Concise Critical Appraisal: Epinephrine Versus Norepinephrine for Cardiogenic Shock

Cardiogenic shock (CS) from acute myocardial infarction (AMI) has a high mortality rate. The majority of these patients receive vasopressors but the choice of agent is based on expert opinion because of a lack of randomized control trials (RCTs). In a study by De Backer et al (N Engl J Med. 2010;362:779-789), a subgroup analysis of patients with CS found that norepinephrine had superior 28-day mortality compared to dopamine. Studies involving patients with septic shock have not found outcome differences for epinephrine versus norepinephrine. It is unknown whether these findings can be extrapolated to CS.

Levy et al (J Am Coll Cardiol. 2018;72:173-182) conducted a prospective, double-blind, multicenter RCT comparing epinephrine to norepinephrine in the setting of CS in patients who underwent AMI treated with percutaneous coronary intervention (PCI). Patients were randomized to epinephrine versus norepinephrine at 0.02 µg/kg/min, and titrated to a mean arterial pressure (MAP) goal of 65-70 mm Hg. Patients included underwent successful PCI for ACS, were aged >18 years, and had evidence of cardiogenic shock. They were excluded if they immediately underwent extracorporeal life support (ECLS), had cardiac arrest with cerebral anoxia or septic shock, did not have insurance, or were considered moribund by the attending physician. Randomization occurred via computer generation, in random blocks of 4 and stratified by participating ICU.

Fifty-seven patients were included in the final analysis. The primary end point of cardiac index evolution was equivalent between the 2 groups between hours 0 and 72 (p = 0.43). The main safety end point of persistent CS was significantly higher in the epinephrine group (p = 0.008). This led to early termination of the study. Dosages, length of vasopressor treatment, and maximal dose were similar between the 2 groups. Hemodynamic end points (MAP, cardiac index, heart rate, stroke volume index) were similar but with a slightly improved cardiac index at hours 2 and 4 (p = 0.011, p = 0.036 respectively), favoring epinephrine. Additionally, the epinephrine group had a significant increase in heart rate between hours 2 and 24 (p < 0.0001), but heart rate was unchanged in the norepinephrine group (p = 0.031). Epinephrine was associated with a significant metabolic acidosis in the first 24 hours (p = 0.0004), as well as increased lactate (p < 0.0001). No significant difference was noted in the Sequential Organ Failure Assessment score (p = 0.044) between the 2 groups. Overall mortality was not different between the 2 groups (p = 0.025). The combined end point of mortality plus ECLS at day 7 was significantly higher in the epinephrine group (p = 0.031).

Though thought-provoking, this study has several limitations. It was stopped early secondary to safety concerns for persistent CS. It was a small study with inclusion criteria for a very predefined patient population—CS from AMI after PCI. It is unclear whether the results may also apply to patients with CS from other etiologies or CS from AMI before PCI. However, epinephrine has been shown to result in similar laboratory findings and effects on cardiac index in other shock subtypes, as this study found. The baseline characteristics of the group were similar but there were more women in the epinephrine group.

Despite limitations, this trial offers evidence for considering norepinephrine rather than epinephrine in patients with CS from AMI after PCI. Many of the proposed benefits of epinephrine did not bear out hemodynamically and did not lead to improved mortality rate. Patients receiving epinephrine had more instances of refractory CS, more incidence of persistent lactic acidosis and, as shown by this analysis, a tendency toward higher mortality. However, because of the study’s limitations, most notably its small size and early termination, further and larger studies are needed to further elucidate a more definitive answer.

Coauthors of this installment of Concise Critical Appraisal:

David Gordon, MD, is a clinical instructor in emergency medicine and a clinical resuscitation fellow in the Department of Emergency Medicine at Stony Brook Medicine.

Brian J. Wright, MD, MPH, is a clinical assistant professor and the program director for the Advanced Resuscitation Training Program in the Department of Emergency Medicine at Stony Brook Medicine. Dr. Wright is an editor of Concise Critical Appraisal.