Epinephrine: Is it really the black sheep of vasoactive agents?

Abstract

Surviving sepsis campaign guidelines recommend nor-epinephrine or dopamine as the fi rst line vasoactive agents for the management of hypotension in septic shock. In contrast, epinephrine is relegated to second or third-line therapy due to adverse eff ects, including hyperlacatemia, arrhythmias, and decrease in splanchnic circulation. In porcine models, epinephrine has been shown to cause a signifi cant reduction in intestinal mucosal pH along with signifi cant mucosal damage as early as the fi rst three hours [2]. Similarly, in human studies, epinephrine has been shown to decrease frac-tional splanchnic blood fl ow [3], increase splanchnic oxygen utilization and CO 2 production, and alter acid base balance. In view of the important role of the integrity of the intestinal epithelium in development of multiple organ dysfunction syndrome and the eff ects of epinephrine on splanchnic circulation, epinephrine was not considered fi rst-line therapy [4]. However, some studies have suggested that these eff ects are transient [5]. Previously, no large comparative trial had been performed. Annane and colleagues conducted a double-blind randomized controlled trial to compare epinephrine to norepinephrine and dobutamine (whenever needed) in septic shock [1]. Th eirs was a moderate-sized, well-designed study with clinically important endpoints. Th e two treatment groups were well balanced at baseline except that the median age was slightly higher in the epinephrine group than in the norepinephrine plus dobutamine group. Unfortunately, no diff erences were seen in short-or long-term mortality, hemodynamic stabilization, resolution of organ dysfunction, or adverse events. In addition, epinephrine did not induce excessive cardiovascular adverse eff ects, including arrhythmias, stroke, or acute coronary events, as compared to norepinephrine. A few weaknesses of the study merit consideration. First, the study was powered to demonstrate an absolute risk reduction in 28-day mortality of 20%. Very few interventions in critical care reduce mortality by this magnitude. Instead, this study demonstrated a non-signifi cant 6% diff erence in mortality (34% for subjects receiving norepinephrine and dobutamine compared to 40% for subjects receiving epinephrine), similar to mortality reduction seen with activated protein C. Second, a large number of subjects (1261/1591) screened for the study were not enrolled, thereby limiting the generalizability of the study. Th ird, by design, all subjects had some exposure to vasopressors prior to enrollment, including >15 μg/kg/min of dopamine or any dose of epinephrine or norepinephrine. Th is exposure, though less than 24 hours, may have confounded the eff ects of vasoactive agents and the ability to detect a diff erence in outcomes. Recommendation In conclusion, this study is unlikely to change current recommendations for use of vasoactive agents in septic shock. Although cardiovascular adverse eff ects were similar for epinephrine and norepinephrine with dobuta-mine, the study was not adequately powered to assess small diff erences in mortality. Th e non-signi fi cantly higher mortality for subjects receiving epinephrine high-lights the need to conduct larger studies before con-sidering epinephrine as a fi rst line agent for manage ment of septic shock. Competing interests The authors declare no competing interests.