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.

Why Most Clinical Trials Fail: The Case of Eritoran and Immunomodulatory Therapies for Sepsis

The experimenter's view of the trees.

The ACCESS trial of eritoran in the March 20, 2013 issue of JAMA can serve as a springboard to consider why every biological and immunomodulatory therapy for sepsis has failed during the last 30 years.  Why, in spite of extensive efforts spanning several decades have we failed to find a therapy that favorably influences the course of sepsis?  More generally, why do most clinical trials, when free from bias, fail to show benefit of the therapies tested?

For a therapeutic agent to improve outcomes in a given disease, say sepsis, a fundamental and paramount precondition must be met:  the agent/therapy must interfere with part of the causal pathway to the outcome of interest.  Even if this precondition is met, the agent may not influence the outcome favorably for several reasons:

• Causal pathway redundancy:  redundancy in causal pathways may mitigate the agent's effects on the downstream outcome of interest - blocking one intermediary fails because another pathway remains active
• Causal factor redundancy:  the factor affected by the agent has both beneficial and untoward effects in different causal pathways - that is, the agent's toxic effects may outweigh/counteract its beneficial ones through different pathways
• Time dependency of the causal pathway:  the agent interferes with a factor in the causal pathway that is time dependent and thus the timing of administration is crucial for expression of the agent's effects
• Multiplicity of agent effects:  the agent has multiple effects on multiple pathways - e.g., HMG-CoA reductase inhibitors both lower LDL cholesterol and have anti-inflammatory effects.  In this case, the agent may influence the outcome favorably, but it's a trick of nature - it's doing so via a different mechanism than the one you think it is.

Falling to Pieces: Hemolysis of the Hemoglobin Hypothesis

A paramount goal of this blog is to understand the evidence as it applies to the epistemology of medical knowledge, hypothesis testing, and overarching themes in the so-called evidence based medicine movement.  Swedberg et al report the results of a large[Amgen funded] randomized controlled trial of darbepoetin [to normalize hemoglobin values] in congestive heart failure (published online ahead of print this weekend) which affords us the opportunity to explore these themes afresh in the context of new and prior data.

The normalization heuristic, simply restated, is the tendency for all healthcare providers including nurses, respiratory therapists, nutritionists, physicians, and pharmacists among others, to believe intuitively or explicitly that values and variables that can be measured should be normalized if interventions to this avail are at their disposal.  As an extension, modifiable variables should be measured so that they can be normalized.  This general heuristic is deeply flawed, and indeed practically useless as a guide for clinical care.

The Cholesterol Hypothesis on the Beam: Dalcetrapib, PCSK9 inhibitors, and "off-target" effects of statins

The last month has witnessed the publication of three lines of research that could tip the balance of the evidence for the cholesterol hypothesis depending how things play out.  Followers of this blog know that I have a healthy degree of skepticism for the cholesterol hypothesis which was emboldened by studies of torcetrapib (blogged here and here) and anacetrapib that have come to light along with the failures of vytorin (ezetimibe; blogged here and here and here) and the addition of niacin to statins to improve cardiovascular outcomes in parallel with improvements in cholesterol numbers.

I think it's finally time to bury the CETP inhibitors. The November 29th NEJM (published online on November 5th) reports the results of the dal-OUTCOMES trial of dalcetrapib in patients with a recent acute coronary syndrome. Almost 16,000 patients were enrolled in this study of high risk patients, providing the study with ample power to detect meaningful improvements in cardiovascular outcomes - but alas, none were detected. The target is HDL, so the LDL hypothesis is not debunked by these data, but I think it is challenged nonetheless.