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. 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.On the basis of these observations (and some preliminary studies described in the following paragraph), it was hypothesized that using available therapeutic tools (e.g., pressors and inotropes) to raise hemodynamic values to "supranormal" levels would provide benefit to patients. (The underlying hypothesis is really that supranormal hemodynamic values CAUSE improved survival - they are part of the causal pathway.) The italicized clause is pivotal. Even if the hypothesis is correct, it must also be the case that the therapeutic tools available to achieve those ends: a.) do so in a way that closely mimics the way the body has evolved to achieve supranormal values in survivors - i.e., there are not redundant causal pathways; b.) that any untoward effects of the available therapeutic tools do not negate their benefits - that is, there is not causal factor redundancy; c.) that there is not time dependency of causal pathways such that if the supranormal hemodynamic state is achieved too late, there is no effect - a runaway train has been released and "the horse is out of the barn". As is now well known, this therapeutic approach failed and its pursuit has largely been abandoned. Moreover, the Swan-Ganz catheter, used with such enthusiasm by those enamored of manipulating measured physiological variables (think of how many unmeasured variables there are for each one we can measure), was dropped like a bad habit after the publication, a year later, of the SUPPORT investigators' observational study in JAMA showing that its use was associated with increased mortality.
Now with the Morelli trial a generation later, we've come full circle. Instead of augmenting catecholamine responses, we're going to inhibit them, reasoning that they're bad:
I will leave it to interested readers to evaluate the supporting references and determine the strength of the biological plausibility of this hypothesis, since I've already said there is no biological precedent for a therapy such as this improving mortality in critical illness. But note the similarities in the reasoning of the two studies performed 18 years apart, but testing diametrically opposed hypotheses!
The most astonishing irony here is this: We enrolled patients to whom we were administering exogenous high dose catecholamines! Would an alternative (and simpler) approach be to reduce exogenous catecholamine administration, while tolerating a lower mean arterial pressure (MAP)? That's a hypothesis that deserves testing. In my treatment of patients with shock due to sepsis of urinary origin (a distinct and I would say special subset of all septic shock patients), I have made several observations, each interesting in isolation, but especially interesting in composite:
- These patients can be profoundly shocked (with very wide pulse pressure, insensitivity to fluids), but they tend to have very good outcomes (cohort data back up this observation)
- Two to three days after admission, when all of the other clinical epiphenomena of sepsis have normalized (creatinine and electrolytes return to normal, lactate clears, patient up, eating, walking about) they often remain hypotensive (MAP less than 60) with a "pressor requirement"
- Stopping pressors at this stage and tolerating hypotension does not seem to lead to untoward outcomes
- In elderly patients with a DNR/DNI order, I have often elected to forego pressor therapy altogether from the outset, and remarkably, this older, frailer, co-morbidity laden population also does very well in spite of the "permissive hypotension"!