The Great Septic Debate (Part 2): Resolution? #FOAMed, #FOAMcc

So, echoing my thoughts form the end of the debate, Steven adds:

Well, I didn’t expect to see my name in a headline, but I suppose it’s a hazard one should expect when they go spreading their arguments across the interwebs!

In truth, I don’t think that Dr. Lynn and I really think that much differently on these issues. We both desire for the science of sepsis to continue developing and to be better than it is. I, personally, would love to be a part of the clinical trials that use genome-based data to determine which treatment arm a patient belongs in. We both deplore any “old guard” attempting to prevent the onward march of discoveries that make our knowledge and abilities more complete. I am actually sorry that some young scientists feel intimidated and that there is anything less than civility and scientific curiosity in our community. Period.

Likewise, I would be shocked if Dr. Lynn did not at least use the observation of infection, SIRS, and organ dysfunction as physical markers of sepsis and warning signs that intervention is necessary. It will be true for a very long time that it is going to be an interaction between two human beings that initiates the diagnosis and treatment of sepsis. A physician will recognize a patient in distress by some means and start the process. For now, these findings are the best we have, and they should prompt us to intervene before the completely diagnostic test results are available. Even when we have the tricorder, something is going to trigger the doc to pull it out of a pocket and use it.

OK, so I have to admit that Dr. Lynn stung me a little with his characterization of TNF-alpha as a “biomarker”. I would rather say that TNF is one of the heavy hitters in the proteomics of sepsis, and I’ll bet that I can get him to concede that point! It stimulates receptors and causes other actions to take place, it’s synthesis and release are regulated and dysregulated; it’s more than just a marker! And I ABSOLUTELY agree that the failure of TNF-directed therapies stems from the fact that they were given both to patients who could benefit from them and patients who, with better characterization, we would have known had no chance of benefitting. The same goes for high dose corticosteroids, anti-endotoxin antibodies, IL-1 directed therapies, and coagulation based therapies. In fact, that’s what I’ve been teaching my trainees for years – if you can call bemoaning the fact that we can’t yet recognize and separate responders from non-responders teaching. We have a desperate need for understanding better, and the science MUST be encouraged. Again, period. Or full stop, for those of you who have that bent! That is, I think, Dr. Lynn’s argument in a nutshell.

I REALLY appreciate the interchange. It is healthy and necessary. The two of us are aiming at the same thing – fewer people dying from sepsis. I haven’t met Dr. Lynn (though I hope to), but I suspect that he spends more hours in his day formulating and doing the new science, while I spend more hours in my day pushing people who think that it isn’t sepsis until it’s shock and multiple organ failure to do something about it before it gets that far. Those are both important parts of the war, but in the end, it is the same war. And we are allies in it.

Steven Q Simpson

And, soon after, Lawrence reaches for that handshake:

I agree completely with Dr. Simpson. We all teach that a good history, physical, basic lab, and a high degree of vigilance for subtle signs of sepsis are pivotal. This includes the use of awareness campaigns which simplify sepsis to something easily understood and screening protocols to assure vigilance. These are great advances.

I also share Dr. Simpson’s concern about empowerment of naysayers who may use the promulgation of the imperfections of sepsis science as a reason not to move forward with early action based detection protocols.

Relevant TNF-alpga, I have to agree that it likely has a fundamental role in some phenotypes of sepsis including the sepsis-like syndrome generated in Ebola patients.

So Dr. Simpson and I probably agree on most sepsis related issues.

To explain a little further, many years ago our research team applied for an NIH grant to define the dynamic relational patterns of all the lab and vitals over time in infected patients. The reviewers did not seem to comprehend why we wanted to do that since a standard for a single unified phenotype of sepsis was already widely accepted. Yet had they realized the need for these types of complete data sets, the entire time time series matrix of vitals, lab, biomarkers, and treatment for each case would have been acquired in PROcess , ARISE, and Promise. This would have occurred if the entire field of scientists had not convinced themselves they already knew that “sepsis/septic shock ” comprised a unified phenotype, “an entity” “a single condition” “a thing or object” definable by a few static thresholds.

So this is why we say the young should call for reform ASAP of sepsis science (not sepsis awareness) and at the upcoming SCCM. Imagine a mult-center trial where these complete time matrices are generated and we define the phenotypes. We can define the phenotypic subtypes and then examine treatments in relation to these.

One might think of sepsis syndrome as analogous to the syndrome of CHF where there is systolic failure, diastolic failure, hypertensive failure, and valvular failure defined phenotypes of CHF.

Perhaps we might have sepsis with capillary membrane failure phenotype and/or, vascular muscle failure phenotype, coagulation control failure , neutrophilic control failure, TNF-alpha mediated immune control failure.

These are simply general gross simplistic considerations, Discussion points.

However the final conclusion of my original post is that, beginning at this SCCM, we must stop trying to explain away the anomalies caused by the past sepsis dogma and accept that these anomalies ARE counter instances. We must accept that we cannot rely on research which uses billing codes as data or by using retrospective controls at the same time the denominator balloons as a function of awareness.

Then we can finally assure that we do not fool ourselves because the world depends only on us. There is no back up. We must accept that we need a new surge of sepsis research ASAP, and…..in a new direction.

This, along with the effort and dedication of Dr. Simpson team, the Sepsis Alliance, and the SSC (now gathering the entire time series matrix of all the diagnostic and treatment data and not just thresholds) will produce an exciting future. If this happens, it would be great to be a young sepsis scientist in 2015.

So yes Dr. Simpson and I actually agree. We are simply fighting the war on sepsis from different fronts.

Most Respectfully
Lawrence Lynn

Thanks again Steven and Lawrence for what I think was both a really informative AND formative discussion.

Philippe

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