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Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke.

ABSTRACT: Remote ischemic conditioning is cardioprotective in myocardial infarction and neuroprotective in mechanical occlusion models of stroke. However, there is no report on its therapeutic potential in a physiologically relevant embolic stroke model (embolic middle cerebral artery occlusion) in combination with intravenous tissue-type plasminogen activator (tPA).We tested remote ischemic perconditioning therapy (RIPerC) at 2 hours after embolic middle cerebral artery occlusion in the mouse with and without intravenous tPA at 4 hours. We assessed cerebral blood flow up to 6 hours, neurological deficits, injury size, and phosphorylation of Akt (Serine(473)) as a prosurvival signal in the ischemic hemisphere at 48 hours poststroke.RIPerC therapy alone improved the cerebral blood flow and neurological outcomes. tPA alone at 4 hours did not significantly improve the neurological outcome even after successful thrombolysis. Individual treatments with RIPerC and intravenous tPA reduced the infarct size (25.7% and 23.8%, respectively). Combination therapy of RIPerC and tPA resulted in additive effects in further improving the neurological outcome and reducing the infarct size (50%). All the therapeutic treatments upregulated phosphorylation of Akt in the ischemic hemisphere.RIPerC is effective alone after embolic middle cerebral artery occlusion and has additive effects in combination with intravenous tPA. RIPerC may be a simple, safe, and inexpensive combination therapy with intravenous tPA.

SUBMITTER: Hoda MN

PROVIDER: S-EPMC3740528 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke.

Hoda Md Nasrul MN Siddiqui Shahneela S Herberg Samuel S Periyasamy-Thandavan Sudharsan S Bhatia Kanchan K Hafez Sherif S SS Johnson Maribeth H MH Hill William D WD Ergul Adviye A Fagan Susan C SC Hess David C DC

Stroke 20120821 10

<h4>Background and purpose</h4>Remote ischemic conditioning is cardioprotective in myocardial infarction and neuroprotective in mechanical occlusion models of stroke. However, there is no report on its therapeutic potential in a physiologically relevant embolic stroke model (embolic middle cerebral artery occlusion) in combination with intravenous tissue-type plasminogen activator (tPA).<h4>Methods</h4>We tested remote ischemic perconditioning therapy (RIPerC) at 2 hours after embolic middle cer ...[more]

PMID: 22910893

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Project description:Rationale: Remote ischemic perconditioning during cerebral ischemia (RIPerC) refers to the application of brief episodes of transient limb ischemia commonly to a limb, it represents a new safe, simple and low-cost paradigm in neuroprotection. Aim and/or Hypothesis: To evaluate the effects of RIPerC on acute ischemic stroke (AIS) patients, applied in the ambulance, to improve functional outcomes compared with standard of care. Sample Size Estimates: A sample size of 286 patients in each arm achieves 80% power to detect treatment differences of 14% in the outcome, using a two-sided binomial test at significance level of 0.05, assuming that 40% of the control patients will experience good outcome and an initial misdiagnosis rate of 29%. Methods and Design: We aim to conduct a multicentre study of pre-hospital RIPerC application in AIS patients. A total of 572 adult patients diagnosed of suspected clinical stroke within 8 h of symptom onset and clinical deficit >0 according to prehospital rapid arterial occlusion evaluation (RACE) scale score will be randomized, in blocks of size 4, to RIPerC or sham. Patients will be stratified by RACE score scale. RIPerC will be started in the ambulance before hospital admission and continued in the hospital if necessary. It will consist of five cycles of electronic tourniquet inflation and deflation (5 min each). The cuff pressure for RIPerC will be 200 mmHg during inflation. Sham will only simulate vibration of the device. Study Outcome(s): The primary outcome will be the difference in the proportion of patients with good outcomes as defined by a mRS score of 2 or less at 90 days. Secondary outcomes to be monitored will include early neurological improvement rate, treatment related serious adverse event rates, size of the infarct volume, symptomatic intracranial hemorrhage, metabolomic and lipidomic response to RIPerC and Neuropsychological evaluation at 90 days. Discussion: Neuroprotective therapies could not only increase the benefits of available reperfusion therapies among AIS patients but also provide an option for patients who are not candidates for these treatments. REMOTE-CAT will investigate the clinical benefit of RIC as a new neuroprotective strategy in AIS. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03375762.

Project description:BACKGROUND:The necessity for rapid evaluation and treatment of acute ischemic stroke with intravenous tPA (tissue-type plasminogen activator) may increase the risk of administrating tPA to patients presenting with noncerebrovascular conditions that closely resemble stroke (stroke mimics). However, there are limited data on thrombolysis safety in stroke mimics. METHODS AND RESULTS:Using data from the Get With The Guidelines-Stroke Registry, we identified 72?582 patients with suspected ischemic stroke treated with tPA from 485 US hospitals between January 2010 and December 2017. We documented the use of tPA in stroke mimics, defined as patients who present with stroke-like symptoms, but after workup are determined not to have suffered from a stroke or transient ischemic attack, and compared characteristics and outcomes in stroke mimics versus those with ischemic stroke. Overall, 3.5% of tPA treatments were given to stroke mimics. Among them, 38.2% had a final nonstroke diagnoses of migraine, functional disorder, seizure, and electrolyte or metabolic imbalance. Compared with tPA-treated true ischemic strokes, tPA-treated mimics were younger (median 54 versus 71 years), had a less severe National Institute of Health Stroke Scale (median 6 versus 8), and a lower prevalence of cardiovascular risk factors, except for a higher prevalence of prior stroke/transient ischemic attack (31.3% versus 26.1%, all P<0.001). The rate of symptomatic intracranial hemorrhage was lower in stroke mimics (0.4%) as compared with 3.5% in ischemic strokes (adjusted odds ratio, 0.29; 95% CI, 0.17-0.50). In-hospital mortality rate was significantly lower in stroke mimics (0.8% versus 6.2%, adjusted odds ratio, 0.31; 95% CI, 0.20-0.49). Patients with stroke mimics were more likely to be discharged to home (83.8% versus 49.3%, adjusted odds ratio, 2.97; 95% CI, 2.59-3.42) and to ambulate independently at discharge (78.6% versus 50.6%, adjusted odds ratio, 1.86; 95% CI, 1.61-2.14). CONCLUSIONS:In this large cohort of patients treated with tPA, relatively few patients who received tPA for presumed stroke were ultimately not diagnosed with a stroke or transient ischemic attack. The complication rates associated with tPA in stroke mimics were low. Despite the potential risk of administering tPA to stroke mimics, opportunity remains for continued improvement in the rapid and accurate diagnosis and treatment of ischemic stroke.

Project description:Background and Purpose- Telemedicine is increasingly utilized for intravenous tPA (tissue-type plasminogen activator) delivery. The comparative safety of leaving tPA-treated patients at a presenting (spoke) hospital (drip-and-stay) or transferring patients to a central treating (hub) hospital (drip-and-ship) is not established. We sought to compare outcomes between drip-and-ship and drip-and-stay patients treated with tPA via telemedicine. We hypothesized that there would be no differences in short-term outcomes of in-hospital mortality, length of stay, or discharge disposition or in 90-day outcomes between groups. Methods- We retrospectively identified patients treated with tPA at 17 spoke hospitals between September 2015 and December 2016. Demographic, clinical, and outcome data were obtained from a prospective telemedicine registry. We used negative binomial, multinomial, and logistic regression analyses to evaluate length of stay, discharge disposition, and inpatient mortality, respectively. We compared the proportion of patients with 90-day modified Rankin Scale score <2 by group. Results- Among 430 tPA-treated patients, 232 (53.9%) were transferred to the hub after treatment. The median arrival National Institutes of Health Stroke Scale score was higher for drip-and-ship (10; interquartile range, 5-18) compared with drip-and-stay patients (6; interquartile range, 4-10; P<0.001). Unadjusted length of stay was longer in drip-and-stay patients (incidence rate ratio, 0.82; 95% CI, 0.71-0.95). There were no significant differences in adjusted length of stay, hospital mortality, or discharge disposition. Among the 64% of patients with complete 90-day modified Rankin Scale score, the proportion with good outcomes (modified Rankin Scale score <2) did not differ between groups. Conclusions- We found no differences in measured outcomes between drip-and-ship and drip-and-stay patients treated in our network, although our study may be underpowered to detect small differences.

Project description:BackgroundThis study aims to assess the efficacy and safety of different doses of intravenous tissue-type plasminogen activator (tPA) for acute ischemic stroke (AIS) by adopting a network meta-analysis (NMA).MethodsStudies comparing different doses of tPA in AIS were identified by retrieving electronic databases. NMAs of outcome measures included favorable functional outcome with a modified Rankin scale score (mRS) of 0 or 1 at 3 months after treatment (3M-FF), the functional independence with a mRS of 0, 1, or 2 at 3 months (3M-FI), symptomatic intracranial hemorrhage (sICH) and 3-month all-cause mortality (3M-M). Symptomatic intracranial hemorrhage (sICH) and 3-month all-cause mortality (3M-M) were assessed. Probability-based ranking and surface under cumulative ranking (SUCRA) were performed to identify the best dose of tPA. Inconsistency was evaluated by node-splitting analysis and a loop-specific approach. Publication bias was analyzed by funnel plots.ResultsA total of 14 studies were included in the quantitative synthesis. The NMA results revealed no difference among low (<0.7 mg/kg), moderate (0.8 mg/kg), and standard (0.9 mg/kg) doses of tPA with regard to efficacy and safety. The SUCRAs of 3M-FF and 3M-FI showed that the standard dose ranked first, the moderate dose ranked second, and the low dose ranked third. The SUCRA of sICH showed that the standard dose ranked first (78.1%), the low dose ranked second (61.0%), and the moderate dose ranked third (11.0%). The SUCRAs of 3-month mortality showed that the standard dose ranked first (73.2%), the moderate dose ranked second (40.8%), and the low dose ranked third (36.1%). No significant inconsistency was shown by node-splitting analysis and no publication bias was shown in funnel plots.ConclusionLower dose tPA was comparable to the standard dose with regard to efficacy and safety. Based on the SUCRA results and American Heart Association/American Stroke Association (AHA/ASA) guidelines, the standard dose was still the optimal selection for AIS.

Project description:Background and Purpose- Acute ischemic stroke patients with history of prior ischemic stroke plus concomitant diabetes mellitus (DM) were excluded from the ECASS III trial (European Cooperative Acute Stroke Study) because of safety concerns. However, there are few data on use of intravenous tissue-type plasminogen activator and symptomatic intracerebral hemorrhage or outcomes in this population. Methods- Using data from the Get With The Guidelines-Stroke Registry between February 2009 and September 2017 (n=1619 hospitals), we examined characteristics and outcomes among patients with acute ischemic stroke treated with tissue-type plasminogen activator within the 3- to 4.5-hour window who had a history of stroke plus diabetes mellitus (HxS+DM) (n=2129) versus those without either history (n=16 690). Results- Compared with patients without either history, those with both prior stroke and DM treated with tissue-type plasminogen activator after an acute ischemic stroke had a higher prevalence of cardiovascular risk factors in addition to history of stroke, DM, and more severe stroke (National Institutes of Health Stroke Scale: median, 8 [interquartile range, 5-15] versus 7 [4-13]). The unadjusted rates of symptomatic intracerebral hemorrhage and in-hospital mortality were 4.3% (HxS+DM) versus 3.8% (without either history; P=0.31) and 6.2% versus 5.5% ( P=0.20), respectively. These differences were not statistically significant after risk adjustment (symptomatic intracerebral hemorrhage: adjusted odds ratio, 0.79 [95% CI, 0.51-1.21]; P=0.28; in-hospital mortality: odds ratio, 0.77 [95% CI, 0.52-1.14]; P=0.19). Unadjusted rate of functional independence (modified Rankin Scale score, 0-2) at discharge was lower in those with HxS+DM (30.9% HxS+DM versus 44.8% without either history; P≤0.0001), and this difference persisted after adjusting for baseline clinical factors (adjusted odds ratio, 0.76 [95% CI, 0.59-0.99]; P=0.04). Conclusions- Among patients with acute ischemic stroke treated with intravenous tissue-type plasminogen activator within the 3- to 4.5-hour window, HxS+DM was not associated with statistically significant increased symptomatic intracerebral hemorrhage or mortality risk.

Dataset Information

Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke.

Publications

Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke.

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