Endothelial Glycocalyx (EGL) and Fluid Management

Endothelial Glycocalyx Layer (EGL), its structure, function and role in fluid management, revised starling law.

1. EGL and Fluid Management Presented by Dr. Qazi Said Rahim

2. Structure of Endothelial Glycocalyx Layer (EGL) The EGL is a gel-like layer covering the luminal surface of vascular endothelial cells. Composition of EGL. Proteoglycans, glycoproteins, and glycosaminoglycans (GAGs). Other Soluble components like proteins (albumin, ATIII, apolipoproteins), hormones, enzymes [superoxide dismutase-3 (SOD3), angiotensin-converting enzyme(ACE)], growth factors, chemokines, and adhesion molecules (selectins, integrins).

3. Structure of EGL Proteoglycans: Syndecan and glypicans form the backbone, attached to the cell membrane. Other proteoglycans like mimecan, perlecan , and biglycan contribute to the soluble portion. GAGs: GAG chains include heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid.

4. Functional Importance of Glycocalyx EGL plays a pivotal role in maintaining vascular homeostasis through Starling's principle, balancing hydrostatic and oncotic pressures. EGL, with its sulphated GAGs, repels negatively charged cells like RBCs, WBCs, and platelets, forming a "cell exclusion zone.“ It acts as a sieve, blocking large molecules (>70 kDa ), but albumin (67 kDa ) binds tightly to the glycocalyx, reducing vascular permeability.

5. Functional Importance of Glycocalyx GAGs (negatively charged) branches are arranged around glycoprotein receptors, act as protective barriers for the adhesion receptors. Two main types of adhesion receptors: Selectins bind to histamine, thrombin, interleukins, and tumor necrosis factor. Immunoglobulins have adhesive molecules for ICAM, VCAM, and PECAM. External/internal insults (thrombosis, inflammation, rapid fluid administration) damage glycocalyx, exposing receptors to harmful ligands, altering signal transduction and significantly impacting microcirculation.

6. Starling equation Starling's model: Net force at arteriolar end pushes fluid out due to high hydrostatic pressure; at venous end, fluid re-enters due to osmotic attraction. Starling equation: Jv = Kf ([Pc− Pi] – σ [π c− π i ])

7. Revised starling equation (a) Intravascular volume includes RBC, plasma, and glycocalyx . (b) Ultrafiltrate is produced by glycocalyx filtration, no venous reabsorption. (c) Lymph is the primary route for fluid return, clearing interstitial fluid.

8. EGL AND FLUID THERAPY Normal Saline 0.9% Crystalloids, such as normal saline (NS), with a high chloride content (e.g., 153 mmol/L) can lead to hyperchloremic metabolic acidosis and damage to the endothelial glycocalyx layer (EGL). Overadministration of acidic crystalloids like NS can result in acute kidney injury (AKI) and impaired clotting functions, partly due to EGL damage. Rapid NS administration can trigger excess plasmin activity and auto- heparinisation from EGL shedding, causing diffuse coagulopathy, especially in trauma or sepsis.

9. EGL AND FLUID THERAPY Balanced crystalloids Balanced crystalloids, such as lactated Ringer and plasmalyte A, with lower chloride content (e.g., Cl 109 mmol/L and Cl 98 mmol/L, respectively), are more physiologically compatible with the EGL. Large clinical trials like SMART and SALTED have demonstrated that major adverse renal events, including AKI and the need for renal replacement therapy, are less frequent with the use of balanced salt solutions with low chloride content compared to NS. However, balanced crystalloids may still pose risks, as they are hypotonic compared to extracellular fluid and can contribute to metabolic alkalosis, particularly in the presence of damaged EGL. Damage to the EGL can alter the distribution of balanced salt solutions, potentially contributing to interstitial edema.

10. EGL AND FLUID THERAPY Colloids Colloids, due to their large molecular size, tend to remain in the intravascular space for an extended period, thereby increasing oncotic pressure. Natural colloids like albumin, with a molecular size of 67 kDa , are part of the soluble portion of the Endothelial Glycocalyx Layer (EGL). Hypoalbuminemia is linked to increased EGL damage in conditions like trauma and sepsis, leading to greater leakage of albumin into the interstitial space.

11. EGL AND FLUID THERAPY Colloids Albumin (5%) infusion is recommended as an early treatment modality in trauma to preserve EGL integrity, except in traumatic brain injury cases. Artificial or semi-synthetic colloids, such as gelatin, dextran, and hydroxyethyl starch (HES), are associated with higher risks of adverse reactions like anaphylactoid responses, coagulopathy, and Acute Kidney Injury (AKI). Despite expectations of wider safety and efficacy, newer generation 6% HES (130/0.42) has shown associations with increased long-term mortality and AKI in trials like those conducted by Scandinavian and CHEST.

12. EGL AND FLUID THERAPY Choice of Fluids and EGL Integrity: Colloid solutions preserve plasma COP, raising capillary pressure, while crystalloids lower COP, thus increasing Jv more. In subnormal capillary pressure, crystalloid infusion is preferred over colloids as it minimizes damage to the EGL due to its lower COP impact.

13. EGL AND FLUID THERAPY Administration Considerations for IV Fluids: Rapid IV fluid administration or hypervolemia can damage the EGL. In hypovolemic or septic shock, IV fluids should be administered through large veins with large bore cannulae to avoid fluid jets and protect the delicate EGL grid. Blood products and IV fluids over 500 mL should be warmed to 37°C to maintain core body temperature and safeguard the EGL Atrial natriuretic peptide (ANP), released from atrial stretching, is a trigger for EGL destruction.

14. EGL AND FLUID THERAPY Guidelines for IV Fluid Maintenance: NICE guidelines recommend routine maintenance of water (value: 25–30 mL/kg/day), Potassium, sodium, chloride, (value: 1 mmol/kg/day), and glucose (value: 50–100 g/day) for patients requiring IV fluids. For old and frail patients with renal impairment and cardiac failure, total fluid amount should be restricted (value: 20–25 mL/kg/day). Caution is advised in obesity, considering ideal body weight, and IV maintenance fluid should not exceed 3 L/day.

15. Effect of Fluid Therapy on EGL and Prognosis: Recent meta-analysis suggests restrictive/goal-directed fluid therapy improves prognosis compared to liberal fluid administration. Liberal fluid administration damages EGL, increasing endothelial leakiness, leading to inflammation, wound infection, coagulation derangement, and increased morbidity and mortality.

16. Thank you