Time Window For Thrombolytic Therapy Research Articles

Efficacy and safety of batroxobin in patients with acute ischemic stroke: A multicenter retrospective analysis.

The objective of this study was to evaluate the effectiveness of batroxobin in improving functional outcomes and reducing stroke recurrence among patients with acute ischemic stroke beyond the therapeutic time window for thrombolytic therapy. This multicenter, retrospective study enrolled 492 patients with acute moderate-to-severe ischemic stroke within 24 h. 238 patients were given standard (basic) therapy. On the basis of standard treatment, 254 patients received an initial intravenous infusion of batroxobin 10 U on day 1, followed by subsequent infusions of batroxobin 5 U on the 3rd and 5th days, respectively. In the batroxobin group, 8.3% of patients experienced recurrence stroke, compared to 17.2% in the control group (HR, 0.433; 95% CI, 0.248 to 0.757; p = 0.003). Furthermore, intravenous batroxobin significantly improved the distribution of 90-120 day disability. Moderate-to-severe bleeding events were reported in three patients (1.2%) in the batroxobin group and one patient (0.4%) in the control group (p = 0.369). Among patients with acute moderate-to-severe ischemic stroke beyond the time window for thrombolytic therapy, treatment with intravenous batroxobin had a lower risk of stroke recurrence and a better recovery of function outcome without increasing bleeding events. Prospective studies are needed to further confirm.

Case report: Ethylene glycol intoxication presenting as a mimic of acute stroke: a report of three cases

Stroke is a major cause of death and disability presenting with acute focal neurological symptoms of vascular origin. Several other disorders may cause symptoms similar to a stroke, referred to as stroke mimics. The misdiagnosis of stroke mimics may lead to potentially harmful treatments, including thrombolysis. Intoxication is a rare, but possible, cause of stroke mimic. We present three cases of ethylene glycol poisoning presenting as an acute stroke mimic within the time window of thrombolytic therapy. Two of three patients (a 54-year-old male and a 78-year-old male) had dysarthria, nystagmus, and truncal ataxia on admission. The third patient with a history of chronic alcoholism presented after an epileptic seizure with mixed aphasia and confusion. Non-contrast cerebral computed tomography and computed tomography angiography were negative in all three cases. As stroke could not be excluded in any of the patients, thrombolysis was performed. However, after some hours, two of the three patients developed agitation, somnolence, and hyperventilation. One patient's consciousness deteriorated rapidly, and he became comatose and tetraplegic. A blood gas analysis showed acidosis in two of the three patients, and toxicological screening revealed ethylene glycol intoxication in all three cases. Due to the appropriate treatment, two of the three patients became symptom-free; however, one of the three patients died. Our cases show that ethylene glycol intoxication in its early phase may mimic acute stroke, resulting in unnecessary thrombolytic therapy. Symptoms not characteristic of a stroke, such as hyperventilation, agitation, and disturbance of consciousness, may appear later and warn of intoxication. The final diagnosis of ethylene glycol intoxication can be established by severe metabolic acidosis and toxicological screening. Close monitoring of symptoms might contribute to the early recognition of ethylene glycol intoxication and its effective treatment.

Pearls for the Emergency Clinician: Posterior Circulation Stroke

BackgroundPosterior circulation (PC) stroke in adults is a rare, frequently misdiagnosed, serious condition that carries a high rate of morbidity. Objective of the ReviewThis review evaluates the presentation, diagnosis, and management of PC stroke in the emergency department (ED) based on current evidence. DiscussionPC stroke presents most commonly with dizziness or vertigo and must be distinguished from more benign diagnoses. Emergency clinicians should consider this condition in patients with dizziness, even in younger patients and those who do not have traditional stroke risk factors. Neurologic examination for focal neurologic deficit, dysmetria, dysarthria, ataxia, and truncal ataxia is essential, as is the differentiation of acute vestibular syndrome vs. spontaneous episodic vestibular syndrome vs. triggered episodic vestibular syndrome. The HINTS (head impulse, nystagmus, and test of skew) examination can be useful for identifying dizziness presentations concerning for stroke when performed by those with appropriate training. However, it should only be used in patients with continuous dizziness who have ongoing nystagmus. Contrast tomography (CT), CT angiography, and CT perfusion have limited sensitivity for identifying PC strokes, and although magnetic resonance imaging is the gold standard, it may miss some PC strokes early in their course. Thrombolysis is recommended in patients presenting within the appropriate time window for thrombolytic therapy, and although some data suggest endovascular therapy for basilar artery and posterior cerebral artery infarcts is beneficial, its applicability for all PC strokes remains to be determined. ConclusionsAn understanding of PC stroke can assist emergency clinicians in diagnosing and managing this disease.

4-Trifluoromethyl-(E)-cinnamoyl]-L-4-F-phenylalanine acid exerts its effects on the prevention, post-therapeutic and prolongation of the thrombolytic window in ischemia-reperfusion rats through multiple mechanisms of action

Ischemic stroke is one of the leading causes of death and disability worldwide. The severe sequelae caused by ischemic thrombolysis and the narrow time window are now the main clinical challenges. Our previous study has reported 4-Trifluoromethyl-(E)-cinnamoyl]-L-4-F-phenylalanine Acid (AE-18) was a promising candidate for Parkinson’s Disease. In this study, the preventive and therapeutic effects of AE-18 on focal cerebral ischemia-reperfusion injury and the mechanisms are explored. In oxygen glucose deprivation/reoxygenation (OGD/R)-induced well-differentiated PC12 cells model, AE-18 (10 or 20 μM) can significantly reduce nerve damage when administered before or after molding. In middle cerebral artery occlusion-reperfusion (MCAO/R) rat model, pre-modelling, or post-modelling administration of AE-18 (5 or 10 mg/kg) was effective in reducing neurological damage, decreasing infarct volume and improving motor disturbances. In addition, AE-18 (5 mg/kg) given by intravenous injection immediately after occlusion significantly reduce the infarct volume caused by reperfusion for different durations, indicating that AE-18 could extend the time window of thrombolytic therapy. Further studies demonstrate that AE-18 exerts the effects in the prevention, treatment, and prolongation of the time window of cerebral ischemic injury mainly through inhibiting excitotoxicity and improving BBB permeability, VEGF and BDNF. These results suggest that AE-18 is a good candidate for the treatment of ischemic stroke.

Effect of Community Education Program on Stroke Symptoms and Treatment on School and College Students from South India: A Longitudinal Observational Study.

Community awareness regarding stroke signs, risk factors, and actions that help reduce the risk and complications of stroke is poorly addressed, as it is thought to be the best approach to control and prevent stroke. Aim: To establish the awareness of stroke and its management among high school and college students using an educational intervention. A questionnaire was administered to students from five high schools and four colleges with different areas of focus, (arts, science and commerce), types (public, semi-public and private), and economic locations before and after an educational lecture on stroke. The lecture covered the following elements: stroke definition, signs, risk factors, actions, time window for thrombolytic therapy, and types of rehabilitation interventions. This study included 1036 participants, of whom 36.3% were male and 56.4% were high school students, and the mean age was 17.15 ± 1.29 (15–22) years. Before the lecture, 147 participants were unaware of a single sign of stroke, and 124 did not know the risk factors. After the intervention, 439 participants knew four signs of stroke, and 196 knew 12 risk factors. Female students had better knowledge about stroke signs (odds ratio (OR), 3.08; 95% confidence interval (95% CI), 2.15–4.43). Hypertension (52.7%) and weakness (59.85%) were the most known signs and risk factors. The proportion of students who selected traditional medicine as the mode of treatment decreased from 34.75% to 8.59% after the lecture. Other rehabilitation methods (e.g., physical therapy, occupational therapy, speech therapy and counseling) were chosen by more than 80% of the students. The results of the current study showed that the awareness on stroke risk factors and management among the school and college students can be significantly improved with regular educational interventions, and therefore stroke can be prevented to some extent.

Post-stroke patients with and without thrombolysis: analysis of deglutition in the acute phase of the disease.

To verify the frequency and severity of dysphagia after ischemic stroke with or without thrombolysis in the acute phase; and the association among dysphagia, demographic characteristics, neurological and functional impairments and thrombolysis. A retrospective study of the medical records of 94 patients who suffered from ischemic stroke during the acute phase of the disease. From these, 52 patients received thrombolytic therapy and 42 patients did not receive such therapy. We collected data on age, sex, comorbidities, therapeutic time window of thrombolytic therapy, level of consciousness, degree of neurological impairment, level of functional dependency and clinical swallowing examination. A descriptive analysis included categorical and continuous variables, and an analysis of the association using the Pearson's Chi-Square Test, in which the value of p ≤ 0.05 was considered as a statistically significant association. The frequency of dysphagia in the thrombolytic patients was 67.3%, the odds ratio was 4.6 higher than the non-thrombolysed patients. The severity of dysphagia was not associated with thrombolysis. There was an association between the presence of dysphagia and functional dependence. Demographic characteristics and neurological impairment were not associated with dysphagia. Thrombolytic patients were more likely to develop dysphagia than non-thrombolysed patients in the acute phase of stroke, with dysphagia associated to functional dependence.

Endovascular Stenting of Vertebral Artery Dissection in Acute Ischemic Stroke

Background: Vertebral artery (VA) dissection causing acute stroke is commonly treated with anticoagulation and rarely requires stenting. While stenting for atherosclerotic stenosis of VA is an established and efficient treatment option, the safety of stenting for VA dissection has not been studied. Case information: We report the technical challenges associated with stenting of a proximal VA dissection in a 74 year-old male with NIHSSS > 20 outside of the time window for thrombolytic therapy presenting with acute basilar artery thrombus and a hypoplastic contralateral VA. Methods: A coronary Drug-Eluting Stent (DES) was implemented in right VA following balloon angioplasty and basilar artery thrombolysis to maintain the patency of the dissected area in proximal VA. Results: The procedure was completed without complication. Postoperative Digital Subtraction Angiography (DSA) confirmed the patency of the vertebrobasilar system. There was no evidence of significant residual stenosis in the right vertebral artery on the follow up Computed Tomography Angiography (CTA) 2 months after the stent placement. Conclusion: Endovascular stenting of proximal VA dissection in the setting of acute ischemic stroke is relatively safe and feasible. It could be particularly considered in patients ineligible for IV thrombolysis with a hypoplastic contralateral VA. Further studies are needed to evaluate the long-term safety and efficacy of stenting for VA dissection.

Beneficial Role of Rosuvastatin in Blood-Brain Barrier Damage Following Experimental Ischemic Stroke.

Hemorrhage transformation is the most challenging preventable complication in thrombolytic therapy and is related to recombinant tissue plasminogen activator (rt-PA)-induced blood–brain barrier (BBB) damage. Intraperitoneal injections of normal or high doses of rosuvastatin were administered to Balb/c mice 20 min prior to middle cerebral artery occlusion (MCAO) surgery for 3 h followed by reperfusion with rt-PA thrombolytic therapy and cerebral blood flow monitoring to investigate whether a high or normal dose of rosuvastatin reduces BBB damage after brain ischemia and rt-PA reperfusion. The integrity of the BBB was ameliorated by normal and high doses of rosuvastatin as determined from Evans blue staining, ultrastructure assessments and immunochemistry at 24 h after reperfusion. The levels of TJ proteins were preserved, potentially by targeting platelet-derived growth factor receptor α (PDGFR-α) and low-density lipoprotein receptor-related protein 1 (LRP1) to inhibit the expression of matrix metalloproteinase proteins (MMPs) by reducing the levels of phosphorylated c-jun-N-terminal kinase (pJNK), phosphorylated mitogen-activated protein kinase (MAPK) p38 (pP38) and increasing the levels of phosphorylated extracellular regulated protein kinases (pERK), and tissue inhibitor of metalloproteinases (TIMPs), as inferred from Western blotting and molecular docking analyses. In summary, rosuvastatin reduced rt-PA therapy-associated BBB permeability by PDGFR-α- and LRP1-associated MAPK pathways to reduce the mortality of mice, and a normal dose of rosuvastatin exerted greater preventative effects on reducing BBB damage than did a high dose in the time window of thrombolytic therapy.

Abstract W MP76: Diagnostic Accuracy and Characteristics of Missed Ischemic Strokes in the Emergency Department

Objectives: The failure to recognize an acute stroke in the ED represents a missed opportunity for potential thrombolytic therapy and for prompt treatment for secondary prevention. The aim of this study was to examine the diagnostic accuracy of acute ischemic strokes at a large academic center and to identify common characteristics of these missed strokes. Methods: A retrospective review was performed on a random sample of patients >18 years old with a discharge diagnosis of ischemic stroke in 2013. All acute strokes were confirmed on CT or MRI. A stroke was “missed” if practitioners in the ED did not initially consider stroke in the differential, or the diagnosis was delayed causing the patient to miss the therapeutic window for thrombolytic therapy. Results: Two hundred ischemic stroke patients were included in the study. The mean patient age was 72 years, and the mean initial NIHSS was 7. There were 36 “missed” strokes (18%) in this population. Of the strokes that were initially misdiagnosed, 20 of 36 (56%) presented in the time window for thrombolytic therapy and potentially could have received intervention. Posterior circulation strokes were more likely to be missed overall (20/58 posterior, 34%, vs 16/142 anterior, 11%, p < 0.001). Seventy-six percent of patients with posterior stroke had stroke in the original differential compared with 96% in those with anterior circulation stroke (p < 0.001). Symptoms independently associated with posterior circulation strokes included nausea/vomiting (OR=6.9, 95% CI: 2.0-23), headache (OR=6.4, 95% CI: 1.5-27) and difficulty walking (OR=3.5, 95% CI: 1.3-9.5). Anterior circulation patients more commonly presented with focal weakness (OR=0.11, 95% CI: 0.05-0.25) and aphasia (OR=0.17, 95% CI: 0.06-0.45). Conclusions: Despite having a certified stroke program in a large academic medical center, 18% of acute ischemic strokes were missed in the ED. Posterior circulation strokes were 3 times more likely than anterior strokes to be missed. Posterior stroke patients were more likely to present with nausea/vomiting, headache and difficulty walking, and these symptoms should serve as triggers to consider ischemic stroke in the ED.

Identification of painless aortic dissection before thrombolytic treatment for acute ischemic stroke

Early detection of acute ischemic stroke secondary to painless aortic dissection is a challenge for emergency physicians, especially when under the stress of the 3-hour golden time window for thrombolytic therapy. We reported a 57-year-old man with acute right hemisphere watershed ischemic stroke caused by painless type A aortic dissection was diagnosed in time with computed tomographic (CT) angiography. The possible detrimental impact which may have been incurred by thrombolytic therapy was avoided. We suggest that cerebral CT angiography, covering from the aortic arch to intracranial arteries, should be performed in acute ischemic stroke patients, particularly in those with watershed CT perfusion deficits, to exclude the possibility of aortic dissection before thrombolytic treatment.

Abstract 213: The Probability of Ischemic Stroke Therapeutic Targets at Extended Time Windows

BACKGROUND. A contributing factor in the decreased efficacy of thrombolysis over time may be a decrease in the probability of the therapeutic target, but this has not been well studied. Detection of therapeutic targets beyond 4.5 hr is the premise for reperfusion trials at extended time windows. We quantified the relationship of time from onset to the probability of detection of therapeutic targets. METHODS. We analyzed a consecutive series of 1103 ischemic stroke patients with NIHSS > 3 and an MRI within 24 hr from last known well. Potential therapeutic targets were occlusion on MRA (ARTERY), M1 or M2 occlusion (MCAO), focal ischemia on perfusion MRI (PERFUSION), and diffusion-perfusion mismatch (MISMATCH). Logistic regression models evaluated hours from onset, NIHSS, age, and sex as predictors of target. RESULTS. ARTERY, PERFUSION, and MISMATCH probabilities decreased over time (p < 0.0001) at approximately 1% per hour. More severe strokes increased the probability of detection by about 1% per NIHSS point. Logistic regression model found significant relationships of MISMATCH to hours, NIHSS, MCAO, and the interaction of NIHSS X MCAO (Table). MCAO patients had higher probabilities of MISMATCH, which decreased more rapidly over time (Graph). The probability of MISMATCH can be estimated by the logistic regression model: e.g., MCAO and NIHSS 12 at 9 hr = 78%; MCAO and NIHSS 14 at 20 hr = 47%. CONCLUSION. The probability of potential targets of reperfusion therapy declines over the first 24 hours from stroke onset. A substantial proportion of patients have a target beyond the proven time window for thrombolytic therapy, and the proportion can be estimated by the logistic regression model.

Stroke‐associated inflammation: is von Willebrand factor a ‘bad guy’?

Stroke‐associated inflammation: is von Willebrand factor a ‘bad guy’?

Expanded indications for stroke thrombolysis—what next?

Restrictions to thrombolytic therapy for stroke—recommended only up to 4.5 h after onset and in those under 80 years of age—limit its use. Results from a recent trial support expansion of both the inclusion criteria and the time window for thrombolytic therapy, but further research is needed.

Brain Protection Therapy in Acute Cerebral Infarction

Many drugs for cerebral infarction that were shown to be effective in animal experiments have shown negative results in human clinical trials. For this reason, a completely new approach is needed to develop brain protection therapies against cerebral infarction. Brain protection therapies can be categorized into 3 types: 1) lengthening the therapeutic time window for thrombolytic therapy, 2) reducing the side effects of thrombolytic therapy, and 3) brain protection drug therapy for patients with contraindications for thrombolytic therapy (including combination therapy). Here, we show our recent results of brain protection therapy. First, combination therapy with 2 effective drugs was tried, and time-lag administration was performed. Combination therapy was effective and lengthened the therapeutic time window. Next, a completely new approach to improve cerebral ischemic damage, namely, H2 gas inhalation therapy, was tried. This therapy was also effective, even in the ischemic core.

The clinical observation of acute myocardial infarction in different time window of thrombolytic therapy

Objective To study the effect of thrombolytic therapy in different times after ST-segment elevation myocardial infarction. Methods Fifty one patients were divided into three groups according to different times after intravenous thromobolytic therapy. The groups were A( ≤3 h) ,B(3-6 h) and C(6-12 h). Results Reperfusion rate of the three groups were 81.2% ,75.9% ,33.3% ,with signficant difference between the former two groups and the later one groups ( P ＜ 0. 05 ). The hemorrhage complication without significant difference of the three groups. Conclusion The reperfusion rate is opposite related with the duration from onset of AMI to thrombolytic. To the patients, within 3 h after onset AMI, the reperfusion is the best, within 3 ～ 6 h is better,while within 6-12 h have not significant effect, but still had some effect. Key words: Acute myocardial infarction; Thrombolytic therapy; Times; The reperfusion rate of blood vessels

Stability of large diffusion/perfusion mismatch in anterior circulation strokes for 4 or more hours

BackgroundThe stability of hypoperfused brain tissue in stroke patients with major artery occlusions is unknown. The purpose of this study was to determine the persistence of a diffusion/perfusion mismatch in patients with ICA or proximal MCA occlusions.MethodsFourteen patients with ICA and/or proximal MCA occlusion and a diffusion/perfusion mismatch at presentation were studied. All were enrolled in a pilot randomized study of normobaric oxygen therapy. None received thrombolytic therapy; 8 received normobaric oxygen and 6 room air. Diffusion/perfusion MRI was performed at baseline, 4 hours, 24 hours, and 1 week. Abnormal DWI, ADC, and MTT volumes were determined using standard image analysis methods.ResultsThe mean time from symptom onset to baseline MRI was 7.5 ± 1 hours. Across all 4 time points there was a significant difference in DWI lesion (ANOVA, P < 0.0001) and abnormal MTT volumes (ANOVA, P < 0.01) with the 24 hour and 1 week abnormal volumes different from the earlier studies. However, comparing baseline and 4 hour scans, there was no significant interval change in the mean abnormal DWI volume (29.4 ± 8.2 ml vs. 28.1 ± 7.4 ml) or abnormal MTT volumes (137 ± 17.7 ml vs. 130.9 ± 13.8). By 24 hours, only 2 patients did not maintain a mismatch of 20% or greater.ConclusionsPatients who present outside the time window for thrombolytic therapy, and who have a large diffusion/perfusion mismatch on MRI may have a stable mismatch for 4 or more hours.

Central retinal artery occlusion: timing and mode of presentation

Central retinal artery occlusion (CRAO) is a sudden, frequently irreversible, monocular vision loss, analogous to acute cerebral ischaemia. Thrombolysis may improve visual outcomes, but it is unclear what the acceptable timing of administration should be. We aim to ascertain, through audit, the timing and mode of presentation of individuals with potentially thrombolysable CRAOs. A retrospective audit of patients with acute thromboembolic CRAO. Thirty-one patients were identified. Mean time from onset of vision loss to presentation was 31 +/- 65 h. Eighteen patients (58%) presented within 20 h of vision loss, and the majority presented first to a general practitioner. Fifteen patients (48%) were reviewed by an in-hospital ophthalmologist within 20 h of vision loss. The mean delay from the referring source to assessment by an in-hospital ophthalmologist was 5.2 h (median 3.3 h, range 50 min to 24 h). This delay was, on average, shorter for patients referred directly to an ophthalmology clinic. Just under half (48%) of our cohort of CRAO patients were reviewed by an in-hospital ophthalmologist within the 20-h therapeutic time window for thrombolytic therapy and thus could qualify for inclusion in a randomized controlled trial according to EAGLE inclusion criteria. If thrombolysis is proven to be a feasible and safe treatment in CRAO then public awareness should be raised of the symptoms and an efficient direct referral pathway to an in-hospital ophthalmologist established to aid treatment delivery.

Intra-Arterial Thrombolysis for Left Middle Cerebral Artery Embolic Stroke During Coronary Angiography

Cerebral thromboembolism is an uncommon but serious complication of cardiac catheterization. Early diagnosis and rapid treatment by reperfusion techniques have been shown to prevent long-term neurological morbidity. We report 2 consecutive cases of successful local intra-arterial thrombolysis (LIT) for embolic stroke of the middle cerebral artery (MCA) during diagnostic coronary angiography that resulted in complete neurological recovery. A 77-year-old woman with severe valvular aortic stenosis was admitted to our catheterization laboratory for a preoperative coronary angiography. Performed from the femoral approach, it showed a normal angiographic pattern. Immediately after the procedure, the patient became stuporous with right hemiplegia and global aphasia. She was hemodynamically stable. The left carotid digital subtraction angiography that was performed immediately revealed total occlusion of the M2 part of the left MCA. There was no extravasation of contrast (Figure 1). We decided to administer selective intra-arterial urokinase infusion. After systemic heparinization (bolus of 5000 UI), a 6F Amplatz Right Guide catheter was placed in the left internal …

Functional recovery after embolic stroke in rodents by activated protein C

A serine protease activated protein C has been shown to be a powerful neuroprotectant in stressed neurons and in hypoxic brain endothelium. In a clinically relevant model of embolic stroke in rodents, we now show that administration of activated protein C alone or in combination with tissue plasminogen activator, or both, 4 hours after embolic stroke improves the functional outcome and reduces brain infarction within 7 days of stroke. In contrast, tissue plasminogen activator alone was not protective. Thus, activated protein C may be useful as a new stand-alone therapy for clinical stroke and to extend the time window of thrombolytic therapy.

Therapeutic time window of thrombolytic therapy following stroke.

Stroke is the third leading cause of death after myocardial infarction and cancer and the leading cause of permanent disability and of disability-adjusted loss of independent life-years in Western countries. Thrombolysis is the treatment of choice for acute stroke within 3 hours after symptom onset. Treatment beyond the 3-hour time window has not been shown to be effective in any single trial; however, meta-analyses suggest a somewhat less but still significant effect within 3 to 6 hours after stroke. It seems reasonable to apply improved selection criteria that would allow one to differentiate patients with a relevant indication for thrombolytic therapy from those who do not have one. We present an overview of a diagnostic approach to acute stroke management that allows the clinician to individualize patient management based on pathophysiologic reasoning and not rigid time windows established by randomized controlled trials. Therefore, this review concentrates on giving the reader an integrated knowledge of the current status of thrombolytic therapy in stroke and then develops a treatment algorithm based on pathophysiologic information rendered by a multiparametric stroke magnetic resonance imaging protocol.