Thursday, March 20, 2014

Sepsis Bungles: The Lessons of Early Goal Directed Therapy

On March 18th, the NEJM published early online three original trials of therapies for the critically ill that will serve as fodder for several posts.  Here, I focus on the ProCESS trial of protocol guided therapy for early septic shock.  This trial is in essence a multicenter version of the landmark 2001 trial of Early Goal Directed Therapy (EGDT) for severe sepsis by Rivers et al.  That trial showed a stunning 16% absolute reduction in mortality in sepsis attributed to the use of a protocol based on physiological goals for hemodynamic management.  That absolute reduction in mortality is perhaps the largest for any therapy in critical care medicine.  If such a reduction were confirmed, it would make EGDT the single most important therapy in the field.  If such reduction cannot be confirmed, there are several reasons why the Rivers results may have been misleading:

There were other concerns about the Rivers study and how it was later incorporated into practice, but I won't belabor them here.  The ProCESS trial randomized about 1350 patients among three groups, one simulating the original Rivers protocol, one to a modified Rivers protocol, and one representing "standard care" that is, care directed by the treating physician without a protocol.  The study had 80% power to demonstrate a mortality reduction of 6-7%.  Before you read further, please wager, will the trial show any statistically significant differences in outcome that favor EGDT or protocolized care?

Indeed, as I wagered before reading the results (with my wife as a witness while we were vacationing in Panama), such differences were not found and there was essentially no signal favoring either of the protocols in this multicenter trial.  While this could be because clinicians in the standard therapy arm were essentially doing EGDT because of its promotion as the standard of care for the decade leading up to the ProCESS trial (let's call this "therapeutic drift"), my conclusion is the same - we don't really need EGDT, a "bundle" of buzzwords, repeated lactate measurements, CVPs, Edwards Lifesciences catheters, ScVO2 measurements, dobutamine, transfusions, etc.  We simply need to be attuned to the early identification and rapid treatment and resuscitation of sepsis.  The editorialist says that this is a "dubious conclusion."  I disagree vehemently.  What is the point of doing this trial if we're going to ignore the negative result?  Do we seek only to confirm?  Would he have advised the ProCESS investigators to not conduct their trial because he will not recommend changing the current practice regardless of the result?  That is dubious position.  ("Never order a test if the result won't change your management.")

There are other lessons to be learnt by willing students of the epistemology and history of evidence in critical care in general and sepsis specifically.  We have seen the rise and fall of drotrecogin-alfa and the promiscuous and corrupt influence of industry on professional societies and guideline development.  We have seen the premature incorporation of evidence based on single center trials into practice guidelines, only to have the evidence later refuted at the multicenter level, the later evidence received with skepticism, and specious practices continued (insulin therapy).  We have seen that few or no therapies in critical care reduce mortality by 5% let alone 10%, yet we continue to use mortality as the primary endpoint and power the studies for a mortality reduction of 10%.  We have a recurring love affair with corticosteroids and an uncanny ability to read between the lines of negative studies to justify their use.  And we enroll tens of thousands of patients into industry sponsored and controlled trials of immunomodulatory therapies for sepsis, knowing full well that industry will manipulate results, obfuscate uncertainties, and promote any approved molecule ferociously even though the prior probability of a Type I error is ridiculously high.

"Those who cannot remember the past are condemned to repeat it."  We would perhaps be wise to incorporate the lessons of history into our interpretation and implementation of "evidence based medicine" lest we embark on other misadventures that we will realize were misguided only a decade or more in retrospect.


  1. Great post as usual Scott. I'm going to read that editorial. "Dubious conclusion"? Based on what argument? Not a statistical one, apparently.

  2. Amen! I like your philosophical point. On a practical level though--now that we know that was nothing superhuman about the Rivers trial--where do we go from here? How do we save those on the margins? For instance, how do we measure resuscitation? Lactate? CVP? UOP? Ultrasound of the IVC? What about pressors--are they helpful? What is the best resuscitation fluid? NS, LR, Colloid? Is there good evidence for any of this beyond the basic point that the very sick need prompt attention and antibiotics?

  3. PulmCCM - Craig Lilly, the editorialist, says that "If one assumes that the treatments for septic shock, as well as the timing of the treatments, that would be administered in all emergency departments, regardless of size or available resources, would be equivalent to those used in the no-protocol (usual-care) group of the ProCESS trial (which included strategies for early recognition of sepsis), one could come to the dubious conclusion that protocols and decision prompts do not have a role in the treatment of septic shock. I prefer to think differently."

    I'm not sure he and I disagree as much as I originally thought, but he seems to be saying that we should retain selected parts of the Rivers protocol (what parts?) regardless of the findings, that's where I take exception. But as far as early identification and resuscitation especially early antibiotics, we're on the same page.

    One practical problem we have in my practice is missing sepsis altogether because of "premature closure" - another diagnosis is settled upon (DKA, drug overdose, stroke, CHF) and they're septic too but nobody gives antibiotics. Which is why I posted on Status Iatrogenicus
    In Praise of Lasix on Status Iatrogenicus
    that I have a very low threshold for antibiotics in ICU admissions of all sorts.

  4. Javad - I would say we resuscitate with holistic rather than simplistic goals such as CVP. I think chasing lactate is a fool's errand. Should I really give more fluids if the lactate is persistently high? I'm not giving blood or dobutamine. Do we think that pressors are going to drive the lactate down? Lactate is an epiphenomenon and it will come down when I give antibiotics and basic hemodynamic support. Or it won't.

    The pressor question is addressed in the next article I'm going to review here about MAP targets in septic shock. I'm gonna bet that relaxing MAP targets or capping pressor doses does not change outcomes. My MAP target in urosepsis is 50 mm Hg.

    The resuscitation fluid question has been answered far beyond what is necessary and I think further trials in this domain are futile and a waste of resources. See:
    Dead in the Water
    There is ANOTHER online first article March 18th NEJM of albumin in sepsis and it too was a FAIL.
    I am impressed by emerging data that LR is superior to NS and that has been my experience and I've switched to LR as my preferred resuscitation fluid. Seems like chloride loads might be bad for people.

    And, yes, as always, identify the problem and treat the root cause. Gorillacillins and source control as appropriate are paramount. A lot of the rest, in my estimation is handwaving and chasing epiphenomena.

  5. metabolic theory of septic shock