Wednesday, November 20, 2013

Chill Out: Homeopathic Hypothermia after Cardiac Arrest

In the Feb 21, 2002 NEJM, two trials of what came to be known as therapeutic hypothermia (or HACA - Hypothermia after Cardiac Arrest) were simultaneously published:  one by the HACA study group and another by Bernard et al.  During the past decade, I can think of only one other therapy which has caused such a paradigm shift in care in the ICU:  Intensive Insulin Therapy (ill-fated as it were).  Indeed, even though the 2002 studies specifically limited enrollment to out of hospital (OOH) cardiac arrest with either Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF), the indications have been expanded at many institutions to include all patients with coma after cardiac arrest regardless of location or rhythm (or any other original exclusion criterion), so great has been the enthusiasm for this therapy, and so zealous its proponents.

Readers of this blog may know that I harbor measured skepticism for HACA even though I recognize that it may be beneficial.  From a pragmatic perspective, it makes sense to use it, since the outcome of hypoxic-ischemic encephalopathy (HIE) and ABI (Anoxic Brain Injury) is so dismal.  But what did the original two studies actually show?
  • The HACA group multicenter trial randomized 273 patients to hypothermia versus control and found that the hypothermia group had higher rates of "favorable neurological outcome" (a cerebral performance category of 1 or 2 - the primary endpoint) with RR of 1.40 and 95% CI 1.08-1.81; moreover, mortality was lower in the hypothermia group, with RR 0.74 and 95% CI 0.58-0.95
  • The Bernard et al study randomized 77 patients to hypothermia versus control and found that survival (the primary outcome) was 49% and 26% in the hypothermia and control groups, respectively, with P=0.046

Monday, November 18, 2013

Dead in the Water: Colloids versus Crystalloids for Fluid Resuscitation in the ICU

It is a valid question:  at what point has a concept been tested ad infinitum such that further testing is not worthwhile?  There are at least three reasons why additional study of a concept may not be justified:

  1. Because the prior probability of success is so low (based on extant trials) that a subsequent trial is unlikely to influence the posterior probability that any success represents the truth.  (This is a Bayesian or meta-analytic worldview.)
  2. Because the low probability of success does not justify the expense of additional trials
  3. Because the low probability of success violates bioethical precepts mandating that trials must have added value for patients and society
And so we have, in the November 6th edition of JAMA, the CRISTAL trial of colloids versus crystalloids for resuscitation in the ICU.  As is customary, I will leave it to interested readers to peruse the manuscript for details.  My task here is to provide some background and nuance.

Saturday, November 16, 2013

The Cardiologist Giveth, then the Cardiologist Taketh Away: Revision of the Cholesterol Guidelines

There has been quite a stir this week with the publication of the newest revision of the ACC/AHA guidelines for the treatment of cholesterol.  The New York Times is awash with articles summarizing or opining on the changes and many of the authors are perspicacious observers:
As the old Spanish proverb states, "rio revuelto, ganancia de pescadores" - when the river is stirred up, the fishermen benefit.  I will admit that I'm gloating a bit since I consider the new guidelines to be a tacit affirmative nod to several posts on the topic of the cholesterol hypothesis (CH).  (More posts here and here and here, among several others - search for "cholesterol" or "causal pathways" on the Medical Evidence Blog search bar.)

Sunday, November 3, 2013

The Intensivist Giveth Then the Intensivist Taketh Away: Esmolol in Septic Patients Receiving High Dose Norepinephrine

Two studies in the October 23/30 issue of JAMA serve as fodder for reflection on the history and direction of critical care research and the hypotheses that drive it.   Morelli et all report the results of a study of Esmolol in septic shock.  To quickly summarize, this was a single center dose ranging study the primary aim of which was to determine if esmolol could be titrated to a heart rate goal (primary outcome), presumably with the later goal of performing a phase 3 clinical trial to see if esmolol, titrated in such a fashion, could favorably influence clinical outcomes of interest.  154 patients with septic shock on high dose norepinephrine with a heart rate greater than 95 were enrolled, and heart rate was indeed lower in the esmolol group (P less than 0.001).  Perhaps surprisingly, hemodynamic parameters, lactate clearance, and pressor and fluid requirements were (statistically significantly) improved in the esmolol group.  Most surprising (and probably the reason why we find this published in JAMA rather than Critical Care Medicine - consider that outlier results such as this may get disproportionate attention), mortality in the esmolol group was 50% compared to 80% in the control group (P less than 0.001).  The usual caveats apply here:  a small study, a single center, lack of blinding.  And regular readers will guess that I won't swallow the mortality difference.  I'm a Bayesian (click here for a nice easy-to-use Bayesian calcluator), there's no biological precedent for such a finding and it's too big a bite for me to swallow. So I will go on the record here as stating that I'm betting against similar results in a larger trial.

I'm more interested in how we formulate the hypothesis that esmolol will provide benefit in septic shock.  I was a second year medical student in 1995 when Gattinoni et al published the results of a trial of "goal-oriented hemodynamic therapy" in critically ill patients in the NEJM.  I realize that critical care research as we now recognize it was in its adolescence then, as a quick look at the methods section of that article demonstrates.  I also recognize that they enrolled a heterogenous patient population.  But it is worth reviewing the wording of the introduction to their article:

Recently, increasing attention has been directed to the hemodynamic treatment of critically ill patients, because it has been observed in several studies that patients who survived had values for the cardiac index and oxygen delivery that were higher than those of patients who died and, more important, higher than standard physiologic values.1-3 Cardiac-index values greater than 4.5 liters per minute per square meter of body-surface area and oxygen-delivery values greater than 650 ml per minute per square meter — derived empirically on the basis of the median values for patients who previously survived critical surgical illness — are commonly referred to as supranormal hemodynamic values.4