ABSTRACT
Administration of 17ß-estradiol has been shown to exert myocardial protective effects in hemorrhagic shock. We hypothesized that similar protective effects could help improve resuscitation from cardiac arrest. Three series of 18, 40, and 12 rats each, underwent ventricular fibrillation for 8 minutes followed by 8 minutes of chest compression and delivery of electrical shocks. In series-1, rats were randomized 1:1 to receive a bolus dose of 17ß-estradiol (1 mg/kg) or 0.9% NaCl before chest compression; in series-2, rats were randomized 1:1:1:1 to receive a continuous infusion of 0.9% NaCl or a 17ß-estradiol solution designed to attain a plasma level of 10(0), 10(2), or 10(4) nM during chest compression; and in series-3, rats were randomized 1:1 to receive a continuous infusion of 17ß-estradiol to attain a plasma level of 10(2) nM or 0.9% NaCl during chest compression, providing inotropic support during the post-resuscitation interval using dobutamine infusion. 17ß-estradiol failed to facilitate resuscitation in each of the 3 series. In series-1 and series-2, resuscitability and short-term survival was reduced in 17ß-estradiol groups attaining statistical significance in series-2 when the three 17ß-estradiol groups were combined (p = 0.035). In series-3, all rats were resuscitated and survived for 180 minutes aided by dobutamine which partially reversed post-resuscitation myocardial dysfunction but without additional benefits on myocardial function in the 17ß-estradiol group. The present study failed to support a beneficial effect of 17ß-estradiol for resuscitation from cardiac arrest and raised the possibility of detrimental cardiac effects compromising initial resuscitability and subsequent survival in a male rat model of ventricular fibrillation and closed chest resuscitation.
ABSTRACT
OBJECTIVE: We previously reported beneficial myocardial effects during chest compression after administration of high-dose erythropoietin. We hypothesized that erythropoietin also elicits post-resuscitation myocardial benefits partly linked to protection of mitochondrial bioenergetic function. METHODS: Two series of 10 rats each underwent ventricular fibrillation for 10 minutes (series-1) and 8 minutes (series-2) and were randomized to erythropoietin (5,000 U/kg) or 0.9% NaCl before chest compression. Dobutamine was infused post-resuscitation in series-2 harvesting their hearts at 120 minutes. RESULTS: During chest compression, a statistically insignificant trend showing progressively higher coronary perfusion pressure in the erythropoietin group was observed consistent with previously reported preservation of left ventricular distensibility. Post-resuscitation, in the absence of dobutamine (series-1) erythropoietin failed to improve post-resuscitation myocardial function or survival; in the presence of dobutamine (series-2) all rats survived and those treated with erythropoietin reversed post-resuscitation myocardial dysfunction yielding higher cardiac work index (CWI; 39±3 vs 25±10 mmHg·ml/kg, p<0.01) and higher mean aortic pressure (MAP; 99±4 vs 83±16, p<0.01) at 120 minutes post-resuscitation. Better myocardial function was associated with lesser increases in plasma cytochrome c, attaining levels which inversely correlated with CWI (p=0.026) and MAP (p=0.025). Hearts from erythropoietin-treated rats had higher phosphorylation levels of cytosolic Akt and higher phosphorylation levels of cytosolic and mitochondrial PKCε and maintained cytochrome c oxidase activity. CONCLUSION: Erythropoietin activated mitochondrial protective mechanisms that helped maintain bioenergetic function enabling reversal of post-resuscitation myocardial dysfunction in the presence of dobutamine.
