Glycocalyx in Critical Illness

Reviewed and revised 24 March 2016

OVERVIEW

• The endothelial glycocalyx (EG) is a thin proteinaceous layer previously thought to be inert, that is now thought to play a key role in vascular integrity and function
• disruption of the glycocalyx may be an important mediator of inflammation, edema, sepsis syndromes and capillary leak syndromes in various surgical and disease states
• the glycocalyx has potential as a novel therapeutic target
• physiological importance may have previously been unappreciated due to disruption by traditional tissue fixation methods

STRUCTURE

Components of the endothelial glycocalyx

• glycoproteins
• proteoglycans (core membrane-bound protein of the syndecan or glypican families with attached GAG side chains)
• glycosaminoglycans (GAGs) (as part of proteoglycans, e.g. heparan or chondroitin sulphate, or  receptor-bound, e.g. hyaluronan)
• associated plasma proteins including albumin

The endothelial glycocalyx is a tight, negatively charged meshwork of biopolymers

• the endothelial glycocalyx forms the basal skeleton that  in vivo interacts dynamically with plasma constituents forming an endothelial surface layer (ESL)
• in normal physiological conditions there is a stable balance between the synthesis of new glycocalyx components and the ‘shedding’ of exiting components
• there is also protein-free space below the glycocalyx (proposed by Adamson et al, 2004)

Endothelial surface layer (ESL)

• ranges from 200 nm to 2 um in thickness
• comprises up to 25% of the vascular space
• forms the interface between the vessel wall and moving blood
• acts as a molecular filter (e.g. experimental evidence shows that 40 kDa dextrans enter the layer whereas 70 kDa dextrans are excluded)

FUNCTION

Proposed functions include

• maintenance of the vascular permeability barrier
• mediation of shear-stress-dependent nitric oxide production
• retention of vascular protective enzymes (e.g. superoxide dismutase)
• retention of coagulation inhibition factors (e.g. antithrombin, the protein C system and tissue factor pathway inhibitor)
• modulation of the inflammatory response by preventing leukocyte adhesion and binding various ligands (e.g. chemokines, cytokines and growth factors)

GLYCOCALYX SHEDDING AND DISRUPTION

Shedding

• loss of glycocalyx constituents

Glycocalyx shedding and disruption is associated with:

• TNFα
• redox stress and oxidised lipoproteins
• lipopolysaccharide
• thrombin
• ischaemia/reperfusion
• hyperglycaemia
• hypervolemia
• hypernatremia
• trauma
• surgery
• growth factors
• artificial colloids such as hydroxyethyl starch (HES) (leads to increased hydraulic conductance and of the ESL and vascular permeability)

Effects of glycocalyx damage:

• capillary leak
• edema
• hypercoagulability
• inflammation
• loss of vascular responsiveness
• platelet aggregation

Once disrupted, the endothelial glycocalyx takes days to recover

ASSESSMENT

Nieuwdorp et al’s optical method

• can assess the thickness of the ESL indirectly in capillaries in vivo
• demonstrates ESL reduction in acute and chronic inflammation

Biomarkers of glycocalyx disruption in sepsis include plasma levels syndecan-1 and GAGs, which are associated with:

• septic shock
• mortality from sepsis
• higher SOFA scores

TRADITIONAL AND REVISED STARLING MODELS OF CAPILLARY FILTRATION

Traditional Starling model

• described by British physiologist Ernest Starling in 1896
• filtration in capillaries (excluding those of the brain) based on the opposition of:
  • an inwardly directed oncotic pressure gradient between the interstitial and the circulatory space, and
  • an outwardly directed hydrostatic pressure gradient across the anatomical vessel wall
• fluid flux varies in different capillary segments
  • high filtration in the arteriolar capillary segment
  • high re-absorption in the venular capillary segment
• low rates of lymphatic flow removes the net filtered fluid that enters the tissues

But…

• the postulated high resorption of interstitial fluid in the venular segments of the microcirculation does not to exist!
• filtration across the vascular barrier is largely independent of the bulk colloid concentration surrounding the vessel

Revised Starling model

• arterioles and capillaries are non-porous, minimal filtration occurs
• venules are porous, allowing colloid and fluid to enter the interstitial space from the endovascular space
• In regions with high intravascular pressure, the inwardly directed oncotic pressure gradient across the glycocalyx in conjunction with the high resistance to flow within the narrow strand gaps of the endothelium prevents flooding of the interstitial space
• Within low-pressure sections free and easy access of plasma constituents towards the parenchymal cells allows a highly effective exchange of nutrients and waste products, but fluid shift is modest if the ESL is intact because of the low hydrostatic and oncotic pressure gradients pertaining in these segment

THERAPIES TARGETING THE GLYCOCALYX

Established therapies (proposed benefits may in part be due to effects on the glycocalyx)

• glucose control
• hydrocortisone in septic shock
• avoiding hypervolemia

Experimental

• TNFα inhibition
• antithrombin III
• infusion of albumin (interacts with glycocalys and promotes vasodilation and increased nutrient blood flow)
• avoidance of natriuretic peptide release
• statins
• sevoflurane

Specific agents are unavailable for potential therapies such as:

• increasing the synthesis of glycocalyx components
• refurbishing the glycocalyx, or
• selectively preventing protease degradation

VIDEO

References and Links

Journal articles

• Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Therapeutic strategies targeting the endothelial glycocalyx: acute deficits, but great potential. Cardiovasc Res. 2010 Jul 15;87(2):300-10. PMID: 20462866. [Free Full Text]
• Burke-Gaffney A, Evans TW. Lest we forget the endothelial glycocalyx in sepsis. Crit Care. 2012 Dec 12;16(2):121. PMC3681368.
• Chappell D, Westphal M, Jacob M. The impact of the glycocalyx on microcirculatory oxygen distribution in critical illness. Curr Opin Anaesthesiol. 2009 Apr;22(2):155-62. PMID: 19307890.
• Woodcock TE, Woodcock TM. Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy. Br J Anaesth. 2012 Mar;108(3):384-94. PMID: 22290457. [Free Full Text]

FOAM and web resources

• EMCrit – Think You Understand Fluids–Cause I don’t have a grasp yet (2013)
• PulmCCM — Respect the glyocalyx – or at least know it exists (2013)