Tuesday, November 10, 2015

What's left of early goal directed therapy after ProCESS, ARISE and ProMISe?

A recent review, seeking to answer that question and summarizing the evidence, concluded:

Conventional management that focuses on early antibiotics and targeted resuscitation has contributed to improvements in survival of patients with septic shock over the last decade. New evidence from the ProCESS, ARISE and PRoMISe trials, however, suggests that structured ‘early goal-directed resuscitation’ with routine placement of a central venous catheter, monitoring of mixed venous oxygen saturation and aggressive red cell transfusion does not improve outcomes in most patients with septic shock. The nuances of fluid and vasopressor administration in early septic shock remain incompletely defined. Further, development and validation of practical methods for accurately assessing optimal fluid administration is needed. Future studies that seek to address these issues will likely benefit from emerging novel techniques, including molecular diagnostics and adaptive trial designs.

EGDT works but, like the Mediterranean diet, it is a bundle of interventions. Questions left unanswered by the Rivers study revolved around which of the components of the bundle were responsible for benefit and how they might be optimally used. These questions were partially answered in ProCESS, ARISE and ProMISe. Now I'm going to rant.

CVP and ScvO2

Findings in the three new trials suggested that invasive monitoring of these parameters was not mandatory for improved outcomes. The findings unleashed an immediate fire-storm of criticism of EGDT which was simplistic and misguided, saying in effect that these interventions were worthless and that EGDT was “dead.” There was no warrant for such statements. What the new trials demonstrated was merely that we still do not know the best way to perform hemodynamic assessment. Patients in the non-EGDT arms of these trials underwent careful noninvasive clinical hemodynamic assessment. So invasive may be no better than noninvasive but no one would argue that critically ill patients don't need ongoing hemodynamic assessment. That means therapy is, whether by invasive or noninvasive means, directed to goals. Viewed from that perspective EGDT is very much alive.

What's ironic is that among those same people who are trashing EGDT there's been a flurry of interest in newer methods of hemodynamic assessment, some of which are cumbersome, based on things like point of care echo and pulse pressure variation. All are aimed at providing EGDT! One of the more popular ones, IVC imaging, is nothing more than a surrogate for CVP. Others aim to estimate cardiac output. We got a chance to try that a couple of decades ago with the PA catheter and look what happened. None of these newer methods have been subjected to the rigors of the RCT. If they ever are, perhaps in a decade or so, they may all go the way of the CVP line, who knows?

There may be a conflict of interest at play. After all, critical care types love point of care echo. Why hasn't there been more interest, for example, in impedance cardiography which is arguably just as well validated and certainly provides more continuous data in real time?


The hematocrit target of 30 used in the Rivers study was not picked out of thin air. It was based on physiologic rationale that the higher the oxygen carrying capacity the better, but that above levels of about 30 increases in blood viscosity begin to counterbalance benefits. The new trials suggested that lower targets are appropriate, but they by no means negate the hemoglobin and hematocrit as useful goals.


Dobutamine was not addressed in the review but it was one of the interventions in the Rivers study. Findings from the new trials suggested that dobutamine did not need to be given in a rigid protocolized fashion. Non-EGDT patients got dobutamine but at a lower frequency. Following the announcement of the new findings there appeared to have be a rising interest in using point of care echo to guide the use of dobutamine in patients with septic shock. In one sense this looks like a retreat from evidence based medicine. That is, there seems to have been a shift in dobutamine usage from the way it was specifically tested in a randomized controlled trial to usage according to physiologic rationale. But it's more complicated than that because dobutamine was part of a bundle. We still don't know exactly what role dobutamine has in septic shock. The most we can say from the study findings is that judgment of the individual clinician is as effective as adherence to a rigid protocol.

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