NOTE: THIS WAS THE H&R2018 PAGE, SO IF YOU ARE LOOKING FOR H&R2019, CLICK HERE!
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.
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:
So this is one of the key discussions I wanted to have in my process of synthesizing my resuscitation algorithm. Dr. Denault is the one guy I’d call a mentor, and I think one of the rare and true clinician-scholar, who is just as comfortable being the anaesthetist/intensivist at the bedside of the crashing patient as he is being the keynote speaker in major conferences, or writing the textbooks that lead the field in acute care/perioperative TEE and critical care POCUS.
So to put some perspective to this discussion, back in 2014 I organized a resuscitation afternoon for internists with Andre and another awesome guy you probably all know, Haney Mallemat (@criticalcarenow). In a quick 15 minute discussion between talks, he shared with me the most recent of his discoveries, portal vein POCUS as a marker of right-sided failure/volume overload in his post-op cardiac patients, and how aggressively managing these resulted in much improved post-operative courses in terms of weaning, vasopressors and even delirium.
So here you are:
So I’ll let you all ponder that and I would really like to hear comments and ideas. Sometime in the next few weeks I’ll be finalizing my resus algorithm – which will not be a recipe approach, as you might suspect if you have been following this blog, and will rely heavily on POCUS and the clinical exam.
cheers and thanks for reading and listening!
Don’t miss Andre running a POCUS workshop on PV/HV at next april!
Ok, so it was pretty cool to see an NEJM issue basically dedicated to septic shock management, I must admit. But let’s dig a little deeper, shall we?
So here is where they are: http://www.nejm.org, and fully available for now.
I won’t go through all the details and numbers, after all they are in the papers, so let’s just analyze them from two principles:
a. the N=1 principle – how was therapy individualized?
b. was there any integrated monitoring of the therapeutic goals?
…and we’ll conclude by looking at the potential practice-changing potential of each of these studies.
So first of all,
High vs Low BP Target in Septic Shock, by Asfar et al.
So basically a negative study except for two findings, the increased incidence of afib in the high target group and the decreased need for renal replacement therapy among chronic hypertensives in the high target group.
so N=1 is not really revealed:
“Refractoriness to fluid resuscitation was defined as a lack of response to the administration of 30 ml of normal saline per kilogram of body weight or of colloids or was determined according to a clinician’s assessment of inadequate hemodynamic results on the basis of values obtained during right-heart catheterization, pulse-pressure measurement, stroke-volume measurement, or echocardiography (although study investigators did not record the values for these variables).”
So lets just hope that the variability evens itself out between the groups, since we don’t really know. The numbers don’t really tell the tale, because the average fluids received (10 liters over 5 days) could mean one patient got 15 and one got 5 – although let’s trust they followed the French Fluid Resus protocol…
So the atrial fibrillation makes total sense – more B agonism should result in that, and the decreased renal failure also does.
As the authors note, the actual BP averages were higher than planned. For those of us practicing critical care, we know most nurses titrating prefer having a little bit of extra BP – even when I prescribe MAP 65, I usually see the 70 or so unless I make a point to tell them. Understandable. They also note the underpowered-ness of their own study, but I think it is still worth looking at their results.
So…bottom line? I think it’s a great study for a couple of reasons.
The first is to remind us to pay a little more N=1 attention to the chronic hypertensives, and that it is probably worth aiming for slightly higher MAPs.
The second, debunking the myth of “levophed, leave’em dead” (which I heard throughout residency at McGill), and the concept of doing everything (ie juicing patient into a michelin man) in order to avoid the “dreaded and dangerous” vasopressors. So really I think an alternative way to conclude this study is that it isn’t harmful to have higher doses of vasopressors. I think this is actually a really good study on which to base assessment of more aggressive vasopressor support vs fluid resuscitation, in the right patients.
It would have been interesting to have echo data on those who developed a fib – were they patients who had normal to hyperdynamic LVs who in truth did not need B agonism at all and would have been fine with phenylephrine? Perhaps…
Cool. I like it.
Albumin Replacement in Patients with Severe Sepsis or Septic Shock, by Caironi et al. The ALBIOS study (a Gattinoni crew)
So basically showed no difference, so pretty much a solid italian remake of the SAFE study in a sense, confirming that albumin is indeed safe overall, and may be better in those with shock. As the authors note, mortality was low, organ failure was low, so study power a little low as well. Note the mean lactates in the 2’s at baseline. The albumin levels of the crytalloid only gorup were also not that low, low to mid 20’s, whereas I often see 15-20 range in my patients, especially if I inherit them after a few days, as I do use albumin myself a fair bit. They also used a target albumin level, not albumin as a resuscitation fluid purely.
In my mind the benefit of albumin would be greatest in those with significant capillary leak, particularly those with intra-abdominal and pulmonary pathology. It would have been nice to see a subgroup analysis where extravascular lung water was looked at (especially coming from a Gattinoni crew!).
Another interesting thing would have been to know the infusion time of the albumin, since animal data tells us that a 3hr infusion decreases extravasation and improves vascular filling vs shorter infusion times. I routinely insist on 3hr infusion per unit, which sometimes results in 9-12hr infusions, almost albumin drips!
I like it. Reinforces that albumin is safe, so makes me even more comfortable in using it in the patients where my N=1 analysis tells me to be wary of third-spacing. Also the fact that they used 20% – in Canada we have 100cc bottles of 25% for the most part – is nice, since the SAFE data used 4%.
A Randomized Trial of Protocol-Based Care for Early Septic Shock – The ProCESS Trial.
So right off that bat my allergy to protocols flares up, so I’ll try to remain impartial. It just goes against the N=1 principle. The absolutely awesome thing about protocols is that it primes the team/system to react – so clearly protocols are better than no-protocol-at-all, but strict adherence would clearly not fit everyone, so that some built-in flexibility should be present.
This being said, the ProCESS study is really interesting, for a number of reasons. They have three groups, and compare basically (1) Rivers’ EGDT to (2) their own protocol (see the S2 appendix online) which gives a little more flexibility and (3) “usual care”. Net result is that all are pretty equal, no change in mortality. As the authors note, their mortality was low, so again may not have been able to detect a difference.
So, what does this mean. To me it’s a little worrisome because I doubt that the “usual care” represents the true usual care found in EDs/ICUs all over the world, so I am concerned that many docs will use this as a reason to justify not changing their practice, similarly to many I’ve heard say they don’t need to cool anymore after the TTM trial. Human nature for some I guess.
Bottom line? You don’t have to follow EGDT if you’re conscientious and reassessing your patient frequently and have done all the other good things (abx, source control, etc). I think that’s really important because giving blood (see my post about S1P) to those with hb > 70 and giving dobutamine to patients with potentially normal or hyper dynamic LVs never made physiological sense to me, and the problem with a multi intervention study such as EGDT is that you can’t tease out the good from the bad or the neutral. Again, studies such as EGDT are pivotal in changing practice and raising awareness, so this is not a knock against a necessary study, just to highlight the point that each study is a step along the way of refining our resuscitation, and the important thing is to move on. In fact, the reason that this is a negative study is probably due to the improvement in “usual care” that EGDT brought along.
Conclusion: No new ground broken, but these studies do make me feel more confident and validated in continuing to not do certain things (strict EGDT) and doing others (albumin and earlier use of vasopressors).
A great surprise this morning: a comment from John. Yup, THE John. So taking a page out of Scott’s book, I thought it would be worth sharing with everyone as its own post, as opposed to just a comment. I think this is must-read material for everyone.
So without any further adue:
“I thought I might add some quirky ideas to your discussion.
We are now getting familiar with the concept of endothelial cells covered by a surface glycocalyx layer, that forms part of the barrier and mechano-sensing functions of the blood-tissue interface. We have discussed in some detail, the role of the glycocalyx in preserving endothelial integrity. I am gonna try and add a bit more spice into the whole transfusion drama.
In recent times, we have started talking a lot about a bioactive phospholipid called sphingosine-1-phosphate (S1P), as a crucial element in preserving vascular barrier integrity by ‘protecting’ the Glycolcalyx. (Most geeky papers on TRALI and other transfusion related complications do mention it).
Because albumin is one of the primary carriers of sphingosine-1-phosphate (S1P), it is possible that S1P, acting via S1P1 receptors, plays the primary role in stabilizing the endothelial glycocalyx. Infact, antagonism of S1P1 receptors have been shown to cause widespread shedding of the glycocalyx, as evidenced by increased serum concentrations of Heparan sulphate and Chondroitin sulphate. (This might probably be one of the mechanisms how albumin is glycocalyx friendly).
RBC transfusions are a double edged sword…..especially in situations of acute anemia as in post hemorrhagic situations ( major GI bleed or trauma.)….I totally agree with you in that the two are conceptually very similar.
Erythrocytes have been identified as an important buffer for sphingosine-1-phosphate . In mice, depletion of plasma S1P by genetic inactivation of S1P synthesizing enzymes (sphingosine kinases 1 and 2) elicits profound pulmonary vascular leak, which can be reversed by restoring circulating S1P via RBC transfusion.
In humans, hematocrit (Hct) predicts plasma S1P levels. There also seems to be a dynamic equlibrium between SIP levels of the plasma, and the circulating RBCs. It has been demonstrated that in anemic individuals, plasma S1P levels are not uniformly restored by RBC transfusion. Rather, the age of the RBC unit at the time of transfusion tended to negatively correlate with the ability of RBC transfusion to replenish plasma S1P. During storage, the S1P content of human RBC markedly declines, likely due to enzymatic degradation. Because erythrocytes serve as a buffer for circulating S1P, aged RBC with low S1P content may be incapable of restoring plasma S1P levels and may actually remove S1P from plasma, which in turn could contribute to increased endothelial permeability, capillary leak, and infiltration of inflammatory cells.
I hope this partly answers your question as to how the glycocalyx may be impacted by inappropriate and irresponsible transfusion triggers. I agree that these are all very novel ideas and as such, exist in the realm of experimental clinical physiology, but my gut tells me that the delicate Glycocalyx may hold the clue to a lot of answers to questions that have plagued us for a long long time!
Cheers, John from India…”
So first of all, thank you very, very much for reading and taking the time to comment and enlighten us.
As John says, this is still in the realm of experimental physiology, but I think there are a lot of situations we are faced with, perhaps grey zone areas where we debate two potential therapeutic avenues, where we can use some of this data. We might debate giving that extra bit of fluid, or debate crystalloid vs albumin, or blood or no blood with an Hb of exactly 70, and I think we have to start weighing in some of this physiological data, even if it isn’t “evidence-based-by-RTC” to help guide these decisions.
The more I look into it the more it seems that our interventions – particularly fluid resuscitation, needs to be reassessed from the ground up both in nature, quantity and rate of infusion while measuring glycocalyx damage – e.g. biomarkers such as S1P, heparan or chondroitin sulfate, etc…
I’ve previously posted and podcasted about my general strategy for fluid resuscitation, and I am definitely in the process of revising it, still unsure what is best. I’d love to hear how John resuscitates his patients…
Mystery John has an uncanny ability to describe complex physiology in the simplest way possible. I am very interested in digging more into his predictions of the possibility of aged erythrocytes removing S1P from circulating plasma.
Dr. John, if you’re out there, could you point us all to some of these studies you’ve mentioned? Any good S1P review papers you’d recommend to those, like me, who are S1P novices?
Thanks for your input! It was a pleasure.
Thank you Derek, for the kind comments…. I think the concept of S1P is still in the process of evolving and assuming a definitive shape, so a good review might be hard to stumble across.
A good research article which cites some excellent references might be —
This year, as part of the pre-congress courses being held prior to the main symposium (may 10th and 11th), we are introducing a half-day symposium entitled: “The Educators‘ Symposium: How to integrate Bedside Ultrasound into Ungergraduate and Graduate Programs,” coordinated by Dr. Catherine Nix of the University of Toronto who has been the driving force behind U of T’s implementation of an ultrasound program for undergraduates.
Here is the preliminary programme, really good stuff for anyone involved in education, whether at the institutional level or even at the departmental level.
program subject to (minor) changes…
Attendants may register for this independently or as part of the whole symposium. You can register at:
Stay tuned for more updates, and the final programme of the main conference should be out by next week. Guess what, it’ll be a great place to meet @criticalcarenow, @bedsidesono, @EGLS_JFandMax, @nobleultrasound, and many more not yet deep into the #FOAMed or twitter-verse, but soon to be.
Ok, so I’d had a couple of glimpses at articles in the past few years which referred to the glycocalyx, but, in truth, I tend to read most of the “bench” studies a little, well…quickly. So basically, when I listened to Paul’s (Marik) recent lecture at Scott’s (Weingart, emcrit.org) New York Sepsis Collaborative, I started to dig a little…and whoa! And then of course, then now-famous expose by John (Doe?) on EmCrit continued to convince me that this is definitely something I need to pay attention to! Its not like there hasn’t already been a high level of scrutiny of the glycocalyx in the field of sepsis. Google it. Its like a whole new world. It just hasn’t yet translated into an effective therapy, but nor has it seemed to spread into general awareness, and it seems like it’s high time it does, since it is the interface between the blood and the body – a “blood-body barrier” of sorts.
So here we go, a crash course on the glycocalyx for the clinician in the trenches…
The existence of an acellular layer lining the endothelium was described by Luft some 40 years ago (1), and in the last decade has come under scrutiny for its role in various pathophysiological states, which seems to be quite exhaustive. This has not yet translated into diagnostic or therapeutic interventions, but it seems its properties, or at least those we are currently aware of, should be kept in mind when we are faced with therapeutic choices given that some of these may have an effect on the glycocalyx.
Its existence was deduced due to the lower capillary hematocrit – meaning that the hematocrit in the capillaries, adjusted for the luminal volume, is lower than that of the large or medium vessels, implying an area where there are no red cells. This was confirmed by electron microscopy and found to be a gel-like epithelial lining which acts as an interface between the blood and the endothelial cells, of a thickness of about 0.5 um at the level of tha capillaries, and thicker in the larger vessels.
So what is it made of? Its is essentially a meshwork of glycoproteins and proteoglycans, anchored to the epithelial cells, in which many soluble molecules are enmeshed. It is important to note that there is a dynamic equilibrium between this layer and the adjacent flowing blood, which will affect the thickness and composition of the glycocalyx. The layer seems to be vulnerable to both enzymatic degradation as well as to shear forces, in variable degrees. Enzymatic removal of components seems to radically alter properties, pointing to a strong synergistic effect of the various components. It is a constantly shedding and regenerating structure.
EM view of the glycocalyx (reproduced with authors’ permission from Reitsma et al.)
(reproduced with authors’ permission from Reitsma et al.)
– Proteoglycans (protein core with chains of glycosaminoglycans) are the “backbone” of the glycocalyx, and consist of syndecans, glipicans, mimecan, perlecans and biglycans.
– Glycosaminoglycans (linear disaccharide polymers of a uronic acid and a hexosamine) are predominantly heparan sulfate (50-90%), then dermatan sulfate, chondroitin sulfate, keratan sulfate and hyaluronan (or hyaluronic acid).
– Glycoproteins are also part of the “backbone” structure and the main types are the endothelial cell adhesion molecules ( -cams, which are selectins, integrins and immunoglobulins) and components of the fibrin/coagulation system. E- and P-selectins as well as others are involved in leukocyte-endothelial interaction and diapedesis, an important aspect of local inflammation.
– Soluble components are also embedded in the glycocalyx such as proteins and soluble proteoglycans and are important in preserving the charge of the layer and play critical roles in functionality.
Function of the glycocalyx (as far as we know…)
It is a key determinant of vascular permeability. Partial enzymatic removal without damage to the endothelial cells themselves result in a radical change in permeability in aminal models. Charge, size and steric hindrance affect permeability. The glycocalyx has a highly net negative charge towards the bloodstream – neutralizing this induces an increase in cellular albumin uptake.
Weinbaum introduced a new model integrating the glycocalyx in the classical (but now outdated and disproven) Starling model of microvascular fluid exchange. The revised Starling principle stresses the importance of an intact glycocalyx.
Its role with cellular elements is interesting, as it contains key elements for interaction (-CAMs) but at the same time physically prevents direct interaction between cells (WBC, RBC, plt) and the endothelium. This clearly points to a pivotal role in controlling the interaction. Damage by various methods consistently shows increased neutrophil-endothelial interaction (often termed “leukocyte rolling”). It isn’t much of a stretch to see how the glycocalyx will thus be involved in the control of local inflammation.
The glycocalyx provides mechanical protection from shear stress to the endothelium. Increased shear leads to upregulation of synthesis, and correspondingly, thicker glycocalyx is found in high shear areas.
Receptor binding, local growth and repair, and vasculoprotection. For instance, ATIII is bound to the glycocalyx (inhibits procoagulants), as well as superoxide dismutase, key in reducing oxidative stress and maintaining MO availability.
Now this is the real question. I think that the first step is acknowledging the presence and importance of the glycocalyx, and trying to discern which of our interventions may have an impact. It is quite clear that enzymes, cytokines and ischemia/reperfusion all damage the glycocalyx and result in increased cellular interaction and permeability. In a way this can explain the entire “SIRS” spectrum with diffuse damage resulting from an insult that may or may not be infectious in origin. Obviously, we know to avoid anything that might cause the above.
I think we can divide our interventions into two types:
a. those that inherently disrupt the glycocalyx –
b. those that secondarily disrupt it via another mediator – eg over-resuscitation and ANP/BNP (John’s “evil twins”) elevation causing breakdown.
Here are some interesting facts, in no particular order of importance:
a. in acute hyperglycemia and in type I diabetes, there is significant loss of glycocalyx volume.
Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van Lieshout MH, Levi M, Meijers JC, Holleman F, Hoekstra JB, Vink H, Kastelein JJ, Stroes ES (2006) Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 55:480–486.
Nieuwdorp M, Mooij HL, Kroon J, Atasever B, Spaan JA, Ince C, Holleman F, Diamant M, Heine RJ, Hoekstra JB, Kastelein JJ, Stroes ES, Vink H (2006) Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55:1127–1132
b. high fat/high cholesterol diet and high LDL levels disrupt the glycocalyx. The co-infusion of superoxide dysmutase and catalase with ox-LDL abolishes the glycocalyx shedding found with ox-LDL infusion only. (not exactly a big surprise, but certainly brings up a therapeutic possibility in acute coronary events, especially NSTEMIs…)
Vink H, Constantinescu AA, Spaan JA (2000) Oxidized lipoproteins degrade the endothelial surface layer: implications for platelet–endothelial cell adhesion. Circulation 101:1500–1502
van den Berg BM, Spaan JA, Rolf TM, Vink H (2006) Atherogenic region and diet diminish glycocalyx dimension and increase intima-to-media ratios at murine carotid artery bifurcation. Am J Physiol Heart Circ Physiol 290:H915–H920
c. hydrocortisone and antithrombin prevent TNF-a induced shedding of the glycocalyx. (we never really knew how steroids help in sepsis; ATIII trials failed, but were they designed with glycocalyx-sparing in mind…?)
e. sepsis and major abdominal surgery damage the glycocalyx (a good example of common pathway pathophysiology…)
Jochen Steppan, M.D., Stefan Hofer, M.D., Benjamin Funke, M.D., Thorsten Brenner, M.D., Michael Henrich, M.D., Ph.D., Eike Martin, M.D.,Jürgen Weitz, M.D., Ursula Hofmann, M.D., Markus A. Weigand, M.D.Sepsis and Major Abdominal Surgery Lead to Flaking of the Endothelial Glycocalix Journal of Surgical Research Volume 165, Issue 1 ,Pages 136-141, January 2011
f. molecules (eg Slit2N, good old aPC) that enhance or preserve barrier function have shown some success in animal models. (the key might be to using a bunch of them at once, not one of them vs placebo)
N. R. London, W. Zhu, F. A. Bozza, M. C. Smith, D. M. Greif, L. K. Sorensen, L. Chen, Y. Kaminoh, A. C. Chan, S. F. Passi, C. W. Day, D. L. Barnard, G. A. Zimmerman, M. A. Krasnow, D. Y. Li, Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and infl uenza. Sci. Transl. Med. 2, 23ra19 (2010).
…and this is just the tip of the iceberg. Seriously, google it…
For now, it is difficult to make any hard recommendations, but it has certainly made me pause to regroup and re-strategize. I think the critical thing is to reframe our thinking and redesign our approach to be a glycocalyx-sparing therapy.
In sepsis therapy, so many molecules have failed, but little emphasis so far has been on targeting the glycocalyx, and in all likelihood, the key is not in finding the “magic bullet” but rather using multiple interventions to bolster it. One could think of this as the sepsis “chain-of-survival”, and now that we can see the complexity of the glycocalyx, it is easy to understand how no one therapy, even if it did do its job, would succeed in preventing the degradation of the other links in the chain, and fail. In all likelihood, a successful strategy will probably involve the following:
1. fancy molecules to prevent glycocalyx damage.
2. fluid choices which are glycocalyx-friendly.
3. fluid in just the right amount (not by macro/volume-responsiveness but by micro/glycocalyx management).
4. rapid diagnosis/abx/source control, etc, all the good stuff we know about.
5. preventing hyperglycemia.
A trial like that would be a monumental undertaking. I can only hope someone does it.
My next step, as a guy in the bedside trenches and not at the bench, after gaining a modicum of understanding on the topic, will be to delve deeper into the effects of currently available fluids on the glycocalyx. Look for a post on that in the next weeks. As a starter, everyone should review Woodcock & Woodcock’s excellent clinical review.
And if anyone has any amazing information to share, please do!!! That’s what #FOAMed is for!!!
Woodcock and Woodcock, BJA 2012, http://bja.oxfordjournals.org/content/early/2012/01/29/bja.aer515.full.pdf+html
Broken Barriers: A New Take on Sepsis Pathogenesis Neil M. Goldenberg,1* Benjamin E. Steinberg,1* Arthur S. Slutsky,2,3,4 Warren L. Lee2,4 Science Translational Medicine, 22 June 2011 Vol 3 Issue 88 88ps25
a great article on understanding the glycocalyx in sepsis by a U of T gang!
Luft JH (1966) Fine structures of capillary and endocapillary layer as revealed by ruthenium red. Fed Proc 25:1773-1783
Reitsma et al, The endothelial glycocalyx: composition, functions, and visualization, Eur J Physiol (2007) 454:345–359
Zhang X, Adamson RH, Curry FR, Weinbaum S (2006) A 1-D model to explore the effects of tissue loading and tissue concentration gradients in the revised Starling principle. Am J Physiol Heart Circ Physiol 291:H2950–H2964
First of all this is a big trial. Bigger that the previous ones that established hypothermia as a standard of care. Does it obviate those previous results? Absolutely not. Those trials were not 32/33 vs 36 but 32/33 vs “whatever happens.”
Hypothermia makes a lot of sense physiologically, but of course that doesn’t mean that it might not have some harmful side effects that have not yet been clearly delineated (besides the current known hemodynamic ones and relatively benign electrolyte and renal alterations).
However, it is pretty clear that, compared to 33 degrees, 36 does just as well, which leans towards saying that all we have to do is avoid fever, or stay in a very mild hypothermia.
Avoiding secondary injury in brain pathology is key (no desat, no hypotension, and no fever), and in anoxic encephalopathy, it is no different. The key thing is that in this trial, the temperature was controlled – ie it would not be acceptable to do no cooling, and just chase the fever(which is very common) with acetaminophen, which would invariably result in significant time spent above 36 (oops, tylenol didn’t really work, ok lets put the blanket, etc …this is gonna be hours).
So is this the end of aggressive cooling? Not necessarily.
For anyone interested in the topic, I suggest reviewing Peter Safar‘s data on dogs and cold aortic flushes – it is absolutely unbelievable to see dogs who had an arrest, got the cold aortic flush (brain temp below 10 degrees), are left stone cold dead for 45 minutes, then resuscitated and are then able to go around a few days later and do doggie things like run and bark and eat… So I don’t think that cooler isn’t necessarily better, but that we haven’t yet delineated what are the pros and cons of each temperature range or how to get there practically and safely.
So what should we do? Well, it would seem reasonable to do either at this point, and accepting a temp between 32-36 (I have usually preferred 33-34 as they rarely drift down into the 20’s as I’ve seen the 32’s do) as being adequate. This may make hemodynamics a bit easier to manage in certain cases.
“Successive transition from one paradigm to another via revolution is the usual developmental pattern of a mature science.”
In other words, a science has growing pains and is bound to have a fair bit of debate and controversy, until a new paradigm becomes dominant. I think that there is a current – in part prompted by the power of socio-professional media which has allowed minds to connect and knowledge to spread – that will see many of the things that are now “Standard of Care” out the door.
So first of all, the following are must-listens, the first a lecture by Paul Marik, whom I have had the chance to collaborate with in the last years and respect greatly, on knowledge, experience, and even more on his refusal to take anything for granted and being in a seemingly-constant quest for the improvement of medicine.
The second link is Scott Weingart’s take on it, which I think is equally awesome.
I think Paul is pushing the envelope in an essential way, and Scott does a fantastic job of seeing or putting it in perspective. Enjoy:
My (very) humble opinion on this is a rather simple, almost philosophical one: why are we seemingly obsessed with treating a predominantly vasodilatory pathology with large amounts of volume? I’ve said this in previous posts and podcasts, but this, in my opinion, is largely cultural and dogmatic. “Levophed – Leave’em dead” is something I heard as a student and resident, and came to take for granted that I should give lots of fluid in hopes of avoiding pressors… But there’s no evidence at all to support this. The common behavior of waiting until someone has clearly failed volume resuscitation before starting pressors befuddles me (think how long it takes to get two liters of fluid in most ERs…). If I was in that bed, I’d much rather spend an hour a bit “hypertensive” (eg with a MAP above 70) than a bit hypotensive while awaiting final confirmation that I do, in fact, need pressors.
I strongly suspect that it’s just a matter of improving vascular tone, giving some volume (which may be that 3 liter mark), and ensuring that the microcirculation/glycocalyx is as undisturbed as possible. Now when I say it may be the 3 liters, I firmly believe this will not apply to everyone, and that it will be 1 liter in some, and 4 in others, and that a recipe approach will be better than nothing, but likely harm some.
I think that blind (eg no echo assessment) of shock is absurd, and for anyone to propose an algorithm that does not include point-of-care ultrasound is only acceptable if they are in the process of acquiring the skill with the intention of modifying their approach in the very near future.
The whole microcirculation/glycocalyx is absolutely fascinating stuff, and undoubtedly will come under scrutiny in the next few years, and it is definitely something I will focus on in upcoming posts & podcasts. Our resuscitation has been macro-focused, and certainly it is time to take a look at the little guys, who might turn out to have most of the answers. For instance, there is some remarkable data on HDAC inhibitors (common valproic acid) and their salutatory effects in a number of acute conditions such as hemorrhagic shock (Dr. Alam) which have nothing to do with macro-resuscitation, and everything to do with cell signaling and apoptosis. Hmmm…
So until a few years ago I reluctantly admit I was one of those who read the title, abstract, intro and quite diagonally went thru methods and results before starting to pay attention at the discussion. On one hand I got to read a lot more articles per unit time, but my analysis was rudimentary at best…
That was until a colleague, good friend, judoka and microbiologist extraordinairePeter Barriga started to shine some light into my epidemiological darkness while teaching me some judo. So while waiting for his textbook to come out, here are a few principles that I’ve found very interesting, revealing, but also somewhat frightening: in part, they explain the lack of strength and consistency found in much of the medical literature…
So let’s look at the publication bias. This refers to the likelihood that a study will be published in a major medical journal. Not surprisingly, journals are generally more interested in positive studies than negative ones. After all, who would be interested in reading a journal where more than half the studies concluded with “well, this didn’t work…” It would feel like a waste of reading time.
Now, let’s look at our whole p value, a number (0.05) which we are culturally in love with. What does it really mean? It means that there is a 1 in 20 or less likelihood of the result being purely chance. So let’s say a popular drug for sepsis is studies by 20 teams, the same study done 20 times could yield 1 positive and 19 negative results – by chance alone.
The question then becomes, which study is picked by a big journal to be published… One of the 19 negative studies or…the positive one?
Fortunately nowadays due to the information age, a study registry exists where all studies – including negative ones – can be found, so that anyone interested enough in a particular topic can dig up all the data and have an accurate assessment, but is that the case for most physicians? Or do most pick up the big titles of the big journals…?
Hmmm… So I think it is incumbent on all of us to examine the main things we do in our practice, and make sure we have carefully looked at the available data surrounding it, and not just blindly applied guidelines, recipes or whatever our seniors and mentors are doing or have shown us.
more to come on how to make our practice GEBM (good evidence based medicine) rather than just EBM…