In a Canine Model of Septic Shock, Cardiomyopathy Occurs Independent of Catecholamine Surges and Cardiac Microvascular Ischemia

Abstract

BackgroundHigh levels of catecholamines are cardiotoxic and associated with stress-induced cardiomyopathies. Septic patients are routinely exposed to endogenously released and exogenously administered catecholamines, which may alter cardiac function and perfusion causing ischemia. Early during human septic shock, left ventricular ejection fraction (LVEF) decreases but normalizes in survivors over 7-10 days. Employing a septic shock model that reproduces these human septic cardiac findings, we investigated the effects of catecholamines on microcirculatory perfusion and cardiac function. MethodsPurpose-bred beagles received intrabronchial Staphylococcus aureus (n=30) or saline (n=6) challenges and septic animals recieved either epinephrine (1mcg/kg/min, n=15) or saline (n=15) infusions from 4 to 44 hours. Serial cardiac magnetic resonance imaging (CMR), invasive hemodynamics and laboratory data including catecholamine levels and troponins were collected over 92 hours. Adenosine-stress perfusion CMR was performed on eight of the fifteen septic epinephrine, and eight of the fifteen septic saline animals. High-dose sedation was titrated for comfort and suppress endogenous catecholamine release. ResultsCatecholamine levels were largely within the normal range throughout the study in animals receiving an intrabronchial bacteria or saline challenge. However, septic versus non-septic animals developed significant worsening of LV; EF, strain, and -aortic coupling that was not explained by differences in afterload, preload, or heart rate. In septic animals that received epinephrine versus saline infusions, plasma epinephrine levels increased 800-fold, pulmonary and systemic pressures significantly increased, and cardiac edema decreased. Despite this, septic animals receiving epinephrine versus saline during and after infusions, had no significant further worsening of LV; EF, strain, or -aortic coupling. Animals receiving saline had a sepsis-induced increase in microcirculatory reserve without troponin elevations. In contrast, septic animals receiving epinephrine had blunted microcirculatory perfusion and elevated troponin levels that persisted for hours after the infusion stopped. During infusion, septic animals that received epinephrine versus saline had significantly greater lactate, creatinine, and alanine aminotransferase levels. ConclusionsCardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor is it principally due to decreased microvascular perfusion-induced ischemia. However, epinephrine itself has potentially harmful long lasting ischemic effects during sepsis including impaired microvascular perfusion that persists after stopping the infusion. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIMyocardial depression of sepsis occurs without high levels of circulating catecholamines. C_LIO_LIWhereas large vessel coronary perfusion is known to be well maintained during sepsis, we show that during the myocardial depression of sepsis, in a model without exogenous catecholamine infusion, no perfusion abnormalities in the coronary microcirculation nor troponin elevations develop, indicating that the cardiac dysfunction of sepsis is not an ischemic injury. C_LIO_LIEpinephrine use during sepsis produces a form of injury tangential to the myocardial depression of sepsis. C_LIO_LIEpinephrine infusions depressed microcirculatory perfusion reserve and increased troponin I levels indicating a secondary prolonged mild ischemic effect on the myocardium. C_LI What are the clinical implications?O_LIProlonged high doses of epinephrine can secondarily contribute to perfusion abnormalities. C_LIO_LIDecoupling the septic heart from microvascular perfusion abnormalities and ischemia may lead to better strategies for managing shock associated with severe infections. In clinical practice in septic patients particularly potentially with coronary artery disease, commonly used vasopressors that are less associated with increased lactate production than epinephrine, alongside adjunct cardiac microcirculatory vasodilators, could help better maintain or improve cardiac performance during septic shock. C_LI