving nicardipine had a consistently lower pressure than the other groups. A significant negative relationship was noted between the maximum blood pressure fall and improvement in cerebral blood flow. There were four patients whose blood pressure dropped by more than 16% of the baseline value on any 24 hours in the first 3 days. All either failed to increase or actually decreased their cerebral blood flow to the affected area. Three of these patients were treated with nicardipine. There was no significant difference in clinical course between the placebo-and drug-treated groups as a whole. CONCLUSIONS: Hypertensive ischemic stroke patients with a moderate elevation of blood pressure in the first few days may not require antihypertensive therapy. Nicardipine and possibly other calcium channel blockers may cause an excessive fall in blood pressure and impair cerebral blood flow in these patients and should therefore be used with caution.

Prevention of stroke with ticlopidine: who benefits most? TASS Baseline and Angiographic Data Subgroup.

We examined the baseline characteristics of patients in the Ticlopidine Aspirin Stroke Study (TASS) to determine if the effects of the two treatments in preventing stroke differed in various subgroups. Patients with the following characteristics did less well on aspirin: elevated creatinine, hypertension or diabetes requiring treatment, or treatment with anticoagulant or antiplatelet drugs prior to their qualifying TIA or stroke. Women and patients with vertebrobasilar symptoms did particularly well on ticlopidine. We performed arteriography in 1,188 patients with carotid qualifying events. The frequency of stroke in patients with abnormal arteriograms ipsilateral to their symptoms was slightly higher than in those with normal carotid arteries. Ticlopidine was more effective in patients without carotid stenosis. Ticlopidine is more effective than aspirin in preventing strokes in patients having warning TIAs. The patients who benefit most from ticlopidine may be women, those who have vertebrobasilar symptoms, those with cerebral ischemic symptoms while on aspirin or anticoagulant therapy, and patients with diffuse atherosclerotic disease rather than high-grade carotid stenosis.