The Subtleties of the SHOC-ED Trial: Don’t Just Read The Abstract! #FOAMed

So this was my comment to my friend Jon’s awesome discussion on the SHOC-ED Trial, which is certainly interesting.

Jon, great post as always! I do agree with most of it, but would have to caution readers about reading it with the filtered glasses that make people too often take home the message that they want to – usually the path of least resistance (or change). I think your main point and most critical one is that there is no protocol or recipe that should ever be applied to resuscitation, especially single-variable-based resuscitation (eg old school orders like CVP>12 lasix and <12 bolus), and substituting the IVC for CVP won’t help. And from a standpoint of volume-responsiveness, I totally agree, with the understanding that as the IVC gets more plethoric, the percentage of responsive patients will decrease, inevitably, but one cannot predict with certainty whether that one patient will or will not. However, the parallel change is that, as the IVC gets more plethoric, the volume tolerance is likely decreasing as well, so that your benefit to risk ratio is dropping. And of course you can’t recipe that just based on IVC, but should be looking at the site of pathology (eg lung, brain abcess, pancreatitis with ACS, etc…), physical exam, to determine your patient’s volume tolerance. Because we all know that most of that miraculous fluid will end up clogging the interstitium, with consequences ranging from cosmetic to fatal (though usually blamed on the patient being “so sick” in the first place, absolving the clinician from any wrongdoing). So comments like the one previous to mine, stating “give volume and see if the response occurs” are, in my mind, a poor approach. We know from studies that you cannot simply remove the fluid you gave and go back to the start with lasix (glycocalyx damage, etc), and we also know that much of the effect of said fluid administration dissipates in minutes to hours (I’m sure Jon can quote these studies off the top of his head!).

As we have discussed in the past, I think POCUS is much underused as a fluid stop point – most of its use is on the ‘let’s find a cool reason to give.’  I would argue that you should hardly ever give fluid to a full IVC (especially if markers of pathological congestion are present – portal vein pulsatility and all), unless you are dealing with temporarily improving tamponade or tension pneumo, because even if you are volume responsive, you are likely not volume tolerant. This also goes to the point that a single, initial POCUS exam will potentially not have the same impact as a whole POCUS-based management which will use it to reassess congestion status, cardiac function, etc.

Having said all this, the most important part of the SHOC-ED article is, in my mind, their discussion, which is full of all the important reasons why the final conclusion is not `we don’t need to do POCUS in shock,’ which is what I see happening (similarly to the TTM reaction), as they outline the cognitive fallacy of putting on trial a diagnostic tool whilst the therapeutics are not yet clearly established. Those only reading the abstract or conclusion will actually miss the important points of this study which the authors clearly explain.

In particular, the ‘rare’ instances of tamponade or aortic aneurysm or PE in their series would be diluted out by the sepsis, but for those patients, it would matter. As the authors state:

‘one might argue that even a single unanticipated emergency procedure would justify the use of POCUS in critically ill patients.

I would have to wholeheartedly agree.




Kylie & Korbin chime in to the Venous Congestion Issue. #FOAMed, #FOAMcc, #FOAMus

So I think much of the awesomeness of #FOAMed is sparking discussion and exchange, and the many little steps in clinical management besides the initial prescriptions. So I thought I would highlight and exploit a couple of really interesting reader comments:

So first, Kylie (@kyliebaker888):

Great to listen guys, thanks, and very timely. I had just read Tremblay’s paper after coming across a very pulsatile PV in a relatively well elderly patient with bad TR. Two questions – which PV are more likely pulsatile in the first place….Tremblay mentions RVF/TR and very thin folk. What is your experience?
Second Question – what did the GB wall/GB fossa look like after the initial very positive fluid balance? Does everyone blow out their GB wall with fluids, or only some?

It is always important to isolate the patients’ whose physiology may change the clinical signs (in this case PV pulsatility) and make their interpretation different. I agree that massive TR, especially chronic, would likely account for pulsatility. I am not certain about the physiology for the very thin patient, but I have heard the same thing from Andre.  So my personal take on a patient with severe TR and a pulsatile PV would be to look at the IVC variation, TR notwithstanding, if it is fixed and plethoric I would diurese – the organs don’t care what the cause of the congestion is.  

As for the GB, I have also seen edema, and then try to correlate with cholestatic enzyme changes that would be out of proportion to the hepatocellular enzymes if there is a primary GB process. This is certainly an imperfect science. In a critically ill septic patient, I have a low threshold to drain the GB if in doubt.

Then Korbin gives his two cents, and then some! 

Great case, loved it. Thoughtful management, brilliant!

I couldn’t help thinking as I listened, that it is so important to avoid over-resuscitation with fluids in the first place. We all know that the majority of crystalloids given will end up as interstitial edema, so any benefit from the increase in stroke volume is temporary at best (consider carefully what you gain and at what cost). Wet lungs=increased mortality, days on the vent, and ICU stays. Wet kidneys=AKI 2-3 days after initial resuscitation and potential RRT. Congested liver=gut edema and continuation of inflammatory cytokines/sepsis syndrome. Too much fluids–>BNP levels rise, high BNP levels in the presence of LPS=glycocalyx shedding, and more interstitial edema everywhere.

Cannot agree more.

I think there is some decent evidence that an early fluid liberal approach combined with a late fluid restrictive approach can potentially benefit a patient in septic shock, but its clear that an overall positive fluid balance does harm. Perhaps, even the early fluid liberal strategy (in sepsis specifically) should be tempered by a careful consideration of what is really going on.

My take here is that, by using POCUS, there is no need for a “general approach.” POCUS takes essentially no time. In about 5 seconds you can confirm a small IVC that can (initially) take fluid, a medium one (that you need to watch) or a full one (yes, it happens – that gets no fluid). So to me there is no need to have a pre-determined approach…

Sepsis is an entity characterized by venous return being limited by a decrease in mean systemic pressure (MSP) due to an increase in venous capacitance, rather than a decrease in fluids that generates the stressed volume (MSP=fluid filling/venous capacitance). The body compensates with an adrenergic response that maintains (or attempts to maintain) MAP by an increase in a catecholamine driven augmentation in cardiac output/contractility. This adrenergic response likely has more to do with the increase in lactate production observed in sepsis, rather than actual tissue hypo-perfusion and anaerobic metabolism mechanism. Increases in CVP inhibit venous return and congest the kidneys and GI tract (the left atrial pressures are the equivalent problem for the lungs, combined with the fact that pulmonary vascular permeability is increased in sepsis as well). Given this, I think in distributive shock, we should fix the lack of MSP by an earlier vasopressor therapy approach, both to supplement and decrease the crystalloid load to the patient, which is un-natural and contrary to their deranged septic physiology.


Also, could the type of crystalloid given be important? NS gives a considerable sodium load compared to LR, and this likely promotes/sustains fluid retention that is difficult to remove during de-resuscitation. The high chloride levels of NS will promote an increase afferent arteriolar vasoconstriction and thus decrease GFR, making it more difficult to diuresis the patient later on, and contribute to AKI beyond the iatrogenic interstitial kidney edema caused by the crystalloids we gave.

Absolutely. NS is given by medical peeps only by cultural habit. Most do not know the pH (zero SID due to chloride) of  a solution they give by the buckets. RL is the best option I have available.

If you are involved in the early phase of resuscitation of a shocked patient, consider the downstream consequences of your fluid strategy that you give your patient that may give you a temporary comfort because they will look better in the short term.

Dr. Maitland and the FEAST study corroborates exactly this.

This is not to say that an aggressive and upfront resuscitation is not critical–it surely is. I’m saying resuscitate smarter, not wetter. Look for stop points for crystalloids–E/e’ ratios, consider PVPI, RV dilation/TAPSE, hepatic vein doppler, IVC dynamics, portal vein pulsatility, intra-renal venous Doppler patterns and renal resistive index. Fix the hemodynamics from an approach of the root of their problem, rather than pushing fluids for every hypotensive patient (whether you are taking care of them early, or late in the time frame of their illness). Fluids do have their place, but be careful and cognizant of their real down side. Look at your patient, think it through, and make the best actions for them.

Ok, now I don’t even get to have a punchline. Thanks Korbin!

So if this interests you, tune in to The Great Fluid Debate at H&R2018, and I look forward to meeting both Kylie and Korbin who will be in attendance and, I’m sure, putting us all on the spot!

And yes, there will be a POCUS workshop on portal and hepatic vein POCUS.

click here if you want to take part: H&R2018




The Hospitalist & The Resuscitationist. Montreal, April 18th & 19th, 2018. #Hres2018


So for this winter, we’ve put together a little gem of a conference which will be a mix of hospitalist and critical care medicine, both with a dash of POCUS for good measure. Our focus here will be short, to the point, highly relevant and highly physiological talks on key topics, in short, 15 minute talks.

What are we going to talk about?

Day 1: The Hospitalist


Day 2: The Resuscitationist



You can figure there will also be late-breakers, “ask the crowd” talks and more.

Workshops? Sure:

Yup. You can ask for a workshop. Enough similar requests will probably make it happen. A few have already asked for Neuro-POCUS, so that is a likely addition.


So, who will be talking?  The lineup already includes Andre Denault, Josh Farkas (@Pulmcrit), Jon-Emile Kenny (@heart_lung), Rory Spiegel (@EMnerd), Hussein Fadlallah, Peter Barriga, Daniel Kaud, Davide Maggio, Michael Palumbo, William Beaubien-Souligny, and a few more to confirm. And who knows who might do an impromptu drop-in…


The short answer is yes. Of course, it does depend on what you do. If you are a hospitalist, involved in critical care or acute care of any kinds, you will find something here for you. Totally awesome for IM residents/FM residents planning on doing some hospital medicine or ICU coverage. Who will get the most bang for his or her buck here? Real docs training or working in the trenches. This isn’t a cutting edge research conference, but a cutting edge clinical application conference.


Oh yes, and the CME, of course:


This will be a small, fun conference. Space is purposely limited, for an intimate feel and to encourage discussion between peers. No need for these exclusive “meet-the-professor lunch” or anything like that: that’s what the whole event is like!


Registration is open! Print, fill, write a cheque and send the form below:


If you’re crazy busy, or have any questions, feel free to email or tweet (@ThinkingCC) to reserve a spot! 

Download the brochure here:

H&R2018 Brochure – Participants




The H&R 2018 Scientific & Organizing Committee:

Dr. Philippe St-Arnaud – ER and Critical Care doc, POCUS instructor and constantly pushing the clinical envelope.

Dr. Carola Zambrana – our Hospitalist on the panel, constantly seeking excellence in care and working on bringing POCUS to the wards.

Dr. Mario Rizzi – our friendly neighborhood respirologist and educator.

Dr. Philippe Rola – Critical Care doc, long time POCUS aficionado and instructor, working at bringing POCUS into the everyday physical exam.


Fluid Stop Points! More POCUS goodness from Korbin Haycock. #FOAMed, #FOAMcc

I am really enjoying this exchange, and I think it is in the true spirit of #FOAMed to foster these discussions, as we have the opportunity to combine and fine tune our understanding of a topic from several really bright people’s view and experience. 


Jon-Emile, excellent points and insight. I should clarify a couple of my comments. To be specific, by “renal vein flow” I am referring to intra-renal venous flow. Apologies for my imprecision! Thanks for pointing that out.

Yes, a lot of these renal and portal Doppler patterns are surrogates of CVP. But I don’t think any of us would use CVP in isolation these days to make any decision what-so-ever on whether fluids were indicated in our patient.

Also, to clarify, I am not using intra-renal venous flow or renal resistive index as measures of non-fluid responsiveness. Rather, I use these measures as a stop point for attempting to solve the patient’s hemodynamic dysfunction with crystalloid regardless of whether or not my straight leg test tells me the patient is still fluid responsive.

And that is a key re-iteration to me. It is important to set these stop points and not only look at whether the cardiac output can be maximized. This has been tried. And failed. Let’s remember that sepsis is not inherently a disease of low flow. It isn’t cardiogenic or hypovolemic shock at the core.

My rationale for the strategy of using intra-renal Doppler, E/e’, and Lung US (now, I can include portal vein pulsatility) as a stop point for IVF administration is that I think the patient is best served to avoid iatrogenic edema of the upstream organs, primarily the lungs and the kidneys. These are the two organs (maybe you could put the endothelium in this category as well–glycocalyx being a whole other can of worms!) most easily damaged by the chase for optimizing every bit of fluid responsiveness. We have good evidence that getting wet lungs and swollen, congested kidneys is a bad thing, and we have these tools to hopefully warn us when we are pushing things too far.

Absolutely. And the whole glycocalyx is something to keep in mind, even if only to me mindful to disrupt it as little as possible.

Of course renal resistive index, intra-renal venous flow, portal vein pulsativity, and whatever else you like will have limitations and confounders. As long as you understand what can cause abnormalities with these tools, you can make an educated guess as to what’s going on. If our creatinine is off and our RRI is high, but intra-renal venous flow and portal vein flow is normal, perhaps the RRI is caused by something other than renal congestion, like ATN. If the portal vein is pulsatile, but the Doppler patterns of the hepatic vein, kidney and the heart look ok, maybe something else is wrong with the liver. But, if all our modalities are in agreement and pointing to congestion, we should perhaps believe that it’s congestion and stop the fluids. 

That is an awesome approach to integrating RRI. I’ve been toying with it for the last couple of days, and much thanks to Korbin, I think that the limitations of RRI can be overcome by using the rest of our clinical and POCUS data.

It isn’t a hard technique, though in some patients getting a good signal can be tricky.

I think that the kidney, being an encapsulated organ, and the fact that much of our crystalloid ends up as interstitial edema, the kidney will develop sub-optimal flow patterns before CVP would cause congestion. The same is true regarding the lung, except that it’s just related to increased pulmonary permeability due to inflammation. Regardless, the idea is to save organs, and the earlier you can detect the problem, the sonner you can stop battering the more delicate organs with fluid.

As I think we have all mentioned, you really have to look at the whole picture, and put it together to tell the story of what is wrong, so we can logically and thoughtfully treat our patients.

I really appreciate this discussion. Thanks!



Thanks to Andre, Jon and Korbin for making this very educative for all!





ps don’t miss the POCUS Workshops on venous assessment at  !!!

A Discussion on Fluid Management Protocols with Rory Spiegel. #FOAMed, #FOAMcc, #POCUS


So Rory (@EMnerd) is in the process of working on a fluid resus protocol for Shock-Trauma, and asked me if we could have a chat about it, which I feel very honored for – and had a brief impostor syndrome crisis – but it’s always great to chat with people who are really bright, really physiological and after the same goal, to make patients better. Always a pleasure to chat with Rory, so here it is.

I really can’t wait to see their protocol, because I think this is a huge and complex endeavor, but has to be done.  I will try to put pen to paper (probably really pixels to a screen but that doesn’t sound as good) and put what I try to do for fluid resus on a diagram of sorts.

Love to hear comments and questions.

PS please skip the first 30 seconds which are a technical blank… Ièm not tech saavy so can’t trim it!




A great comment by Dr. Korbin Haycock

One issue to consider is the degree of pulmonary vascular leakage. If, as in the case of sepsis, the pulmonary vasculature is more prone to the development of lung interstitial edema, lower LVEDP’s possibly will still result in as much lung wetness as higher LVEDP’s. Therefore, reliance of E/e’ ratios may not be the best measure of a fluid resuscitative endpoint in sepsis (and aren’t we really talking about sepsis resuscitation here?). I believe that it’s relatively clear that EVLW will adversely affect outcomes, but pushing for every bit of increased stroke volume/fluid responsiveness is less clear to be beneficial, even if it makes sense from a DO2/VO2 perspective (which may not be the real issue in sepsis anyway, as mitochondrial utilization of the DO2 provided may be the real problem, rather than DO2/VO2 balance). If the assumption is that the kidneys and lungs are the most delicate organs and most at risk to over aggressive fluid administration, and will impact mortality/LOS in the ICU, perhaps a combined strategy of attention to E/e’ ratios, development of B-lines, or the renal resistive index increasing would be a signal for a different strategy rather than fluids to increase venous return (i.e. switching from crystalloids to norepinephrine or vasopressin if the CO is elevated and will tolerate a minor ding from the increase in SVR). If any of those three variables indicate a problem, stop the fluids, switch to a vasopressor. If the issue is the CO rather than the SVR, use an inotrope instead. Of course RV/LV interactions as mentioned in the comments above must be considered. No point in giving fluids to an empty LV if the RV is failing–you’ll just congest the kidneys.

Fluids in Sepsis: An EmCrit Webinar! #FOAMed, #FOAMcc

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So a few weeks ago Scott (@EmCrit) asked me to be part of a pretty cool webinar organized by the Greater New York Hospital Association about fluids in sepsis. The gang consisted of David Gaiesky, Emmanuel Rivers and moderated by Scott himself. And for some obscure reason, he asked me to be part of it – much to my honour (terror, also), naturally.  It was only afterwards that he told me it was to help stir the pot and be controversial, challenge the “old school” etc… He seemed to have overlooked that I am Canadian, and inherently and perhaps overly polite and considerate – at least live and in “person”!

We talk about a bunch of stuff around fluids, which, how much, how to assess, etc.

Anyhow, I hope I got a few ideas across, but it was really cool to hear that these gurus do use ultrasound – don’t necessarily strictly adhere to, for instance, EGDT, and also advocate that guidelines are guidelines and not necessarily gold standards.

Here is the link to the webinar for those interested:


And here is the figure for the section where I refer to fluid responsiveness/tolerance:

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I further talk about this in a previous post here.

Scott and I also recorded a debrief which should be coming up in the next weeks on EmCrit – link to follow!




Cerebral & Somatic NIRS (Near InfraRed Spectroscopy) in shock states: tailoring therapy. (PART 1) #FOAMed, #FOAMcc

So I’d mentioned using NIRS to monitor and tailor therapy a few months ago, and promised a more in-depth discussion to come, so here we go.

For this not familiar with the technology or the concept, NIRS measures tissue saturation, predominantly venous. Hence physiologically it is akin to central/mixed venous gases, but localized. Cerebral NIRS found its foothold in the OR with carotid and cardiac surgery, but its use is now expanding. Given typical knowledge translation time of a decade, it should end up joining ETCO2 as a routine vital in monitored units, but probably not soon enough.

So in our unit at Santa Cabrini Hospital in Montreal, we’ve had this technology for about a year (the INVOS system), and have been studying its uses. In this time, three applications have stood out:

  1. Finding the “Sweet Spot” for vasopressors.
  2. Confirmation that therapeutic interventions are hemodynamically appropriate.
  3. Cardiac arrest: CPR adequacy, prognostication and detecting ROSC.


  1. Finding the “Sweet Spot” – I think (hope) that anyone reading this with professional interest understands that pressure does not necessarily equal perfusion.  With that in mind, adjusting vasopressors to a pressure makes little sense, and represents at best a guesstimate of perfusion, which is what we really are after. We can all agree, however, that a certain minimum pressure is required, but whether that is 65, 55 or 45 MAP no one can say for sure.  So the way I like to use it is to establish a baseline and watch the direction of the tissue saturation with vasopressor therapy. If the saturation begins to drop off, we may have reached a point at which excessive vasoconstriction is worsening tissue perfusion, and that inflexion point may represent the upper beneficial limit of the vasopressor – this may happen to be under 60 or 65 of MAP.  However, it is key to understand that this inflexion point is reflective of the current state of hemodynamics, such that a change in volume status or cardiac output, in one direction or the other, would likely change the position of this physiological point.  For example,  a volume depleted patient may reach a decreasing tissue saturation point at 55 MAP, but, once volume replete, may reach a higher MAP of 65 or above before a drop in saturation is seen.  Conversely, a patient whose best tissue saturations were around 65 MAP who suffers an MI and sudden drop in cardiac output may now see his perfusion compromised at that same MAP, which would now be achieved with a greater vasoconstriction, less cardiac output and consequently, poorer flow… I posted a case discussion which illustrates this.
  2. Confirmation that therapeutic interventions are hemodynamically appropriate – I feel this is really important. When a patient’s life is literally on the line, and knowing that our interventions are seldom without potential nefarious side effects, it is poor medicine to be introducing a therapy without having some form of monitoring – preferably multiple – that we are headed in the right direction, or at least not making things worse. Of course, we already do this – with BP, sat, lactate, CCO, ultrasound, ETCO2 – but I think using a realtime measure of tissue saturation adds to this. It is also my firm opinion that integrated, multimodality monitoring is necessary – at least until someone develops some form of mitochondrial monitoring which tells us that the cytoenergetics are sufficient to survive. Until then we are stuck with surrogate markers and many of them (e.g. lactate) are the result of complex processes that preclude them being a simple indicator of perfusion adequacy. For instance, when giving a fluid bolus/infusion – after having determined that the patient is likely fluid responsive AND tolerant – one should expect to see an increase in ETCO2 (other parameters being constant), an increase in CO, an increase in NIRS values. The absence of such response should make one reconsider the intervention, because without benefit, we are left only with side effects.

Here is a patient’s cerebral (top) and and somatic (thigh – bottom) and CO values. This patient had an RV infarct and was in shock.



Following initiation of dobutamine, this is what occurred:


Given that we cannot always predict the response to an inotrope – depending on the amount of recruitable myocardium, it is reassuring to see an improving trend. This enabled us to decrease the vasopressor dose significantly.

Note that, so far, and unless some good evidence comes out, I don’t use a goal value, and so far, I have not identified a value that is predictive of prognosis. However, downward trends usually bode very poorly. For instance, I had a severe chronic cardiomyopathy patient whose cerebral saturation was 15%!!!  But more surprisingly, she was awake, alert and hemodynamically stable. Adaptation.

Part 2 and the stuff on cardiac arrest coming soon!

Please, anyone using NIRS in shock, share your experience!





Enteral Fluid Resuscitation? The WHO to the rescue in the ED/ICU? (ORT part 1) #FOAMed, #FOAMcc, #FOAMer

So something has been trotting around my head for a few months, and it actually stems from a small and not-so-proud moment I experienced during a conversation with my wife, while she was still a resident.

She was telling me some of the stories of the day, and how one of her supervisors who had a mixed outpatient and ED practice, always pushed them to use PO fluids, get rid of IVs and get the patients home.  I kind of scoffed, in a sadly typical acute care physician mode, saying how you had to be a bit more aggressive and give them IV fluids to revert their dehydration a bit faster.

Then I caught myself. Hmmm. What exactly am I saying this (con brio) on the basis of. Knowledge, or belief?    I tried to find knowledge but came up woefully short. It seems I’m doing this out of habit, what I’ve seen/learned/believed in the two decades since someone handed me an MD degree. Damn.

So, I do believe in evolution. We have evolved platelets to stop bleeding, fibroblasts and osteoblasts that can fix bones, white cells that go mop up the messes, and all kinds of other good stuff.  One thing we do NOT have is small openings in vascular structures that allow unprocessed, man-made fluids directly into the bloodstream. We make these. We insert tubing into normally sterile environment and infuse a vast number of medications directly into this fragile matrix of cells and organic colloid – with the best of intentions.

In our physiology, however, the ONLY way fluid ever enters the vascular spaces is by diffusion from the outside of the endothelial cell into the lumen, molecule by molecule and ion by ion.

So let me seemingly diverge for a bit…

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Prior to the 1970’s, restricting oral intake was a “cornerstone” therapy of diarrheal illness, due to the pervasive belief that the GI tract needed time to heal and recover before resuming normal function. This was felt to be crucial. Hence, only IV therapy was used (in developed countries), and in the underdeveloped world, the death toll was appalling – especially among children.   In the 40’s, Dr. Darrow of Yale started actually studying the GI tract fluid and electrolyte issue, and advocating oral rehydration with mixed fluids. He was able to bring infant mortality radically down in his practice, but it would take over twenty years before a groups started to formally look at this in the 60’s.  Finally, in the late 70’s, the WHO pushed this out into the field, and the childhood worldwide mortality from acute diarrheal illness dropped by over 70%, from over 5 million deaths a year to a bit over 1 million – at that time.

Oral Rehydration Therapy (ORT) is now felt to be one of the most significant advances in modern medicine. Compared to that impact, all the critical care and cardiology trials are about as significant as a drop in a bucket. We’re not talking about composite end points and subgroup odds ratios of 0.85…

For a great review on this check out The History of Oral Rehydration Therapy by Joshua Nalibow Ruxin (google it).  A great story of science and humanity, good and bad.

So, back to 2015 ED/ICU’s.

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The question now becomes the following: why – in the presence of a functional gut – do I choose to entirely rely on non-physiological IV fluid resuscitation?

I can already hear the roars and the outrage and the cries of heresy.  And heresy is certainly what this is (Heresy is any provocative belief or theory that is strongly at variance with established beliefs or customs – Wikipedia). But that doesn’t make it wrong.

So I would ask everyone – particularly the naysayers, to examine their knowledge and see if they actually have any at all that supports the strong conviction that IV fluids are the way to go in ALL cases (my N=1  principle precludes going for the one-size-fits-all therapeutic approach).

Now everyone agrees that, once patients are better, they should be on feeds with little maintenance fluids. I don’t think many will debate that. So that should be the basis to wonder whether, in the presence of a functional gut, a variable proportion of fluid resuscitation in acute illness should be enteral…

I’ll let everyone digest that.

Comments more than welcome.

More to come in Part 2.





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… 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.


The Great Septic Debate: Science vs Science (Part 1), by Dr. Lawrence Lynn and Dr. Steven Q. Simpson, #FOAMed, #FOAMcc

So after I put up Lawrence’s comment as a standalone post, a rapid-fire exchange began between him and Dr. Steven Q. Simpson, who is another one of these really bright guys I’ve had the pleasure of interacting with on the FOAMsphere.  I thoroughly enjoyed their debate and most definitely think there is a lot to gain from listening to both of their points of view. So if anyone missed it, go back to my last post a few days ago and catch Lawrence’s opening punch, and without further a due,  here is Steven’s counter:

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.

Ok, gotta chime in. The N=1 is, to me, undeniable and cannot be circumvented. Although I understand the necessity for trials, the data cannot be blindly extrapolated to all patients, but rather should represent a step forward, a proof of concept perhaps, another little brick in our understanding. The issue is just at which level one is looking. I fail to see how one has to throw away any accumulated knowledge – if anything some of that knowledge should point to N=1 cases rather than away from it.  How can we on one hand acknowledge the vast variation of organ functions, system responses, etc, and imagine that one shoe could fit all in the best possible fashion?  Antibiotics? No argument at that level, but the N=1 may apply at the level of the dose. We routinely give the same dose to a range of patients, some of which we weight base, some we base on creatinine, but a fair bit of evidence has come around recently to suggest that, paticularly in young and (previously) healthy patients, they may have increased clearance in certain phases of sepsis and that if we were to look at serum levels, we are actually under-dosing.  Serum level-based dosing is coming. But ceftriaxone 1g q24h for everyone may not be best for all, even if it is best for most, and waayy better than no ceftriaxone at all. A great lecture by Jeff Lipman on ICN can be found here:

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.

Ok, gotta give a thumbs up for Steven here, I think this is a great point. The quest for perfection, in science as much as in life, is an antidote for happiness, or good, in most cases, and that those things which are discovered along the way which are good should not be discarded because they are not perfect.  They should represent something to use until something better comes along, and often we may need that footing to get to the next level. There is in my mind absolutely no doubt that EGDT and the Surviving Sepsis Campaign has saved lives, both by detection/awareness and by promoting some therapy and vigilance. This is a massive accomplishment, period.

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.

Steven Q Simpson.

Well, it didn’t stop there: Lawrence replies…

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
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.

This, to me, is huge. This is the era of big data, and we need to have huge amounts of it to pore through and begin to see patterns and associations that were not necessarily (and arbitrarily) pre-determined.  One of these, for instance, that (due to the difficulty in obtaining the data) is never taken into account is the phase of sepsis. No patient presents at Time 0.  They have all waited a variable amount of time, and their individual rate of progression through the stages likely varies. Hence, treatment may vary also. Degree of capillary leak? This in turn may depend on the particular pattern of an individual (eg IL’s and TNF etc) to a particular bacteria. We do not all react the same way to antigens do we?  I don’t have a problem with peanut butter or shellfish. Some people seem to. It’s all immune-mediated.  There are countless amounts of these possibilities which only big data will bring out. Back to you, Lawrence. 

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.

Most Respectfully

Lawrence Lynn

Well, that rebuttal was not to go unnoticed.  

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 definitely agree with Steven here in terms of the need for practical application, and about the escalating confusion, but as physicians, we have to be comfortable with knowing that we are not practicing perfect medicine any more than our predecessors.  Better, but not perfect, and we have to accept this uncertainty as we slowly get more and more answers. Yet at the same time we are bound to do the best we can for our patients and keep a pragmatic, practical approach. Not easy.

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.

The tricorder may not be as far away as we might think, Steven, there is data out there for early detection of sepsis using EKG data in kids (, and the era of wearable tech is just beginning. 

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.

Now Lawrence did have a few more things to add…

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 Promise. 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”.

Most Respectfully,

Lawrence Lynn

Wow. So I think the real winner of this debate is in fact the reader, especially the young ones who can go on to carry the torch. In my opinion this fascinating debate between two experienced academics and clinicians, is really just about perspective. In actual fact, I’m fairly certain they both would treat the same septic patient in a similar fashion, with some fluids, antibiotics and vasopressors, but what we are talking about extends to the future of sepsis care, where both points of view are in fact necessary, the open-thought, “revolutionary” approach of Lawrence, as well as the practical one based on still-imperfect state of knowledge defended by Steven.   I do think that some of Lawrence’s rhetoric is likely a cause of inflammation and perhaps the cause would be best served by more “political” terminology, but my blog being the furthest thing from politically correct, it fits in well here. In his defence, he does acknowledge the immense contribution to the science from those he also takes a jab at. I think it is also a function of “the system” of institutions, journals and associations which inadvertently creates some of this paternalism, rather than it being really promulgated by the “thought leaders” themselves.  Having had the occasion  to interact with some of them myself, they are not all closed minded and religious – in fact, I find more of your “run-of-the-mill” intensivists to have that zealous follower’s attitude of not questioning what so-and-so says, whereas so-and-so himself is more likely to openly admit that hey, they weren’t sure if this was the best target/therapy/etc… but hey, gotta try something and see what happens.  So I hope this debate can help open a few minds, raise a few questions and provide some solid med-tertainment. 

Thank you and accolades to both Dr. Lynn and Dr. Simpson.