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?

Troponin Predicts Outcome in Heart Failure - But So What?

In today's NEJM, Peacock and others (http://content.nejm.org/cgi/content/short/358/20/2117 ) report that cardiac troponin is STATISTICALLY associated with hospital mortality in patients with acute decompensated heart failure, and that this association is independent of other predictive variables. Let us assume that we take the results for granted, and that this is an internally and externally valid study with little discernible bias.

In the first paragraph of the discussion, the authors state that "These results suggest that measurement of troponin adds important prognostic information to the initial evaluation of patients with acute decompensated heart failure and should be considered as part of an early assessment of risk."

Really?


The mortality in patients in the lowest quartile of troponin I was 2.0% and that in the highest quartile was 5.3%. If we make the common mistake of comparing things on a relative scale, this is in an impressive difference - in excess of a twofold increase in mortality. But that is like saying that I saved 50% off the price of a Hershey Kiss which costs 5 cents - so I saved 3 cents! As we approach zero, smaller and smaller absolute differences can appear impressive on a relative scale. But health should not be appraised that way. If you are "buying" something, be it health or some other commodity, you shouldn't care about your relative return on your investment, only the absolute return. You have after all, only some absolute quantity of money. Charlie (from the Chocolate Factory) may find 3 cents to be meaningful, but we are not here talking about getting a 3% reduction in mortality - we are talking about predicting for Charlie whether he will have to pay $0.05 for his kiss or $0.02 for it, and even if our prediction is accurate, we do not know how to help him get the discounted kiss - he's either lucky or he's not.

Imagine that you are a patient hospitalized for acute decompensated heart failure. Does it matter to you if your physician comes to you carrying triumphantly the results of your troponin I test and informs you that because it is low, your mortality is 2% rather than 5%? It probably matters very little. It matters even less if your physician is not going to do anything differently given the results of that test. Two percent, 5 percent, it doesn't matter if it can't be changed.

Then there is the cost associated with this test. My hospital charges on the order of $200 for this test. Consider the opportunity costs - what else could that $200 be spent on, in the care of American patients, and perhaps even more importantly in the context of global health and economics? Also consider the value of the test to a patient who might have to pay out of pocket for it - is it worth $200 to discriminate within an in-hospital mortality range of 2-5%?

This study, while meticulously conducted and reported, underscores the important distinction between statistical significance and clinical significance. With the aid of a ginormous patient registry, the authors clearly demonstrated a statistically significant result that is at least mildly interesting from a biological perspective (is it interesting that a failing heart spills some of its contents into the blodstream and that they can be detected by a highly sensitive assay?) But the clinical significance of the findings appears to be negligible, and I worry that this report will encourate the already rampant mindless use of this expensive test which, outside of the context of clinical pre-test probabilities, already serves to misguide care and run up healthcare costs in a substantial proportion of the patients in whom it is ordered.