Respect the glyocalyx - or at least know it exists - PulmCCM

http://pulmccm.org/main/2013/critical-care-review/respect-glyocalyx-l...

Advertisement

Latest

Popular

Updates

Guidelines

Board Review

About

Jobs

CME

Search

Ventilator-Induced Lung Injury Review (Part 2 of 2, NEJM)

Get Weekly Email Updates

First Name
De c

Last Name

14
2013

Respect the glyocalyx or at least know it exists

Critical Care, Free Full Text, Infectious Disease and Sepsis Add comments

Email

ZIP/Postal Code

The Glycocalyx: An Overview for the Clinician.

by Dr. Phillipe Rola Ok, so Id 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, wellquickly. So basically, when I listened to Pauls (Marik) recent lecture at Scotts (Weingart, emcrit.org) New York Sepsis Collaborative, I started to dig a littleand 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 hasnt 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 hasnt yet translated into an effective therapy, but nor has it seemed to spread into general awareness, and it seems like its 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, 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. Major components of the glycocalyx: 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

Submit

Advertisement

Most Viewed This Month Hypothermia did not help after out-ofhospital cardiac arrest, in largest study yet (NEJM) Shock Review (NEJM) Part 1: Mechanisms and Therapies Do colloids save lives in hypovolemic shock? (JAMA) Shock Review (NEJM) Part 2: Goals of Therapy Idiopathic pulmonary fibrosis strongly linked to herpesvirus infection Breath tests can accurately diagnose lung cancer "CPAP cures metabolic syndrome" paper in NEJM: retracted! Statins don't help in ventilator-associated pneumonia treatment (JAMA) Olodaterol, a new once-daily LABA, proven effective for COPD It's official Someone's being too negative (Crit Care Med)

ACCP 9th Edition Guidelines for DVT, PE, Anticoagulation (February 2012)

Surviving Sepsis Guidelines 2013 Update

Most Viewed All Time ACCP Guidelines for Diagnosis and Management of DVT/PE/VTE, 9th edition (Review) Surviving Sepsis Guidelines Updated: Preview from SCCM Meeting How to manage anticoagulation perioperatively (ACCP Recommendations) Mechanical Ventilation in ARDS: 2012 Update How to start & manage warfarin/coumadin for acute DVT/PE (ACCP Recs) Initial Treatment of Acute Deep Venous Thrombosis (DVT) of the Leg (ACCP/Chest Guidelines) Treating acute pulmonary embolism with anticoagulant therapy (ACCP Guidelines) Meet the New ARDS: Expert panel announces new definition, severity classes

1 of 5

12/16/2013 4:56 PM

Respect the glyocalyx - or at least know it exists - PulmCCM

http://pulmccm.org/main/2013/critical-care-review/respect-glyocalyx-l...

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 isnt 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.

(JAMA) Chronic obstructive pulmonary disease 2012 update (COPD Review, Lancet) Surviving Sepsis Guidelines 2013 Review & Update

TOPICS BEST OF 2012 (45) N Engl J Med (127) JAMA (71) AJRCCM (127) CHEST (138) Crit Care Med (journal) (48) Review Articles (286) Randomized Controlled Trials (188) Free Full Text (121) ARDS and ALI (42) Asthma (60) Cardiovascular Disease (100) Chronic Critical Illness (22) Clinic and Consults (173) COPD (103) Critical Care (275) Cystic Fibrosis (16) Diffuse Lung Disease & Interstitial Lung Disease (57) GI and Nutrition (26) Infectious Disease and Sepsis (156) Interventional Pulmonology (56) Lung Cancer (82) Lung Transplantation (25) Mechanical Ventilation (101) Neurology Critical Care (20) Pleural Disease (20) Policy, Ethics, Education (165) Pulmonary Embolism / DVT / VTE (60) Pulmonary Hypertension (25) Radiology & Imaging (74) Sleep, Obesity-related disease (62) Uncategorized (13) Palliative Care (5)

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 (Johns 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 et al, Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes 55:480486. Nieuwdorp M et al. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55:11271132. b. high fat/high cholesterol diet and high LDL levels disrupt the glycocalyx. The coinfusion 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)

Advertisement

2 of 5

12/16/2013 4:56 PM

Respect the glyocalyx - or at least know it exists - PulmCCM

http://pulmccm.org/main/2013/critical-care-review/respect-glyocalyx-l...

Vink H et al. Oxidized lipoproteins degrade the endothelial surface layer: implications for plateletendothelial cell adhesion. Circulation 101:15001502. van den Berg BM et al. 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:H915H920 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 et al. TNF- 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 degrades the pulmonary endothelial glyocalyx and results in neutrophil adhesion and ALI. (TNF-a activates heparanase, now the surface adhesion molecules are available for the leukocytes to attach to) Eric P Schmidt et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis, Nature Medicine 18,12171223 (2012) e. sepsis and major abdominal surgery damage the glycocalyx (a good example of common pathway pathophysiology) Jochen Steppan et al. 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 et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and infl uenza. Sci. Transl. Med. 2, 23ra19 (2010).

Conclusion: 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-ofsurvival, 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. And if anyone has any amazing information to share, please do!!! Thats what #FOAMed is for!!! Other suggested viewing/reading:

3 of 5

12/16/2013 4:56 PM

Respect the glyocalyx - or at least know it exists - PulmCCM

http://pulmccm.org/main/2013/critical-care-review/respect-glyocalyx-l...

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 http://warrenleelab.com/uploads /Science_Translational_Medicine_2011_Pathogenesis_of_Sepsis.pdf a great article on understanding the glycocalyx in sepsis by a U of T gang! emcrit: http://emcrit.org/blogpost/best-fluids-comment-ever/ http://emcrit.org/podcasts/fluids-severe-sepsis/ http://emcrit.org/podcasts/paul-marik-fluids-sepsis/ 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) 454:345359 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:H2950H2964 Dr. Philippe Rola is Chief of Service of Intensive Care, Santa Cabrini Hospital and President of the Critical Care & Ultrasound Institute. He blogs at thinkingcriticalcare.com.

You may also like -

New lung cancer prediction tool promises better use of screening CT (NEJM)

Knowing When, When Knowing Is Impossible (Paul McLean)

Hydroxyethyl starches kill people with severe sepsis; use crystalloid instead (RCT, NEJM)

Predicting survival from COPD exacerbations: DECAF score shows promise (Thorax)

Non-small cell lung cancer (NSCLC): Advances in Diagnosis and Treatment (Update/Review)

Liked this post? Get a weekly email update (no spam, ever), and explore our library of pulmonary and critical care guidelines, practice updates and review articles.

Posted by Pulmonary Central

One Response to Respect the glyocalyx or at least know it exists

Megan Anders says:
December 16, 2013 at 9:24 am Great intro/overview post! I agree we are going to be hearing much more about this clinically in the near future. Thanks. Reply

1.

Leave a Comment

Ventilator-Induced Lung Injury Review (Part 2 of 2, NEJM)

4 of 5

12/16/2013 4:56 PM

Respect the glyocalyx - or at least know it exists - PulmCCM

http://pulmccm.org/main/2013/critical-care-review/respect-glyocalyx-l...

Contact Facebook Twitter Advertise Creative Commons License. Use of PulmCCM.org implies acceptance of our Terms of Use.

Suffusion theme by Sayontan Sinha

5 of 5

12/16/2013 4:56 PM