Hemodynamic-Directed Cardiopulmonary Resuscitation Improves Neurologic Outcomes and Mitochondrial Function in the Heart and Brain

Abstract

Objectives: Less than half of the thousands of children who suffer in-hospital cardiac arrests annually survive, and neurologic injury is common among survivors. Hemodynamic-directed cardiopulmonary resuscitation improves short-term survival, but its impact on longer term survival and mitochondrial respiration-a potential neurotherapeutic target-remains unknown. The primary objectives of this study were to compare rates of 24-hour survival with favorable neurologic outcome after cardiac arrest treated with hemodynamic-directed cardiopulmonary resuscitation versus standard depth-guided cardiopulmonary resuscitation and to compare brain and heart mitochondrial respiration between groups 24 hours after resuscitation.

Design: Randomized preclinical large animal trial.

Setting: A large animal resuscitation laboratory at a large academic children's hospital.

Subjects: Twenty-eight 4-week-old female piglets (8-11 kg).

Interventions: Twenty-two swine underwent 7 minutes of asphyxia followed by ventricular fibrillation and randomized treatment with either hemodynamic-directed cardiopulmonary resuscitation (n = 10; compression depth titrated to aortic systolic pressure of 90 mm Hg, vasopressors titrated to coronary perfusion pressure ≥ 20 mm Hg) or depth-guided cardiopulmonary resuscitation (n = 12; depth 1/3 chest diameter, epinephrine every 4 min). Six animals (sham group) underwent anesthesia and instrumentation without cardiac arrest. The primary outcomes were favorable neurologic outcome (swine Cerebral Performance Category ≤ 2) and mitochondrial maximal oxidative phosphorylation utilizing substrate for complex I and complex II (OXPHOSCI+CII) in the cerebral cortex and hippocampus.

Measurements and main results: Favorable neurologic outcome was more likely with hemodynamic-directed cardiopulmonary resuscitation (7/10) than depth-guided cardiopulmonary resuscitation (1/12; p = 0.006). Hemodynamic-directed cardiopulmonary resuscitation resulted in higher intra-arrest coronary perfusion pressure, aortic pressures, and brain tissue oxygenation. Hemodynamic-directed cardiopulmonary resuscitation resulted in higher OXPHOSCI+CII (pmol oxygen/s × mg/citrate synthase) in the cortex (6.00 ± 0.28 vs 3.88 ± 0.43; p < 0.05) and hippocampus (6.26 ± 0.67 vs 3.55 ± 0.65; p < 0.05) and higher complex I respiration (pmol oxygen/s × mg) in the right (20.62 ± 1.06 vs 15.88 ± 0.81; p < 0.05) and left ventricles (20.14 ± 1.40 vs 14.17 ± 1.53; p < 0.05).

Conclusions: In a model of asphyxia-associated pediatric cardiac arrest, hemodynamic-directed cardiopulmonary resuscitation increases rates of 24-hour survival with favorable neurologic outcome, intra-arrest hemodynamics, and cerebral and myocardial mitochondrial respiration.

Figure 1.. Coronary Perfusion Pressure during Cardiopulmonary Resuscitation.

Coronary perfusion pressure during ten minutes of cardiopulmonary resuscitation in depth-guided cardiopulmonary resuscitation (DG-CPR; dashed gray line) vs. hemodynamic-guided cardiopulmonary resuscitation (HD-CPR; solid black line). Error bars represent SEM. Coronary perfusion pressures differed between groups using generalized estimating equation regression model (p < 0.001).

Figure 2.. Myocardial Mitochondrial Respiration.

Comparisons of measures of mitochondrial respiration in the right and left ventricular myocardium 24 hours after return of spontaneous circulation (treatment groups) or 24 hours post-anesthesia (sham). (a) Right and (d) left ventricle complex I respiration (OXPHOS_CI) with complex I substrates malate, pyruvate, and glutamate. (b) Right and (e) left ventricle complex II respiration (ETC_CII) with the addition of succinate and inhibition of complex I respiration with rotenone. (c) Right and (f) left ventricle maximal non-phosphorylating oxidative phosphorylation (ETC_CI+CII) with the titration of the protonophore, FCCP, in the presence of complex I and complex II substrates. ANOVA with multiple comparisons of treatment groups to sham (*, p <0.05; **, p <0.01; ***, p <0.001). ANOVA with multiple comparisons between treatment groups (#, p <0.05; ##, p <0.01; ###, p <0.001). Definition of abbreviations: DG-CPR = depth-guided CPR; HD-CPR = hemodynamic-directed CPR.

Figure 3.. Cerebral Mitochondrial Respiration.

Comparisons of measures of mitochondrial respiration in the cerebral cortex (a-c) and hippocampus (d-f) 24 hours after return of spontaneous circulation (treatment groups) or 24 hours post-anesthesia (sham). (a) Cortical and (d) hippocampal complex I respiration (OXPHOS_CI) with complex I substrates malate and pyruvate. (b) Cortical and (e) hippocampal complex II respiration (ETC_CII) with the addition of succinate and inhibition of complex I respiration with rotenone. (c) Cortical and (f) hippocampal maximal oxidative phosphorylation convergence respiration (OXPHOS_CI+CII) with both complex I and complex II substrates. Statistical analyses performed with ANOVA with multiple comparisons of treatment groups to sham (*, p <0.05; **, p <0.01; ***, p <0.001) and ANOVA with multiple comparisons between treatment groups (#, p <0.05; ##, p <0.01; ###, p <0.001). Definition of abbreviations: DG-CPR = depth-guided CPR; HD-CPR = hemodynamic-directed CPR.