Dataset Information

Toll-like receptor 4 deficiency or inhibition does not modulate survival and neurofunctional outcome in a murine model of cardiac arrest and resuscitation.

ABSTRACT:

Background

Patients experiencing cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) often die or suffer from severe neurological impairment. Post resuscitation syndrome is characterized by a systemic inflammatory response. Toll-like receptor 4 (TLR4) is a major mediator of inflammation and TLR4 has been implicated in the pathogenesis of post-resuscitation encephalopathy. The aim of this study was to evaluate whether TLR4 deficiency or inhibition can modulate survival and neurofunctional outcome after CA/CPR.

Methods

Following intubation and central venous cannulation, CA was induced in wild type (C57Bl/6J, n = 38), TLR4 deficient (TLR4-/-, n = 37) and TLR4 antibody treated mice (5mg/kg MTS510, n = 15) by high potassium. After 10min, CPR was performed using a modified sewing machine until return of spontaneous circulation (ROSC). Cytokines and cerebral TNFalpha levels were measured 8h after CA/CPR. Survival, early neurological recovery, locomotion, spatial learning and memory were assessed over a period of 28 days.

Results

Following CA/CPR, all mice exhibited ROSC and 31.5% of wild type mice survived until day 28. Compared to wild type mice, neither TLR4-/- nor MTS510 treated wild type mice had statistically significant altered survival following CA/CPR (51.3 and 26.7%, P = 0.104 and P = 0.423 vs. WT, respectively). Antibody-treated but not TLR4-/- mice had higher IL-1? and IL-6 levels and TLR4-/- mice had higher IL-10 and cerebral TNFalpha levels. No differences existed between mice of all groups in early neurological recovery, locomotion, spatial learning ability or remembrance.

Conclusion

Therapeutic strategies targeting TLR4 may not be suitable for the reduction of mortality or neurofunctional impairment after CA/CPR.

SUBMITTER: Bergt S

PROVIDER: S-EPMC6675321 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Toll-like receptor 4 deficiency or inhibition does not modulate survival and neurofunctional outcome in a murine model of cardiac arrest and resuscitation.

Bergt Stefan S Grub Andrea A Mueller Melanie M Bajorat Rika R Barilar Ivan I Vollmar Brigitte B Roesner Jan Patrick JP Wagner Nana-Maria NM

PloS one 20190801 8

<h4>Background</h4>Patients experiencing cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) often die or suffer from severe neurological impairment. Post resuscitation syndrome is characterized by a systemic inflammatory response. Toll-like receptor 4 (TLR4) is a major mediator of inflammation and TLR4 has been implicated in the pathogenesis of post-resuscitation encephalopathy. The aim of this study was to evaluate whether TLR4 deficiency or inhibition can modulate survival and neurofu ...[more]

PMID: 31369614

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Project description:BackgroundCardiac 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.MethodsFemale 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.ResultsTLR2 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-1β levels and increased corticosterone plasma concentrations (both P < 0.05).ConclusionDeficiency 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.

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:OBJECTIVE:To describe neurobehavioral outcomes and investigate factors associated with survival and survival with good neurobehavioral outcome 1 year after in-hospital cardiac arrest for children who received extracorporeal cardiopulmonary resuscitation. DESIGN:Secondary analysis of the Therapeutic Hypothermia after Pediatric Cardiac Arrest In-Hospital trial. SETTING:Thirty-seven PICUs in the United States, Canada, and the United Kingdom. PATIENTS:Children (n = 147) resuscitated with extracorporeal cardiopulmonary resuscitation following in-hospital cardiac arrest. INTERVENTIONS:Neurobehavioral status was assessed using the Vineland Adaptive Behavior Scales, Second Edition, at prearrest baseline and 12 months postarrest. Norms for Vineland Adaptive Behavior Scales, Second Edition, are 100 (mean) ± 15 (SD). Higher scores indicate better functioning. Outcomes included 12-month survival, 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. MEASUREMENTS AND MAIN RESULTS:Of 147 children receiving extracorporeal cardiopulmonary resuscitation, 125 (85.0%) had a preexisting cardiac condition, 75 (51.0%) were postcardiac surgery, and 84 (57.1%) were less than 1 year old. Duration of chest compressions was greater than 30 minutes for 114 (77.5%). Sixty-one (41.5%) survived to 12 months, 32 (22.1%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points from baseline, and 39 (30.5%) survived to 12 months with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. On multivariable analyses, open-chest cardiac massage was independently associated with greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and greater 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. Higher minimum postarrest lactate and preexisting gastrointestinal conditions were independently associated with lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, decreased by less than or equal to 15 points and lower 12-month survival with Vineland Adaptive Behavior Scales, Second Edition, greater than or equal to 70. CONCLUSIONS:About one third of children survived with good neurobehavioral outcome 1 year after receiving extracorporeal cardiopulmonary resuscitation for in-hospital arrest. Open-chest cardiac massage and minimum postarrest lactate were associated with survival with good neurobehavioral outcome at 1 year.

Project description:The modern treatment of cardiac arrest is an increasingly complex medical procedure with a rapidly changing array of therapeutic approaches designed to restore life to victims of sudden death. The 2 primary goals of providing artificial circulation and defibrillation to halt ventricular fibrillation remain of paramount importance for saving lives. They have undergone significant improvements in technology and dissemination into the community subsequent to their establishment 60 years ago. The evolution of artificial circulation includes efforts to optimize manual cardiopulmonary resuscitation, external mechanical cardiopulmonary resuscitation devices designed to augment circulation, and may soon advance further into the rapid deployment of specially designed internal emergency cardiopulmonary bypass devices. The development of defibrillation technologies has progressed from bulky internal defibrillators paddles applied directly to the heart, to manually controlled external defibrillators, to automatic external defibrillators that can now be obtained over-the-counter for widespread use in the community or home. But the modern treatment of cardiac arrest now involves more than merely providing circulation and defibrillation. As suggested by a 3-phase model of treatment, newer approaches targeting patients who have had a more prolonged cardiac arrest include treatment of the metabolic phase of cardiac arrest with therapeutic hypothermia, agents to treat or prevent reperfusion injury, new strategies specifically focused on pulseless electric activity, which is the presenting rhythm in at least one third of cardiac arrests, and aggressive post resuscitation care. There are discoveries at the cellular and molecular level about ischemia and reperfusion pathobiology that may be translated into future new therapies. On the near horizon is the combination of advanced cardiopulmonary bypass plus a cocktail of multiple agents targeted at restoration of normal metabolism and prevention of reperfusion injury, as this holds the promise of restoring life to many patients for whom our current therapies fail.

Project description:BackgroundMaternal in-hospital cardiac arrest is a rare event with the potential for resuscitation treatment delays because of the difficulty accessing hospital obstetrical units and limited simulation training or resuscitation experience of obstetrical staff. However, it is unclear whether survival rates and processes of care differ between women with a maternal in-hospital cardiac arrest and those with a nonmaternal in-hospital cardiac arrest.ObjectiveWe aimed determine whether to there are delays in process measures and differences in survival outcomes between pregnant and nonpregnant women who have in-hospital cardiac arrest.Study designUsing data from 2000 to 2019 in the Get With The Guidelines-Resuscitation registry, we compared resuscitation outcomes between women aged 18 to 50 years with a maternal or nonmaternal in-hospital cardiac arrest. Using a nonparsimonious propensity score, we matched patients with a maternal in-hospital cardiac arrest to as many as 10 women with a nonmaternal in-hospital cardiac arrest. We constructed conditional logistic regression models to compare survival outcomes (survival to discharge, favorable neurologic survival [discharge cerebral performance score of 1], and return of spontaneous circulation) and processes of care (delayed defibrillation [>2 minutes] and administration of epinephrine [>5 minutes]) between women with a maternal in-hospital cardiac arrest vs those with a nonmaternal in-hospital cardiac arrest.ResultsOverall, 421 women with a maternal in-hospital cardiac arrest were matched by propensity score to 2316 women with a nonmaternal in-hospital cardiac arrest. The mean age among propensity score-matched women with a maternal in-hospital cardiac arrest was 31.4 (standard deviation, 6.5) years, where 33.7% were of Black race and 86.9% had an initial nonshockable cardiac arrest rhythm. Unadjusted survival rates were higher in women with a maternal in-hospital cardiac arrest than in women with a nonmaternal in-hospital cardiac arrest: survival to discharge of 45.1% vs 26.5%, survival with cerebral performance category 1 status of 36.1% vs 17.7%, and return of spontaneous circulation of 75.8% vs 70.6%. After adjustment, there was no difference in the likelihood of survival to discharge (odds ratio, 1.19; 95% confidence interval, 0.82-1.73) or return of spontaneous circulation (odds ratio, 0.94; 95% confidence interval, 0.65-1.35) between women with a maternal in-hospital cardiac arrest and those with a nonmaternal in-hospital cardiac arrest. However, women with a maternal in-hospital cardiac arrest were more likely to have favorable neurologic survival (odds ratio, 1.57; 95% confidence interval, 1.06-2.33). Compared with women with a nonmaternal in-hospital cardiac arrest, women with a maternal in-hospital cardiac arrest had similar rates of delayed defibrillation (42.5% vs 34.4%; odds ratio, 1.14 [95% confidence interval, 0.41-3.18]; P=.31) and delayed administration of epinephrine (13.8% vs 10.6%; odds ratio, 0.96 [95% confidence interval, 0.50-1.86]; P=.09).ConclusionAlthough concerns have been raised about resuscitation outcomes in women with a maternal in-hospital cardiac arrest, the rates of survival and resuscitation processes of care were not worse in women with a maternal in-hospital cardiac arrest.

Dataset Information

Toll-like receptor 4 deficiency or inhibition does not modulate survival and neurofunctional outcome in a murine model of cardiac arrest and resuscitation.

Background

Methods

Results

Conclusion

Publications

Toll-like receptor 4 deficiency or inhibition does not modulate survival and neurofunctional outcome in a murine model of cardiac arrest and resuscitation.

Similar Datasets

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