Mark Angelos

Cardiac resuscitability with cardiopulmonary bypass after increasing ventricular fibrillation times in dogs

Previous studies in dogs have shown resuscitation from prolonged cardiac arrest to conscious survival to be more effective with the use of cardiopulmonary bypass (CPB) than with standard advanced cardiac life support. This study compared cardiovascular resuscitability with CPB only after varying periods of cardiac arrest without artificial circulatory support in a canine model. Group 1 (ten) was subjected to ventricular fibrillation for 15 minutes; group 2 (ten) for 20 minutes; and group 3 (ten) for 30 minutes. All received total CPB after ventricular fibrillation without advanced cardiac life support to defibrillation at two to five minutes and partial CPB to four hours. In all three groups CPB with epinephrine generated normal coronary perfusion pressure and increased ventricular fibrillation amplitude significantly. In groups 1 and 2, CPB reperfusion allowed for successful defibrillation in less than five minutes, weaning from CPB in all dogs at four hours, and stable spontaneous circulation thereafter. In group 3, only five of ten dogs could be weaned from bypass at four hours, and all died early with myocardial necroses. It was concluded that CPB may be of value in the setting of prolonged cardiac arrest when advanced cardiac life support has not been provided or is unable to restore spontaneous heart-beat.

A comparison of cardiopulmonary resuscitation with cardiopulmonary bypass after prolonged cardiac arrest in dogs. Reperfusion pressures and neurologic recovery

Resuscitability and outcome after prolonged cardiac arrest were compared in dogs with standard external cardiopulmonary resuscitation (CPR) vs. closed-chest emergency cardiopulmonary bypass (CPB). Ventricular fibrillation (VF) was with no blood flow from VF 0 min to VF 10 min. Subsequent CPR basic life support (BLS) was from 10 min to VF 15 min. Then, group I (n = 13) received CPR advanced life support (ALS) from VF 15 min until restoration of spontaneous circulation to occur not later than VF 40 min. Group II (n = 14) received CPR-ALS from VF 15 min to VF 20 min without defibrillation, and then total CPB to defibrillation attempts started at VF 20 min, followed by assisted CPB to 2 h. Total ischemia time (no-flow time plus CPR time of MAP less than 50 mmHg) was unexpectedly shorter in group I (14.3 +/- 2.5 min) than in group II (18.6 +/- 2.3 min) (P less than 0.01). During CPR-BLS, coronary perfusion pressures were 25 +/- 9 mmHg in group I and 18 +/- 8 mmHg in group II (NS). Epinephrine during CPR-ALS, before countershock, raised coronary perfusion pressure to 40 +/- 10 mmHg in group I and 27 +/- 10 mmHg in group II (NS). In group II, coronary perfusion pressure increased during total CPB to 58 +/- 16 mmHg (P less than 0.01 vs. group I). Spontaneous normotension was restored in 11/13 dogs of group I and all 14 dogs of group II (NS). Ten dogs in each group followed protocol and survived to 96 h. Five of ten in group I and six of ten in group II were neurologically normal (NS). We conclude that: (1) Reperfusion with CPB yields higher coronary perfusion pressures than reperfusion with CPR-ALS; and (2) even after no blood flow for 10 min, optimized CPR can result in cardiovascular resuscitability and neurologic recovery, similar to those achieved by CPB.

Postischemic inotropic support of the dysfunctional heart

Objective To determine relative adenine nucleotide regeneration and improvement in left ventricular (LV) function using three commonly used adrenergic agents—epinephrine, dobutamine, and phenylephrine—during reperfusion after a period of global ischemia. After initial resuscitation from cardiac arrest, adrenergic agents are frequently required to support postischemic LV dysfunction. However, the relative effectiveness and associated bioenergetic changes associated with these agents in the postischemic heart are unclear. Design Prospective, controlled laboratory study. Setting University research laboratory. Subjects Isolated, perfused Sprague-Dawley rat hearts. Interventions After 20 mins of global ischemia, isolated rat hearts were reperfused for 30 mins with Krebs-Henseleit solution alone (control, n = 8), or with the addition of equipotent doses of epinephrine 1 &mgr;M (n = 8), dobutamine 0.3 &mgr;M (n = 8), or phenylephrine 50 &mgr;M (n = 8). In a second experiment, an &agr;-1 antagonist, prazosin was given with phenylephrine to block the presumed &agr;-1 agonist effect of phenylephrine. Measurements and Main Results A constant volume balloon was placed in the left ventricle to measure LV pressure and derived parameters of LV function. Adenine nucleotide concentrations were derived at various time points using high-performance liquid chromatography. During reperfusion, the phenylephrine group had significant improvement in LV function and cardiac efficiency in contrast to epinephrine and dobutamine. Total adenine nucleotides tended to be highest in the phenylephrine group with significant increases in adenosine diphosphate and adenosine monophosphate and no significant loss of adenosine triphosphate. The phenylephrine-induced increase in heart rate and developed pressure could be blocked with an &agr;-1 antagonist, prazosin. Conclusions In the isolated reperfused heart, phenylephrine, mediated by &agr;-1 agonism, significantly improves postischemic LV dysfunction without worsening the overall myocardial metabolic state.

Factors influencing variable outcomes after ventricular fibrillation cardiac arrest of 15 minutes in dogs

Animal experiments with cardiac arrest and cardiopulmonary resuscitation (CPR) despite controlled insult and postinsult life support, have yielded variable individual outcomes. This report concerns 10 dog experiments with a standardized model of VF cardiac arrest with no flow for 10 min followed by CPR basic life support (BLS) from VF 10 to 15 min and then CPR advanced life support (ALS) with epinephrine at 15 min. Defibrillating countershocks began at 17 min, for restoration of spontaneous circulation. After controlled ventilation to 20 h and intensive care to 96 h, outcome was evaluated using the overall performance category (OPC) 1 (normal) (n5) vs. OPC 2-4 (impaired) (n5) (P less than 0.001). We searched for correlations between normal vs. impaired outcome in various prearrest, arrest and postarrest factors that are suspected to influence postarrest neurologic deficit. Prearrest variables were similar in the normal and impaired groups. Resuscitation variables were similar in both. Coronary perfusion pressure during CPR-ALS was higher in the normal outcome group (P = 0.03). Among postarrest variables, postarrest reperfusion pressure pattern (initial hypertensive bout), blood glucose, cardiac output, Hct, pHa, PaO2 and PaCO2 were the same. Our data support the importance of maximizing coronary perfusion pressure not only for restoration of heart beat but also as a possible predictor of improved cerebral outcome.

Myocardial metabolic changes during reperfusion of ventricular fibrillation : a 31P nuclear magnetic resonance study in swine

OBJECTIVE Myocardial metabolic requirements during reperfusion of ventricular fibrillation are poorly understood. The objective of this study was to determine if controlled reperfusion after a clinically relevant global ischemia period of 10 mins was sufficient to prevent or reverse myocardial ischemia as indicated by changes in myocardial high energy phosphates, myocardial intracellular pH, and great cardiac vein lactate. DESIGN Prospective laboratory study with controlled reperfusion. SETTING Research laboratory at a university medical center. SUBJECTS Five swine weighing 19 +/- 3 kg. INTERVENTIONS Ten minutes of nonperfused ventricular fibrillation followed by reperfusion with cardiopulmonary bypass (flow 30 mL/kg/min) for 50 mins. MEASUREMENTS AND MAIN RESULTS Myocardial adenosine triphosphate (ATP), phosphocreatine, and intracellular pH were determined using in vivo 31P nuclear magnetic resonance. Myocardial blood flow, measured by 15-mu radiolabeled microspheres, was significantly increased above baseline during reperfusion. Phosphocreatine was depleted during the 10 mins of nonperfused ventricular fibrillation, but recovered to 122 +/- 18% of baseline with reperfusion and was 112 +/- 18% at 60 mins (p < .005). ATP concentrations decreased to 51 +/- 16% of baseline after 10 mins of nonperfused ventricular fibrillation, improved to 67 +/- 9% of baseline with early reperfusion, and were 65 +/- 9% of baseline at 60 mins (p < .02). Myocardial intracellular pH improved from 6.11 +/- 0.18 after 10 mins of nonperfused ventricular fibrillation, to 6.89 +/- 0.20 with early reperfusion, and then decreased to 6.85 +/- 0.35 at 60 mins ventricular fibrillation (p < .001). Despite myocardial blood flows higher than baseline during the reperfusion period, great cardiac vein/aortic lactate gradient increased over the reperfusion period. CONCLUSION Prolonged reperfusion with supranormal myocardial blood flow does not restore normal myocardial aerobic metabolism in the fibrillating myocardium after a 10-min nonperfused ventricular fibrillation period.

Norepinephrine-induced hypertension following cardiac arrest: Effects on myocardial oxygen use in a swine model

STUDY OBJECTIVE Recent studies suggest that norepinephrine-induced hypertension early after cardiac arrest ameliorates cerebral hypoperfusion and improves neurologic outcome. The purpose of this study was to evaluate the effects of early norepinephrine-induced hypertension on postresuscitation myocardial blood flow and oxygen use. DESIGN Prospective, controlled laboratory study. PARTICIPANTS Ten swine. INTERVENTIONS All animals underwent 10 minutes of ventricular fibrillation cardiac arrest followed by 5 minutes of low-flow cardiopulmonary bypass (10 mL/kg.min), norepinephrine (0.12 mg/kg), and defibrillation. Animals then were assigned to a hypertension group (mean aortic pressure, 95 mm Hg) or a control group (mean aortic pressure, 75 mm Hg) by titrating a norepinephrine infusion to attain the prescribed aortic pressure. RESULTS Myocardial blood flow, perfusion pressure, and oxygen metabolism were compared between groups at different times using analysis of variance with a post-hoc Tukey test. Groups had similar myocardial blood flow during ventricular fibrillation, total defibrillation energy, and time to restoration of spontaneous circulation. Fifteen minutes after restoration of spontaneous circulation, the hypertension group had significantly elevated myocardial blood flow, 965 +/- 314 mL/min.100 g versus 325 +/- 67 mL/min.100 g in the control group (P < .001), myocardial oxygen consumption of 51.2 +/- 26.9 mL O2/min.100 g versus 6.4 +/- 3.4 mL O2/min.100 g (P < .001), and myocardial oxygen extraction of 46% +/- 20% versus 14% +/- 4% (P < .01). CONCLUSION In the early resuscitation period, increasing the norepinephrine dose to induce mild hypertension significantly increases oxygen use in the postischemic myocardium.

Potential Role of Exosomes in Mending a Broken Heart: Nanoshuttles Propelling Future Clinical Therapeutics Forward

Stem cell transplantation therapy is a promising adjunct for regenerating damaged heart tissue; however, only modest improvements in cardiac function have been observed due to poor survival of transplanted cells in the ischemic heart. Therefore, there remains an unmet need for therapies that can aid in attenuating cardiac damage. Recent studies have demonstrated that exosomes released by stem cells could serve as a potential cell-free therapeutic for cardiac repair. These exosomes/nanoshuttles, once thought to be merely a method of waste disposal, have been shown to play a crucial role in physiological functions including short- and long-distance intercellular communication. In this review, we have summarized studies demonstrating the potential role of exosomes in improving cardiac function, attenuating cardiac fibrosis, stimulating angiogenesis, and modulating miRNA expression. Furthermore, exosomes carry an important cargo of miRNAs and proteins that could play an important role as a diagnostic marker for cardiovascular disease post-myocardial infarction. Although there is promising evidence from preclinical studies that exosomes released by stem cells could serve as a potential cell-free therapeutic for myocardial repair, there are several challenges that need to be addressed before exosomes could be fully utilized as off-the-shelf therapeutics for cardiac repair.