rt-PA Infusion Research Articles

Pharmacokinetics and pharmacodynamics of low doses of recombinant tissue plasminogen activator to establish a model for biosimilarity comparisons

BackgroundRecombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent and essential in emergency medical care. Given recent supply shortages, the availability of biosimilar products is an urgent medical need. However, biosimilarity trials are difficult to perform in critically ill patients. ObjectivesThe aim of this pilot study was to investigate the pharmacokinetics and pharmacodynamics of low rt-PA doses to establish a model for testing proposed biosimilars in healthy volunteers. MethodsEight healthy volunteers received 0.02 to 0.05 mg/kg rt-PA on 3 study days; blood samples were obtained every 4 minutes after the end of the bolus infusion to measure rt-PA antigen levels by enzyme immunoassay, and the pharmacodynamics were assessed with rotational thromboelastometry. ResultsBolus infusion of low rt-PA doses was safe and well tolerated. Maximal plasma concentrations and the area under the curve increased dose-dependently. Time-concentration curves were clearly separated between the lower and the higher doses. As expected, the half-live of rt-PA was short (4.5-5 min), and representative for therapeutic doses. The intrasubject coefficient variations were moderate (<25%). Bolus infusion of rt-PA dose-dependently shortened lysis time and lysis onset time in both dose groups and caused maximum clot lysis of 100% in all participants. ConclusionIn conclusion, the pharmacokinetics of rt-PA was dose linear and displayed limited intrasubject variability even at subtherapeutic doses. The half-life and thus clearance of rt-PA was representative of full therapeutic doses. The lysis time was shortened in a dose and time-dependent fashion and was clearly distinguishable between doses. Thus, the model appears to be suitable and sensitive to test biosimilarity.

Acute Myocardial Infarction after Intravenous Thrombolysis for Acute Ischemic Stroke: Case Series and Systematic Review

Background and objectivesIntravenous thrombolysis (IV–rtPA) has been suggested as a potential cause of myocardial infarction (MI) after acute ischemic stroke (AIS), with randomized clinical trials showing a higher number of cardiac events within the thrombolysis group. We assessed the prevalence and MI mechanisms after IV–rtPA for AIS. MethodsRetrospective review of consecutive AIS patients admitted to six stroke units and systematic literature review searching for AIS patients who suffered a MI less than 24 h after IV–rtPA. In those with available coronary angiography, MI etiology was defined as atherosclerotic or embolic. Patients’ characteristics were compared between groups. ResultsFifty-two patients were included. Thirty-two patients (61.5%) derived from hospital cases, after reviewing 6958 patients treated with IV–rtPA [0.5% (95% CI 0.38–0.54) of total hospital cases]. After coronary angiography (n = 25, 48.1%), 14 (54%) patients were considered to have an atherosclerotic MI, and 11 (46%) due to coronary embolism. Patients with an embolic MI more frequently had a cardioembolic AIS (72.7% vs 28.6%; p-value = 0.047) and an intracardiac thrombus (27.3% vs 0.0%; p-value = 0.044). Although not statistically significant, patients with an embolic MI had apparent lower time intervals between starting IV–rtPA infusion and MI occurrence [2 h (0.2–3.0) vs 3 h (1.0–15.0); p-value = 0.134]. ConclusionsMI within the first 24 h after IV–rtPA for AIS is an infrequent event, and more frequently non-embolic. However, the prevalence of embolic MI was superior to what is found in the general population with MI. There was an association between the pathophysiology of AIS and MI. The low number of events and publication bias may have limited our conclusions.

Tissue plasminogen activator for the treatment of adults with critical COVID-19: A pilot randomized clinical trial

Tissue plasminogen activator for the treatment of adults with critical COVID-19: A pilot randomized clinical trial

Thrombolysis with Systemic Recombinant Tissue Plasminogen Activator in Children: A Multicenter Retrospective Study

Objective:This study aimed to evaluate systemic thrombolysis experiences with recombinant tissue plasminogen activator (rtPA).Materials and Methods:Retrospective data were collected from 13 Turkish pediatric hematology centers. The dose and duration of rtPA treatment, concomitant anticoagulant treatment, complete clot resolution (CCR), partial clot resolution (PCR), and bleeding complications were evaluated. Low-dose (LD) rtPA treatment was defined as 0.01-0.06 mg/kg/h and high-dose (HD) rtPA as 0.1-0.5 mg/kg/h.Results:Between 2005 and 2019, 55 thrombotic episodes of 54 pediatric patients with a median age of 5 years (range: 1 day to 17.75 years) were evaluated. These patients had intracardiac thrombosis (n=16), deep vein thrombosis (DVT) (n=15), non-stroke arterial thrombosis (n=14), pulmonary thromboembolism (PE) (n=6), and stroke (n=4). The duration from thrombus detection to rtPA initiation was a median of 12 h (range: 2-504 h) and it was significantly longer in cases of DVT and PE compared to stroke, non-stroke arterial thrombosis, and intracardiac thrombosis (p=0.024). In 63.6% of the episodes, heparin was initiated before rtPA treatment. LD and HD rtPA were administered in 22 and 33 of the episodes, respectively. Concomitant anticoagulation was used in 90% and 36% of the episodes with LD and HD rtPA, respectively (p=0.0001). Median total duration of LD and HD rtPA infusions was 30 h (range: 2-120 h) and 18 h (2-120 h), respectively (p=0.044). Non-fatal major and minor bleeding rates were 12.5% and 16.7% for LD and 3.2% and 25.8% for HD rtPA, respectively. At the end of the rtPA infusions, CCR and PCR were achieved in 32.7% and 49.0% of the episodes, respectively. The most successful site for thrombolysis was intracardiac thrombosis. HD versus LD rtPA administration was not correlated with CCR/PCR or bleeding (p>0.05).Conclusion:Systemic thrombolytic therapy may save lives and organs effectively if it is used at the right indications and the right times in children with high-risk thrombosis by experienced hematologists with close monitoring of recanalization and bleeding.

Carboxypeptidase U (TAFIa) Is Rapidly Activated and Deactivated Following Thrombolysis and Thrombectomy in Stroke Patients.

The antifibrinolytic enzyme carboxypeptidase U (CPU, TAFIa, CPB2) is an appealing target for the treatment of acute ischemic stroke (AIS). Increased insights in CPU activation and inactivation during thrombolysis (rtPA) with or without endovascular thrombectomy (EVT) are required to develop CPU inhibitors as profibrinolytic agents with optimal benefits/risks. Therefore, CPU kinetics during ischemic stroke treatment were evaluated. AIS patients with documented cerebral artery occlusion receiving rtPA (N = 20) or rtPA + EVT (N = 16) were included. CPU activation during thrombolysis was measured by an ultrasensitive HPLC-based CPU activity method and by an ELISA measuring both CPU and inactivated CPU (CPU + CPUi). Intravenous blood samples were collected at admission and throughout the first 24h. Additional in situ blood samples were collected in the rtPA + EVT cohort proximal from the thrombus. The NIHSS score was determined at baseline and 24h. CPU activity and CPU + CPUi levels increased upon rtPA administration and reached peak values at the end of thrombolysis (1h). High inter-individual variability was observed in both groups. CPU activity decreased rapidly within 3h, while CPU + CPUi levels were still elevated at 7h. CPU activity or CPU + CPUi levels were similar in in situ and peripheral samples. No correlation between CPU or CPU + CPUi and NIHSS or thrombus localization was found. The CPU system was rapidly activated and deactivated following thrombolysis and thrombectomy in stroke patients, suggesting that a CPU inhibitor would have to be administered during rtPA infusion and over the next few hours. The high CPU generation variability suggests that some patients may not respond to the treatment. EudraCT number2017-002760-41.

Intrapulmonary Artery Thrombolysis in Acute Pulmonary Embolism: Case Series from King Chulalongkorn Memorial Hospital Experience

Acute pulmonary embolism (PE) is a life-threatening condition. In patient who has contraindication for systemic thrombolysis and inappropriate for surgical embolectomy, there is a role of catheter interventions. However, the data are limited. The aim of the present report was to assess a role of intrapulmonary artery thrombolysis bolus in acute PE. A retrospective review of the use of intrapulmonary artery thrombolysis in acute PE. The data were collected from 14 patients with massive or submassive PE who had contraindication or inappropriate for systemic thrombolysis and unsuitable for surgical embolectomy. After intrapulmonary thrombolysis was given, patients were followed clinically and hemodynamically until discharged and after 1 month. Pulmonary pressure was collected at pre and post intervention. Of the 14 patients (age 59±19 years, 78.6% female), 86% were diagnosed as submassive PE. Mean dose of tissue plasminogen activator (rt-PA) was 28±14 mg given as bolus and continuous infusion (19±10 hours). One patient died after completion of intrapulmonary infusion rt-PA at day 90, which did not relate to PE and the treatment. After intervention, mean PA pressure was significantly reduced from 32.3±6.0 to 21.0±4.3 mmHg (p&lt;0.001). Three patients (21%) had minor bleeding (hematoma at access site). The present case series showed that intrapulmonary infusion of rt-PA was effective and safe in patient with massive and submassive PE who had contraindication or inappropriate to systemic thrombolysis or inoperable surgical thrombectomy. Keywords: Acute pulmonary embolism; Intrapulmonary thrombolysis; Tissue plasminogen activator; Surgical thrombectomy

Effect of Tissue Plasminogen Activator on Treatment Outcome and Neuronal Degeneration in Acute Ischemic Stroke

Background: Acute ischemic stroke [AIS] is a leading worldwide neurological morbidity with significant disability. Recombinant tissue plasminogen activator [r-TPA] is approved for the treatment of AIS.Neuron-specific enolase [NSE] is a marker of brain damage in patients with traumatic brain injury, stroke, and hypoxic encephalopathy. Aim of the work: The present study assessed the prognostic value of serum NSE in r-TPA treatment of patients with AIS. Patients and methods: The present prospective study included 53 patients with AIS. They comprised 25 patients who didn’t receive r-TPA and 28 patients who received r-TPA. The clinical severity of the stroke was assessed using National Institute of Health Stroke Scale [NIHSS]. A modified Rankin score was used to evaluate the degree of disability in the affected patients. Radiological imaging included echocardiography, brain computed tomography, and carotid and vertebrobasilar duplex. NSE was assessed at 24 h after r-TPA infusion. Results: Patients subjected to r-TPA treatment had significantly lower NSE one day of stroke when compared with another group [23.7 ±14.3 versus 11.9 ± 8.9; p=0.001]. Also, patients with r-TPA treatment had a significantly higher frequency of favorable outcome at day 90 [67.8 % versus 44.0 %; p=0.001]. Interestingly, NSE levels one day after stroke were significantly lower in patients with favorable outcome [14.39 ±9.6 versus 19.83 ±14.9; p=0.048] and showed significant correlation with infarct size [r=0.63;p=0.001] and NIHSS after 24h [r=0.67;p=0.001]. Conclusion: r-TPA treatment resulted in a significant decrease in NSE levels. These levels were significantly correlated with infarct size, NIHSS at 24 hours, and MRS at 90 days.

Effects of Early Changes in Blood Pressure During Intravenous Thrombolysis on the Prognosis of Acute Ischemic Stroke Patients.

Background: Intravenous thrombolysis (IVT) therapy is currently one of the best medical treatments available for patients with acute ischemic stroke. Studies have shown that blood pressure (BP) changes in patients treated with IVT are significantly correlated with prognosis.Objective: Our study aimed to determine the relationship between BP changes during recombinant tissue plasminogen activator (rt-PA) infusion and the 3-month prognosis evaluated using the modified Rankin Scale (mRS) and determine the factors influencing BP changes during rt-PA infusion.Methods: Consecutive patients who were treated with IVT and admitted to our stroke center between May 2015 and October 2017 were analyzed retrospectively. Patients were divided into two groups according to their 3-month prognosis status: patients with mRS ≤ 2 were defined as “favorable outcome group” and those with mRS ≥ 3 as “unfavorable outcome group”. First, the factors affecting prognosis after thrombolysis were analyzed. Second, we analyzed the relationship between BP and the prognosis. BP was taken before and at regular intervals of 15 min during the rt-PA infusion (1 h). The average value of BP during thrombolysis was calculated and compared to the baseline BP. BP decrease was defined as the difference between the baseline BP and the average BP, provided it was greater than 0 mmHg. Third, univariate and multivariate analyses were performed to identify factors that may contribute to BP decrease.Results: In total, 458 patients were included. Patients with a lower baseline National Institute of Health Stroke Scale (NIHSS) score (8.25 ± 5.57 vs. 13.51 ± 7.42, P < 0.001), a higher Alberta Stroke Program Early CT Score (ASPECTS; 8.65 ± 1.82 vs. 8.13 ± 2.00, P = 0.005), decreased BP during thrombolysis (69.4% vs. 59.8%, P = 0.037), and steady BP (SD < 10 mmHg) were more likely to have a favorable outcome (73.9% vs. 60.6%, P = 0.019). High baseline BP (OR > 1), hypertension history (OR < 1), and baseline ASPECTS (OR > 1) were independent factors of BP change during thrombolysis.Conclusion: Patients with decreased or steady BP during thrombolysis were more likely to have a favorable outcome. Baseline ASPECTS, baseline NIHSS score, and hypertension history influenced BP changes during thrombolysis.

Intravenous r-tPA Dose Influence on Outcome after Middle Cerebral Artery Ischemic Stroke Treatment by Mechanical Thrombectomy.

Background and Objectives: Pretreatment with intravenous thrombolysis (IVT) is still recommended in all eligible acute ischemic stroke patients with large-vessel occlusion before mechanical thrombectomy (MTE). However, the added value and safety of bridging therapy versus direct MTE remains controversial. We aimed at evaluating the influence of r-tPA dose level in patients with middle cerebral artery (MCA) occlusion treated with MTE. Materials and Methods: We prospectively compared clinical and radiological outcomes in 38 bridging patients, with 65 receiving direct MTE for MCA stroke admitted to Vilnius University Hospital Santaros Clinics. Following our protocol, r-tPA infusion was stopped just before MTE in the operating room. Therefore, we divided all bridging patients into three groups according to the amount of r-tPA they received: bolus, partial dose or full dose. Functional independence at 90 days was assessed by a modified Rankin Scale score, i.e., from 0–2. The safety outcomes included 90-day mortality and any intracerebral hemorrhage (ICH). Results: Baseline characteristics and functional outcome at 90 days did not differ between the bridging and direct MTE groups. Shorter MTE procedure and hospitalization time (p = 0.025 and p = 0.036, respectively) were observed in the direct MTE group. An IVT treatment subgroup analysis showed higher rates of symptomatic ICH (p < 0.001) and longer intervals between imaging to MTE (p = 0.005) in the full r-tPA dose group. Conclusions: In patients with an MCA stroke, direct MTE seems to be a safe and equally effective as bridging therapy. The optimal r-tPA dose remains unclear. Randomized trials are needed to accurately evaluate the added value of r-tPA in patients treated with MTE.

Dynamic increase in neutrophil levels predicts parenchymal hemorrhage and function outcome of ischemic stroke with r-tPA thrombolysis

The higher level of neutrophil on admission has been reported to predict worse 3-month outcomes in ischemic stroke patients. Our study was to explore the dynamic changes of neutrophil and lymphocyte after r-tPA thrombolysis of ischemic stroke and the relationship with parenchymal hemorrhage (PH) and 3-month function outcome. A total of 208 acute ischemic stroke (AIS) patients with intravenous thrombolysis were included and then received 3-month follow-up in the present study. Blood samples for neutrophil and lymphocyte counts were obtained on admission, at 24h and at 7days after r-tPA infusion. The associations of increase in neutrophil, lymphocyte, and neutrophil to lymphocyte ratio (NLR) with PH or 3-month poor outcome were examined by logistic regression. Increasing trends in the neutrophil and NLR were observed in AIS patients after r-tPA treatment. Increased level of neutrophil at 24h after r-tPA infusion but not that on admission was associated with PH (OR = 2.86, P = 0.029) and 3-month poorer functional outcomes (OR = 2.67, P = 0.009). Moreover, patients were divided into four groups according to the percent change in neutrophil within 24h following r-tPA treatment, and we found that there was a trend of incremental OR when compared higher increase group with lower ones. Dynamic increase in neutrophil and NLR after stroke may predict PH and 3-month poor outcome in AIS patients receiving r-tPA treatment. Therefore, neutrophil and NLR may serve as activity markers for PH and 3-month poor prognosis in AIS patients with intravenous thrombolysis.

Intermediate pulmonary embolism: Diagnosis and management

Intermediate (“submassive”) pulmonary embolism (PE) is proven acute PE without shock but with elevated troponin, BNP, or NT-proBNP, with either contrast-enhanced chest CT or echocardiographic evidence for right ventricular (RV) dysfunction, usually enlargement. However, definitions of intermediate PE vary widely: Some allow a single abnormality of any of the five (two imaging; three biomarker) results, and some would accept normal findings in all five but ECG evidence of RV strain. The quite varied criteria means recommendations for intermediate PE management frequently are not derived from the same type of patient. Diagnosis: Intermediate PE is considered after a diagnostic CT PA-gram with filling defects. The imaging study RV:LV cavity dimensions can be measured in the same image, but a ratio >1.0 is not predictive for adverse outcomes. Abnormal interventricular septum position and reflux of IV contrast into the IVC are associated with poorer outcomes. Echocardiography can measure RV and LV cavity dimensions in the 4-chamber view, but measurements without echo contrast are unreliable. Dynamic views of the RV can show impaired contraction, and/or reduced tricuspid annular plane systolic excursion (TAPSE), and/or elevated estimated pulmonary artery systolic pressure. But in a recent study by expert investigators, 27/83 (33%) of patients presenting to the Emergency Department with persistent dyspnea but CT PA-grams negative for PE had RV dysfunction by one or more of these echocardiogram criteria1. “RV dysfunction” is prevalent in dyspneic patients; in the acute PE patient, it may not be related to the PE. Thrombolysis: A randomized trial of weight-based IV tenecteplase vs placebo2 added to heparin compared outcomes in 500 patients in each group with intermediate PE, defined as requiring CT or echocardiographic RV dysfunction and elevated troponin. At day 30 tenecteplase deaths were 12 vs 16, respectively (p = 0.42) but significantly more strokes (12; 10 hemorrhagic, incidence 2.4%) vs 1 (incidence 0.2%) (p = 0.003), and extracranial bleeds occurred in 32 (6.3%) tenecteplase patients vs 6 (1.2%), (p < 0.001). Chronic thromboembolic pulmonary hypertension (CTEPH) was 2.6% in both groups after 3 years. An accompanying editorial3 concluded: No routine systemic thrombolysis; instead, observe for deterioration, for example, shock. To reduce bleeding, catheter-directed thrombolysis (CDT) for intermediate PE (mostly case series, sometimes ultrasound-enabled catheters; up to 20 mg rt-PA) has been reported. In the only randomized study (30 patients/group), ULTIMA4, 90-day mortality (0 vs 1), RV/LV ratio, and TAPSE were the same as with anticoagulation. 24-hour pulmonary artery pressure results were superior with CDT. Recommendations: In intermediate PE, observe carefully. Bolus IV heparin 80 U/kg actual body weight during the diagnostic work-up, infuse 18 U/kg actual body weight if the PE diagnosis is proven or likely. Obtain baseline BNP or NT-proBNP and follow every 6–12 h to help assessment. If hypotension occurs, consider half- or full-dose rt-PA5. If systemic thrombolysis is contraindicated, try catheter-directed thrombolysis by mechanical fragmentation or with 10–20 mg rt-PA infusion into the most important clot.When active bleeding, impaired hemostasis, and high bleeding risk are concerns, give IV heparin without a bolus, 200–300 U/hour, and observe 6–8 h for hemostasis. Increase by 100 U every 8 h if tolerated without excessive bleeding until 600–800 U/h, then continue until bleeding risk remits. Consider a retrievable IVC filter.

PAI-1 5G/5G genotype is an independent risk of intracranial hemorrhage in post-lysis stroke patients.

ObjectiveThrombolysis by recombinant tissue plasminogen activator (rt‐PA) is the main pharmacological therapy in acute ischemic stroke (IS); however, it is only effective in a subset of patients. Here we aimed to investigate the role of plasminogen activator inhibitor‐1 (PAI‐1), an effective inhibitor of t‐PA, and its major polymorphism (PAI‐1 4G/5G) in therapy outcome.MethodsStudy population included 131 consecutive IS patients who all underwent thrombolysis. Blood samples were taken on admission, 1 and 24 h after rt‐PA infusion. PAI‐1 activity and antigen levels were measured from all blood samples and the PAI‐1 4G/5G polymorphism was determined. Clinical data including NIHSS were registered on admission and day 1. ASPECTS was assessed using CT images taken before and 24 h after thrombolysis. Intracranial hemorrhage (ICH) was classified according to ECASS II. Long‐term outcome was defined 90 days post‐event by the modified Rankin Scale (mRS).ResultsPAI‐1 activity levels dropped transiently after thrombolysis, while PAI‐1 antigen levels remained unchanged. PAI‐1 4G/5G polymorphism had no effect on PAI‐1 levels and did not influence stroke severity. PAI‐1 activity/antigen levels as measured on admission were significantly elevated in patients with worse 24 h ASPECTS (<7). Logistic regression analysis including age, sex, NIHSS on admission, BMI, history of arterial hypertension, and hyperlipidemia conferred a significant, independent risk for developing ICH in the presence of 5G/5G genotype (OR:4.75, 95%CI:1.18–19.06). PAI‐1 levels and PAI‐1 4G/5G polymorphism had no influence on long‐term outcomes.InterpretationPAI‐1 5G/5G genotype is associated with a significant risk for developing ICH in post‐lysis stroke patients.

A Case of Oropharyngeal Angioedema Following Intravenous Recombinant Tissue Plasminogen Activator (rt-PA) and Mechanical Thrombectomy.

A 72-year-old housewife presented with ischemic cerebrovascular stroke. Intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) followed by mechanical thrombectomy under general anesthesia were attempted. The patient developed stridor and tongue swelling, in addition to hypotension and bradycardia, 60 min after completion of the rt-PA infusion. The airway was intubated, and intramuscular adrenaline, together with intravenous hydrocortisone and diphenhydramine, were administered. On the second day, the tongue edema subsided, and the cuff leak test was negative. However, extubation was not attempted due to the development of brain edema. A tracheostomy was later performed, and the patient was weaned off mechanical ventilation.

Abstract WMP75: A Modified, Recombinant Tissue Plasminogen Activator-Responding Photothrombotic Stroke Model

Introduction: Photodynamical dye-based stroke models (e.g. Rose Bengal RB/photothrombosis) have several attractive features, including simple surgical procedures, consistent infarct size, and low mortality rate. Yet, because RB/photothrombosis mainly induces platelet-rich but fibrin-poor clots, it responds to recombinant tissue plasminogen activator (rtPA)-based lytic therapy poorly making it less suitable for studying reperfusion injury or improving lytic therapy. Hypothesis: We hypothesize the addition of thrombin to Rose Bengal dye in photothrombosis will increase the fibrin component in clots, making it more susceptible to rtPA-thrombolysis. Methods: Based on the standard RB/photothrombotic stroke procedures (intravenous injection of 50 mg/kg RB, we mixed a subthreshold level of bovine thrombin with RB to create a thrombin-Rose Bengal (TRB)/photothrombotic stroke model. We compared the clot composition, effects of rtPA treatment on cerebral blood flow reperfusion, and the infarct size following rtTA treatment initiated at 30, 60, or 120 min after photothrombosis. Results: We report four sets of results. First, the addition of thrombin did not increase mortality rate or infarct size, when compared to standard RB/photothrombosis. Second, immunostaining showed a scant amount of fibrin at the border of RB/photothrombosis-induced clots. In contrast, fibrin was mixed with erythrocytes throughout TRB/photothrombosis-induced clots. Third, laser speckle contrast imaging indicated that intravenous infusion of rtPA (10 mg/kg) at 30 min after TRB/photothrombosis improved blood flow in the MCA-supplied area, but the same treatment had little effect in RB/photothrombosis. Finally, the therapeutic window of rtPA-treatment is at least 2 h in TRB/photothrombosis (n&gt;10 in each group). Conclusions: Our results confirm the notion by Dr. Brant Watson et al. that rtPA lytic treatment confers little benefits in RB/photothrombosis, likely due to its fibrin-poor clots. Yet, the addition of subthreshold thrombin (TRB/photothrombosis) elevates the fibrin component in clot, making it far more responsive to rtPA-thrombolysis. The modified, rtPA-responding thrombotic stroke model may have broad applications in experimental stroke research.

Post-thrombolysis rupture of small lenticulostriate aneurysms: A report of 2 consecutive cases

The 2018 American Heart Association/American Stroke Association (AHA/ASA) guidelines stated that the administration of intravenous recombinant tissue-type plasminogen activator (rTPA) for acute ischaemic stroke is probably safe for patients with small (i.e. <10 mm) unruptured intracranial aneurysms. We present 2 cases of small (2 and 5 mm) lenticulostriate artery (LSA) aneurysms which ruptured immediately following rtPA infusion. The ensuing acute intracranial haemorrhages resulted in the death of one patient and severe functional impairment for the other. Given the limited literature available, the natural history of LSA aneurysms is largely unknown. This report suggests that LSA aneurysms, regardless of size, be considered separately from other conventional aneurysms as “high-risk” lesions and a contraindication to thrombolysis.

Rheumatoid meningitis presenting with a stroke-like attack treated with recombinant tissue plasminogen activator: a case presentation

BackgroundRheumatoid meningitis presenting with a stroke-like attack (RMSA) is a rare manifestation of rheumatoid arthritis (RA). When the patients arrive within the time-window for recombinant tissue plasminogen activator (rt-PA) infusion therapy, no diagnostic protocol has been established.Case presentationA 55-year-old woman was brought by ambulance to our hospital with complaints of sudden-onset dysarthria and left arm numbness. The National Institutes of Health Stroke Scale (NIHSS) score was 5, and the Alberta Stroke Program Early CT Score was 8. She was diagnosed with acute embolic stroke. At 4 h, 6 min after onset, intravenous administration of rt-PA (alteplase, 0.6 mg/kg) was started. Her neurological deficits improved rapidly, and her NIHSS score was 1. Brain MRI was then performed. There was no hemorrhagic transformation, but the MRI findings were not compatible with ischemic stroke. She had a past history of RA diagnosed 6 months earlier, and she had been treated with methotrexate (10 mg daily). She was diagnosed with RMSA, and continuous infusion of methylprednisolone 1000 mg daily was started for 3 days. The high signal intensity on the FLAIR image disappeared.ConclusionCT-based decision-making for rt-PA injection is reasonable, but MRI is needed for the early diagnosis of RMSA. In this case, it is particularly important that neither adverse events nor bleeding complications were observed, suggesting the safety of CT-based thrombolytic therapy in RMSA.

Increase in neutrophils after recombinant tissue plasminogen activator thrombolysis predicts poor functional outcome of ischaemic stroke: a longitudinal study.

Neutrophils, a pivotal immune responder to ischaemic brain insult, have been involved in neuroplasticity and increase after stroke. Recombinant tissue plasminogen activator (r-tPA), a promising treatment improving neuroplasticity, promotes neutrophil degranulation. However, the dynamic profile of neutrophils after r-tPA treatment and their effect on neurological recovery after stroke are not well studied. Cell counts of neutrophils, lymphocytes and their ratio (NLR) were measured on admission and 24 h after r-tPA infusion in 372 consecutively recruited acute ischaemic stroke patients (mean age 64 years). Death or major disability at 3 months after stroke was diagnosed based on the modified Rankin Scale (mRS ≥ 3) obtained by neurologists who were blinded to any hospital records. The longitudinal associations of percentage increase in neutrophils, lymphocytes and the NLR with death or major disability were examined by logistic regression adjusting for covariates including neurological deficits at baseline. Neutrophils exhibited a steeper increase after r-tPA infusion in patients with death or major disability than in those without (P < 0.001). A 10% increase in neutrophils after r-tPA infusion was associated with an 83% increased risk for death or major disability within 3 months after stroke onset [odds ratio (OR) 1.99, P = 0.009]. Increased neutrophils at 24 h after r-tPA (OR 6.30, P < 0.001 after log transformation) but not on admission significantly predicted increased risks for death or major disability within 3 months after stroke onset. A similar phenomenon was also observed for the NLR. A dynamic increase in neutrophils after stroke significantly predicts 3-month death or major disability in acute ischaemic stroke patients receiving r-tPA treatment.

Abstract 20970: Atrial Fibrillation and Intra-Arterial Treatment of Acute Ischemic Stroke: Is the Romance Deeper Than Embolism?

Introduction: Recent evidence remains inconclusive about the impact of atrial fibrillation (AF) on prognosis after intravenous thrombolysis and/or intra-arterial (IA) acute stroke treatment (AIS). Hypothesis: AF (either first episode or chronic) adversely affects stroke outcomes in patients undergoing IA treatment for AIS. Methods: We analyzed data from the 434 subjects in the IA treatment arm of Interventional Management of Stroke (IMS) III trial. The trial included AIS patients who were eligible for IV rtPA infusion within three hours after stroke onset. The subjects that were randomized to the IA treatment arm later received a protocol approved endovascular treatment. Demographics, vascular risk factors, and outcome measures were compared between patients with and without atrial fibrillation. The main outcomes considered were early neurological deterioration and hemorrhagic complications, excellent (mRS: scores of 0-2) functional outcome at 3 months, and good quality of life (EQ-5D index 0.5-1.0) at one year from randomization. Adjusted logistic regression analysis was performed to compare these outcomes. Results: Of the 434 patients who were studied (mean ± SD age, 66.3 ± 12.3 years, with 50.2% of patients being men), 153 had AF either chronic or diagnosed at baseline EKG and 281 had no AF. The patients with AF were significantly older (age 71.2±8.2 vs. 63.6±13.3 years), had more severe strokes (NIHSS&gt;=20) at baseline assessment (40.5% vs. 24.9%). The subjects with AF had higher adjusted odds of early neurological deterioration (OR 1.3, 95%CI 0.6-1.9, p=0.81), symptomatic intracranial hemorrhage (OR 1.7; 95% CI 0.7-3.8; p=0.27), and subarachnoid hemorrhage (OR 1.4; 95% CI 0.7-2.7; p=0.31). The subjects with AF had lower odds of having good functional outcome 3 months after randomization (OR 0.8; 95% CI 0.4-1.1; p=0.06). The two groups did not differ in their adjusted odds of symptomatic ICH, parenchymal hematomas, 90 days mortality, and quality of life after one year. Conclusions: In the patients undergoing IA treatment for AIS, AF may adversely impact early recovery in neurological function and long-term functional outcomes but not the rates of hemorrhagic complications, mortality, or good quality of life.

Intravenous thrombolytic therapy for acute anterior ischemic stroke: Experience at the French Military Teaching Hospital in Toulon from 2003 to 2014

IntroductionIntravenous thrombolysis with rt-PA is the key treatment for acute ischemic stroke (IS), and has largely been developed at the Military Teaching Hospital in Toulon since 2003. This report is of the results of our practices compared with those in the literature, as well as our attempts to identify factors predictive of a favorable outcome after thrombolysis. MethodsAll patients treated with rt-PA for IS in the carotid territory between 2003 and 2014 were prospectively included. Disability was assessed at 3 months by modified Rankin Scale (m-RS) scores; outcome was considered unfavorable if the m-RS score was >2. Multivariate analyses were also performed to identify parameters correlating with poor and favorable outcomes. ResultsOf the 289 patients prospectively enrolled in the study [mean initial National Institutes of Health Stroke Scale (NIHSS) score: 14.3], 52.5% had an m-RS score >2 at 3 months of follow-up. Three independent predictive factors for poor functional outcomes at the 3-month follow-up were identified: NIHSS score>12 on admission (P=0.048); NIHSS score>8 at discharge (P<0.001); and early neurological worsening within the first 24h (P=0.015). Early neurological improvement within 24h of rt-PA infusion was significantly associated with recanalization of the stroke-related occluded cerebral artery (P<0.001, r=0.37). ConclusionAfter 12 years of practice, our stroke unit has produced results similar to those of the major clinical studies in terms of safety and efficacy. High NIHSS scores on admission and a lack of neurological improvement during the first 24h of thrombolysis due to failure of early recanalization were identified as independent predictive factors of poor functional outcomes.

Physicians are not well informed about the new guidelines for the treatment of acute stroke.

Treatment of cerebrovascular disease has advanced rapidly in the last two decades. Recent data has added challenges to the treatment of ischemic stroke in the acute phase. To evaluate the knowledge of physicians about the treatment of ischemic stroke in the acute phase. An online questionnaire was submitted to all physicians enrolled in the Regional Council of Medicine in Brazil. 456 physicians from different specialties answered the questions. Most of them did not know that mechanical endovascular thrombectomy is often considered as the gold standard treatment in cases of ischemic stroke in the acute phase; and 85% of them did not realize that thrombectomy together with intravenous thrombolysis was possible. The maximum time to act in an acute event also presented many divergences, even with regard to the infusion of rtPA. The lack of structure, medication and absence of a neurologist were considered the main barriers to treatment. Physicians are not well informed about the new guidelines for the treatment of acute stroke. Most physicians incorrectly answered most of the questions on the questionnaire.