The effects of esmolol on the control of coronary blood flow and myocardial oxygen supply-demand balance in sepsis

Purpose: Sepsis is life-threatening acute organ dysfunction secondary to infection and a major cause of morbidity and mortality in critically ill patients. Sepsis accounts for ~5% of the U.S.'s hospital costs. Hallmarks of sepsis include cognitive impairment, elevated heart rate, low blood pressure, metabolic acidosis, immune dysfunction, respiratory dysfunction, capillary leakiness, thermal dysregulation, multiple organ dysfunction, and shock. Currently, the standard treatment of care includes fluid therapy, antibiotics, and vasopressors; however, these treatments are not optimal, as the mortality rate approaches 26%. The current standard of care for sepsis does not address increases in heart rate, but recent trials show that esmolol (a short-acting, highly selective beta blocker) reduces mortality. Esmolol effectively controls heart rate without increasing adverse effects. Importantly, the mechanisms of action of esmolol during sepsis are not well understood, particularly regarding the coronary circulation. The purpose of this study is to investigate the effects of esmolol on the control of coronary blood flow and myocardial oxygen supply-demand balance in sepsis. We chose the pig as a model because they closely resemble humans in terms of heart rate, blood pressure, and alveolar ventilation, making it a robust large animal model for translational research. We hypothesize that treatment with esmolol during acute sepsis will increase survival, maintain coronary perfusion pressure, and improve myocardial oxygen delivery. We also predict that esmolol will improve mixed venous oxygen saturation and attenuate lactic acidosis. The following specific aim will be addressed: Identify coronary vascular mechanisms underlying the protective effect of esmolol during acute sepsis. Methods: Yorkshire pigs (61.3 ± 9 kg, n=11) were used. Our model of acute sepsis is an anesthetized, open-chest pig instrumented for measurements of coronary blood flow, arterial pressure, and blood sampling (arterial, mixed venous, and coronary venous). Lipopolysaccharide (LPS; 10 μg/kg) was infused intravenously over 2 h. At the end of LPS infusion, medical intervention was started and lasted 4 h. Three medical interventions were compared: 1) no treatment 2) standard treatment of saline plus norepinephrine (NE, to maintain blood pressure) and 3) experimental treatment of the combination of saline, NE, and esmolol (to maintain blood pressure and reduce heart rate). A sham group where no LPS or treatment was given was compared to the other three medical interventions to account for values affected by the anesthesia. Hemodynamic variables were measured constantly, while blood samples were taken every 30 min. Results: Only the sham and the experimental group treated with esmolol in addition to the standard treatment had a 100% survival rate, whereas the standard treatment group had a 75% survival rate. The control group had a 0% survival rate. The addition of esmolol to standard treatment effectively reduced heart rate in comparison to every other treatment group. Additionally, the addition of esmolol was better able to maintain mean arterial pressure, coronary blood flow, myocardial oxygen delivery, and extraction closer to baseline than the standard treatment or the control groups. Indicating that esmolol improved myocardial oxygen supply and demand balance. Furthermore, esmolol attenuated the reduction of coronary venous PO2 in septic patients. However, esmolol did not attenuate the reduction of mixed venous PO2 or elevated lactic acid in the porcine sepsis model. Conclusions: The outcomes of the study provide greater insight into the coronary vascular mechanisms of esmolol treatment that promote survival in sepsis. The impact of our studies will be a more solid mechanistic foundation upon which to design clinical trials of esmolol patients with sepsis.