When Hell Freezes Over: Trials of Temperature Manipulation in Critical Illness

The bed is on fire

Two articles published online ahead of print in the NEJM last week deal with actual and attempted temperature manipulation to improve outcomes in critically ill patients.

The Eurotherm3235 trial was stopped early because of concerns of harm or futility.  This trial enrolled patients with traumatic brain injury (TBI) and elevated intracranial pressure (ICP) and randomized them to induced hypothermia (which reduces ICP) versus standard care.  There was a suggestion of worse outcomes in the hypothermia group.  I know that the idea that we can help the brain with the simple maneuver of lowering body temperature has great appeal and what some would call "biological plausibility" a term that I henceforth forsake and strike from my vocabulary.  You can rationalize the effect of an intervention any way you want using theoretical biological reasoning.  So from now on I'm not going to speak of biological plausibility, I will call it biological rationalizing.  A more robust principle, as I have claimed before, is biological precedent - that is, this or that pathway has been successfully manipulated in a similar way in the past.  It is reasonable to believe that interfering with LDL metabolism will improve cardiovascular outcomes because of decades of trials of statins (though agents used to manipulate this pathway are not all created equal).  It is reasonable to believe that intervening with platelet aggregation will improve outcomes from cardiovascular disease because of decades of trials of aspirin and plavix and others.  It is reasonable to doubt that manipulation of body temperature will improve any outcome because there is no unequivocal precedent for this, save for warming people with hypothermia from exposure - which basically amounts to treating the known cause of their ailment.  This is one causal pathway that we understand beyond a reasonable doubt.  If you get exposure, you freeze to death.  If we find you still alive and warm you, you may well survive.

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

Goldilocks Meets Walter White in the ICU: Finding the Temperature (for Sepsis and Meningitis) that's Just Right

In the Point/Counterpoint  section of the October issue of Chest, two pairs of authors spar over whether fever should be controlled in sepsis by either pharmacological or external means.  Readers of this blog may recall this post wherein I critically appraised the Schortgen article on external cooling in septic shock that was in AJRCCM last year.  Apparently that article made a more favorable impression on some practitioners than it did on me, as the proponents of cooling in the Chest piece hang their hats on this article (and their ability to apply physiological principles to medical therapeutics).  (My gripes with the Schortgen study were many, including a primary endpoint that was of little value, cherrypicking the timing of the secondary mortality endpoint, and the lack of any biological precedent for manipulation of body temperature improving mortality in any disease.)

Reading the Point and Counterpoint piece (in addition to an online first article in JAMA describing a trial of induced hypothermia in severe bacterial meningitis - more on that later) allowed me to synthesize some ideas about the epistemology (and psychology) of medical evidence and its evaluation that I have been tossing about in my head for a while.  Both the proponent pair and the opponent pair of authors give some background physiological reasoning as to why fever may be, by turns, beneficial and detrimental in sepsis.  The difference, and I think this is typical, is that the proponents of fever reduction:  a.) seem much more smitten by their presumed understanding of the underlying physiology of sepsis and the febrile response; b.) focus more on minutiae of that physiology; c.) fail to temper their faith in application of physiological principles with the empirical data; and d.) grope for subtle signals in the empirical data that appear to rescue the sinking hypothesis.

Sause for the Goose, Sauce for the Gander: Low Tidal Volume Ventilation in the Operating Theatre

PIBW is based on height, not weight.

Following my usual procedure, I read the title and abstract of the methods of this article on Intraoperative Low Tidal Volume Ventilation in this week's NEJM, and I made a wager with myself on what the outcome would be.  Because there are both biological plausibility and biological precedent for low tidal volume, and because it is one of the few interventions in critical care in which I have supreme confidence (yes, you can conclude that I'm biased), my prior probability for this intervention is high and I wagered that the study would be positive.  If you have not already done so, read the methods in the abstract and make your own wager before you read on.

This trial is solid but not bombproof.  Outcomes assessors were blinded and so were post-operative care providers, but anesthesiologists administering tidal volumes were not.  Outcomes themselves, while mostly based on consensus definitions (sometimes a consensus of collective ignorance), are susceptible to ascertainment and misclassification biases.  The outcome was a composite, something that I like, as will be elaborated in a now published letter in AJRCCM.  A composite outcome allows an additive effect between component outcomes and effectively increases study power.  This is essential in a study such as this, where only 400 patients were enrolled and the study had "only" 80% power to detect a reduction in the primary outcome from 20% to 10%.  As we have shown, detecting a difference of this magnitude in mortality is a difficult task indeed, and most critical care studies seeking such a difference are effectively underpowered.  How many effective (in some aspect other than mortality) therapies have been dismissed because of this systemic underpowering in critical care research is anybody's guess.

A Centrum a Day Keeps the Cancer at Bay?

Alerted as usual by the lay press to the provocative results of a non-provocative study, I read with interest the article in the October 17th JAMA by Gaziano and colleagues: Multivitamins in the Prevention of Cancer in Men. From the lay press descriptions (see: NYT summary and a less sanguine NYT article published a few days later,) I knew only that it was a positive (statistically significant) study, that the reduction in cancer observed was 8%, that a multivitamin (Centrum Silver) was used, and the study population included 14,000 male physicians.

Needless to say, in spite of a dormant hope something so simple could prevent cancer, I was skeptical. Despite decades, perhaps eons of enthusiasm for the use of vitamins, minerals, and herbal remedies, there is, to my knowledge (please, dear reader, direct me to the data if this is an omission) no credible evidence of a durable health benefit from taking such supplements in the absence of deficiency. But supplements have a lure that can beguile even the geniuses among us (see: Linus Pauling). So before I read the abstract and methods to check for the level of statistical significance, the primary endpoint, the number of endpoints, and sources of bias, I asked myself: "What is the probability that taking a simple commercially available multivitamin can prevent cancer?" and "what kind of P-value or level of statistical significance would I require to believe the result?" Indeed, if you have not yet seen the study, you can ask yourself those same questions now.

Fever, external cooling, biological precedent, and the epistemology of medical evidence

It is rare occasion that one article allows me to review so many aspects of the epistemology of medical evidence, but alas Schortgen et al afforded me that opportunity in the May 15th issue of AJRCCM.

The issues raised by this article are so numerous that I shall make subsections for each one. The authors of this RCT sought to determine the effect of external cooling of febrile septic patients on vasopressor requirements and mortality. Their conclusion was that "fever control using external cooling was safe and decreased vasopressor requirements and early mortality in septic shock." Let's explore the article and the issues it raises and see if this conclusion seems justified and how this study fits into current ICU practice.

PRIOR PROBABILITY, BIOLOGICAL PLAUSIBILITY, and BIOLOGICAL PRECEDENTS

These are related but distinct issues that are best considered both before a study is planned, and before its report is read. A clinical trial is in essence a diagnostic test of a hypothesis, and like a diagnostic test, its influence on what we already know depends not only on the characteristics of the test (sensitivity and specificity in a diagnostic test; alpha and power in the case of a clinical trial) but also on the strength of our prior beliefs. To quote Sagan [again], "extraordinary claims require extraordinary evidence." I like analogies of extremes: no trial result is sufficient to convince the skeptical observer that orange juice reduces mortality in sepsis by 30%; and no evidence, however cogently presented, is sufficient to convince him that the sun will not rise tomorrow. So when we read the title of this or any other study, we should pause to ask: What is my prior belief that external cooling will reduce mortality in septic shock? That it will reduce vasopressor requirements?