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Podcast #18 Lessons from ADRENAL and Re-Thinking Sepsis

I was joined this week by Coffee Brown to discuss the landmark ADRENAL study. We debate whether ADRENAL should make us change our practice and whether steroids help or hurt patients with sepsis. I say they hurt. Coffee says they help.

Notes: Here is one table of anti-inflammatory treatments that have failed, from an old paper Eichacker, 2002. From the text:

Efforts to suppress the host’s excessive active immune response by administration of monoclonal antibodies against TNF, blocking IL-1 activity with receptor antagonists, and antibodies to endotoxin have been unsuccessful.failure of anti-inflammatory agents in sepsis.png

We have posted more recent tables in previous entries. The point is that every few years someone publishes something like this. It’s like clockwork. The bottom line always remains the same – no benefit.

One paper Castellheim et al. 2009, not mentioned in the podcast, includes a viewpoint similar to mine: ”

From this perspective the traditional understanding of the inflammatory response in sepsis and critical illness as an initial overwhelming, disproportional and exaggerated reaction followed by ‘immune paralysis’ may need to be reconsidered. The inflammatory response may be regarded as the organism’s utmost and adequate attempt to definitely cope with the danger.”

John C. Marshall’s article on Lipopolysaccharide is a great read that informed my viewpoint. Marshall wrote about sepsis:

Screen Shot 2018-01-28 at 7.55.30 PM“Randomized trials have an important impact in establishing optimal approaches to contemporary management of diseases. However, the questions evaluated through such trials are shaped and constrained by conceptual models of the disease being
studied, and it is appropriate, from time to time, to reevaluate the model in light of an accumulating body of scientific data. Such a reevaluation in sepsis promises to be both timely and rewarding.”

True in 2005. True when Marshall wrote this in 2014:

Screen Shot 2018-01-28 at 8.03.05 PM

“The current challenge for sepsis research lies in a failure of concept and reluctance to abandon a demonstrably ineffectual research model.”

Even truer now.

Alverdy and Krezalek recently wrote about the misguided belief that: “pharmacologic interference will stop the insidious inflammatory disorder common to all sepsis. The many failures of clinical trials informed by this approach are testament to the failed thinking of this mechanistic framework…As one author declared “medicine needs evolution” and this is certainly the case with sepsis research.” (emphasis added)

Alverdy and Krezalek’s observation is a good reminder that abstract submissions are now open for the 4th annual meeting of ISEMPH – The International Society for Evolution, Medicine and Public Health in beautiful Park City, Utah. I am organizing a special symposium on Evolution, Emergency and Critical Illness.

Coffee and I also talked about the FEAST trial. More here. FEAST was also the subject of this podcast: Drowning in good intentions. The Hypress trial of corticosteroids in sepsis, was the topic of this previous podcast.

You can read more about my favorite failed sepsis drug Xigris here. Listen also to the Xigris podcast.

We mention the Bickell 1994 trial that studied IV fluids in trauma patients. In that study, fluids were associated with increased death; Coffee called this “pop the clot.” I wrote about that more here: Fluid resuscitation in trauma: Is less more?

Coffee and I mention John Ioannidis, a physician who has spent his career exposing bad science.  Read John Ioannidis’s now classic article Why most published research findings are false. An easily digestible write up of that paper appeared in the journal Atlantic. Lies, damned lies, and medical science.

Both the above are must reads for anyone embarking on a career in medicine or bioscience.

More recently, John Ioannidis followed up his previous work with this article: How to make more published research true.

Join Coffee and me next week on the podcast when we explore this question – if septic shock is a host defense, how does it work? Be prepared for rampant speculation (hypothesis generation), and we’ll review whether evidence support this notion. We promise to keep it shorter than this week’s episode.

Copyright © Joe Alcock MD



Categories: Uncategorized

Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine

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