Journal of Pediatric Critical Care

P - ISSN : 2349-6592    |    E - ISSN : 2455-7099

Symposium article
Year : 2015 | Volume : 2 | Issue : 4 | Page : 21-23

The Endothelial Glycocalyx and Sepsis

Ashit Hegde

Head of Intensive Care Medicine, PD Hinduja Hospital & Medical Research Centre, Mumbai

Correspondence Address:

Ashit Hegde
Head of Intensive Care Medicine, PD Hinduja Hospital & Medical Research Centre, Mumbai

Received:9-Oct-2015/Accepted:16-Oct-2015/Published online:15-Nov-2015

Source of Funding:None Conflict of Interest:None

DOI:10.21304/2015.0204.00091


Every medical student is familiar with Starling’s model1 of the vascular barrier:
1. The higher hydrostatic pressure in the vascular compartment drives fl uid out of the arterioles into the interstitium.
2. The much lower oncotic pressure in the interstitium limits the amount of fl uid that crosses the endothelium.
3. Most of the fluid that escapes from the arteriolar end is reabsorbed at the venular end, lymphatics reabsorb the remainder.



The Starling principle
Jv/A, volume fi ltered per unit area; Lp, hydraulic conductance; Pc, capillary hydrostatic pressure; Pis, interstitial hydrostatic pressure; r, osmotic refl ection co-effi cient; pc, capillary oncotic pressure; pis, interstitial oncotic pressure

Subsequent research revealed that there were a few fl aws in Starling’s original hypothesis:3

1. The albumin content & oncotic pressure of the interstitium is much higher than that predicted by Starling also changes in the albumin content of the interstitium do not seem to affect movement of fl uid across the vasculature.
2. Almost no reabsorption of fl uid takes palce at the venular end, all fl uid that is reabsorbed is via the lymphatics.
3. Even though the interstitial oncotic pressure is just marginally lower than that of the plasma, the actual amount of fl uid that leaves the vasculature is much lower than that predicted by Starling’s Equation (which is why the lymphatic channels are not overwhelmed).

The discovery of and subsequent research on the Endothelial Glycocalyx Layer (EGL) has helped resolve these holes in Starling’s theory.

The EGL is a negatively charged gel–like web of membrane-bound glycoproteins and proteoglycans present on the luminal side of the endothelial cells. It’s associated with various glycosaminoglycans (GAGs). It is the active interface between blood and the capillary wall and it is this layer that determines the competence of the vascular barrier.4,5



Electron microscopic pictures showing an intact endothelial glycocalyx in coronary vessels of a guinea pig heart {taken from Chappell et al.6}


The Endothelial Glycocalyx
There exists a protein free space below the glycocalyx (the sub glycocalyx space). It is the difference in the oncotic pressure between this space and the plasma that limits the amount of fluid that escapes into the interstitium.



Revised Starling’s Hypothesis3
The glycocalyx does not exist only to explain the fl aws in Starling’s model. It has several other important functions. (Protection of Endothelium from shear stress, Ischemia reperfusion Injury etc) This article will dwell on the the glycocalyx and sepsis:

In addition to its barrier function, the healthy EGL covers the endothelium and prevents circulating WBCs and platelets from coming into contact with their receptors located on the endothelium.7



The chemokines released during sepsis & SIRS cause denudation of the EGL and the barrier function is undermined thus contributing to capillary leak and interstitial edema. The worsening interstitial edema affects the delivery of oxygen across the microvasculature. Degradation of the EGL in sepsis exposes the WBCs to their adhesion receptors on the endothelium thereby amplifying the infl ammatory process and causing further disruption of the vascular barrier and worsening of the capillary leakage. Platelets also come into contact with their endothelial receptors causing a procoagulant and antithrombolytic state.9



The Perturbed Glycocalyx The Perturbed Glycocalyx
Inappropriate fl uid therapy in sepsis may also contribute to degradation of the EGL. Fluids (especially colloids) exhibit a phenomenon known as context sensitivity. In hypovolemic or normovolemic patients almost all of the infused colloids remain within the vascular bed. In hypervolemic patients the volume effect is only 40%.10 This is because hypervolemia causes degradation of the EGL through release of ANP (Atrial Natriuretic Peptide). This could also possibly explain why Colloids performed better than crystalloids in studies done on hypovolemic patients but did not do so well in other studies.



The Context Sensitivity of Colloids
Taken from Jacob et al3
In the management of Sepsis, measures that protect the EGL may help limit capillary leak, decrease interstitial edema improve oxygen delivery, limit infl ammation and coagulopathy. This is the subject of much research.
Some of many potential therapies that may preserve the EGL are:11
Antioxidants
Steroids
TNF α receptor antagonists
Antithrombin III
Infusions of Hyaluron & Chondroitin Sulfate

Unfortunately, as of now proof of effi cacy of any of these measures is lacking.
Until such proof is available a few simple measures might help protect the EGL:
Avoidance of Hyperglycemia
Avoidance of Hypervolemia
Maintenance of adequate levels of Sr Albumin

References
1. Starling EH. On the absorption of fl uids from the connective tissue spaces. J Physiol 1896;19:312-326
2. C. S. Alphonsus and R. N. Rodseth The endothelial glycocalyx: a review of the vascular barrier Anaesthesia 2014, 69, 777–784
3. Levick JR, Michel CC. Microvascular fl uid exchange and the revised Starling principle. Cardiovascular Research 2010; 87: 198–210
4. Weinbaum S, Tarbell JM, Damiano ER. The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 2007;9:121-67
5. Pries AR, Secomb TW, Gaehtgens P. The endothelial surface layer. Pfl ugers Arch 2000;440(5):653-66
6. Chappell D, Jacob M, Hofmann-Kiefer K, et al. Hydrocortisone preserves the vascular barrier by protecting the endothelial glycocalyx. Anesthesiology 2007;107:776- 84
7. Florian Brettner, Daniel Chappell, Matthias Jacob. The concept of the glycocalyx - Facts that infl uence perioperative fl uid management. Trends in Anaesthesia and Critical Care 2012;2:191-198
8. Eric P. Schmidt, Warren L. Lee, Rachel L. Zemans, et. al. On, Around, and Through: Neutrophil-Endothelial Interactions in Innate Immunity : Physiology : 2011:5:334-347
9. Daniel Chappell, Martin Westphal, Matthias Jacob. The impact of the glycocalyx on microcirculatory oxygen distribution in critical illness. Current Opinion in Anaesthesiology 2009, 22:155 – 162
10. Jacob M, Chappell D & Rehm M. Clinical update: perioperative fl uid management. Lancet 2007;369:1984– 1986
11. Bernhard F. Becker, Daniel Chappell, Dirk Bruegger, Thorsten Annecke, Matthias Jacob. Therapeutic strategies targeting the endothelial glycocalyx: acute defi cits, but great potential. Cardiovascular Research : 2010 :87: 300–310