So I feel really honoured that some fantastically bright and forward-thinking people take precious time out of their days to read my rants, and even more so to leave some comments. I sometimes feel that the message contained in these is actually more important than what I spewed out in the first place, so here is quite an essay by Dr. Lawrence Lynn:
Excellent. This may be the Critical Care Quote of 2014.
“The N=1 principle: remember that we are never treating hundreds of patients at once, and we do not have to decide what is best for most (which is what an RCT generally answers) but what is best for the one patient we are treating.”
In fact when RCTs use a simplistic unified guessed phenotype as a surrogate of a complex disease (e.g. sepsis) in a highly heterogeneous population of critically ill subjects, one cannot even say that the RCT tells what is best for “most” since the first question a scientist trying to understand the validity of the “true state” under test would say is “most of what”, Of course when a free (unboxed) scientist learns that the true state was defined by a guess the discussion is over.
This SCCM will be the 25th anniversary of the guessed sepsis and septic shock criteria. It marks 25 years of failed and non-reproducible sepsis trials using the guessed criteria as standards. The beribboned SCCM speakers will rise to the podium and speculate on and on about what all of these studies might mean. None of them will formally call for reform of the science. Thomas Kuhn shows us that they cannot call for reform any more than those holding the guessed geocentric model could call for reform. “Though they may lose faith.. they will not abandon the dogma which led them to crisis” .
So it is up to you, the young women and men to speak up and demand reform. 25 years if failure is enough. How long will you sit silently in the audience and listen to P values responsive to guesses from a few well meaning docs from another era.
Stand up as a group at this SCCM and demand reform. Let this anniversary ring in a new chapter in critical care research.
If you have not read this editorial below, read it before the SCCM. No one argues that this is not the true history of sepsis science but no one has the courage to stand up and demand reform.
Maybe the 25 year anniversary of failure as a function of using guesses as gold standards could provide the impetus. The world depends on you. There is no backup.
Here is the solution for a scientific revolution. First read this guide to Dr. Kuhn’s book “The Structure of Scientific Revolutions”. (especially chapter 4)
Then the young docs (and any of the old guard willing to break from the 25 year old dogma) should move together at the SCCM meeting, and plan to do so before the meeting in social media to collectedly call for reform of the science.
If only one calls for reform, of course grants, promotions, etc can dry up for that person. That is of course what those on academic tenure tracks are afraid of. Young academics are taught to rub elbows with the thought leaders, not to formally and publically question the leaders fundamental dogma. Sure you can go your own way a little off the path, for example, questioning whether or not a given threshold is the right one. However this freedom is a façade, as one cannot question whether there actually is a unified phenotype of “sepsis” definable by simple thresholds without risking much.
However, as Dr. Kuhn teaches, with any reform movement in science, once critical mass is reached there will be no repercussions because the old guard will actually join and move with the paradigm shift. They will even try to lead the shift as they see that leading with the old dogma is not possible and they desire to remain thought leaders and certainly do not wish to be among the last clinging to the old dogma.
The crisis Dr. Kun describes in chapter 4 is upon us. Look around. Do you see that the public cannot help save themselves. It is up to us to begin this revolution. Don’t let this crisis go to waste. Again, it is up to us. There is no back up.
I feel sorry for the Arise team. How much time was wasted? How many man hours? How much time, resources, and good data, which could have been acquired to determine the many actual phenotypes of sepsis was lost. Yet, it was known by some that the unified phenotype of sepsis/septic shock was guessed. Why didn’t anyone tell the ARISE team their “true state” was a guess. Wouldn’t ARISE have been performed differently if that was know to the statisticians.
Why didn’t anyone tell those in Zambia before they treated infected HIV patients with EGDT? Did anyone who came through the supra normal values era really think that Rivers treatment group was representative of the broad population of severely infected patients? One size fits all in sepsis? Really? That doesn’t even work for socks …phenotypes of feet differ.
You men and women are very smart. This blog.. Ollie’s, Scott’s. These are awesome for an old trench warrior – who spent his life at the critical care beside – to read. You understand the complexity. One day you will see that I am one of your greatest allies. You will see that you have been working in a well meaning paternal science and Dr. Kuhn warns of the loss derived from well meaning paternal science. .
I know I cannot expect all of you to rise up and call for reform. Dr. Kuhn says you cannot. He says that cannot happen until another fundamental pathway upon which the science can rest is found. That will not happen until the science moves to identify the varied phenotypes of sepsis.
Once I thought (many years ago) that armed with his teachings we might not be doomed to make the same mistakes. I have learned over the past decades that, while science changes…scientists do not.
One thing I lament is the loss of a good tool like SVcO2. I wrote about the complexity of SVO2 and how to consider these complexities when using SVO2 as a physiologic marker (a tool) in 1985s, This is long before anyone thought one could select a SVO2 value and write a protocol. No one thought in those simple terms in those days. Now, in the era of threshold science, it’s “guess the threshold, come to a consensus on the guess, apply for a grant and…. study it in a RCT (without telling the statistician that the “true state” is a guess)..
All I can say is, don’t let them study bedside ultrasound with the simplistic thresholds and a guessed unified (one size fits all) phenotype or that tool like the SVcO2 might be quickly discredited also..
If you let leaders define their own guessed protocols and control them from a central authority you will wind up using only the tools which they think, as a function of their simplistic “true state” threshold world, are proven..
Now that’s certainly food for thought at a deeper level!
Lawrence, we will certainly have to discuss SCVO2 at some point – I also agree that, well integrated with other modalities, it can provide insight into hemodynamic optimization.
These arguments are well intentioned, but they are, in my opinion, off the mark on a couple of levels.
First, the “N of 1” notion. If this were REALLY true, then we could toss out the collective knowledge of patient care that we have garnered through a lifetime of our own experience, not to mention the experience of others. Why would I use antibiotics in THIS infected patient if the experience of “most” patients is of no use to me or my patient? You may protest that this isn’t what was meant by the proposition. The collective experience of “most” patients with antibiotics seems too obvious for us to ignore. And the notion is too compelling – if you can kill bacteria in “most” patients, why not in this one?
Yes, this feels to you as a reductio ad absurdum argument. But I say this – if the “N of 1” argument has legs, then it should stand up across the board, for all clinical circumstances – or, at least for most. I can easily dream up an infinite number of clinical circumstances where this “each patient is an individual and will behave differently from most patients” argument falls down. So can you. Frankly, the entire argument isn’t even actually trying to achieve N=1. Do you not seek to define a phenotype, so that those with that phenotype will be treated in one way or another? Everyone? Or only some? Why define a phenotype, unless those who have it can be expected to behave in one way or another with some form of treatment? Why have the biological sciences at all, if we cannot from them derive some truths that are universal?
We will use antibiotics in this patient precisely because science tells us that a combination of them is highly likely to kill some combination of bacteria, and because the collective experience of the literature, our teachers, and ourselves tells us that this patient stands a high likelihood of responding like “most” patients. In truth, I typically see the “N of 1” argument trotted out when the arguer simply doesn’t like the opposing argument, which is illustrated by your post. In this case, the opposing argument is that the currently accepted definition of sepsis has substantive meaning, and that it is something more than a guess.
The author who calls our working definitions of sepsis, severe sepsis, and septic shock a “guess” simply does not have a long enough memory. I, myself, have vivid memories of the patient who set my career on a whole different path, the patient for whom I first asked myself, “Does this man have sepsis?” It was October of my internship, 1983, and I was called to the CCU to evaluate a man who was febrile, tachycardic, tachypneic, and with altered mental status. It was the CCU, so I first checked physical exam, EKG, and cardiac enzymes. Nothing. I called my supervising resident to come, and I asked him, “Do you think this is sepsis?” To which he replied, “I don’t know, maybe, what makes you say that?” I didn’t have a real answer, but it didn’t take long in the library for me to figure out that no one else did, either. The best definitions of the time suggested a need for demonstrated bacteremia. That seemed a bit wrong to me, because it seemed silly to wait for 24 hours or more to prove that before initiating treatment. Luckily for me, it also seemed wrong to a man who had previously been an assistant professor at my own institution (the University of Kansas), Roger Bone. It seems that, beginning in the late 1970’s, while working at KU, he had proposed a syndromic definition of the condition and had set about determining whether his definition had some validity. In 1983 he had not published that, yet. But, by the time I was his fellow at Rush he had evaluated his definitions, risk-stratified patients according to them, and used them to study therapeutic strategies. It was on the basis of his investigations that the critical care community found our current working definitions to be preferable to older definitions and published them in 1992.
“Not enough”, you may say. Roger would agree with you, and so do I. Even in the late 1980’s he was looking for better ways to characterize patients with severe sepsis, and so were those of us who worked with him. The initial segment of my academic career was spent in characterizing the TNF response to gram negative and gram positive bacteria and in determining whether patients’ responses could be phenotyped on that basis. Were he alive now, Roger would applaud any and all attempts to better stratify on his definitions, or even to replace them. As long as the replacements are characterized, tested, and demonstrated to have meaning and efficacy. Until now, there are few phenotypes characterized, and none has jumped the hurdles of prospective efficacy testing. Many involve laboratory testing that is simply not available to the average intensivist. Ideas abound, and attempts to test them abound. Your post sounds as if there are no attempts being made to replace what we have, but the attempts are there. They just haven’t jumped all the hurdles, yet. I agree, though, we must keep trying.
I want to take a moment to mock myself. One of the reasons I deplored rheumatology as a specialty during my residency was the absolute reliance on syndromic definitions. But it wasn’t just that. It seems that a rheumatologist can just set aside whatever portion of the definition that he or she doesn’t like. ANA negative lupus? What are you talking about? Either it is or it isn’t caused by antibodies to DNA, right? Or, if the syndrome “overlaps” we have mixed connective tissue disease. Yes, they have made some progress through the years. We know that this or that antibody is “more likely” to be associated with this or that disease. Or this or that gene mutation. But we are rather mushy all around in our definitions of diseases as syndromes. Sound at all familiar? It is beyond me why it drives me crazy in rheumatology, but in critical care I have some equanimity about it. Perhaps it is because it all plays out much faster in the ICU. I don’t know.
Meanwhile, if you think that where we are with diagnosing severe sepsis now is a guess, then you have not been out of your ivory tower in awhile. I have spent the better part of the last decade attempting to teach people in hospitals across the nation, but especially in my own state, that these definitions have some meaning. Teaching them that one does not have to wait until shock is present to get aggressive. Coercing them to collect data on whether they are recognizing, whether they are treating, whether they are effecting better outcomes. I can assure you that the data collected show this: without organized efforts they do not recognize, nor treat aggressively, while with organized efforts they recognize better, treat better, and save more lives. In my own institution, the mortality rate for severe sepsis, which sat at 49% in 2004, was down to 9% in 2014. With effort, with constant training, and with vigilance. All while using the SAME “guess” at diagnosis. Meanwhile, it remains a hard sell to hospitals across the nation. Do not believe for an instant that what you know about sepsis translates to the average hospital in this nation or this continent. Yet, they grasp at every argument made by academic skeptics who rail against the “confines of a bad definition” and “the limits placed on us by protocols” to illustrate why they don’t need any particular efforts in their own locale.
The people who will achieve recognition at the upcoming SCCM meeting have understood something that is missing from the arguments in your blog post – that the perfect is the enemy of the good. Had they pitched in trying to find a perfect phenotype to attack, they may have been successful by now. I doubt it, because they have, in fact, continued the search for better phenotypes, along with their current treatment endeavors. But even if they had found the perfect phenotype after all these years, they would have left tens, if not hundreds of thousands of patients dying. Since we are, after all, in the business of saving lives, we must not allow the search for the perfect phenotype to be at odds with our best possible use of what we currently know. What if the American people had said to Henry Ford, “We don’t want your stupid black Tin Lizzy. When you’ve got air conditioning, quadrophonic sound, heated seats, rear cameras, adjustable wipers – hell, when you’ve got a car that will drive itself – then come back and talk to us. We don’t want anything, until we’ve got everything”? What would we be driving now? Horses? Who knows? Our current diagnostic criteria and therapeutic approaches may be Tin Lizzies, but they are helping to save lives far better than the previous horses. And, by the way, the ideas promoted by these people are only just now seeping into the establishment. It is actually the establishment that has resisted most the idea that we should make hay with what we have, rather than watching septic people die while we work on finding just the right phenotype.
Another stop for self mockery. I’d be wealthy man if I had a nickel for every time someone heard me say, “If we’d spent the billions of dollars that have been used to set up an organ procurement system and improving allograft transplants on actually developing artificial organs, we’d have had them by now, and all of this other stuff would go by the wayside.” I guess we all have our axes to grind, eh?
We all dream of a day when a stat test can give us the phenotype/genotype information to individually tailor our treatment. Many people, including myself, are constantly evaluating how to get us there. But it serves no purpose to denigrate the activities of the realists, also including myself, who take the very best info we currently have and attempt every day to make the very most of it.
You make many excellent points in your courageous defense of present sepsis science. No one else has the courage to defend it. I respect much of what you have said and no one can argue that the SSC and individuals like you have made a important difference.Those of you who have dedicated your lives to improving sepsis awareness warrant tremendous respect.
However, it is clear you misunderstand. We are not critical of the sepsis awareness efforts, nor do we doubt that this has had a positive impact.. This is about science, not paternal expediency. Perhaps it was expedient in the past to control the science but now it is time to do real science, studying real “true states”, and generating real statistics.
Our problem is not with SSC public health efforts, we applaud them. Our problem is with confusing the simple guesses of the 1980s for the “true state” of sepsis and septic shock and applying statistics and drawing broad conclusions about “sepsis” when the results really only relate to a group defined by the guess and not a specific clinical condition.. That is pathologic science which has not, and will not, render reproducible results.
You say the sepsis criteria were derived from data? Where is that published? Was a band count of 10, a HR of 100-10, and a SBP of 100-10 and a RR of 2 times 10 derived from data? The first step to reform of sepsis science is to present the data so we can examine its validity or to admit, in open forum, that they were guessed.
This is also about transparency of clinical trails. In the discussion section of any trial, the important limitations of the trial should be identified. Yet, in not a single sepsis trial in 25 years was the limitation of using guessed criteria (or simple static thresholds for a dynamic relational condition) as the “true state” mentioned. Nor was it mentioned that a different set of guessed criteria might have rendered different results for the trial. Whether that ubiquitous omission, which pervades the entire standard science of sepsis, is due to expediency or because the researchers have fooled themselves into believing their own guesses were gold standards is impossible to tell.
We also fool students when we give too much decision weight to static thresholds and this can cause harm. A patient with a WBC of 11, 9% bands, and a platelet count of 120 may be profoundly ill. with advanced sepsis. Static thresholds can provide a false sense of security. When such data fragments are promulgated from a central authority to ne trusted and relied upon for critical decision making and applied without an understanding of the physiology and the dynamic relational patterns of unexpected death, this may harm as many patients as are helped.
This is discussed in http://www.ncbi.nlm.nih.gov/pubmed/21314935
This article shows how well meaning, paternal oversimplification can be a pitfall.
Here is a solution:
First: SCCM needs a formal declaration of Glasnost. Allow scientist to openly call for reform of sepsis science without begin labeled as “academic skeptics” for not promulgating the failing dogma. Why do you think everyone stays silent, the young academics cannot risk being called an “academic skeptic” by the thought leaders. You make my point when you attempt to bring that hammer down on me in the end of your argument..
It is ironic to be called an “academic skeptic” by those who, argue for “science” as a function of paternal and utilitarian pragmatism . Using guesses as the true state because it is perceived as pragmatic is not academic, its pathologic science (as described by Langmuir) and generally occurs because good scientists have fooled themselves or are acting under social forces and political expediency..
Here I have to speak to all the young readers. Do not be afraid to be called an academic skeptic or “denier”.. Do not be afraid to speak out against dogma. Popper identifies volitional falsification as a manifestation of a true scientist and so it is. However, Kuhn points out that thought leaders will not abandon their dogma despite falsification.. He points out that that is where Popper’s idealized concept (of science as progressing though events of falsification) fails. Thought leaders will ignore results which falsify their own dogma (even on the 25th anniversary of the failed dogma).
As a matter of fact, be afraid of accomplishing nothing if you are not willing to take risk and speak up and challenge your mentors at the most fundamental level. If he or she does not like that, find a new mentor. Remember that when the dogma fails, and a the scientific paradigm shifts, the thought leaders will scurry to the new paradigm with the same zeal which they employed to protect the old one.
Second: Continue the sepsis awareness process . (Do not worry, Glasnost will not derail those efforts.) Provide awareness along with more advanced education about the dynamic relational patterns of the lab and vitals in sepsis (Teach nurses the type I pattern of death rather than placing reliance on a WBC of 12). For example we should teach that the WBC often falls to normal in sepsis after it rises and that while WBC is useful, reliance on any WBC or band threshold is a pitfall.
Third: Determine the phenotypes of sepsis with a large clinical trail which collects all the data. What are the different dynamic relational patterns of sepsis. These are the signatures of the different phenotypes of sepsis. The sub sets of the patterns of sepsis death.
I respect your response. None of the thought leaders dare enter the social media when their fundamental dogma is questioned. They stay where they can close discussion. However youhad the courage to read my article and publically challenge the premise. I am very thankful that there are courageous men and women like you out there passionate about saving lives and advancing science.
I would be happy to continue this discussion in open forum here. Bring reinforcements, the heavy hitters of the old guard. I am ready to be shown that I am wrong in public and that sepsis science does not need to be reformed. No more paternal control of thought.. Glasnost.
And to all the readers,… unless I am proven wrong, in one voice, call for glasnost and reform of sepsis science at the upcoming SCCM.
I don’t think the thought leaders will be doing any more defending. I’m still hoping they do.
To all the young scientists, I wanted to illustrate the objective, very real, and instant results of paternal control of sepsis science which goes beyond SVcO2 and protocols. See the ambitious study linked below. This type of research occurs when researchers rely on the fundamentals of the past (which they should be able to rely on) and no one is told (perhaps for paternal reasons as cited in the earlier comment) that the sepsis criteria were simply guessed. We have already indicated that the ARISE team was almost certainly not told that the standard sepsis “true state” for research was guessed and not derived from data.
Note this linked massive genome-wide study attempting to match the guessed unified phenotype of sepsis to actual SNPs. The genetic information is real but the unified sepsis phenotype is a guess so, of course, the findings are minimal.
This is why we cannot have a situation where we suppress dissent to produce a picture of solid science for the purpose of moving government and hospital administrators toward a well intentioned goal. This may seem like a good idea and may even be beneficial for a while. The problem is that many researchers do not get the memo. They don’t know sepsis science is paternally pathological. They think it is real (fundamentals based on solid data) so they waste time and dreams researching a “true state” which is not based in science. We cannot afford to waste research in the interest of maintaining the appearance of lack of dissent.
A steadfast insistence that present sepsis science isn’t really science does not constitute an argument. I see from the hyperlink you include that you are definitely interested in genomic, possibly proteomic explanations for the syndrome. The particular article is, indeed, science, but in what way is it usable for patients? There is no scenario in which the information in it helps me to either diagnose a septic patient or treat them. Unless that science is pursued much, much farther. This reminds me of one of my favorite quotes: “We have not succeeded in answering all our problems. The answers we have found only serve to raise a whole set of new questions. In some ways we feel we are as confused as ever, but we believe we are confused on a higher level and about more important things.” That didn’t originate with sepsis, nor even with medicine, but a careful look will, I think, reveal that the thought applies. It also reminds me of where my own career in sepsis research began, investigating the role of TNF alpha in the pathophysiology of sepsis. The observations are still pertinent, but they have not helped me or anyone else to save lives. Observational associations will not help us, unless they are turned into real diagnostic tests or adequate targets for intervention.
I feel as if you are tilting at windmills when you attack the “old guard”, whoever that is. There is no such thing as paternal control of science, although I will grant you that the history of science is full of attempts at control. Science always wins. Along those lines, I am personally acquainted with the principals of the Surviving Sepsis Campaign and I know all of them to be encouraging of new science, not suppressive of it. The campaign, itself, has changed its recommendations based on new evidence. The members of the campaign are intellectually honest. Period. They would never suppress evidence, nor try to hold down good science. I am convinced that you are mistaken on that account.
Something else is troubling me about your argument. I don’t think anyone believes that the combination of infection, SIRS, and organ dysfunction is some sort of a complete descriptor of the state of sepsis. In reality it is, as Roger Bone described it, a syndrome that is recognizable to human beings who, as of yet, do not have x-ray vision or chemical sensors built in. So far, we don’t have even the tricorder. Roger recognized the syndrome not by guessing, but by careful observation of the patients he cared for (much like your observations about WBC). He did clinical studies to validate his observations and show that the syndrome was associated with a mortality consequence. It will, by the way, always be true that even when we have “the” stat lab test for sepsis, human beings in the form of physicians will need to recognize the need for sending it. And it will still be true that the sooner treatment is initiated, the more likely a patient will be to survive. Unless we develop the diagnostic tricorder, we are always going to need to initiate treatment based on data that we derive from physical examination.
All of that in no way negates your argument that more and better understanding of the pathophysiology of sepsis, its genomics, its proteomics, its epiphenomena is necessary and desirable. The steps you propose are the steps we need. So do it.
We do not say the sepsis science is not “science”. We say that it is pathological science. Langmuir describes “pathologic science” as a science advanced by a group of often brilliant scientists who use the scientific method BUT make a fundamental mistake which they do not recognize. They are encouraged by threshold interactions which carries the enthusiasm forward with many papers often for decades. Eventually the “dramatic” results of earlier trials prove NON-REPRODUCIBLE. The number of disciples falls off and eventually the mistake is discovered and the science disappears. We are simply disclosing the mistake and explaining WHY the trials have failed. We are calling for transparency and are not attacking anyone.
Sepsis science is a classic example of Langmuir’s “pathologic science” . The sepsis criteria were considered the STANDARD for defining the “true state” in all sepsis research and this was the mistake in the scientific method which absolutely requires a VALIDATED “true state”. Even accepting your arguments that the sepsis criteria comprise an choice by someone brilliant like Rodger Bone, who we all respected, this does not change anything. Best guessing is best guessing no matter who does it. In Rodger’s days the “true state” of sepsis was thought to represent a “unified phenotype of sepsis” but we now know that a unified phenotype of sepsis may not even exist. All the large RCT trails using the unified phenotype as defined by the guessed “true state” have proven non-reproducible.
It is as if we are in the 1950s trying to figure how to treat “growths” on the body and we defined a expert guessed set of criteria for a unified phenotype of a growth or “neoplasm” and then treated all of neoplasm by the same protocol and had some initial encouraging results due to fortuitous patient mix and threshold interactions. In the end additional research using the unified phenotype would be non reproducible.
This is why the genomic wide investigation or any other investigation using an expert guess as the “true state” fails. I simply cited that genomic article to show why ALL research efforts based on pathologic science fail and how this is a waste perpetuated by lack of transparency.
We are working to define the actual phenotypes of sepsis. This education is simply to open minds.
It is said that failure to intubate the trachea occurs due to failure to recognize that one has not intubated the trachea. So it is that failure to recognize that sepsis science is pathologic prevent resources from moving the science from its failed position of generating non reproducible results.
I want to thank you for engaging in defense of sepsis science. This kind of dialog is what the young researchers need to see. If you do not think they are afraid, you are wrong. One young scientist recently told me that the old guard is just going to have to retire before the science can move on. They have careers, they know the politics of academia and… they are afraid.
If you desire to assure they will not be afraid, even if you do not call for reform, please join us and call for transparency. Let the limitations and origins of using simple threshold criteria for a complex dynamic relational condition be widely promulgated. I have confidence that once we set them free of the sepsis dogma and the grants can flow to fund a new direction for sepsis research, this new generation of young scientists will deliver the breakthroughs we have witnessed in so many other fields of science.
To further explain for the young docs who may think they can rely on thought leaders without examining the fundamentals for themselves:
A contemporary example of “pathologic science” was the science of peptic ulcer disease in the 1980s. This is before most readers time but Dr. Simpson will remember it well. Here brilliant scientists (almost all of them) “knew” that peptic ulcer disease comprised a single unified phenotype fundamentally caused by hydrogen ions. They performed massive research directed toward that perceived phenotype and at times, it worked. This went on for decades and seemed irrefutable given that in some settings excess hydrogen ion (e.g. Zollinger-Ellison syndrome) was the fundamental cause of peptic ulcers. They resisted the argument that there was another phenotype which was caused by bacteria. Eventually they could not hold. No one believes in the acid theory of peptic ulcer disease anymore but a zealous “acid theory denier” could find him or herself quite lonely and isolated in academia the early 1980s. This is what Dr. Kuhn says WILL happen and not even Dr. Kuhn knew how to prevent it.
The thought leaders don’t have to reform sepsis science, they just have to formally promulgate that just maybe it should be FUNDAMENTALLY reformed. However this must be described by the leaders as a potential fundamental reform not a new consensus for a new set of thresholds. Then the gates will open for the young docs with fresh ideas.
The thought leaders have accomplished so much and have saved so many lives. That legacy will not be lost. There is no downside. Join us, and call for reform or at least suggest that formal consideration fundamental might be a good idea.
Now after reading this, if you reread the linked article below, you will see that it is not an attack on thought leaders but rather it is simple a story of good science on its normal path full of deviations on its way toward truth. It is a story which is repeated over and over by ALL of US as we try to solve the worlds problems.
One final point. Although I am not familiar with your specific TNF alpha study, I will provide an explanation as to why all those biomarker trials failed.
Your study probably used the sepsis/septic shock criteria as a unified phenotype defining the “true state”. In hundreds of biomarker trials that has never been reproducible in over 2 decades.
TNF, IL6,. Procalcitonin, CRP, may each be useful for some phenotypes but since there is no unifying phenotype of sepsis they do not work well for that. One cannot identify a biomarker for a condition which does not exist or exists only in the minds of a thought leader group and their disciples.
This exposes another consequence of pathologic science. Industry realizes the science is sick and stops funding trials. This is the case today.
I have provided a plausible and well reasoned but politically unpalatable explanation as to why your studies and all the other biomarker studies failed. They all had a common fundamental flaw which rendered the science pathologic ( i e they all used of a guessed unified phenotype which does not exist as a standard for statistical analysis.)
So, I feel sorry for you just as I do for the ARISE team. You were probably unknowingly researching the 1980s unified phenotype of the sepsis dogma and no one can be successful doing that. This is hardly your fault. Everyone believed in the universal phenotype of sepsis in those days.
Of course we know better now . We are trying to generate epiphanies among excellent researchers like you which will open minds. We are trying to keep the young from following their well meaning mentors into the cul de sac.
We are at a dead end with industry pulling out and gov. grants still chasing the dogma ( Paternal control of the science as a function of funding) . Yet shaking off the dogma we have learned much and future is very bright.
If you collected enough timed data on each case and get IRB approval we could re study your data to see if TNF proves useful certain phenotypes of sepsis within your subject group. We could do this for all biomarker trials and even ARISE if they collected enough timed relational data to characterize the phenotypes.
Anyone reading this, let me know if you have the data and desire to restudy your data against a wide range of dynamic relational sepsis phenotypes. We can provide funding for that effort.
I want to applaud again the courage of Dr. Simpson. We have reached out to many other sepsis thought leaders for over a year and they decline to defend their science. Perhaps they remain silent hoping for salvation as a function some miracle. Perhaps they are so convinced that they do not see the need to defend their dogma. More likely they are afraid. Subconsciously they must know there is no intellectual defense beyond the pragmatic arguments made by Dr. Simpson. No one is doubting that they are honest and not true believers of their own dogma.
I will leave you with a quote from Karl Popper who died 3 years after the sepsis dogma were promulgated.
“Normal science, in Kuhn’s sense exists. It is the activity of the non-revolutionary or more precisely, the not-so-critical professional: of the science student who accepts the ruling of the dogma of the day… In my view the ‘normal’ scientist is a person we ought to feel sorry for… He has been taught in a dogmatic spirit: he is a victim of indoctrination. I can only say that I see a very great danger in it and in the possibility of its becoming normal.”
Send links to these blog posts to the sepsis thought leaders and sepsis grant reviews and those who participated in ARISE, Process, and Promiss. The fundamental flaw common in these studies will not be corrected (or reasonably masked) by a metanalysis which of course comprises the desperate new hope of present sepsis science.
As true believers we cannot expect the thought leaders to even see the need to defend their dogma but perhaps Karl Popper’s words will make them realize that they should be calling for consideration of reform of sepsis science as a matter of course, all the time, if only to avoid the risk of becoming “normal scientists”.