Much Ado About Nothing? The Relevance of New Sepsis Definitions for Clinical Care Versus Research

What's in a name?  That which we call a rose, by any other name would smell as sweet. - Shakespeare, Romeo and Juliet Act II Scene II

The Society of Critical Care Medicine is meeting this week, JAMA devoted an entire issue to sepsis and critical illness, and my twitter feed is ablaze with news of release of a new consensus definition of sepsis.  Much laudable work has been done to get to this point, even as the work is already generating controversy (Is this a "first world" definition that will be forced upon second and third world countries where it may have less external validity?  Why were no women on the panel?).  Making the definition of sepsis more reliable, from a sensitivity and specificity standpoint (more accurate) is a step forward for the sepsis research enterprise, for it will allow improved targeting of inclusion criteria for trials of therapies for sepsis, and better external validity when those therapies are later applied in a population that resembles those enrolled.  But what impact will/should the new definition have on clinical care?  Are the-times-they-are-a-changing?

Diagnosis, a fundamental goal of clinical medicine is important for several reasons, chief among them:

1. To identify the underlying cause of symptoms and signs so that treatments specific to that illness can be administered
2. To provide information on prognosis, natural history, course, etc for patients with or without treatment
3. To reassure the physician and patients that there is an understanding of what is going on; information itself has value even if it is not actionable

Thus redefining sepsis (or even defining it in the first place) is valuable if it allows us to institute treatments that would not otherwise be instituted, or provides prognostic or other information that is valuable to patients.  Does it do either of those two things?

A Focus on Fees: Why I Practice Evidence Based Medicine Like I Invest for Retirement

He is the best physician who knows the worthlessness of the most medicines."  - Ben Franklin

This blog has been highly critical of evidence, taking every opportunity to strike at any vulnerability of a trial or research program.  That is because this is serious business.  Lives and limbs hang in the balance, pharmaceutical companies stand to gain billions from "successful" trials, investigators' careers and funding are on the line if chance findings don't pan out in subsequent investigations, sometimes well-meaning convictions blind investigators and others to the truth; in short, the landscape is fertile for bias, manipulation, and even fraud.  To top it off, many of the questions about how to practice or deal with a particular problem have scant or no evidence to bear upon them, and practitioners are left to guesswork, convention, or pathophysiological reasoning - and I'm not sure which among these is most threatening.  So I am often asked, how do you deal with the uncertainty that arises from fallible evidence or paucity of evidence when you practice?

I have ruminated about this question and how to summarize the logic of my minimalist practice style for some time but yesterday the answer dawned on me:  I practice medicine like I invest in stocks, with a strategy that comports with the data, and with precepts of rational decision making.

Investors make numerous well-described and wealth destroying mistakes when they invest in stocks.  Experts such as John Bogle, Burton Malkiel, David Swenson and others have written influential books on the topic, utilizing data from studies in economics (financial and behavioral).  Key among the mistakes that investors make are trying to select high performers (such as mutual funds or hedge fund managers), chasing performance, and timing the market.  The data suggest that professional stock pickers fare little better than chance over the long run, that you cannot discern who will beat the average over the long run, and that the excess fees you are charged by high performers will negate any benefit they might otherwise have conferred to you.  The experts generally recommend that you stick with strategies that are proven beyond a reasonable doubt: a heavy concentration in stocks with their long track record of superior returns, diversification, and strict minimization of fees.  Fees are the only thing you can guarantee about your portfolio's returns.

Diamox Results in Urine: General and Specific Lessons from the DIABOLO Acetazolamide Trial

The trial of acetazolamide to reduce duration of mechanical ventilation in COPD patients was published in JAMA this week.  I will use this trial to discuss some general principles about RCTs and make some comments specific to this trial.

My arguable but strong prior belief, before I even read the trial, is that Diamox (acetazolamide) is ineffectual in acute and chronic respiratory failure, or that it is harmful.  Its use is predicated on a "normalization fallacy" which guides practitioners to try attempt to achieve euboxia (normal numbers).  In chronic respiratory acidosis, the kidneys conserve bicarbonate to maintain normal pH.  There was a patient we saw at OSU in about 2008 who had severe COPD with a PaCO2 in the 70s and chronic renal failure with a bicarbonate under 20.  A well-intentioned but misguided resident checked an ABG and the patient's pH was on the order of 7.1.  We (the pulmonary service) were called to evaluate the patient for MICU transfer and intubation, and when we arrived we found him sitting at the bedside comfortably eating breakfast.  So it would appear that if the kidneys can't conserve enough bicarbonate to maintain normal pH, patients can get along with acidosis, but obviously evolution has created systems to maintain normal pH.  Why you would think that interfering with this highly conserved system to increase minute ventilation in a COPD patient you are trying to wean is beyond the reach of my imagination.  It just makes no sense.

This brings us to a major problem with a sizable proportion of RCTs that I read:  the background/introduction provides woefully insufficient justification for the hypothesis that the RCT seeks to test.  In the background of this paper, we are sent to references 4-14.  Here is a summary of each:

4.)  A review of metabolic alkalosis in a general population of critically ill patients
5.)  An RCT of acetazolamide for weaning COPD patients showing that it doesn't work
6.)  Incidence of alkalosis in hospitalized patients in 1980
7.)  A 1983 translational study to delineate the effect of acetazolamide on acid base parameters in 10 paitnets
8.)  A 1982 study of hemodynamic parameters after acetazolamide administration in 12 patients
9.)  A study of metabolic and acid base parameters in 14 patients with cystic fibrosis 

10.) A retrospective epidemiological descriptive study of serum bicarbonate in a large cohort of critically ill patients

11.)  A study of acetazolamide in anesthetized cats

12 - 14).  Commentary and pharmacodynamic studies of acetazolamide by the authors of the current study