Levophed-openia

The debate on the treatment of circulatory shock is over(-ish?). Ever since the NEJM put out its big RCT on the treatment of all-comer shock[i], we know that norepinephrine is the vasopressor of choice. Septic, cardiogenic….doesn’t matter. Norepinephrine is superior to dopamine. Bummer, right? Choice of vasoactive agent was so sexy. And now, it’s so easy. Shock-y? Start Levo’…[ii]

Moreover, big-time intensivist and debunk-er of CVP[iii], Paul Marik was just recently featured on EMcrit for a lecture he gave to the sepsis collaborative on new paradigms of septic shock management[iv]. It’s a fantastic listen, and in it, he advocates less fluids and earlier pressors.

Catecholamine vasoactives “fix” shock by agonizing alpha- and beta-adrenergic receptors. And we’re terrified of antagonizing these effects thanks to the COMMIT trial,[v] which showed higher mortality and more decompensated heart failure in those with acute MI treated with beta-blockers. The rationale makes sense; why give a negative inotrope/chronotrope to someone who may not acutely perfuse so well…

Imagine the surprise generated by this study published in JAMA: Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial.[vi] What!!?!? You’re gonna take those dependent on norepi-lifeblood and then blunt the drug’s effect? What IRB approved this madness?

The results are even more surprising. But first, let’s talk methods. It was a small, single-center randomized-controlled trial. It was unblinded. They took ~150 patients with septic shock and optimized them for 24 hours according to a pseudo-early-goal directed therapy algorithm. If they were norepinephrine dependent and had HR >95, they were randomized to esmolol or control. Esmolol was titrated to a heart rate of 80-94. Primary outcome was mortality; secondary outcomes were hemodynamic parameters, including stroke volume, MAP, cardiac index, and norepinephrine requirement.

Mortality was 50% in the esmolol group vs 80% in the control (p was < 0.001). There was no significant increase in the norepi requirement in the esmolol group. Stroke volume improved in the esmolol group, and there was no difference in cardiac index. Shocking, right?

The study is limited by being unblinded, small size, single-center, slight differences in baseline characteristics between study groups among others. But as a pilot study, the results are striking.

The why and how of these results are speculative. We know catecholamines have deleterious effects, including tachycardia-induced myocardial dysfunction, increased insulin resistance, increase thrombogencity etc. We also know that catecholamine levels, duration of therapy, and tachycardia are independent predictors of mortality. [vii, viii]

Note well, this patient population is not what we see in the ED. These are resuscitated patients, 24 hours into therapy. However, the findings raise important questions about catecholamine therapy and its pitfalls.

For the burgeoning ED-critical care enthusiast, these questions shed light on the slippery slope and a logical fallacy. We must separate the pathophysiology from the accepted therapy. We have to see that norepinephrine deficiency is not the problem and the therapy is just that; a therapy with potential benefits but also with detriments.

Assessment and plan: Get more info and reassess.

i De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779-789

ii Vincent , Jean-Louis De Backer , Daniel . (2013) Circulatory Shock. New England Journal of Medicine 369:18, 1726-1734

iii Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest. 2008;134:172–178

iv http://emcrit.org/podcasts/paul-marik-fluids-sepsis/

v COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group. Early intravenous then oral metoprolol in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet, 366 (2005), pp. 1622–1632

vi Morelli A, Ertmer C, Westphal M, et al. Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial. JAMA. 2013;310(16):1683-1691.

vii Benedict CR, Rose JA. Arterial norepinephrine changes in patients with septic shock. Circ Shock. 1992;38(3):165-172.

viii Schmittinger CA, Torgersen C, Luckner G, Schröder DC, Lorenz I, Dünser MW. Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study. Intensive Care Med. 2012;38(6):950-958.