The Intensivist Giveth Then the Intensivist Taketh Away: Esmolol in Septic Patients Receiving High Dose Norepinephrine

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

HFOV Fails as a Routine Therapy for moderate-to-severe ARDS. Musings on the Use and Study of “Rescue Therapies”.

Ferguson et al report the results of the OSCILLATE randomized controlled trial of HFOV for moderate to severe ARDS in this week’s NEJM.  (A similar RCT of HFOV, the OSCAR trial, is reported in the same issue but I limit most of my commentary to OSCILLATE because I think it’s a better and more interesting trial and more data are presented in its report.)  A major question is answered by this trial, but an important question remains open:  is HFOV an acceptable and rational option as “rescue therapy” in certain patients with “refractory” ARDS?  I remain undecided about this question, and its implications are the subject of this post.

Before I segue to the issue of the study and efficacy of rescue therapies, let’s consider some nuances of this trial:

·         Patients in both groups received high doses of sedatives (average midazolam dose for the first week: 8.3 mg/hour in the HFOV group versus 5.9 mg/hour in the control group – a 41% increase in HFOV).  Was this “too much” sedation?  What if propofol had been used instead?

·         Patients in the HFOV group received significantly more paralytics.  If you believe the Papazian data (I don’t) paralytics should confer a mortality benefit in early ARDS and this should contribute to LOWER mortality in the HFOV group.  What if paralytics had been used less frequently?

·         Does HFOV confer a nocebo effect by virtue of its “unnatural” pattern of ventilation, its “requirement” for more sedation and paralysis, or the noise associated with its provision, or its influence on the perceptions of caregivers and patient’s families (recognizing that deaths after withdrawal of life support were similar in HFOV versus conventional ventilation (55 versus 49%, P=0.12)?

·         The respiratory frequency in the HFOV group (5.5 Hz) was at the low end of the usual range (3-15 Hz).  If a higher frequency (and a lower tidal volume) had been delivered, would the result have changed?  (Probably not.)

·         What about the high plateau pressure in the control group (32 cm H2O) despite the low tidal volume of 6.1 ml/kg PBW?  Why was not tidal volume reduced such that plateau pressure was lower than the commonly recommended target of 30 cm H2O?  Did this make a difference?  (Probably not.)

·         Why was mortality higher in the minority (12%) of control patients who were changed to HFOV (71% mortality)?  Is this related to confounding by indication or reflective of the general harmful effects of HFOV?

·         Why was there a difference between the OSCILLATE study and the OSCAR study, reported in the same issue, in terms of mortality?  Because OSCILLATE patients were sicker?  Because OSCAR control patients received higher tidal volumes, thereby curtailing the advantage of conventional ventilation?  I find this last explanation somewhat compelling.