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Erythropoietin facilitates the return of spontaneous circulation and survival in victims of out-of-hospital cardiac arrest
Grmec S, Strnad M, Kupnik D, Sinkovic A, Gazmuri RJ
Slovenia

BACKGROUND: Erythropoietin activates potent protective mechanisms in non-hematopoietic tissues including the myocardium. In a rat model of ventricular fibrillation, erythropoietin preserved myocardial compliance enabling hemodynamically more effective CPR. OBJECTIVE: To investigate whether intravenous erythropoietin given within 2 min of physician-led CPR improves outcome from out-of-hospital cardiac arrest. METHODS: Erythropoietin (90,000 IU of beta-epoetin, n=24) was compared prospectively with 0.9% NaCl (concurrent controls=30) and retrospectively with a preceding group treated with similar protocol (matched controls=48). RESULTS: Compared with concurrent controls, the erythropoietin group had higher rates of ICU admission (92% vs 50%, p=0.004), return of spontaneous circulation (ROSC) (92% vs 53%, p=0.006), 24-h survival (83% vs 47%, p=0.008), and hospital survival (54% vs 20%, p=0.011). However, after adjusting for pretreatment covariates only ICU admission and ROSC remained statistically significant. Compared with matched controls, the erythropoietin group had higher rates of ICU admission (92% vs 65%, p=0.024) and 24-h survival (83% vs 52%, p=0.014) with statistically insignificant higher ROSC (92% vs 71%, p=0.060) and hospital survival (54% vs 31%, p=0.063). However, after adjusting for pretreatment covariates all four outcomes were statistically significant. End-tidal PCO(2) (an estimate of blood flow during chest compression) was higher in the erythropoietin group.

Effects of Erythropoietin during CPR

The P_ETCO₂ during chest compression was higher in the erythropoietin group than in either of the two control groups. Because a uniform ventilation protocol was used, changes in P_ETCO₂ levels were likely a manifestation of changes in forward blood flow, and consistent with the generation of higher forward blood flow in the erythropoietin group. Although ? as allude above ? the possibility of rescuer bias providing more effective chest compression can not be fully excluded, rescuers were trained to provide consistent chest compression. Moreover, the values of P_ETCO₂ in both control groups were representative of high quality chest compression. Concurrent measurement of chest compression depth and rate would have helped excluding this possibility.

Attributing the higher P_ETCO₂ levels to an erythropoietin effect on the myocardium would be in agreement with the hypothesis developed based on the rat experiments. In this hypothesis we propose that erythropoietin prevents loss of myocardial compliance during chest compression enabling hemodynamically more effective chest compression. Decreases in myocardial compliance have been described in humans as myocardial firmness during open chest resuscitation after failure of closed-chest resuscitation and found to compromise resuscitability. In various animal models, targeting ischemia and reperfusion injury by limiting sarcolemmal Na⁺ entry prevents reductions in myocardial compliance also enabling hemodynamically more effective chest compression. Such effect was linked in recent studies to preservation of mitochondrial function. Erythropoietin through non-genomic mechanisms can also protect mitochondrial function Further work is required to validate this hypothesis and to elucidate the specific mechanisms of action.

The presumably more favorable hemodynamic effects observed in the erythropoietin group were associated with greater ease for resuscitation. When compared with matched controls, the erythropoietin group was resuscitated 13.5 minutes earlier receiving fewer doses of epinephrine and less 0.9 % NaCl solution, and manifested milder metabolic acidosis upon hospital admission. When compared with concurrent controls, the erythropoietin group received less 0.9% NaCl and displayed a trend towards shorted CPR duration and fewer doses of epinephrine.

Accordingly, the various findings of this study were consistent. The improved resuscitation and survival outcomes associated with erythropoietin were preceded by an improved hemodynamic efficacy of chest compression - evidenced by a higher P_ETCO₂ - which, in turn, facilitated the return of spontaneous circulation in shorter time and with fewer resuscitation interventions. CONCLUSIONS: Erythropoietin given during CPR facilitates ROSC, ICU admission, 24-h survival, and hospital survival. This effect was consistent with myocardial protection leading to hemodynamically more effective CPR.

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