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Single dose of 17?-estradiol provides transient neuroprotection in female juvenile mice after cardiac-arrest and cardiopulmonary resuscitation.

ABSTRACT: Each year there are approximately 7000 out of hospital cardiac arrests in the pediatric population, with 30% resuscitation rate and a 6-10% rate of survival to hospital discharge. Survivors of cardiac arrest exhibit learning and memory deficits that are devastating during the school years. Delayed neuronal cell death occurs in the hippocampus following cardiac arrest and likely contributes to memory impairments. Circulating endogenous estrogen in young adult females has been shown to provide protection against ischemic cell death, as does chronic exogenous administration of 17?-estradiol (E2). Chronic estrogen benefit can have undesirable feminizing effects, particularly in pre-adolescents. Here, we tested if a single-dose of E2 is neuroprotective in our pediatric cardiac arrest mouse model performed in juvenile mice. We subjected P21P25 C57Blk6 male and female mice to 8?min of cardiac arrest followed by cardiopulmonary resuscitation (CA/CPR). This developmental stage preceded the hormonal onset and serum estradiol and testosterone levels were not different in males and females. A single dose of E2 (100?g/kg) or vehicle was administered 30?min after resuscitation. Neuronal cell death measured 3 days after CA/CPR showed reduced hippocampal cell death in E2-treated females, but not males. Benefit of E2 in females was blocked by the P38 MAPK inhibitor, SB203580. Hippocampal-dependent memory function was equally impaired in E2-and vehicle-treated females measured in the contextual fear conditioning task at 7 days. Our findings demonstrate female-specific transient neuroprotection with E2 that does not provide sustained functional benefit.

SUBMITTER: Quillinan N

PROVIDER: S-EPMC7841936 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Single dose of 17β-estradiol provides transient neuroprotection in female juvenile mice after cardiac-arrest and cardiopulmonary resuscitation.

Quillinan N N Dingman A L AL Deng G G Tatum S S Orfila J E JE Clevenger A C AC Klawitter J J Traystman R J RJ Herson P S PS

Neurochemistry international 20181122

Each year there are approximately 7000 out of hospital cardiac arrests in the pediatric population, with 30% resuscitation rate and a 6-10% rate of survival to hospital discharge. Survivors of cardiac arrest exhibit learning and memory deficits that are devastating during the school years. Delayed neuronal cell death occurs in the hippocampus following cardiac arrest and likely contributes to memory impairments. Circulating endogenous estrogen in young adult females has been shown to provide pro ...[more]

PMID: 30471325

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Project description:To investigate the effects of the combination of extracorporeal cardiopulmonary resuscitation and thrombolytic therapy on the recovery of vital organ function after prolonged cardiac arrest.Laboratory investigation.University laboratory.Pigs.Animals underwent 30-minute untreated ventricular fibrillation cardiac arrest followed by extracorporeal cardiopulmonary resuscitation for 6 hours. Animals were allocated into two experimental groups: t-extracorporeal cardiopulmonary resuscitation (t-ECPR) group, which received streptokinase 1 million units, and control extracorporeal cardiopulmonary resuscitation (c-ECPR), which did not receive streptokinase. In both groups, the resuscitation protocol included the following physiologic targets: mean arterial pressure greater than 70 mm Hg, cerebral perfusion pressure greater than 50 mm Hg, PaO2 150 ± 50 torr (20 ± 7 kPa), PaCO2 40 ± 5 torr (5 ± 1 kPa), and core temperature 33°C ± 1°C. Defibrillation was attempted after 30 minutes of extracorporeal cardiopulmonary resuscitation.A cardiac resuscitability score was assessed on the basis of success of defibrillation, return of spontaneous heart beat, weanability from extracorporeal cardiopulmonary resuscitation, and left ventricular systolic function after weaning. The addition of thrombolytic to extracorporeal cardiopulmonary resuscitation significantly improved cardiac resuscitability (3.7 ± 1.6 in t-ECPR vs 1.0 ± 1.5 in c-ECPR). Arterial lactate clearance was higher in t-ECPR than in c-ECPR (40% ± 15% vs 18% ± 21%). At the end of the experiment, the intracranial pressure was significantly higher in c-ECPR than in t-ECPR. Recovery of brain electrical activity, as assessed by quantitative analysis of electroencephalogram signal, and ischemic neuronal injury on histopathologic examination did not differ between groups. Animals in t-ECPR group did not have increased bleeding complications, including intracerebral hemorrhages.In a porcine model of prolonged cardiac arrest, t-ECPR improved cardiac resuscitability and reduced brain edema, without increasing bleeding complications. However, early electroencephalogram recovery and ischemic neuronal injury were not improved.

Project description:BackgroundVeno-arterial extracorporeal membrane oxygenation has increasingly emerged as a feasible treatment to mitigate the progressive multiorgan dysfunction that occurs during cardiac arrest, in support of further resuscitation efforts.ObjectivesBecause the recent systematic review commissioned in 2018 by the International Liaison Committee on Resuscitation Advanced Life Support task did not include studies without a control group, our objective was to conduct a review incorporating these studies to increase available evidence supporting the use of extracorporeal cardiopulmonary resuscitation (ECPR) for cardiac arrest patients, while waiting for high-quality evidence from randomized controlled trials (RCTs).MethodsMEDLINE, Embase, and Science Citation Index (Web of Science) were searched for eligible studies from database inception to July 20, 2020. The population of interest was adult patients who had suffered cardiac arrest in any setting. We included all cohort studies with 1 exposure/1 group and descriptive studies (ie, case series studies). We excluded RCTs, non-RCTs, and observational analytic studies with a control group. Outcomes included short-term survival and favorable neurological outcome. Short-term outcomes (ie, hospital discharge, 30 days, and 1 month) were combined into a single category.ResultsOur searches of databases and other sources yielded a total of 4302 citations. Sixty-two eligible studies were included (including a combined total of 3638 participants). Six studies were of in-hospital cardiac arrest, 34 studies were of out-of-hospital cardiac arrest, and 22 studies included both in-hospital and out-of-hospital cardiac arrest. Seven hundred and sixty-eight patients of 3352 (23%) had short-term survival; whereas, 602 of 3366 (18%) survived with favorable neurological outcome, defined as a cerebral performance category score of 1 or 2.ConclusionsCurrent clinical evidence is mostly drawn from observational studies, with their potential for confounding selection bias. Although studies without controls cannot supplant case-control or cohort studies, several ECPR studies without a control group show successful resuscitation with impressive results that may provide valuable information to inform a comparison.

Project description:BACKGROUND:The prognosis in refractory out-of-hospital cardiac arrest (OHCA) with ongoing cardiopulmonary resuscitation (CPR) at hospital arrival is often considered dismal. The use of extracorporeal cardiopulmonary resuscitation (eCPR) for perfusion enhancement during resuscitation has shown variable results. We aimed to investigate outcome in refractory OHCA patients managed conservatively without use of eCPR. METHODS:We included consecutive OHCA patients with refractory arrest or prehospital return of spontaneous circulation (ROSC) in the Copenhagen area in 2002-2011. RESULTS:A total of 3992 OHCA patients with resuscitation attempts were included; in 2599, treatment was terminated prehospital, and 1393 (35%) were brought to the hospital either with ROSC (n?=?1285, 92%) or with refractory OHCA (n?=?108, 8%). Of patients brought in with refractory OHCA, 56 (52%) achieved ROSC in the emergency department. There were no differences between patients with refractory OHCA or prehospital ROSC with regard to age, sex, comorbidities, or etiology of OHCA. Time to emergency medical services (EMS) arrival was similar, whereas time to ROSC (when ROSC was achieved) was longer in refractory OHCA patients (EMS, 6 (5-9] vs. 7 [5-10] min, p?=?0.8; ROSC, 15 [9-22] vs. 27 [20-41] min, p?<?0.001). Independent factors associated with transport with refractory OHCA instead of prehospital termination of therapy were OHCA in public (OR, 3.6 [95% CI, 2.2-5.8]; p?<?0.001), witnessed OHCA (OR, 3.7 [2.0-7.1]; p?<?0.001), shockable rhythm (OR, 3.0 [1.9-4.7]; p?<?0.001), younger age (OR, 1.2 [1.1-1.2]; p?<?0.001), and later calendar year (OR, 1.4 [1.2-1.6]; p?<?0.001). Thirty-day survival was 20% in patients with refractory OHCA compared with 42% in patients with prehospital ROSC (p?<?0.001). Four of 28 refractory OHCA patients with duration of resuscitation >?60 min achieved ROSC. No difference in favorable neurological outcome in patients surviving to discharge was found (prehospital ROSC 84% vs. refractory OHCA 86%; p?=?0.7). CONCLUSIONS:Survival after refractory OHCA with ongoing CPR at hospital arrival was significantly lower than among patients with prehospital ROSC. Despite a lower survival, the majority of survivors with both refractory OHCA and prehospital ROSC were discharged with a similar degree of favorable neurological outcome, indicating that continued efforts in spite of refractory OHCA are not in vain and may still lead to favorable outcome even without eCPR.

Project description:Prolonged cardiac arrest (CA) causes microvascular thrombosis which is a potential barrier to organ reperfusion during extracorporeal cardiopulmonary resuscitation (ECPR). The aim of this study was to test the hypothesis that early intra-arrest anticoagulation during cardiopulmonary resuscitation (CPR) and thrombolytic therapy during ECPR improve recovery of brain and heart function in a porcine model of prolonged out-of-hospital CA.DesignRandomized interventional trial.SettingUniversity laboratory.SubjectsSwine.InterventionsIn a blinded study, 48 swine were subjected to 8 minutes of ventricular fibrillation CA followed by 30 minutes of goal-directed CPR and 8 hours of ECPR. Animals were randomized into four groups (n = 12) and given either placebo (P) or argatroban (ARG; 350 mg/kg) at minute 12 of CA and either placebo (P) or streptokinase (STK, 1.5 MU) at the onset of ECPR.Measurements and main resultsPrimary outcomes included recovery of cardiac function measured by cardiac resuscitability score (CRS: range 0-6) and recovery of brain function measured by the recovery of somatosensory-evoked potential (SSEP) cortical response amplitude. There were no significant differences in recovery of cardiac function as measured by CRS between groups (p = 0.16): P + P 2.3 (1.0); ARG + P = 3.4 (2.1); P + STK = 1.6 (2.0); ARG + STK = 2.9 (2.1). There were no significant differences in the maximum recovery of SSEP cortical response relative to baseline between groups (p = 0.73): P + P = 23% (13%); ARG + P = 20% (13%); P + STK = 25% (14%); ARG + STK = 26% (13%). Histologic analysis demonstrated reduced myocardial necrosis and neurodegeneration in the ARG + STK group relative to the P + P group.ConclusionsIn this swine model of prolonged CA treated with ECPR, early intra-arrest anticoagulation during goal-directed CPR and thrombolytic therapy during ECPR did not improve initial recovery of heart and brain function but did reduce histologic evidence of ischemic injury. The impact of this therapeutic strategy on the long-term recovery of cardiovascular and neurological function requires further investigation.

Dataset Information

Single dose of 17?-estradiol provides transient neuroprotection in female juvenile mice after cardiac-arrest and cardiopulmonary resuscitation.

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Single dose of 17β-estradiol provides transient neuroprotection in female juvenile mice after cardiac-arrest and cardiopulmonary resuscitation.

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