The Colloid Osmotic Pressure Across the Glycocalyx: Role of Interstitial Fluid Sub-Compartments in Trans-Vascular Fluid Exchange in Skeletal Muscle

Abstract

The primary purpose of these investigations is to integrate our growing knowledge about the endothelial glycocalyx as a permeability and osmotic barrier into models of trans-vascular fluid exchange in whole organs. We describe changes in the colloid osmotic pressure (COP) difference for plasma proteins across the glycocalyx after an increase or decrease in capillary pressure. The composition of the fluid under the glycocalyx changes in step with capillary pressure whereas the composition of the interstitial fluid takes many hours to adjust to a change in vascular pressure. We use models where the fluid under the glycocalyx mixes with sub-compartments of the interstitial fluid (ISF) whose volumes are defined from the ultrastructure of the inter-endothelial cleft and the histology of the tissue surrounding the capillaries. The initial protein composition in the sub-compartments is that during steady state filtration in the presence of a large pore pathway in parallel with the “small pore” glycocalyx pathway. Changes in the composition depend on the volume of the sub-compartment and the balance of convective and diffusive transport into and out of each sub-compartment. In skeletal muscle the simplest model assumes that the fluid under the glycocalyx mixes directly with a tissue sub-compartment with a volume less than 20% of the total skeletal muscle interstitial fluid volume. The model places limits on trans-vascular flows during transient filtration and reabsorption over periods of 30–60 min. The key assumption in this model is compromised when the resistance to diffusion between the base of the glycocalyx and the tissue sub-compartment accounts for more than 1% of the total resistance to diffusion across the endothelial barrier. It is well established that, in the steady state, there can be no reabsorption in tissue such as skeletal muscle. Our approach extends this idea to demonstrate that transient changes in vascular pressure favoring initial reabsorption from the interstitial fluid of skeletal muscle result in much less fluid exchange than is commonly assumed. Our approach should enable critical evaluations of the empirical models of trans-vascular fluid exchange being used in the clinic that do not account for the hydrostatic and COPs across the glycocalyx.

Vascular refilling coefficient is not a good marker of whole-body capillary hydraulic conductivity in hemodialysis patients: insights from a simulation study

“…The classic approach allowed us to refer directly to the discussed works by Tabei et al as well as to other studies mentioned above, all of which employed the classic Starling principle. In order to reflect the extended Starling principle, our model would need to be substantially extended by either: (1) adding a sub-glycocalyx compartment (or possibly more sub-compartments of the interstitial fluid, as proposed by Curry and Michel 21 ) with the description of convection and diffusion of macromolecules between that compartment and the interstitial fluid, which would depend on the flow rate (velocity) of the filtration flow through the orifices in the junction strand, or (2) employing a spatially distributed model of pressure and protein concentration fields behind the glycocalyx, as done by Hu and Weinbaum 28 , or (3) modelling the capillary wall as a two-membrane system (glycocalyx + endothelium), as done by Facchini et al 49 , 50 . Any of the above approaches would increase substantially the level of complexity of our already relatively complex model, but, more importantly, as outlined below, we believe that the possible error introduced by using the classic approach should not affect our conclusions with respect to the deficiencies of Kr.…”

“…when fluid is absorbed from tissues, as for the majority of the modelled dialysis sessions (mainly due to increase in plasma oncotic pressure and partly due to decrease in capillary blood pressure), the oncotic pressure of the sub-glycocalyx fluid is no longer lower than that of the interstitial fluid; in fact, it is even higher due to reflection of macromolecules from the glycocalyx layer and their accumulation in the sub-glycocalyx space 21 (the magnitude of this effect would depend on the rate of fluid absorption and the velocity of fluid through the junction strand openings that would affect the diffusion of macromolecules back to the interstitial fluid). In most tissues with continuous (non-fenestrated) endothelia, such as skeletal muscles and skin, such absorption of fluid from the tissue following a reduction in capillary blood pressure or increase in plasma oncotic pressure is possible only transiently until a new steady state is established across the glycocalyx (a state of filtration, as indicated by the Michel-Weinbaum model 22 , 23 , 53 and as shown experimentally, albeit only in frog and rat microvessels 51 , 53 )—this takes usually 15–30 minutes 10 , 48 but may continue for more than an hour 17 , 21 . During HD, however, there is no step-like change in the conditions for microvascular exchange, as typically considered in the studies devoted to the extended Starling principle, nor a more gradual but still relatively quick change of microvascular conditions as in hemorrhage or following an infusion in fluid therapy 54 , 55 .…”

“…The microvascular water and solute exchange was modelled using the well-established three-pore model of the capillary wall 26 , 27 with three pathways for solute and/or water transport reflecting the structural properties of continuous (non-fenestrated) capillaries: (1) small pores representing the inter-endothelial clefts covered by the glycocalyx layer 10 , 21 , (2) large pores representing large gaps in the endothelium and glycocalyx or vesicular transport of macromolecules 20 , 28 , and (3) ultrasmall pores representing aquaporins—a water-exclusive pathway 10 . We assumed that the large, small, and ultrasmall pores have radii of 250 Å, 45 Å, and 2 Å, respectively 26 , to which we attributed 5%, 85%, and 10% of the total (whole-body) capillary hydraulic conductivity, respectively 25 (the latter has been assumed at 4.5 mL/min/mmHg 2 , 29 ).…”

“…( 1 ) reflects the original Starling hypothesis of microvascular fluid exchange 6 and hence represents the classic Starling principle 16 . This principle has been recently revised 10 , 17 or rather extended 17 to account for the effect of the glycocalyx layer (a relatively thin fibrous meshwork of proteoglycans and glycoproteins present on the luminal side of the endothelium 18 ), which is believed to be the main barrier for the transcapillary transport of macromolecules 19 – 21 . According to the Michel-Weinbaum model 16 , 22 , 23 , behind this layer, in the clefts between the endothelial cells, there is a space that is ‘insulated’ from the bulk interstitial fluid by the tight junction strand with a limited amount of pore-like openings, so that the oncotic and hydrostatic/hydraulic pressure behind the glycocalyx are different than in the interstitial fluid, and hence for the calculation of microvascular fluid exchange one should use the trans-glycocalyx instead of trans-endothelial pressure gradients.…”

Appropriate Human Serum Albumin Fluid Therapy and the Alleviation COVID-19 Vulnerabilities; An Explanation of the HSA Lymphatic Nutrient Pump

“…In healthy patients the moderation of nutrients with albumin is assumed to be minimal however any illness or damage to the lungs will cause this equilibrium to change. In COVID-19 infected lung COVID-19 virions antibodies and waste replace nutrient ligands changing both nutrients and colloidal pressure [19]. The aerated plasma is then pumped by the heart to the organs and periphery.…”