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.
Einstein is quoted as saying "The more I learn, the more I realize I don't know." Perhaps the noble imperative to leverage physiological discoveries to alleviate human suffering undermines recognition of one's ignorance and impotence in relation to physiology and its application in therapeutics. As I discussed in this post about why immunomodulatory therapies in sepsis universally fail, we are generally ignorant about whether any factor we are studying is a part of the causal pathway of interest or not. Even if a given factor is part of the causal pathway to death or other important clinical outcomes, there are at least 3 other reasons its treatment by pharmacological or other means may not influence those outcomes:
- Causal pathway redundancy: redundancy in causal pathways may mitigate the effects of fever treatment on the downstream outcome of interest - blocking fever fails because another pathway remains active
- Causal factor redundancy: Fever has both beneficial and untoward effects in different causal pathways - its beneficial effects may outweigh/counteract its detrimental ones through different pathways
- Time dependency of the causal pathway: the timing of treatment of fever is critical for interrupting the causal pathway