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The appearance of the endothelial glycocalyx in Question 18 from the second paper of 2014 demonstrates that this topic has high penetrance and popularity among the college examiners.

For a more thorough overview, the pathologically curious reader is directed to Weinbaum et al (2007)- The Structure and Function of the Endothelial Glycocalyx Layer. Additionally, there is an entire website devoted to the activities of a glycocalyx research team, which features professional-looking diagrams and a list of recent publications.

For the rest of us, a brief summary will suffice. Owing to certain cognitive defects on the part of the author, the summary offered below can hardly be described as brief. Fortunately, a brilliant LITFL CCC alternative waits to rescue the time-poor exam candidate. In point form, its content can be compressed as follows:

Composition and function of the glycocalyx

  • Hydrated gel layer: glycoproteins, polysaccharides and proteoglycans
  • Forms the interface between the vessel wall and moving blood.
  • Plays the main role in transvascular fluid exchange
  • When damaged, is responsible for the "leaky capillaries" of sepsis
  • Damage also leads to platelet activation and DIC

Damage to the glycocalyx is caused by:

  • Hyperglycaemia
  • Hyperlipidaemia
  • Smoking
  • Sepsis and inflammation
  • Aggressive fluid resuscitation

Glycocalyx is repaired or protected by:

  • Albumin
  • Steroids
  • Normoglycaemia and cautious fluid therapy

Constitutents of the endothelial glycocalyx

  • The glycocalyx is a thin (500-2000nm) hydrated gel-like layer on the luminal surface of the vascular endothelium.
  • The name means "sweet husk", referring to the high polysaccharide content.
  • It is in fact composed of a vast variety of macromolecules, including:
    • Glycoproteins
    • Polysaccharides
    • Proteoglycans
    • Glycosaminoglycans, such as heparin sulfate, chondroitin sulfate and hyaluronic acid
  • These molecules are characterised by a polyanionic charge; this helps repel circulating platelets.
  • The exact composition varies greatly according to the local microenvironment
  • At any given time, it also contains constintuents of the routine molecular traffic which passes through it or lodges within it, such as:
    • Plasma proteins
    • Enzymes and enzyme inhibitors
    • Growth factors
    • Cytokines
    • Amino acids
    • Cations
    • Water

The glycocalyx is fragile but self-repairing. The passage of a white cell through a tight-fitting capillary can shred it completely, and yet it will restore itself in less than 1 second by adsorbing plasma constituents.

Additionally, it must be mentioned that certain tissues possess capillaries which are intentionally denuded of glycocalyx. Specific examples include the choroid plexus, secretory areas of endocrine glands, hepatic sinusoids and the reticuloendothelial system of the spleen. Functionally, glomerular capillaries also act as if they have no glycocalyx (they actually do have it, but the endothelium there is full of massive fenestrations).

Functions of the glycocalyx

Immunological and barrier functions

  • Forms the interface between the vessel wall and moving blood.
  • Acts as the exclusion zone between blood cells and the endothelium
  • Acts as a barrier against leakage of fluid, proteins and lipids across the vascular wall.
  • Interacts dynamically with blood constituents.
  • Acts the "molecular sieve" for plasma proteins, forming the basis of the Starling principle and acting as the origin of the oncotic forces which control the transcapillary movement of water.
  • Modulates adhesion of inflammatory cells and platelets to the endothelial surface.
  • Functions as a sensor and mechanotransducer of the fluid shear forces to which the endothelium is exposed; thus the glycocalyx mediates shear-stress-dependent nitric oxide production.
  • Retains protective enzymes (eg. superoxide dismutase).
  • Retains anticoagulation factors, eg:
    • Tissue factor inhibitor
    • Protein C
    • Antithrombin

Role of the glycocalyx in transvascular fluid exchange

An excellent BJA review by the Woodcocks (2012) describes in exhausting detal the 2010 Levick and Michel revision to the original Starling model of hydrostatic-oncotic interactions influencing the distribution of volume between the intravascular and extravascular spaces. A more detailed discussion of Starling's Principle is carried out in the Fluid Physiology section; it is a deep rabbit hole and diving into it can be omitted in this discussion as the CICM fellowship exam candidate is already at least dimly aware of the concepts (having presumably passed some sort of primary exam).

In brief, the key glycocalyx-related features of the revised Starling model are as follows:

  • The glycocalyx is the semipermeable membrane, not the endothelium
  • The oncotic pressure gradient is between the plasma and the subglycocalyx space (not the plasma and the interstitial space).
  • While the glycocalyx is intact, the net outward movement of fluid is opposed by, but not reversed, by the oncotic pressure gradient between the plasma and the subglycocalyx space.
  • Thus there is no "reabsorption" in the venules as was previously thought.
  • The effect of interstitial fluid oncotic pressure on the net microvascular fluid exchange is minimal.
  • If the porosity of the glycocalyx is increased by inflammation, and/or if the capillary pressure and blood flow increase, the net movement of fluid out of the capillary increases dramatically.
  • This underlies the "leaky capillary" phenomenon seen in inflammation and sepsis.

Dysfunction of the endothelial glycocalyx

Causes of glycocalyceal dysfunction

Consequences of having a disrupted glycocalyx

Importance of glycocalyx in sepsis

A good opinion piece from Critical Care (2012) is available to address this exact issue.

It is, however, somewhat limited in scope. The true pathology nerd will get more from this article on endothelial dysfunction.

In brief summary:

  • TNFα-mediated inflammation, inflammatory mediator release and resuscitation hypervolemia (among many other things) lead to glycocalyx degradation.
  • Glycocalyx degradation catalyses several simultaneous pathophysiological events:
    • Capillary leak;
      • thus, tissue and organ oedema
      • thus, impaired microcirculatory oxygen distribution
      • thus, impaired organ system function
    • Increased platelet activation and increased local hypercoagulability
      • thus, local microthrombosis with resuting microvascular shunting
        • thus, impaired tissue perfusion and lactic acidosis
      • systemically, this may result in DIC
    • Loss of vascular responsiveness
      • thus, vasoplegia and hypotension

Is there any direct evidence for this?

Assessment of glycocalyceal integrity and function

If one takes the glycocalyx seriously, one finds oneself treating it as a neglected organ system.

Therefore, it must have its equivalent of the ECG, and its equivalent of the troponin.

Monitoring glycocalyx integrity directly

Monitoring glycocalyx integrity indirectly

  • Dextran-40 (molecular weight around 40,000 Da) is small enough to penetrate the glycocalyx, and distributes into it when infused into the bloodstream.
  • Dextran-70 (molecular weight around 70,000 Da) is too large to penetrate the glycocalyx, and distributes only into the blood volume. Alternatively, one can use labelled erythrocytes.
  • Both Dextran species can be infused simultaenously, and their volumes of distribution can be measured.
  • The difference between these volumes is therefore (theoretically) an accurate representation of the volume of the glycocalyx.
  • Practically, it is impossible to be sure about this tracer dilution method, because nobody knows what the Dextran-40 partition coefficient is between the plasma and the glycocalyx (and how it changes in disease states)

Biomarkers of glycocalyx damage

  • Basically, these are components of the glycocalyx, macromolecules which (clearly) don't belong in the bloodstream. Finding these molecules in great number is therefore suggestive that the glycocalyx is being damaged (i.e. it is sloughing off from the endothelium and floating around in the bloodstream)
  • Markers used by investigators have included the following molecules:

Strategies to protect and repair the glycocalyx

A 2014 review of this vascular barrier identified 236 papers and 19 studies interested in its defence.

The well-accepted measures are as follows:

There are also experimental treatments and wild speculation:

References

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Weinbaum, Sheldon, John M. Tarbell, and Edward R. Damiano. "The structure and function of the endothelial glycocalyx layer." Annu. Rev. Biomed. Eng. 9 (2007): 121-167.

Han, Yuefeng, et al. "Large-deformation analysis of the elastic recoil of fibre layers in a Brinkman medium with application to the endothelial glycocalyx."Journal of fluid mechanics 554 (2006): 217-235.

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Chappell, Daniel, et al. "Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx." Crit Care 18 (2014): 538.

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Nieuwdorp, Max, et al. "Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo." Diabetes 55.2 (2006): 480-486.

Johansson, Pär I., et al. "A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients." Annals of surgery 254.2 (2011): 194-200.

Grundmann, Sebastian, et al. "Perturbation of the endothelial glycocalyx in post cardiac arrest syndrome." Resuscitation 83.6 (2012): 715-720.

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