Two studies in the October 23/30 issue of JAMA serve as fodder for reflection on the history and direction of critical care research and the hypotheses that drive it.
Morelli et all report the results of a study of Esmolol in septic shock. To quickly summarize, this was a single center dose ranging study the primary aim of which was to determine if esmolol could be titrated to a heart rate goal (primary outcome), presumably with the later goal of performing a phase 3 clinical trial to see if esmolol, titrated in such a fashion, could favorably influence clinical outcomes of interest. 154 patients with septic shock on high dose norepinephrine with a heart rate greater than 95 were enrolled, and heart rate was indeed lower in the esmolol group (P less than 0.001). Perhaps surprisingly, hemodynamic parameters, lactate clearance, and pressor and fluid requirements were (statistically significantly) improved in the esmolol group. Most surprising (and probably the reason why we find this published in JAMA rather than Critical Care Medicine - consider that outlier results such as this may get disproportionate attention), mortality in the esmolol group was 50% compared to 80% in the control group (P less than 0.001). The usual caveats apply here: a small study, a single center, lack of blinding. And regular readers will guess that I won't swallow the mortality difference. I'm a Bayesian (
click here for a nice easy-to-use Bayesian calcluator), there's no
biological precedent for such a finding and it's too big a bite for me to swallow. So I will go on the record here as stating that I'm betting against similar results in a larger trial.
I'm more interested in how we formulate the hypothesis that esmolol will provide benefit in septic shock. I was a second year medical student in 1995 when
Gattinoni et al published the results of a trial of "goal-oriented hemodynamic therapy" in critically ill patients in the NEJM. I realize that critical care research as we now recognize it was in its adolescence then, as a quick look at the methods section of that article demonstrates. I also recognize that they enrolled a heterogenous patient population. But it is worth reviewing the wording of the introduction to their article:
Recently, increasing attention has been directed to the hemodynamic treatment of critically ill patients, because it has been observed in several studies that patients who survived had values for the cardiac index and oxygen delivery that were higher than those of patients who died and, more important, higher than standard physiologic values.1-3 Cardiac-index values greater than 4.5 liters per minute per square meter of body-surface area and oxygen-delivery values greater than 650 ml per minute per square meter — derived empirically on the basis of the median values for patients who previously survived critical surgical illness — are commonly referred to as supranormal hemodynamic values.4
