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.

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.

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?