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Animal Models and Experimental Medicine Sep 2021Stroke is a devastating disease with high morbidity and mortality. Animal models are indispensable tools that can mimic stroke processes and can be used for... (Review)
Review
Stroke is a devastating disease with high morbidity and mortality. Animal models are indispensable tools that can mimic stroke processes and can be used for investigating mechanisms and developing novel therapeutic regimens. As a heterogeneous disease with complex pathophysiology, mimicking all aspects of human stroke in one animal model is impossible. Each model has unique strengths and weaknesses. Models such as transient or permanent intraluminal thread occlusion middle cerebral artery occlusion (MCAo) models and thromboembolic models are the most commonly used in simulating human ischemic stroke. The endovascular filament occlusion model is characterized by easy manipulation and accurately controllable reperfusion and is suitable for studying the pathogenesis of focal ischemic stroke and reperfusion injury. Although the reproducibility of the embolic model is poor, it is more convenient for investigating thrombolysis. Rats are the most frequently used animal model for stroke. This review mainly outlines the stroke models of rats and discusses their strengths and shortcomings in detail.
Topics: Animals; Disease Models, Animal; Infarction, Middle Cerebral Artery; Rats; Reperfusion; Reproducibility of Results; Stroke
PubMed: 34557647
DOI: 10.1002/ame2.12179 -
Lancet (London, England) Dec 2020Among patients with out-of-hospital cardiac arrest (OHCA) and ventricular fibrillation, more than half present with refractory ventricular fibrillation unresponsive to... (Comparative Study)
Comparative Study Randomized Controlled Trial
Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial.
BACKGROUND
Among patients with out-of-hospital cardiac arrest (OHCA) and ventricular fibrillation, more than half present with refractory ventricular fibrillation unresponsive to initial standard advanced cardiac life support (ACLS) treatment. We did the first randomised clinical trial in the USA of extracorporeal membrane oxygenation (ECMO)-facilitated resuscitation versus standard ACLS treatment in patients with OHCA and refractory ventricular fibrillation.
METHODS
For this phase 2, single centre, open-label, adaptive, safety and efficacy randomised clinical trial, we included adults aged 18-75 years presenting to the University of Minnesota Medical Center (MN, USA) with OHCA and refractory ventricular fibrillation, no return of spontaneous circulation after three shocks, automated cardiopulmonary resuscitation with a Lund University Cardiac Arrest System, and estimated transfer time shorter than 30 min. Patients were randomly assigned to early ECMO-facilitated resuscitation or standard ACLS treatment on hospital arrival by use of a secure schedule generated with permuted blocks of randomly varying block sizes. Allocation concealment was achieved by use of a randomisation schedule that required scratching off an opaque layer to reveal assignment. The primary outcome was survival to hospital discharge. Secondary outcomes were safety, survival, and functional assessment at hospital discharge and at 3 months and 6 months after discharge. All analyses were done on an intention-to-treat basis. The study qualified for exception from informed consent (21 Code of Federal Regulations 50.24). The ARREST trial is registered with ClinicalTrials.gov, NCT03880565.
FINDINGS
Between Aug 8, 2019, and June 14, 2020, 36 patients were assessed for inclusion. After exclusion of six patients, 30 were randomly assigned to standard ACLS treatment (n=15) or to early ECMO-facilitated resuscitation (n=15). One patient in the ECMO-facilitated resuscitation group withdrew from the study before discharge. The mean age was 59 years (range 36-73), and 25 (83%) of 30 patients were men. Survival to hospital discharge was observed in one (7%) of 15 patients (95% credible interval 1·6-30·2) in the standard ACLS treatment group versus six (43%) of 14 patients (21·3-67·7) in the early ECMO-facilitated resuscitation group (risk difference 36·2%, 3·7-59·2; posterior probability of ECMO superiority 0·9861). The study was terminated at the first preplanned interim analysis by the National Heart, Lung, and Blood Institute after unanimous recommendation from the Data Safety Monitoring Board after enrolling 30 patients because the posterior probability of ECMO superiority exceeded the prespecified monitoring boundary. Cumulative 6-month survival was significantly better in the early ECMO group than in the standard ACLS group. No unanticipated serious adverse events were observed.
INTERPRETATION
Early ECMO-facilitated resuscitation for patients with OHCA and refractory ventricular fibrillation significantly improved survival to hospital discharge compared with standard ACLS treatment.
FUNDING
National Heart, Lung, and Blood Institute.
Topics: Adult; Advanced Cardiac Life Support; Aged; Cardiopulmonary Resuscitation; Extracorporeal Membrane Oxygenation; Female; Humans; Male; Middle Aged; Out-of-Hospital Cardiac Arrest; Outcome Assessment, Health Care; Patient Discharge; Reperfusion; Safety; Survival; Time Factors; Treatment Outcome; Ventricular Fibrillation; Young Adult
PubMed: 33197396
DOI: 10.1016/S0140-6736(20)32338-2 -
Intensive Care Medicine Apr 2021The European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) have collaborated to produce these post-resuscitation care...
The European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) have collaborated to produce these post-resuscitation care guidelines for adults, which are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations. The topics covered include the post-cardiac arrest syndrome, diagnosis of cause of cardiac arrest, control of oxygenation and ventilation, coronary reperfusion, haemodynamic monitoring and management, control of seizures, temperature control, general intensive care management, prognostication, long-term outcome, rehabilitation and organ donation.
Topics: Adult; Cardiopulmonary Resuscitation; Critical Care; Heart Arrest; Humans; Myocardial Reperfusion; Resuscitation; Seizures
PubMed: 33765189
DOI: 10.1007/s00134-021-06368-4 -
European Heart Journal Apr 2023During the last 5-7 years, tremendous progress was achieved in the reperfusion treatment of acute ischaemic stroke during its first few hours from symptom onset. This... (Review)
Review
During the last 5-7 years, tremendous progress was achieved in the reperfusion treatment of acute ischaemic stroke during its first few hours from symptom onset. This review summarizes the latest evidence from randomized clinical trials and prospective registries with a focus on endovascular treatment using stent retrievers, aspiration catheters, thrombolytics, and (in selected patients) carotid stenting. Novel approaches in prehospital (mobile interventional stroke teams) and early hospital (direct transfer to angiography) management are described, and future perspectives ('all-in-one' laboratories with angiography and computed tomography integrated) are discussed. There is reasonable chance for patients with moderate-to-severe acute ischaemic stroke to survive without permanent sequelae when the large-vessel occlusion is removed by means of modern pharmaco-mechanic approach. Catheter thrombectomy is now the golden standard of acute stroke treatment. The role of cardiologists in stroke is expanding from diagnostic help (to reveal the cause of stroke) to acute therapy in those regions where such up-to-date Class I. A treatment is not yet available.
Topics: Humans; Stroke; Brain Ischemia; Prospective Studies; Endovascular Procedures; Thrombectomy; Ischemic Stroke; Stents; Reperfusion; Treatment Outcome
PubMed: 36477996
DOI: 10.1093/eurheartj/ehac684 -
Journal of Cardiology Feb 2023Owing to recent advances in early reperfusion strategies, pharmacological therapy, standardized care, and the identification of vulnerable patient subsets, the prognosis... (Review)
Review
Owing to recent advances in early reperfusion strategies, pharmacological therapy, standardized care, and the identification of vulnerable patient subsets, the prognosis of acute myocardial infarction has improved. However, there is still considerable room for improvement. This review article summarizes the latest evidence concerning clinical diagnosis and treatment of acute myocardial infarction.
Topics: Humans; Myocardial Infarction; Myocardial Reperfusion; Thrombolytic Therapy; Prognosis; Percutaneous Coronary Intervention; Treatment Outcome; Myocardial Revascularization
PubMed: 35882613
DOI: 10.1016/j.jjcc.2022.07.003 -
Oxidative Medicine and Cellular... 2021Myocardial ischemia is a disease with high morbidity and mortality, for which reperfusion is currently the standard intervention. However, the reperfusion may lead to... (Review)
Review
Myocardial ischemia is a disease with high morbidity and mortality, for which reperfusion is currently the standard intervention. However, the reperfusion may lead to further myocardial damage, known as myocardial ischemia/reperfusion injury (MI/RI). Oxidative stress is one of the most important pathological mechanisms in reperfusion injury, which causes apoptosis, autophagy, inflammation, and some other damage in cardiomyocytes through multiple pathways, thus causing irreversible cardiomyocyte damage and cardiac dysfunction. This article reviews the pathological mechanisms of oxidative stress involved in reperfusion injury and the interventions for different pathways and targets, so as to form systematic treatments for oxidative stress-induced myocardial reperfusion injury and make up for the lack of monotherapy.
Topics: Humans; Myocardial Ischemia; Oxidative Stress; Reperfusion
PubMed: 34055195
DOI: 10.1155/2021/6614009 -
Nature Reviews. Neurology Apr 2022For over 40 years, attempts to develop treatments that protect neurons and other brain cells against the cellular and biochemical consequences of cerebral ischaemia in... (Review)
Review
For over 40 years, attempts to develop treatments that protect neurons and other brain cells against the cellular and biochemical consequences of cerebral ischaemia in acute ischaemic stroke (AIS) have been unsuccessful. However, the advent of intravenous thrombolysis and endovascular thrombectomy has taken us into a new era of treatment for AIS in which highly effective reperfusion therapy is widely available. In this context, cytoprotective treatments should be revisited as adjunctive treatment to reperfusion therapy. Renewed efforts should focus on developing new drugs that target multiple aspects of the ischaemic cascade, and previously developed drugs should be reconsidered if they produced robust cytoprotective effects in preclinical models and their safety profiles were reasonable in previous clinical trials. Several development pathways for cytoprotection as an adjunct to reperfusion can be envisioned. In this Review, we outline the targets for cytoprotective therapy and discuss considerations for future drug development, highlighting the recent ESCAPE-NA1 trial of nerinetide, which produced the most promising results to date. We review new types of clinical trial to evaluate whether cytoprotective drugs can slow infarct growth prior to reperfusion and/or ameliorate the consequences of reperfusion, such as haemorrhagic transformation. We also highlight how advanced brain imaging can help to identify patients with salvageable ischaemic tissue who are likely to benefit from cytoprotective therapy.
Topics: Brain; Brain Ischemia; Cytoprotection; Endovascular Procedures; Humans; Ischemic Stroke; Reperfusion; Stroke; Thrombectomy; Treatment Outcome
PubMed: 35079135
DOI: 10.1038/s41582-021-00605-6 -
International Journal of Stroke :... Mar 2024Disparities in the availability of reperfusion services for acute ischemic stroke are considerable globally and require urgent attention. Contemporary data on the... (Review)
Review
BACKGROUND
Disparities in the availability of reperfusion services for acute ischemic stroke are considerable globally and require urgent attention. Contemporary data on the availability of reperfusion services in different countries are used to provide the necessary evidence to prioritize where access to acute stroke treatment is needed.
AIMS
To provide a snapshot of published literature on the provision of reperfusion services globally, including when facilitated by telemedicine or mobile stroke unit services.
METHODS
We searched PubMed to identify original articles, published up to January 2023 for the most recent, representative, and relevant patient-level data for each country. Keywords included thrombolysis, endovascular thrombectomy and telemedicine. We also screened reference lists of review articles, citation history of articles, and the gray literature. The information is provided as a narrative summary.
RESULTS
Of 11,222 potentially eligible articles retrieved, 148 were included for review following de-duplications and full-text review. Data were also obtained from national stroke clinical registry reports, Registry of Stroke Care Quality (RES-Q) and PRE-hospital Stroke Treatment Organization (PRESTO) repositories, and other national sources. Overall, we found evidence of the provision of intravenous thrombolysis services in 70 countries (63% high-income countries (HICs)) and endovascular thrombectomy services in 33 countries (68% HICs), corresponding to far less than half of the countries in the world. Recent data (from 2019 or later) were lacking for 35 of 67 countries with known year of data (52%). We found published data on 74 different stroke telemedicine programs (93% in HICs) and 14 active mobile stroke unit pre-hospital ambulance services (80% in HICs) around the world.
CONCLUSION
Despite remarkable advancements in reperfusion therapies for stroke, it is evident from available patient-level data that their availability remains unevenly distributed globally. Contemporary published data on availability of reperfusion services remain scarce, even in HICs, thereby making it difficult to reliably ascertain current gaps in the provision of this vital acute stroke treatment around the world.
Topics: Humans; Stroke; Ischemic Stroke; Thrombectomy; Ambulances; Reperfusion
PubMed: 37853529
DOI: 10.1177/17474930231210448 -
Molecular Therapy : the Journal of the... Mar 2022Blood-brain barrier (BBB) damage can be a result of central nervous system (CNS) diseases and may be a cause of CNS deterioration. However, there are still many unknowns...
Blood-brain barrier (BBB) damage can be a result of central nervous system (CNS) diseases and may be a cause of CNS deterioration. However, there are still many unknowns regarding effective and targeted therapies for maintaining BBB integrity during ischemia/reperfusion (I/R) injury. In this study, we demonstrate that the circular RNA of FoxO3 (circ-FoxO3) promotes autophagy via mTORC1 inhibition to attenuate BBB collapse under I/R. Upregulation of circ-FoxO3 and autophagic flux were detected in brain microvessel endothelial cells in patients with hemorrhagic transformation and in mice models with middle cerebral artery occlusion/reperfusion. In vivo and in vitro studies indicated that circ-FoxO3 alleviated BBB damage principally by autophagy activation. Mechanistically, we found that circ-FoxO3 inhibited mTORC1 activity mainly by sequestering mTOR and E2F1, thus promoting autophagy to clear cytotoxic aggregates for improving BBB integrity. These results demonstrate that circ-FoxO3 plays a novel role in protecting against BBB damage, and that circ-FoxO3 may be a promising therapeutic target for neurological disorders associated with BBB damage.
Topics: Animals; Autophagy; Blood-Brain Barrier; Brain Ischemia; Endothelial Cells; Forkhead Box Protein O3; Humans; Infarction, Middle Cerebral Artery; Mechanistic Target of Rapamycin Complex 1; Mice; RNA, Circular; Reperfusion; Reperfusion Injury
PubMed: 34763084
DOI: 10.1016/j.ymthe.2021.11.004 -
JAMA Sep 2021Mechanical thrombectomy using a stent retriever or contact aspiration is widely used for treatment of patients with acute ischemic stroke due to anterior circulation... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Thrombectomy With Combined Contact Aspiration and Stent Retriever vs Stent Retriever Alone on Revascularization in Patients With Acute Ischemic Stroke and Large Vessel Occlusion: The ASTER2 Randomized Clinical Trial.
IMPORTANCE
Mechanical thrombectomy using a stent retriever or contact aspiration is widely used for treatment of patients with acute ischemic stroke due to anterior circulation large vessel occlusion, but the additional benefit of combining contact aspiration with stent retriever is uncertain.
OBJECTIVE
To determine whether mechanical thrombectomy for treatment of anterior circulation large vessel occlusion stroke with initial contact aspiration and stent retriever combined results in better final angiographic outcome than with standard stent retriever alone.
DESIGN, SETTING, AND PARTICIPANTS
This trial was a multicenter randomized, open-label, blinded end point evaluation that enrolled 408 patients from October 16, 2017, to May 29, 2018, in 11 French comprehensive stroke centers, with a 12-month outcome follow-up. Patients with a large vessel occlusion in the anterior circulation were included up to 8 hours after symptom onset. The final date of follow-up was June, 19, 2019.
INTERVENTIONS
Patients were randomly assigned (1:1 allocation) to receive initial thrombectomy with contact aspiration and stent retriever combined (205) or stent retriever alone (203).
MAIN OUTCOMES AND MEASURES
The primary outcome was the rate of expanded Thrombolysis In Cerebral Infarction score of 2c or 3 (eTICI 2c/3; ie, scores indicate near-total and total reperfusion grades) at the end of the procedure.
RESULTS
Among the 408 patients who were randomized, 3 were excluded, and 405 (99.3%) patients (mean age, 73 years; 220 [54%] women and 185 [46%] men) were included in the primary analysis. The rate of eTICI 2c/3 at the end of the endovascular procedure was not significantly different between the 2 thrombectomy groups (64.5% [131 of 203 patients] for contact aspiration and stent retriever combined vs 57.9% [117 of 202 patients] for stent retriever alone; risk difference, 6.6% [95% CI, -3.0% to 16.2%]; adjusted odds ratio [OR], 1.33 [95% CI, 0.88 to 1.99]; P = .17). Of 14 prespecified secondary efficacy end points, 12 showed no significant difference. A higher rate of successful reperfusion was achieved in the contact aspiration combined with stent retriever group vs the stent retriever alone group (eTICI 2b50/2c/3, 86.2% vs 72.3%; adjusted OR, 2.54 [95% CI, 1.51 to 4.28]; P < .001) and of near-total or total reperfusion (eTICI 2c/3, 59.6% vs 49.5%; adjusted OR, 1.52 [95% CI, 1.02 to 2.27]; P = .04) after the assigned initial intervention alone.
CONCLUSIONS AND RELEVANCE
Among patients with acute ischemic stroke due to large vessel occlusion, an initial thrombectomy technique consisting of contact aspiration and stent retriever combined, compared with stent retriever alone, did not significantly improve the rate of near-total or total reperfusion (eTICI 2c/3) at the end of the endovascular procedure, although the trial may have been underpowered to detect smaller differences between groups.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03290885.
Topics: Aged; Arterial Occlusive Diseases; Combined Modality Therapy; Device Removal; Female; Humans; Ischemic Stroke; Male; Reperfusion; Stents; Thrombectomy; Treatment Outcome
PubMed: 34581737
DOI: 10.1001/jama.2021.13827