Narrated and Abridged: There is (No) Evidence for That: Epistemic Problems in Critical Care Medicine

Below is the narrated video of my powerpoint presentation on Epistemic Problems in Critical Care Medicine, which provides a framework for understanding why we have both false positives and false negatives in clinical trials in critical care medicine and why we should be circumspect about our "evidence base" and our "knowledge".  This is not trivial stuff, and is worth the 35 minutes required to watch the narration of the slideshow.  It is a provocative presentation which gives compelling reasons to challenge our "evidence base" in critical care and medicine in general, in ways that are not widely recognized but perhaps should be, with several suggestions about assumptions that need to be challenged and revised to make our models of reality more reliable.  Please contact me if you would like me to give an iteration of this presentation at your institution.

Evolution Based Medicine: A Philosophical Framework for Understanding Why Things Don't Work

An afternoon session at the ATS meeting this year about "de-adoption" of therapies which have been shown to be ineffective was very thought provoking and the contrasts between it and the morning session on ARDS are nothing less than ironic.   As I described in the prior post about the baby in the bathwater, physicians seem to have a hard time de-adopting therapies.  Ask your colleagues at the next division conference if you should abandon hypothermia after cardiac arrest and rather just treat fever based on the TTM trial and the recent pediatric trial, and see what the response is.  Or, suggest that hyperglycemia (at any level in non-diabetic patients) in the ICU be observed rather than treated.  Or float the idea to your surgical colleagues that antibiotics be curtailed after four days in complicated intraabdominal infection, and see how quickly you are ushered out of the SICU.  Tell your dietition that you're going to begin intentionally underfeeding patients, or not feeding them at all and see what s/he say(s).  Propose that you discard sepsis resuscitation bundles, etc.  We have a hard time de-adopting.  We want to take what we have learned about physiology and pharmacology and apply it, to usurp control of and modify biological processes that we think we understand. We (especially in critical care) are interventionists at heart.

The irony occurred at ATS because in the morning session, we were told that there is incontrovertible (uncontroverted may have been a better word) evidence for the efficacy of prone positioning in ARDS (interestingly, one of the only putative therapies for ARDS that the ARDSnet investigators never trialed), and it was strongly suggested that we begin using esophageal manometry to titrate PEEP in ARDS.  So, in the morning, we are admonished to adopt, and in the afternoon we are chided to de-adopt a host of therapies.  Is this the inevitable cycle in critical care and medical therapeutics?  A headlong rush to adopt, then an uphill battle to de-adopt?

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.