Rivers started it all off and things seemed unbelievable…in fact, perhaps, to good to be true!

EGDT was a phrase we were going to hear more and more on ITU and any meeting we sat in. But what’s happened recently!! It has all been flipped on it’s head.

The problem came when 3 large RCT’s couldn’t really mirror what Emmanuel was telling us! Indeed, a large individual patient data meta-analysis performed looking at three randomized trials confirmed that EGDT did not result in better outcomes compared with usual care. The PRISM investigators concluded:

“In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics”.

Another group noticed the only thing that really made a difference, aside from everything else we were faffing about with was time to antibiotics! 12 randomized trials (six fully published and six in abstract form) and 31 observational studies that included a total of approximately 20,000 patients with severe sepsis or septic shock were evaluated.  Time-to-first antibiotics explained 96–99% of the entire survival difference between EGDT and controls!

“Survival discordance was not associated with differences in early goal-directed therapy bundle compliance or hemodynamic goal achievement. Our results suggest that it was associated with faster and more appropriate antibiotic co-intervention in the early goal-directed therapy arm compared with controls in the observational studies but not in the randomized trials. Early goal-directed therapy was associated with increased mortality in patients with high-disease severity”.

Another key thing was that the treatment effect of EGDT seemed to depend on the how sick patients were from the start according to APACHE II, SOFA and by the presence of shock. In fact it was those who were the ‘sickest’ according to these criteria who faired worse!

Another study looked at inflammatory biomarker profiles amongst those enrolled into ProCESS. Again, it was those who were less severely ill (lowest biomarker quartile), who faired better. Within those disease severity classifications, the following were considered, however they weren’t statistically significant due to low powering from small sample sizes on sub-analysis:

  1. Eligibility criteria met by refractory hypotension and hyperlactatemia
  2. Lactate level before randomization
  3. Vasopressor infusion.

So this treatment interaction means that EGDT further increased their mortality! This rings similar bells to APC!  It also means it’s a qualitative interaction as well (low severity benefit; high don’t).

So, we have seen this in:

  1. Tight glucose control in the ICU
  2. Low tidal volume ventilation for acute respiratory distress syndrome

The sicker patients therefore may require our ‘intuition’, on their management that a fixed protocol disallows user flexibility over.

So, the sickest, we want the ‘works’ for and why wouldn’t we. But within the boundaries of a fixed and perhaps aggressive treatment protocol, we are pushing too far. These patients, with little physiological reserve left succumb to fluid overload, cardiac arrhythmias, and transfusion-related acute lung injury – pulmonary edema, tissue hypoxia, and end-organ damage resulting. The less sick cohort possibly have more of this reserve…’more fuel in the tanks’ as it were!

We know well that fluid overload leads to un-arguable increase in morbidity and mortality; excusing other co-interventions though:

  • Large cohort audits demonstrate that higher cumulative fluid balance at day 3 but not in the first 24 hours after ICU admission was independently associated with an increase in the hazard of death.
  • This study showed a more positive fluid balance both early in resuscitation and cumulatively over 4 days was associated with an increased risk of mortality in septic shock. So CVP may be used to gauge fluid balance <=12 hrs into septic shock but becomes an unreliable marker of fluid balance thereafter. Optimal survival in the VASST study occurred with a positive fluid balance of approximately 3 L at 12 hrs.
  • And here, for much the same

Is there another single co-variable at play here then? Because of the tight nature of confounder exclusion in large RCT’s, this is unlikely. Differences in age, country, hospital location, era, systolic pressure, mean arterial pressure, lactate, bundle compliance, and hemodynamic goal achievements were not associated with survival differences between studies.

Every patient’s tolerance to interventions differs, the way twins respond to the same stimuli differs, we all differ! And it is for these reasons the one size fits all principle simply does not apply! So some will get exaggerated responses, whilst other get suppressed responses, all down to genetic variations in cardiovascular, pulmonary, and renal physiologies that are then severely perturbed by sepsis. We are dealing with a lot of entropy with sepsis.

The future of all of this might lie with some of those biomarkers we seem to be reading more and more about in published research. Will monitoring these in real time reveal the exact and optimum point for us to go wading in with our interventions; like EGDT?

So…where do we go from here? We need to look at physiologic and molecular biomarkers to better define the progression of the sepsis continuum. This means…more tight, highly powered, confounder eliminating RCT’s I’m afraid!

JW

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