The Endothelial Glycocalyx:

What is it and why should I care?

All cell membranes are coated with a slimy polysaccharide matrix termed the glycocalyx (glyco = “sweet” and calyx = “husk” from the Latin word for “conceal). The apical aspect of endothelial cells within the lumen of blood vessels, is covered with this long neglected physiologically and metabolically active structure that regulates vascular permeability. The endothelial glycocalyx (EG) is a meshwork of proteins and sugars, consisting of proteoglycans, glycosaminoglycans, and glycoproteins, in a gel-like structure that acts as a physical barrier and orchestrates fluid filtration, coagulation, inflammation, and signal transduction. It is powerfully relevant to health and disease and clinical consideration of the EG is a bit of a shakeup to what we do and why.

This is just a cute mini donkey. No direct relationship to Starling.

What is the Revised Starling Equation?

In the 1890s (the decade in which Munch painted The Scream, Bram Stoker published Dracula, & the first women gained suffrage in New Zealand), Starling asserted that fluid flux across the vascular wall was a balance between transudation and absorption. This work formed the basis of the dominant paradigm of vascular physiology for the next century. It is not often that such foundational concepts are retooled by physiologists!

Starling didn’t actually express these concepts in this way and this equation was not formulated until nearly a quarter century after his death.

In the early 1990s (nod to Seinfeld, Nirvana, and Forrest Gump), actual measurements - rather than theoretical predictions - of interstitial oncotic pressure revealed that fluid flux (Jv) across the healthy endothelium was much less than projected by the traditional Starling’s Equation. Over the next couple of decades, a body of similar evidence accumulated leading to the Revised Starling Equation (RSE). Essentially, the RSE indicates that the familiar hydrostatic and oncotic pressure gradients we learned about in undergrad are achieved not across the capillary wall by itself but across the functional and physical barrier that is the EG. Note that Starling’s Forces were not disproven or thrown out entirely, just revised a little. It’s not that your bio teacher back in the day was wrong; it’s just that there’s more to the whole picture. These forces still form the basis of our understanding, but the revision better explains the actually observed fluid flux from the vasculature to the interstitium.

What does the RSE mean?

Starling’s original concept indicated that high hydrostatic pressure at the arterial side of a capillary network would lead to filtration whereas reabsorption would occur at the venous end of the capillary. What has been documented in the last few decades is that reabsorption does not normally occur, except transiently when capillary hydrostatic pressure is acutely lowered (note that the kidney and GI tract capillaries function a little differently). In addition, interstitial colloid oncotic pressure (COP) was originally thought to be 0, but Levick (1991) demonstrated that interstitial COP was about 40% of the plasma COP and protein concentration in the interstitium has minimal effect on fluid flux; however, an oncotic gradient is created due to a filtering of protein from fluid moving across the glycocalyx, leading to a relatively protein-free subglycocalyx space.

These two ideas – at steady state, the hydrostatic pressure gradient ensures that filtration occurs throughout the length of the capillary bed and that the interstitial protein concentration is basically irrelevant – are important to thinking about vascular permeability in health and disease states, and these ideas can be used to explain some disparities in fluid management theory and reality. In particular, it brings some clarity to the fact that there is not a much of a volume benefit when colloid solutions (artificial or natural) are administered for resuscitation (Futier et al. 2020) nor do they improve clinical outcomes (Lewis et al. 2018). In addition, raising plasma COP reduces, but does not reverse fluid flux, and explains why artificial or natural colloids cannot reverse interstitial edema.

In addition to being the central figure in the revision of traditional Starling’s forces, the integrity of the EG is essential to vascular health. Things that degrade the EG include sepsis, inflammation, trauma, hyperglycemia, and hypervolemia. In this post, I proposed that we need to think about both the total volume delivered and the rate of fluid administration when making anesthetic fluid therapy decisions. That is important because hypervolemia is just as bad as hypovolemia and the major objective of perianesthetic fluid therapy should be administering enough volume to maintain effective circulating volume while avoiding fluid overload.

Man, this physiology stuff is heavy!

What’s Next?

These concepts have gained traction in the literature in the last decade (which also saw Beyonce’s Lemonade, Jordan Peele’s Get Out, and, the hit show Hamilton) but there is some pushback . One thing is certain, however: the protection and restoration of the EG in a myriad of disease states has become a major research focus. I think it is likely that our understanding of the fundamental forces governing fluid movement across the endothelial surface layer will continue to develop, as will our interpretation of how to apply that understanding to clinical fluid therapy decisions.

Thanks to Drs. Marc Raffe and Bill Muir for feedback on this article! Readers who want more detail may enjoy this recent article in Frontiers in Veterinary Science.