Management of postcardiac arrest myocardial dysfunction

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 98%

Bradycardia During Therapeutic Hypothermia Is Associated With Good Neurologic Outcome in Comatose Survivors of Out-of-Hospital Cardiac Arrest*

Stær-Jensen

Sunde

Olasveengen

et al. 2014

“…This syndrome is characterized by cardiovascular instability and neurological injury resulting in a survival rate of 10% for out of hospital cardiac arrest (3). Global ischemia-reperfusion (IR) injury of the myocardium during cardiac arrest resuscitation is a known contributor to post cardiac arrest myocardial dysfunction and a likely contributor to the failure to achieve ROSC (3, 4). Mild hypothermia attenuates IR injury in cellular and animal models of cardiac arrest (5–7) and is now used clinically to improve human survival and neurological outcomes (8, ).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Mitochondrial Fission Protein Dynamin-Related Protein 1 Improves Survival in a Murine Cardiac Arrest Model

Sharp

Beiser

Yao

et al. 2015

Objectives Survival following sudden cardiac arrest is poor despite advances in cardiopulmonary resuscitation (CPR) and the use of therapeutic hypothermia. Dynamin related protein 1 (Drp1), a regulator of mitochondrial fission, is an important determinant of reactive oxygen species generation, myocardial necrosis, and left ventricular function following ischemia/reperfusion injury, but its role in cardiac arrest is unknown. We hypothesized that Drp1 inhibition would improve survival, cardiac hemodynamics, and mitochondrial function in an in vivo model of cardiac arrest. Design Laboratory investigation. Setting University laboratory Interventions Anesthetized and ventilated adult female C57BL/6 wild-type mice underwent an 8-min KCl induced cardiac arrest followed by 90 seconds of CPR. Mice were then blindly randomized to a single intravenous injection of Mdivi-1 (0.24 mg/kg), a small molecule Drp1 inhibitor or vehicle (DMSO). Measurements and Main Results Following resuscitation from cardiac arrest, mitochondrial fission was evidenced by Drp1 translocation to the mitochondrial membrane and a decrease in mitochondrial size. Mitochondrial fission was associated with increased lactate and evidence of oxidative damage. Mdivi-1 administration during CPR inhibited Drp1 activation, preserved mitochondrial morphology, and decreased oxidative damage. Mdivi-1 also reduced the time to return of spontaneous circulation (ROSC) 116±4 vs. 143±7 sec (p<. 001) during CPR and enhanced myocardial performance post-ROSC. These improvements were associated with significant increases in survival (65% vs. 33%) and improved neurological scores up to 72 hours post cardiac arrest. Conclusions Post cardiac arrest inhibition of Drp1 improves time to ROSC and myocardial hemodynamics resulting in improved survival and neurological outcomes in a murine model of cardiac arrest. Pharmacological targeting of mitochondrial fission may be a promising therapy for cardiac arrest.

“…Many drugs have been tested to protect the myocardium from stunning and related injury, but with mixed clinical outcomes (5). Targeted temperature management using active cooling improves long-term neurologically-intact survival following CA (6–8) and has been proposed to aid cardiac recovery as well. In laboratory studies, cooling reduces cell death following myocardial ischemia (9) by activating Akt and Erk1/2, which are both members of the reperfusion injury salvage kinase pathway (10, 11).…”

Section: Introductionmentioning

confidence: 99%

Lipid Emulsion Rapidly Restores Contractility in Stunned Mouse Cardiomyocytes

Li¹,

Fettiplace²,

Chen³

et al. 2014

Objective Cooling following cardiac arrest can improve survival significantly. However, delays in achieving target temperature may decrease the overall benefits of cooling. Here we test whether lipid emulsion, a clinically approved drug reported to exert cardioprotection, can rescue heart contractility in the setting of delayed cooling in stunned mouse cardiomyocytes. Design Cell culture study Setting Academic research laboratory Subjects Cardiomyocytes isolated from 1–2-day old C57BL6 mice Interventions Cardiomyocytes were exposed to 30 minutes of ischemia followed by 90 minutes reperfusion and 10 minutes isoproterenol with nine interventions: 1) no additional treatment; 2) intra-ischemic cooling at 32°C initiated 10 min prior to reperfusion; 3) delayed cooling started 20 minutes after reperfusion; 4) lipid emulsion + delayed cooling; 5) lipid emulsion (0.25%) administered at reperfusion; 6) lipid emulsion + intra-ischemic cooling; 7) delayed lipid emulsion; 8) lipid emulsion + delayed cooling + Akt inhibitor (API-2, 10 μM) and 9) lipid emulsion + delayed cooling + Erk inhibitor (U0126, 10 μM). Inhibitors were given to cells 1 h prior to ischemia. Measurements and Main Results Contractility was recorded by real-time phase-contrast imaging and analyzed with pulse image velocimetry in MATLAB. Ischemia diminished cell contraction. The cardioprotective effect of cooling was diminished when delayed but was rescued by lipid emulsion. Further, lipid emulsion on its own improved recovery of the contractility to an equal extent as intra-ischemic cooling. However, co-treatment of lipid emulsion and intra-ischemic cooling did not further improve the recovery compared to either treatment alone. Moreover, Akt and Erk inhibitors blocked lipid emulsion-induced protection. Conclusion Lipid emulsion improved contractility and rescued contractility in the context of delayed cooling. This protective effect required Akt and Erk signaling. Lipid emulsion might serve as a treatment or adjunct to cooling in ameliorating myocardial ischemia/reperfusion injury.