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Mario E Alamilla-Sanchez,1 Miguel A Alcala-Salgado,2 Beatriz Cerezo Samperio,1 Pamela Prado Lozano,1 Juan Daniel Diaz Garcia,1 Carolina Gonzalez Fuentes,1 Martin Benjamin Yama Estrella,1 Enrique Fleuvier Morales Lopez1 1Department of Nephrology, Centro Medico Nacional “ 20 de Noviembre”, Mexico City, Mexico; 2Department of Nephrology, Hospital “Christus Muguerza”, Saltillo, Coahuila, MexicoCorrespondence: Mario E Alamilla-Sanchez, Tel +52 5541334931, Email silenoz1@hotmail.comAbstract: The Starling principle is a model that explains the transvascular distribution of fluids essentially governed by hydrostatic and oncotic forces, which dynamically allow vascular refilling according to the characteristics of the blood vessel. However, careful analysis of fluid physiology has shown that the principle, while correct, is not complete. The revised Starling principle (Michel-Weinbaum model) provides relevant information on fluid kinetics. Special emphasis has been placed on the endothelial glycocalyx, whose subendothelial area allows a restricted oncotic pressure that limits the reabsorption of fluid from the interstitial space, so that transvascular refilling occurs mainly from the lymphatic vessels. The close correlation between pathological states of the endothelium (eg: sepsis, acute inflammation, or chronic kidney disease) and the prescription of fluids forces the physician to understand the dynamics of fluids in the organism; this will allow rational fluid prescriptions. A theory that integrates the physiology of exchange and transvascular refilling is the “microconstant model”, whose variables include dynamic mechanisms that can explain edematous states, management of acute resuscitation, and type of fluids for common clinical conditions. The clinical-physiological integration of the concepts will be the hinges that allow a rational and dynamic prescription of fluids.Keywords: Starling principle, transvascular exchange, glycocalyx, capillary refilling, volume kinetics

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.

Ernest Starling first presented a hypothesis about the absorption of tissue fluid to the plasma within tissue capillaries in 1896. In this Chapter we trace the evolution of Starling's hypothesis to a principle and an equation, and then look in more detail at the extension of the Starling principle in recent years. In 2012 Thomas Woodcock and his son proposed that experience and experimental observations surrounding clinical practices involving the administration of intravenous fluids were better explained by the revised Starling principle. In particular, the revised or extended Starling principle can explain why crystalloid resuscitation from the abrupt physiologic insult of hypovolaemia is much more effective than the pre-revision Starling principle had led clinicians to expect. The authors of this chapter have since combined their science and clinical expertise to offer clinicians a better basis for their practice of rational fluid therapy.

Ion transport through the endothelial glycocalyx layer is closely associated with many vascular diseases. Clarification of ion behaviors around the endothelial glycocalyx layer under varying circumstances will benefit pathologies related to cardiovascular and renal diseases. In this research, a series of large-scale molecular dynamics simulations are conducted to study the response of ion transport to the changing blood flow velocity and the shedding of endothelial glycocalyx sugar chains. Results indicate that blood flow promotes the outward Na+ transport from the near-membrane region to the lumen via the endothelial glycocalyx layer. Scrutiny of sugarchain dynamics and their interactions with Na+ suggests that corner conformation of endothelial glycocalyx sugar chains confines the movement of the Na+, whereas stretching conformation facilitates the motion of Na+ ions. The flow impact on ion transport of Na+ is nonlinear. Based on the findings, the Starling principle and its revised version, which are prevailingly used to predict the ion transport of the endothelial glycocalyx layer, are further improved. An estimation based on the further revised Starling principle indicates that physiological flow changes the osmotic part of transendothelial water flux by 8% compared with the stationary situation. [ABSTRACT FROM AUTHOR]

Over 50% of the human body is comprised of fluids that are distributed in defined compartments. Although compartmentalized, these fluids are dynamically connected. Fluids, electrolytes, and acid-base balance in each compartment are tightly regulated, mostly in an energy-dependent manner to achieve their designed functions. For over a century, our understanding of the microvascular fluid homeostasis has evolved from hypothesized Ernest Starling principle to evidence-based and the revised Starling principle, incorporating the functional endothelial surface layer. The kidney is a highly vascular and encapsulated organ that is exquisitely sensitive to inadequate (insufficient or excess) blood flow. The kidney is particularly sensitive to venous congestion, and studies show that reduced venous return triggers a greater degree of kidney damage than that from lacking arterial flow. Thus, fluid overload can induce severe and sustained kidney injury. In the setting of established acute kidney injury, fluid management can be challenging. Impaired capacity of urine output and urine concentration and dilution should be taken into consideration when designing fluid therapy. [ABSTRACT FROM AUTHOR]

Reflux cannot be interpreted without knowledge of the function of the calf muscle pump. The presence or absence of reflux alone has an insufficient predictive value for excellent functional treatment results. Valves are not simple moving slips but have an autonomous 4-step cycle movement that helps the calf muscle pump to be very effective. New calculations of the Starling equilibrium have shown that capillary filtration fraction returns mainly by the lymphatics. All these new findings help the phlebologist design a more precise and thus better treatment plan in phlebology practice. [ABSTRACT FROM PUBLISHER]

Microvascular fluid exchange (flow Jv) underlies plasma/interstitial fluid (ISF) balance and oedematous swelling. The traditional form of Starling's principle has to be modified in light of insights into the role of ISF pressures and the recognition of the glycocalyx as the semipermeable layer of endothelium. Sum-of-forces evidence and direct observations show that microvascular absorption is transient in most tissues; slight filtration prevails in the steady state, even in venules. This is due in part to the inverse relation between filtration rate and ISF plasma protein concentration; ISF colloid osmotic pressure (COP) rises as Jv falls. In some specialized regions (e.g. kidney, intestinal mucosa), fluid absorption is sustained by local epithelial secretions, which flush interstitial plasma proteins into the lymphatic system. The low rate of filtration and lymph formation in most tissues can be explained by standing plasma protein gradients within the intercellular cleft of continuous capillaries (glycocalyx model) and around fenestrations. Narrow breaks in the junctional strands of the cleft create high local outward fluid velocities, which cause a disequilibrium between the subglycocalyx space COP and ISF COP. Recent experiments confirm that the effect of ISF COP on Jv is much less than predicted by the conventional Starling principle, in agreement with modern models. Using a two-pore system model, we also explore how relatively small increases in large pore numbers dramatically increase Jv during acute inflammation. [ABSTRACT FROM PUBLISHER]

Simple Summary: High vessel permeability, poor perfusion, low lymphatic drainage, and dense abundant stroma elevate interstitial fluid pressures (IFP) in pancreatic ductal adenocarcinoma (PDAC). The present study aims to monitor longitudinal changes in simulated tumor IFP and velocity (IFV) values using a dynamic contrast-enhanced (DCE)-MRI-based computational fluid modeling (CFM) approach in PDAC. Nine PDAC patients underwent DCE-MRI acquisition on a 3-Tesla MRI scanner at pre-treatment (TX (0)), immediately after the first fraction of stereotactic body radiotherapy (SBRT, (D1-TX)), and six weeks post-TX (D2-TX). The partial differential equation of IFP formulated from the continuity equation using the Starling Principle of fluid exchange and Darcy velocity–pressure relationship was solved in COMSOL Multiphysics software to generate IFP and IFV parametric maps using relevant tumor tissue physiological parameters. Initial results suggest that after validation, IFP and IFV can be imaging biomarkers of early response to therapy that may guide precision medicine in PDAC. The present study aims to monitor longitudinal changes in simulated tumor interstitial fluid pressure (IFP) and velocity (IFV) values using dynamic contrast-enhanced (DCE)-MRI-based computational fluid modeling (CFM) in pancreatic ductal adenocarcinoma (PDAC) patients. Nine PDAC patients underwent MRI, including DCE-MRI, on a 3-Tesla MRI scanner at pre-treatment (TX (0)), after the first fraction of stereotactic body radiotherapy (SBRT, (D1-TX)), and six weeks post-TX (D2-TX). The partial differential equation of IFP formulated from the continuity equation, incorporating the Starling Principle of fluid exchange, Darcy velocity, and volume transfer constant (Ktrans), was solved in COMSOL Multiphysics software to generate IFP and IFV maps. Tumor volume (Vt), Ktrans, IFP, and IFV values were compared (Wilcoxon and Spearman) between the time- points. D2-TX Ktrans values were significantly different from pre-TX and D1-TX (p < 0.05). The D1-TX and pre-TX mean IFV values exhibited a borderline significant difference (p = 0.08). The IFP values varying <3.0% between the three time-points were not significantly different (p > 0.05). Vt and IFP values were strongly positively correlated at pre-TX (ρ = 0.90, p = 0.005), while IFV exhibited a strong negative correlation at D1-TX (ρ = −0.74, p = 0.045). Vt, Ktrans, IFP, and IFV hold promise as imaging biomarkers of early response to therapy in PDAC. [ABSTRACT FROM AUTHOR]

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Curry and Michel.)

Ernest Starling first presented a hypothesis about the absorption of tissue fluid to the plasma within tissue capillaries in 1896. In this Chapter we trace the evolution of Starling's hypothesis to a principle and an equation, and then look in more detail at the extension of the Starling principle in recent years. In 2012 Thomas Woodcock and his son proposed that experience and experimental observations surrounding clinical practices involving the administration of intravenous fluids were better explained by the revised Starling principle. In particular, the revised or extended Starling principle can explain why crystalloid resuscitation from the abrupt physiologic insult of hypovolaemia is much more effective than the pre-revision Starling principle had led clinicians to expect. The authors of this chapter have since combined their science and clinical expertise to offer clinicians a better basis for their practice of rational fluid therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Woodcock and Michel.)

Ion transport through the endothelial glycocalyx layer is closely associated with many vascular diseases. Clarification of ion behaviors around the endothelial glycocalyx layer under varying circumstances will benefit pathologies related to cardiovascular and renal diseases. In this research, a series of large-scale molecular dynamics simulations are conducted to study the response of ion transport to the changing blood flow velocity and the shedding of endothelial glycocalyx sugar chains. Results indicate that blood flow promotes the outward Na + transport from the near-membrane region to the lumen via the endothelial glycocalyx layer. Scrutiny of sugar-chain dynamics and their interactions with Na + suggests that corner conformation of endothelial glycocalyx sugar chains confines the movement of the Na + , whereas stretching conformation facilitates the motion of Na + ions. The flow impact on ion transport of Na + is nonlinear. Based on the findings, the Starling principle and its revised version, which are prevailingly used to predict the ion transport of the endothelial glycocalyx layer, are further improved. An estimation based on the further revised Starling principle indicates that physiological flow changes the osmotic part of transendothelial water flux by 8% compared with the stationary situation. NEW & NOTEWORTHY The biophysical roles of negatively charged oligosaccharides of the endothelial glycocalyx have gained increasing attention due to their importance in regulating microvascular fluid exchange. The Starling principle and its revisions are at the heart of the understanding of fluid homeostasis in the periphery. Here, the blood flow changes the conformations of glycocalyx sugar chains, thereby influencing availability of Na + for transport. Based on the findings, the Starling principle and its revision are further improved.