The Glycocalyx: an overview for the clinician. #FOAMed, #FOAMcc

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, 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.

glycocalyx em pic

EM view of the glycocalyx (reproduced with authors’ permission from Reitsma et al.)

glycocalix pic2

(reproduced with authors’ permission from Reitsma et al.)

Major components:

– 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…)

a. gatekeeper

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.

b. mechanotransduction

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.

c. microenvironment

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.

Clinical implications…

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…?)

Daniel Chappell MD, Klaus Hofmann-Kiefer, Matthias Jacob, Markus Rehm, Josef Briegel, Ulrich Welsch, Peter Conzen, Bernhard F. Becker TNF-α induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin Basic Research in Cardiology, January 2009, Volume 104, Issue 1, pp 78-89

 d. endotoxemia damages the pulmonary vascular endothelium and results in ALI (now the neutrophils can attach and activate inflammation…)

Eric P Schmidt, Yimu Yang, William J Janssen, Aneta Gandjeva, Mario J Perez, Lea Barthel, Rachel L Zemans, Joel C Bowman, Dan E Koyanagi, Zulma X Yunt, Lynelle P Smith, Sara S Cheng, Katherine H Overdier, Kathy R Thompson, Mark W Geraci, Ivor S Douglas, David B Pearse & Rubin M Tuder The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis, Nature Medicine 18,1217–1223 (2012)

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!!!

Suggested viewing/reading:

Woodcock and Woodcock, BJA 2012,

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

Click to access Science_Translational_Medicine_2011_Pathogenesis_of_Sepsis.pdf

a great article on understanding the glycocalyx in sepsis by a U of T gang!


all must-listen/watch material!

other refs.

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

Enough with the “Normal” Saline!!!!! #FOAMed, #FOAMcc

Enough with the “Normal” Saline!
So its been about a year since a JAMA article ( finally showed that the downside of 0.9% saline isn’t just theoretical, but has some associated clinical morbidity (bad for the kidneys!).  Sadly enough, it still seems to be the routine fluid used for boluses. Whether the ER, hospitalist or intensivist, residents, students…it seems people are reluctant to let go.
Today, rounding in the ICU, I was changing an order for a bolus from another doc from NS to RL, and a nurse asked me why.  I gave her a capsule summary and she was in disbelief.  “Come on Phil, they wouldn’t call it normal saline if it wasn’t!”
I’m an internist by training, so naturally I grew up using NS, since that’s what all the attendings and residents used around me.  Ringer‘s was the stuff the surgeons used, so well, I guess it had to be wrong…no?
So forward to 2001 and John Kellum‘s lecture on acid-base I’ve previously mentioned, and my exploring Stewart’s Physicochemical Approach, and wait, I look at the back of a bag of NS, and find out, much to my dismay, that the stuff I’ve been using like holy water has a pH of 5.6.  And who have I been giving liters and liters of this stuff to?  Yup, mostly patients with acidosis. Hmmm. Interesting. So although I don’t necessarily advocate correcting metabolic acidosis for the sake of doing so (see my previous post on bicarb), I’m not a proponent of worsening acidosis either, even if by another mechanism.
I think there are a number of factors that have resulted in this situation.  For starters, there is the issue of false advertising – the “normal saline” monicker has been influencing subliminal thought for decades (think Malcolm Gladwell thin-slicing), making physicians feel they are giving and inherently “good” substance.  Then there’s the whole tribalism thing with the surgeons vs non-surgeons making all the non-surgeons polarize away from RL (not that RL is perfect, just a bit better, and certainly closer to “normal”). Finally, there’s this sad, sad factor that makes people, even (or maybe even more) smart people reluctant to accept that they have been doing something wrong (or, for those who are offended right now, not ideal) for a long time (I sure was) and prefer to fight it and rationalize it for a few more years until, eventually, the evidence becomes overwhelming or the changing of the guard has fully taken place.
I think what we should be hanging on to is not a drug or a fluid but rather what we learned in the first couple of years of med school: physiology.  Now mind you, at that point we (or most of us) didn’t have a clue how to use it for anything more that answering multiple choice questions, but at some point, we have to go back to it and realize that is what we should be basing our assessment of our therapeutic acts and decisions.
So…if I have a situation where I am low on chloride, I might want to use NS. But otherwise, let try to give something whose composition is a bit closer to our own than NS is.  So, for my students and residents, don’t let me see you prescribing boluses of NS.  If you really, really need to, wait until your next rotation please.
ps for a great review of the original aritcle, please see Matt’s on PulmCCM at :
Reply:  by Marco Vergano
Totally agree!
I have been struggling for years with the bad habit of some of my colleagues prescribing NS as the most harmless and physiologic replacement fluid. Here in Italy we don’t have such a clear separation between internists and surgeons about NS/RL choice: the bad habit of easily prescribing NS is ubiquitous.
Given the results you mentioned about the increased incidence of renal failure with NS, I am wondering if the ban on ALL starch solutions would have been necessary after the introduction of new balanced starch/electrolyte solutions.
What I really don’t like about RL is that it’s not only hypotonic, but also low in sodium. In our ICU we often have many ‘neuro’ patients (trauma or vascular) and sodium variations become a major issue. Also I prefer Ringer’s acetate over lactate on most of the patients who struggle to ‘manage’ their own lactate.
So my favorite solution remains our good old “Elettrolitica reidratante III” (very similar to Plasma-lyte).

Bedside Ultrasound: The Sluggish IVC – something to look for… #FOAMed, #FOAMcc

So take a look at this:

I’m sure most experienced bedside sonographers come across this all the time.  For those who are starting out, and until now have just been looking at size and variation, take a second to look at the flow.  You can actually see the flow stop and start, which tells you your cardiac output is bad.  It could be bad because of the RV, the LV, the pericardium, the tension pneumothorax, anything, but it’s bad.  So just in case you were only gonna look at the IVC, keep looking! You will find something abnormal downstream, perhaps that you can do something about (not fluids, though).

I have seen this disappear and clear up with – when possible – correction of the problem, back to the normally anechoic IVC we usually see.



ps note there is also a mirror artifact in the right lower portion of the field, making it look as though there are two beating hearts.

NEJM Circulatory Shock Review by Vincent & DeBacker: the sweet and the not-so sweet… #FOAMed, #FOAMcc

So if anyone hasn’t read it, here it is:

Click to access Circulatory%20Shock%20-%20NEJM%202013.pdf

I read the article by critical care icons Dr. Jean-Louis Vincent and Dr. De Backer with interest  as I am always keen to find out what the cutting edge is… So here is my take on their review.

The not-so-sweet:

The inclusion of CVP in the assessment. Ouch. No evidence whatsoever. Evidence for lack of correlation to fluid responsiveness… I wonder if they themselves were cringing a little about including it, particularly form the fact that they just put high vs low rather than commit to a value, which makes me think they realize it’s a bit of a trap. (It reminds me a bit of those night-time orders I still sometimes see which say if u/o < 30 cc/hr give a bolus if CVP under 12 or lasix if over 12.  So basically depending on whether that patient’s head is elevated, or if he’s turned on one side or the other, he may go from “needing fluids” to “needing diuretics”…).

The sweet:

First of all, they obviously did an elegant job on description of shock states, and particularly of highlighting the common-ness of mixed etiology shock.

I like that they admitted that the end-point for fluid resuscitation is “difficult to define.”  Any answer other than that would really speak to non-physiological thinking, as I’ve referred to in prior posts/podcasts.

Dopamine: good job on trying to take it off the shelf for shock. As far as I’m concerned, only useful when you’ve run out of norepinephrine, although there is the odd time when you have a septic AND bradycardic patient where it could come in handy…

Bringing some focus on the microcirculation: no recommendations, but that’s appropriate since there are none to be made yet, but this is where the money is in the future, as far as I’m concerned. Once we figure out how to manage the microcirculation (we do ok with the macro circulation) we might forge ahead. But good to point the finger in that direction.

The super-sweet!

I do (not surprisingly) really, really like the fact that they included ultrasound in their assessment protocol, and emphasizing that focused echocardiography should be done as soon as possible.  Very nice. Finally.

Hopefully, this pushes mainstream ED and critical care physicians to realize they need basic bedside ultrasound skills…


Overall, I think it is a good review, certainly worth the read for trainees. I would like to see focus on re-examining and questioning our approach, which could spur readers to embark on research with a different angle. For instance, why do we assume that we need to fill patients to the point of no longer being fluid responsive in order to avoid vasopressors? Is there any evidence for that? Not that I know of…

But, for having put an emphasis on point-of-care ultrasound, it gets a big round of applause from me!



CCUS Annual Symposium 2014 – The Ultrasound-Assisted Physical Exam! stay tuned!

This year, we’re putting together a really, really interesting event.  Bedside ultrasound being a hot topic and at the brink of revolutionizing clinical examination and practice, we figured that this year, we’d go back to basics to some degree with a general ultrasound approach, but also a step further in looking at it from an integration perspective, meaning how to approach clinical problems with ultrasound as an added tool.

Talks will be clinical problem-based – e.g. the patient with dyspnea, the patient with renal failure, etc, essentially showing participants how to integrate their growing ultrasound skills into routine use.  There will be a ton of faculty led workshops to review all the basic ultrasound skills (lung, cardiac, abdominal, vascular) on live models and on advanced CAE simulators, both adult and pediatric.

Our faculty will be fantastic, including Andre Denault, Haney Mallemat (@criticalcarenow), JF and Max (@EGLS_JFandMax), Edgar Hockmann, Catherine Nix, Alberto Goffi, Massimiliano Meineri, Matt Hoffmann (, Jeff Burzynski, Jason Fisher, Alyssa Abo and many more…

The two day core event will take place in Montreal, on may 10th and 11th, and, equally interesting will be a pre-congress set of courses on may 9th, including:

EGLS (echo-guided life support)

Focused TEE

Bedside ultrasound for nurses (vascular access, IVC volume status assessment)

Critical Care Procedures (drains, tracheostomy, central lines)


Registration is not yet open but will be in the next few weeks, so for anyone interested please visit and join (it’s free!) and we’ll email you when its up and running.

Please forward/link this to all your forward-thinking colleagues~




CCUS 2013 Lectures – #FOAMed, #FOAMcc

This past may we had an amazing two day conference, the theme of which was challenging dogmatic practice and myths in acute care medicine.  Many of the lectures are now available to watch on our website at, you need to be a member to access – which is free, just register.


Lectures on bedside ultrasound, shock, ECMO in the ED, physiology and a lot of really, really good stuff.


We will be adding more in the next weeks!





fluid resuscitation: a physiological approach – an N=1 podcast, #FOAMed, #FOAMcc

This is my approach to fluid resuscitation – sorry for the lack of precision which, to me, is actually key.  It would be against the N=1 principle to give out a recipe…but here’s a way to think about it:

Sorry the last bit cut off – my iphone can only email an 8 minute audio clip! Which I wasn’t aware of until today.  Anyway all that was lost at the end was “thanks for listening and I’d really like to hear comments and others’ practices!”

And here’s a disclaimer:  I don’t think this is the be-all and end-all. My resuscitation is a work in progress, both in terms of new fluids coming up, and in terms of identifying subgroups or individuals who would benefit from a different approach, so I’m definitely eager to hear from anyone who does things differently – but physiologically!

Please see Dr. John Myburgh’s excellent review on fluid resus in NEJM sep 26th issue!

Oh and here’s the diagram!

Physiological Fluids



Bedside Ultrasound Picture Quiz 2 #FOAMed, #FOAMcc

73 yr old woman recovering from septic shock with abdominal distension and difficulty tolerating enteral feeds…


what do you see?




scroll below for the answer…..
















BUPQ2 Answer


Extensive third spacing from resuscitation has resulted in bowel edema and ascites.  Another “benign” effect of massive crystalloid use… A bedside 22g US guided tap confirms benign transudate.

The Ideal Resuscitation Fluid – an N=1 Podcast #FOAMed, #FOAMcc

So here is the first in a series of mini-talks geared towards having us think about fluid resuscitation, which, for those in acute care of almost any type (ER, wards, ICU, anasthesia, surgery, etc…) is part of our daily routine. And that’s exactly what it shouldn’t be, routine. It should be carefully thought out and adapted to each individual clinical situation we’re facing.

So I’ve decided to approach this from a completely different angle, not looking at what we do, what’s available, and see what has been stacked up against what, etc, etc… Instead, I’ve decided to start the discussion from a completely theoretical standpoint and talking about something that doesn’t exist:  The Ideal Resuscitation Fluid.

Please, let me know your thoughts!


(sorry the last 40 seconds were cut – now the “full” 5 minutes are up!  apologies, I am techno-challenged!)

Why do we bother checking CVP? #FOAMed, #FOAMcc

I was recently scanning the literature in preparation for our symposium, and came across what should have been a 2003 instead of a 2013 publication in the March issue of the CCM Journal, entitled “Point-of-Care Ultrasound to estimate Central Venous Pressure:  A Comparison of Three Techniques.”

I have to admit this is a pet peeve of mine, from the standpoint of a clinical physiologist, which is, as far as I’m concerned, what any physician looking after critically ill patients should be, at least some of the time.

So our real question is: is my patient fluid-responsive?  And perhaps a corollary question would be: is he fluid tolerant?

As a longtime bedside sonographer, physiology, experience and slowly growing evidence all support my using IVC sonography as a tool to assess volume responsiveness.  It isn’t perfect, and personally, I find the common M-mode, two-point measurement to be inadequate compared to a global assessment of the IVC, but it certainly is far closer to “the truth” we seek than CVP.

This then begs the question: why on earth would we be seeking to correlate one type of data to another which is clearly more removed from “the truth” we seek?

The use of CVP is largely cultural and deeply ingrained. There are some limited ways and pathologies in which it can be useful, but not as a measure of preload.  My friend Paul Marik published a piece that was both enlightening and entertaining in Chest a couple of years ago which I would have thought would have been the final nail in the coffin for the use of CVP as a preload tool, but it endures…even in the latest surviving sepsis guidelines

A testament to religion over science.

Philippe Rola

note that this was first posted in my buddy Matt’s awesome website pulmccmcentral ( please check it out!