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.

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.

Does the cognitive measure Cog-4 show improvement among patients treated with thrombolysis after acute stroke?

BACKGROUND: Although the established measure of disability post stroke, the modified Rankin Scale emphasizes motor function and may underestimate the importance of cognitive impairment in more disabled patients. A subset of four items from the National Institutes of Health Stroke Scale has been proposed to assess cognitive function after stroke (Cog-4), and to correlate with modified Rankin Scale. Items correspond to orientation, executive function, language, and inattention. We investigated responsiveness of Cog-4 to treatment with thrombolysis and whether it offers information that supplements modified Rankin Scale. METHODS: We included 6268 patients from the Virtual International Stroke Trials Archive: 2734 received intravenous thrombolysis and 3534 were treated conservatively. We compared day 90 outcomes between treated and untreated groups, by modified Rankin Scale (illustrative) and by Cog-4 (primary measure) adjusting for age, baseline National Institutes of Health stroke scale, hemispheric lateralisation as well as baseline Cog-4 and baseline National Institutes of Health Stroke Scale excluding baseline Cog-4 separately. Analysis of Cog-4 was repeated within strata of 90 day modified Rankin Scale. Statistical analyses included proportional odds logistic regression and Cochran-Mantel-Haenszel test. RESULTS: Modified Rankin Scale showed a difference between treatment groups of expected magnitude (odds ratio 1·56; 95% confidence interval 1·43-1·72; P < 0·001). After adjustment for imbalance in baseline prognostic factors, the distribution of Cog-4 scores at 90 days was better in thrombolysed patients compared with nonthrombolysed patients (odds ratio 1·31; 95% confidence interval 1·18-1·47; P = 0·006). However, Cog-4 analysis stratified by 90-day modified Rankin Scale was neutral between treatment groups (OR 1·01; 95% CI 0·90-1·14), and Cog-4 was not responsive to treatment group even within modified Rankin Scale categories 4 and 5 despite substantial cognitive deficits in these patients. CONCLUSION: Although Cog-4 may be responsive to treatment effects, it does not provide additional information beyond modified Rankin Scale assessment.

Safety of high doses of urokinase and reteplase for acute ischemic stroke.

BACKGROUND AND PURPOSE: ET is considered in selected patients with AIS with persistent arterial occlusion after receiving IVT. Limited data exist on the safety of IA high doses of UK and RT for ET. We investigated any correlation between IA doses of UK or RT and safety outcomes in patients who underwent ET. MATERIALS AND METHODS: We identified all patients from our stroke registry who received UK or RT for ET from 1998 to 2008. Demographics, baseline National Institutes of Health Stroke Scale scores, recanalization rates, rates of attempted MT, mortality, SICH, and discharge modified Rankin Scale scores were collected. RESULTS: Of 197 patients; 72 received UK and 125 received RT. More than 90% of patients in both groups had received prior IVT. The median IA dose of UK was 200,000 U (range, 25,000-1,500,000 U) and of RT was 2 mg (range, 1-8 mg). Concurrent MT was attempted in 59.7% of UK-treated patients and 72.0% of RT-treated patients, with SICH rates of 4.2% and 8.0%, respectively. Logistic regression adjusting for prior IVT and MT revealed no correlation between SICH and doses of UK (OR, 1.00; 95% CI, 0.99-1.00; P = .94) or RT (OR, 0.803; 95% CI, 0.48-1.33; P = .39). There was no correlation between mortality and doses of UK (OR, 1.00; 95% CI, 0.99-1.00; P = .51) or RT (OR, 1.048; 95% CI, 0.77-1.42; P = .75). CONCLUSIONS: High IA doses of UK and RT may be safe when given with or without MT in patients with AIS despite receiving a full dose of intravenous recombinant tissue plasminogen activator. These results need prospective validation.

The effect of transcatheter injections on cell viability and cytokine release of mononuclear cells.

BACKGROUND AND PURPOSE: Several studies suggest that various types of cellular therapies enhance recovery after stroke in animal models. IA-based delivery of cells to the brain is under investigation for stroke, but it is unknown whether cells are injured as a result of being injected through a catheter or exposed to iodinated contrast medium or solutions containing heparin. MATERIALS AND METHODS: We assessed the effect of catheterization with the Excelsior SL-10 catheter or exposure to heparin or iodine contrast on human bone marrow MNCs. Viability and cell injury were assessed by trypan blue exclusion, caspase-3 activity, and lipid peroxidation. Cellular function of MNCs was assessed by their production and release of VEGF, IL-10, and IGF-1. RESULTS: Flow rates of 10 million cells from 0.5 to 2 mL/min did not alter MNC viability; however, 5 mL/min of MNCs did reduce viability by 19%. Iodine and low-dose heparin exposure did not affect cell viability; however, high-dose heparin was cytotoxic. Catheter delivery at 2 mL/min did not affect levels of VEGF, IL-10, or IGF-1. CONCLUSIONS: MNCs do not appear to be damaged by heparin, iodine contrast, and the Excelsior SL-10 catheter at flow rates up to 2 mL/min. However, higher flow rates did reduce viability, and high-dose heparin did cause cell death.

Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia.

BACKGROUND: Patients with acute neurologic symptoms may have other causes simulating ischemic stroke, called stroke mimics (SM), but they may also have averted strokes that do not appear as infarcts on neuroimaging, which we call neuroimaging-negative cerebral ischemia (NNCI). We determined the safety and outcome of IV thrombolysis within 3 hours of symptom onset in patients with SM and NNCI. METHODS: Patients treated with IV tissue plasminogen activator (tPA) within 3 hours of symptom onset were identified from our stroke registry from June 2004 to October 2008. We collected admission NIH Stroke Scale (NIHSS) score, modified Rankin score (mRS), length of stay (LOS), symptomatic intracerebral hemorrhage (sICH), and discharge diagnosis. RESULTS: Among 512 treated patients, 21% were found not to have an infarct on follow-up imaging. In the SM group (14%), average age was 55 years, median admission NIHSS was 7, median discharge NIHSS was 0, median LOS was 3 days, and there were no instances of sICH. The most common etiologies were seizure, complicated migraine, and conversion disorder. In the NNCI group (7%), average age was 61 years, median admission NIHSS was 7, median discharge NIHSS was 0, median LOS was 3 days, and there were no instances of sICH. Nearly all SM (87%) and NNCI (91%) patients were functionally independent on discharge (mRS 0-1). CONCLUSIONS: Our data support the safety of administering IV tissue plasminogen activator to patients with suspected acute cerebral ischemia within 3 hours of symptom onset, even when the diagnosis ultimately is found not to be stroke or imaging does not show an infarct.

Intraventricular hemorrhage: Anatomic relationships and clinical implications.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is frequently associated with intraventricular hemorrhage (IVH), which is an independent predictor of poor outcome. The purpose of this study was to examine the relationship between ICH volume and anatomic location to IVH, and to determine if ICH decompression into the ventricle is truly beneficial. METHODS: We retrospectively analyzed the CT scans and charts of all patients with ICH admitted to our stroke center over a 3-year period. Outcome data were collected using our prospective stroke registry. RESULTS: We identified 406 patients with ICH. A total of 45% had IVH. Thalamic and caudate locations had the highest IVH frequency (69% and 100%). ICH volume and ICH location were predictors of IVH (p < 0.001). Within each location, decompression ranges (specific volume ranges where ventricular rupture tends to occur) were established. Patients with IVH were twice as likely to have a poor outcome (discharge modified Rankin scale of 4 to 6) (OR 2.25, p = 0.001) when compared to patients without IVH. Caudate location was associated with a good outcome despite 100% incidence of IVH. Spontaneous ventricular decompression was not associated with better outcome, regardless of parenchymal volume reduction (p = 0.72). CONCLUSIONS: Intraventricular hemorrhage (IVH) occurs in nearly half of patients with spontaneous intracerebral hemorrhage (ICH) and is related to ICH volume and location. IVH is likely to occur within the "decompression ranges" that take into account both ICH location and volume. Further, spontaneous ventricular decompression does not translate to better clinical outcome. This information may prove useful for future ICH trials, and to the clinician communicating with patients and families.

Myocardial injury in patients with intracerebral hemorrhage treated with recombinant factor VIIa.

We report myocardial injury in 20 recombinant factor VIIa (rFVIIa) treated and 110 nontreated patients with intracerebral hemorrhage. Patients were treated or received standard medical management. All received EKG and cardiac enzyme testing. Elevated troponin occurred in 20% treated vs 3% nontreated (p = 0.02). Myocardial infarction occurred in 10% vs 1% (p = 0.01). We found a significant increase in myocardial injury in rFVIIa treated patients.

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.

Postpartum cerebral angiopathy: atypical features and treatment with intracranial balloon angioplasty.

Postpartum cerebral angiopathy (PCA) is an uncommon cause of ischemic and hemorrhagic stroke in young women. It is usually clinically benign and not relapsing. We describe a patient with nonhemorrhagic PCA who had an atypical progressive neurological deficit from bilateral hemisphere watershed ischemia despite treatment with aggressive medical therapy and intracranial balloon angioplasty.

Lack of clinical significance of early ischemic changes on computed tomography in acute stroke.

CONTEXT: The prevalence and clinical significance of early ischemic changes (EICs) on baseline computed tomography (CT) scan of the head obtained within 3 hours of ischemic stroke are not established. OBJECTIVE: To determine the frequency and significance of EIC on baseline head CT scans in the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA (recombinant tissue plasminogen activator) Stroke Trial. DESIGN AND SETTING: The original study, a randomized controlled trial, took place from January 1991 through October 1994 at 43 sites, during which CT images were obtained within 3 hours of symptom onset and prior to the initiation of rt-PA or placebo. For the current analysis, detailed reevaluation was undertaken after October 1994 of all baseline head CT scans with clinical data available pretreatment (blinded to treatment arm). PATIENTS: Of 624 patients enrolled in the trial, baseline CT scans were retrieved and reviewed for 616 (99%). MAIN OUTCOME MEASURES: Frequency of EICs on baseline CT scans; association of EIC with other baseline variables; effect of EICs on deterioration at 24 hours (>/=4 points increase from the baseline National Institutes of Health Stroke Scale [NIHSS] score); clinical outcome (measured by 4 clinical scales) at 3 months, CT lesion volume at 3 months, death at 90 days; and symptomatic intracranial hemorrhage (ICH) within 36 hours of treatment. RESULTS: The prevalence of EIC on baseline CT in the combined rt-PA and placebo groups was 31% (n = 194). The EIC was significantly associated with baseline NIHSS score (rho = 0.23; P<.001) and time from stroke onset to baseline CT scan (rho = 0.11; P =.007). After adjusting for baseline variables, there was no EIC x treatment interaction detected for any clinical outcome, including deterioration at 24 hours, 4 clinical scales, lesion volume, and death at 90 days (P>/=.25), implying that EIC is unlikely to affect response to rt-PA treatment. After adjusting for NIHSS score (an independent predictor of ICH), no EIC association with symptomatic ICH at 36 hours was detected in the group treated with rt-PA (P>/=.22). CONCLUSIONS: Our analysis suggests that EICs are prevalent within 3 hours of stroke onset and correlate with stroke severity. However, EICs are not independently associated with increased risk of adverse outcome after rt-PA treatment. Patients treated with rt-PA did better whether or not they had EICs, suggesting that EICs on CT scan are not critical to the decision to treat otherwise eligible patients with rt-PA within 3 hours of stroke onset.

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.

Acute stroke care in non-urban emergency departments.

OBJECTIVE: To evaluate the practice patterns for stroke care in rural emergency departments (ED). METHODS: The authors prospectively evaluated clinical practice decisions for all ED patients in two non-urban East Texas communities using active and passive surveillance methods. Data collected included demographics, risk factors, symptoms, and treatment. Data analysis consisted of descriptive statistics and logistic regression analysis. RESULTS: During the study period, 429 patients presented with validated strokes. Risk factors included hypertension (65%), previous stroke (41%), coronary artery disease (33%), diabetes (25%), current smoking (17%), and atrial fibrillation (11%). In the ED, neurology consultation occurred in 32%, head CT in 88%, and ECG in 85%. Heparin was used in 9%, and 5% received aspirin. Blood pressure was lowered in 19% from a mean high of 189(+/-38)/97(+/-26), average reduction 34 points (18%) systolic. Motor symptoms were more likely to prompt a neurology consultation (OR = 2.47). Heparin was used more commonly for patients with atrial fibrillation (OR = 2.93). Socioeconomic factors did not alter care. IV recombinant tissue plasminogen activator was used in 1.4% of ischemic stroke cases. CONCLUSIONS: Acute stroke care in this representative non-urban community frequently does not follow published guidelines or clinical trial results. Whereas a high percentage of patients receive CT, aggressive blood pressure treatment occurs commonly and at pressures below current recommendations. The use of heparin is common, more so than aspirin treatment. These facts argue for educational interventions aimed at non-urban physicians to improve evidence-based medical practice.

Early overuse and disuse of the affected forelimb after moderately severe intraluminal suture occlusion of the middle cerebral artery in rats.

We have previously shown that early forced overuse of the affected forelimb worsens outcome following moderately severe transient focal cortical ischemic stroke in rats using a distal middle cerebral artery occlusion (MCAo) model. This effect may be site-dependent, because we have also found that early forced use of the affected limb after unilateral 6-OHDA induced degeneration of ascending nigrostriatal dopamine neurons markedly enhanced functional outcome and is neuroprotective. The present study examines the effects of early overuse and disuse following a moderately severe proximal MCAo model, by means of intraluminal suture occlusion. Ischemia was produced in male Long-Evans rats with 60 min of occlusion, or sham surgery was performed. Early overuse or disuse of the affected forelimb was forced by immobilizing either the ipsilateral or contralateral forelimb, respectively, in a plaster cast or the animal was left uncasted. Casts were removed on day 10 and sensorimotor testing was performed weekly during days 17-38. Animals were sacrificed on day 45 and brains were fixed for later cresyl violet staining. The MCAo+contralateral cast group performed worse than all other groups on tests of forelimb sensorimotor function. All MCAo groups regardless of cast condition had significant atrophy of the ischemic striatum, but there was no significant atrophy of the ischemic cortex in any group. Forced disuse, but not overuse, of the affected forelimb immediately following proximal ischemia using the intraluminal suture model has detrimental effects on functional outcome, without exaggerating anatomical damage. The effects of disuse and overuse during the first 10 days after stroke differ depending on cortical or subcortical involvement.

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.

Combination Therapy Stroke Trial: recombinant tissue-type plasminogen activator with/without lubeluzole.

BACKGROUND: A neuroprotective drug may be safe and effective if given very early and in combination with recombinant tissue-type plasminogen activator (rt-PA) to acute stroke patients. No clinical trial has yet tested this hypothesis. OBJECTIVE: To assess the feasibility, safety and efficacy of simultaneously combining the neuroprotective drug lubeluzole with rt-PA. METHOD: Patients who qualified for and received rt-PA within 3 h of symptom onset were randomly allocated 1:1 to lubeluzole (7.5 mg i.v. over 1 h, then continuous 5-day infusion of 10 mg/day) or placebo. Infusion of the study medication was started before the end of the 1-hour rt-PA infusion. Inclusion criteria were the same as those of the FDA-approved guidelines for rt-PA, plus National Institutes of Health Stroke Scale (NIHSS) >5 and absence of serious ventricular arrhythmia, atrioventricular block or Q-T >450 ms. EKG was continuously monitored until 48 h after treatment. The primary outcomes were adverse events, especially hemorrhage and severe arrhythmia, and functionality as determined by the Barthel Index divided into >70,0-70 and dead. RESULTS: 89 patients were randomized at 34 centers over 8 months. The study was terminated by the sponsor before the planned enrollment of 200 patients when a concurrent phase 3 trial of lubeluzole versus placebo given up to 8 h after stroke was negative. In our study, the mean NIHSS was 14.5, and the mean time from symptom onset to rt-PA was 2.5 h and to randomization to lubeluzole or placebo 3.2 h. Mortality was 26%, intracerebral hemorrhage occurred in 10% and serious adverse events in 51%. There were no differences between the two treatment groups in any of these variables, outcomes or in the Barthel Index or other measures of functionality. CONCLUSION: Combining neuroprotective drugs such as lubeluzole simultaneously with rt-PA is feasible and safe. The efficacy of this strategy, using a potentially more effective neuroprotective agent, should be evaluated in an adequately powered clinical trial.

Arterial status after intravenous TPA therapy for ischaemic stroke. A need for further interventions.

BACKGROUND: Intravenous tissue plasminogen activator (TPA) is an approved therapy for acute ischaemic stroke in the United States. We aimed to noninvasively monitor the therapy to determine arterial recanalisation and persisting vascular abnormalities. METHODS: We prospectively studied consecutive patients with symptoms of ischaemic stroke who received intravenous TPA and were monitored by 2 MHz transcranial Doppler (TCD) to determine occlusion and recanalisation (TIMI grades equivalent). For outcome assessment we used the National Institutes of Health Stroke Scale (NIHSS) score. RESULTS: Sixty patients were studied (age 71+/-15 years, pre-TPA NIHSS 18+/-6.1, TPA bolus at 141+/-68 min after stroke onset). The internal carotid artery (ICA) was occluded in 25%, middle cerebral artery (MCA) in 80%; combined (ICA+MCA) occlusion was found in 19%; and basilar artery (BA) was occluded in 7%. Also, 2% had normal TCD and 8% of patients had no temporal windows. Complete recanalisation on TCD of all insonated arteries was found in 19 patients (32%) at 44+/-22 min after a TPA bolus. However, 67% of MCA, 25% of BA, and all ICA occlusions did not completely recanalise (TIMI grades 0-2). If flow impairment persisted for more than two hours after a TPA bolus, these patients continued to have significant neurological deficits at 24 hours (15.0+/-8.2 vs 6.3+/-7.3 NIHSS points, p<0.001 in non-parametric statistics). High-grade residual stenoses with microembolic signals were seen on TCD in the MCA and BA (n=3) suggesting continuing clot dissolution. In patients without complete recanalisation (n=36, or 60%), TCD identified lesions potentially amenable to further interventions. CONCLUSIONS: Persisting arterial occlusion after intravenous TPA therapy leads to poor short-term outcome. Noninvasive monitoring of TPA therapy with TCD can identify these high-risk patients for combined interventions such as intra-arterial thrombolysis, mechanical clot disruption, stenting or anticoagulation.

A broad diagnostic battery for bedside transcranial Doppler to detect flow changes with internal carotid artery stenosis or occlusion.

BACKGROUND AND PURPOSE: The authors establish accuracy parameters of a broad diagnostic battery for bedside transcranial Doppler (TCD) to detect flow changes due to internal carotid artery (ICA) stenosis or occlusion. METHODS: The authors prospectively studied consecutive patients with stroke or transient ischemic attack referred for TCD. TCD was performed and interpreted at bedside using a standard insonation protocol. A broad diagnostic battery included major criteria: collateral flow signals, abnormal siphon or terminal carotid signals, and delayed systolic flow acceleration in the middle cerebral artery. Minor criteria included a unilateral decrease in pulsatility index (< or = 0.6 or < or = 70% of contralateral side), flow diversion signs, and compensatory velocity increase. Angiography or carotid duplex ultrasound (CDU) was used to grade the degree of carotid stenosis using North American criteria. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of TCD findings were determined. RESULTS: Seven hundred and twenty patients underwent TCD, of whom 517 (256 men and 261 women) had angiography and/or CDU within 8.8 +/- 0.9 days. Age was 63.1 +/- 15.7 years. For a 70% to 99% carotid stenosis or occlusion, TCD had sensitivity of 79.4%, specificity of 86.2%, PPV of 57.0%, NPV of 94.8%, and accuracy of 84.7%. For a 50% to 99% carotid stenosis or occlusion, TCD had sensitivity of 67.5%, specificity of 83.9%, PPV of 54.5%, NPV of 90.0%, and accuracy of 81.6%. TCD detected intracranial carotid lesions with 84.9% accuracy and extracranial carotid lesions with 84.4% accuracy (sensitivity of 88% and 79%, specificity of 85% and 86%, PPV of 24% and 54%, and NPV of 99% and 95%, respectively). The prevalence of the ophthalmic artery flow reversal was 36.4% in patients with > or = 70% stenosis or occlusion. If present, this finding indicated a proximal ICA lesion location in 97% of these patients. CONCLUSIONS: In symptomatic patients, bedside TCD can accurately detect flow changes consistent with hemodynamically significant ICA obstruction; however, TCD should not be a substitute for direct carotid evaluation. Because TCD is sensitive and specific for a > or = 70% carotid stenosis or occlusion in both extracranial and intracranial carotid segments, it can be used as a complementary test to refine other imaging findings and detect tandem lesions.

Headache in the emergency department.

OBJECTIVE: To perform an observational study of the demographics, clinical factors, and therapeutic efficacy in patients presenting to the emergency department with a chief complaint of headache. BACKGROUND: Acute headache presentations to the emergency department are a therapeutic dilemma for physicians. METHODS: Patients presenting with nontraumatic headache to the emergency department of Hermann Hospital in Houston, Texas, during a 16-month period were prospectively ascertained by active and passive surveillance. The medical record was abstracted. Demographic and clinical information are presented with descriptive statistics. Relative benefit of individual therapies are compared with odds ratios (95% confidence intervals). RESULTS: Of the 38 730 patients who were prospectively screened, 455 presented with a chief complaint of headache. Seventy-six percent were women, and the mean age was 37 years. Non-Hispanic whites were more likely diagnosed with migraine compared with Hispanics or African Americans (P<.001). Three percent had subarachnoid hemorrhage. Neurologist follow-up was ordered in 10%. The median time in the emergency department was 265 minutes. With the initial treatment, 44% resolved, 47% improved, and 9% had no change; none worsened. In comparison with all other therapies used, there was a trend suggesting the superiority of antiemetics (odds ratio, 2.66; 95% confidence interval, 0.81 to 8.61). Acetaminophen was less helpful (odds ratio, 0.27; 95% confidence interval, 0.10 to 0.70). When comparing specific agents to therapies which could be used at home, antiemetics led to headache resolution most often (odds ratio, 3.18; 95% confidence interval, 1.40 to 7.22); ketorolac showed a similar trend (odds ratio, 2.05; 95% confidence interval, 0.86 to 4.89). CONCLUSIONS: Headache in the emergency department is a phenomena of young women who spend a long time waiting and receive many tests. A variety of therapies are used. Antiemetics may be especially useful for headache resolution.