Dataset Information

Impact of Toll-like receptor 2 deficiency on survival and neurological function after cardiac arrest: a murine model of cardiopulmonary resuscitation.

ABSTRACT:

Background

Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with poor survival rate and neurofunctional outcome. Toll-like receptor 2 (TLR2) plays an important role in conditions of sterile inflammation such as reperfusion injury. Recent data demonstrated beneficial effects of the administration of TLR2-blocking antibodies in ischemia/reperfusion injury. In this study we investigated the role of TLR2 for survival and neurofunctional outcome after CA/CPR in mice.

Methods

Female TLR2-deficient (TLR2(-/-)) and wild type (WT) mice were subjected to CA for eight min induced by intravenous injection of potassium chloride and CPR by external chest compression. Upon the beginning of CPR, n = 15 WT mice received 5 µg/g T2.5 TLR2 inhibiting antibody intravenously while n = 30 TLR2(-/-) and n = 31 WT controls were subjected to injection of normal saline. Survival and neurological outcome were evaluated during a 28-day follow up period. Basic neurological function, balance, coordination and overall motor function as well as spatial learning and memory were investigated, respectively. In a separate set of experiments, six mice per group were analysed for cytokine and corticosterone serum levels eight hours after CA/CPR.

Results

TLR2 deficiency and treatment with a TLR2 blocking antibody were associated with increased survival (77% and 80% vs. 51% of WT control; both P < 0.05). Neurofunctional performance was less compromised in TLR2(-/-) and antibody treated mice. Compared to WT and antibody treated mice, TLR2(-/-) mice exhibited reduced IL-6 (both P < 0.05) but not IL-1? levels and increased corticosterone plasma concentrations (both P < 0.05).

Conclusion

Deficiency or functional blockade of TLR2 is associated with increased survival and improved neurofunctional outcome in a mouse model of CA/CPR. Thus, TLR2 inhibition could provide a novel therapeutic approach for reducing mortality and morbidity after cardiac arrest and cardiopulmonary resuscitation.

SUBMITTER: Bergt S

PROVIDER: S-EPMC3774715 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Impact of Toll-like receptor 2 deficiency on survival and neurological function after cardiac arrest: a murine model of cardiopulmonary resuscitation.

Bergt Stefan S Güter Anne A Grub Andrea A Wagner Nana-Maria NM Beltschany Claudia C Langner Sönke S Wree Andreas A Hildebrandt Steve S Nöldge-Schomburg Gabriele G Vollmar Brigitte B Roesner Jan P JP

PloS one 20130916 9

<h4>Background</h4>Cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) is associated with poor survival rate and neurofunctional outcome. Toll-like receptor 2 (TLR2) plays an important role in conditions of sterile inflammation such as reperfusion injury. Recent data demonstrated beneficial effects of the administration of TLR2-blocking antibodies in ischemia/reperfusion injury. In this study we investigated the role of TLR2 for survival and neurofunctional outcome after CA/CPR i ...[more]

PMID: 24066159

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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:BackgroundDespite the benefits of extracorporeal cardiopulmonary resuscitation (ECPR) in cohorts of selected patients with cardiac arrest (CA), extracorporeal membrane oxygenation (ECMO) includes an artificial oxygenation membrane and circuits that contact the circulating blood and induce excessive oxidative stress and inflammatory responses, resulting in coagulopathy and endothelial cell damage. There is currently no pharmacological treatment that has been proven to improve outcomes after CA/ECPR. We aimed to test the hypothesis that administration of hydrogen gas (H2) combined with ECPR could improve outcomes after CA/ECPR in rats.MethodsRats were subjected to 20 min of asphyxial CA and were resuscitated by ECPR. Mechanical ventilation (MV) was initiated at the beginning of ECPR. Animals were randomly assigned to the placebo or H2 gas treatment groups. The supplement gas was administered with O2 through the ECMO membrane and MV. Survival time, electroencephalography (EEG), brain functional status, and brain tissue oxygenation were measured. Changes in the plasma levels of syndecan-1 (a marker of endothelial damage), multiple cytokines, chemokines, and metabolites were also evaluated.ResultsThe survival rate at 4 h was 77.8% (7 out of 9) in the H2 group and 22.2% (2 out of 9) in the placebo group. The Kaplan-Meier analysis showed that H2 significantly improved the 4 h-survival endpoint (log-rank P = 0.025 vs. placebo). All animals treated with H2 regained EEG activity, whereas no recovery was observed in animals treated with placebo. H2 therapy markedly improved intra-resuscitation brain tissue oxygenation and prevented an increase in central venous pressure after ECPR. H2 attenuated an increase in syndecan-1 levels and enhanced an increase in interleukin-10, vascular endothelial growth factor, and leptin levels after ECPR. Metabolomics analysis identified significant changes at 2 h after CA/ECPR between the two groups, particularly in D-glutamine and D-glutamate metabolism.ConclusionsH2 therapy improved mortality in highly lethal CA rats rescued by ECPR and helped recover brain electrical activity. The underlying mechanism might be linked to protective effects against endothelial damage. Further studies are warranted to elucidate the mechanisms responsible for the beneficial effects of H2 on ischemia-reperfusion injury in critically ill patients who require ECMO support.

Project description:BackgroundDispatcher-assisted cardiopulmonary resuscitation (DA-CPR) increases neurologically intact survival in out-of-hospital cardiac arrest (OHCA) according to several studies. This systematic review summarizes neurologically intact survival outcomes of DA-CPR in comparison with bystander-initiated CPR and no bystander CPR in OHCA.MethodsThe systematic review was conducted according to the PRISMA guidelines. All studies including adult and/or pediatric OHCAs that compared DA-CPR with bystander-initiated CPR or no bystander CPR were included. Primary outcome was neurologically intact survival at discharge, one-month or longer. Studies were searched for in PubMed (MEDLINE), EMBASE, and the Cochrane Library databases. The risk of bias was evaluated using the Newcastle-Ottawa Scale.ResultsThe search string generated 4742 citations of which 33 studies were eligible for inclusion. Due to overlapping study populations, the review included 14 studies. All studies were observational. The study populations were heterogeneous and included adult, pediatric and mixed populations. Some studies reported only witnessed cardiac arrests, arrests of cardiac ethiology, and/or shockable rhythm. The individual studies scored between six and nine on the Newcastle-Ottawa Scale of risk of bias. The median neurologically intact survival at hospital discharge with DA-CPR was 7.0% (interquartile range (IQR): 5.1-10.8%), with bystander-initiated CPR 7.5% (IQR: 6.6-10.2%), and with no bystander CPR 4.4% (IQR: 2.0-9.0%) (four studies). At one-month neurologically intact survival with DA-CPR was 3.1% (IQR: 1.6-3.4%), with bystander-initiated CPR 5.7% (IQR: 5.0-6.0%), and with no bystander CPR 2.5% (IQR: 2.1-2.6%) (three studies).ConclusionBoth DA-CPR and bystander-initiated CPR increase neurologically intact survival compared with no bystander CPR. However, DA-CPR demonstrates inferior outcomes compared with bystander-initiated CPR. Early CPR is crucial, thus in cases where bystanders have not initiated CPR, DA-CPR provides an opportunity to improve neurologically intact survival following OHCA. Variability in OHCA outcomes across studies and multiple confounding factors were identified.

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.

Dataset Information

Impact of Toll-like receptor 2 deficiency on survival and neurological function after cardiac arrest: a murine model of cardiopulmonary resuscitation.

Background

Methods

Results

Conclusion

Publications

Impact of Toll-like receptor 2 deficiency on survival and neurological function after cardiac arrest: a murine model of cardiopulmonary resuscitation.

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