The endothelial glycocalyx, the modified Starling principle, and rational fluid therapy

History has witnessed intense debates on the behavior of intravenously administered fluids in critically ill patients. The basic concepts of capillary permeability have changed in recent times. There has been an increasing understanding of the crucial role played by the glycocalyx that lines the endothelium on the behavior of intravenously administered fluids.

The Starling principle

According to the Starling principle, movement of fluid across the capillary barrier is driven by the difference in the hydrostatic and colloid osmotic pressures between the capillaries and the interstitial space. The higher hydrostatic pressure within the capillaries tends to drive fluid out to the interstitium; the higher colloid osmotic pressure of the plasma tends to retain fluid within the capillaries. Thus, according to the Starling principle, the filtered volume per unit area is as follows:

Jv/A = Lp [(Pc–Pis) – σ (πc–πis)] (Fig. 1)

 

Fig 1. The Starling principle that governs the net movement of fluid from the capillaries to the interstitium. The difference between the capillary and interstitial hydrostatic pressures (Pc–Pis) tends to drive fluid out; the difference in colloid osmotic pressures (πc–πis) tends to retain fluid within the capillary lumen. 

Jv/A: filtered volume per unit area; Lp: hydraulic conductance; Pc: capillary hydrostatic pressure; Pis: interstitial hydrostatic pressure; σ: osmotic reflection coefficient; πc: capillary colloid osmotic pressure; πis: interstitial colloid osmotic pressure

The endothelial glycocalyx layer

Recent changes in the understanding of vascular permeability have led to changes in the concepts that guide transendothelial fluid movement. The key to the revised concept is the presence of the glycocalyx layer that lines the lumen of the vascular endothelium. The existence of this layer was unknown at the time that Starling proposed his hypothesis.

The glycocalyx is composed of proteoglycans including syndecans and glypicans. Attached to the central core of the proteoglycans are glycosaminoglycan (GAG) side chains, including heparan, chondroitin, dermatan, and keratin. The endothelial glycocalyx plays a crucial role in regulating vascular permeability. Furthermore, it regulates coagulation, fibrinolysis, and modulates shear stress on the vasculature. The glycocalyx suffers damage in several types of critical illnesses including sepsis, trauma, and following major surgery. Besides, ischemia-reperfusion injury, hypervolemia, hyperglycemia, and hypernatremia are known to cause shedding of the glycocalyx layer. Damage to the glycocalyx results in increased vascular permeability, platelet aggregation, adhesion of leukocytes, and leads to a prothrombotic state, typically seen is sepsis.

Revisions to the Starling principle

Based on the pivotal function of the glycocalyx, several important modifications have been made to the Starling principle.

Capillary filtration is less than predicted by the Starling principle

It has been consistently observed that filtration out of the capillaries to the interstitial space is much less than predicted by the Starling principle. This phenomenon is due to the presence of the sub-glycocalyx layer, a protein-free layer between the glycocalyx and the endothelium. The absence of protein essentially means that the sub-glycocalyx layer has a negligible colloid osmotic pressure. Thus, the Starling equation for calculation of the filtered fluid needs to be revised; specifically, the force that opposes filtration is the difference between the capillary (πc) and sub-glycocalyx (πg) colloid osmotic pressures. Clearly, (πc – πg) is much higher than (πc – πis), thereby, reducing the filtered volume per unit area, Jv/A.

Jv/A = Lp [(Pc– Pis) – σ (πc – πg)] (Fig. 2)

 

Fig 2. The modified Starling principle. The difference between the capillary and interstitial hydrostatic pressures (Pc–Pis) tends to drive fluid out; however, the force that tends to retain fluid within the capillaris is the difference in colloid osmotic pressure between the capillary and the subglycocalyx layer (πc – πg)

Jv/A: filtered volume per unit area; Lp: hydraulic conductance; Pc: capillary hydrostatic pressure; Pis: interstitial hydrostatic pressure; σ: osmotic reflection coefficient; πc: capillary colloid osmotic pressure; πg: colloid osmotic pressure of the glycocalyx 

In clinical practice, at normal or low levels of Pc, the filtered volume is similar during intravenous administration of both crystalloids and colloids. This explains why in recent studies, resuscitation volumes required to achieve hemodynamic endpoints were similar with both crystalloids and colloids. In two trials of critically ill patients, 100 ml of normal saline was comparable to 62–76 ml of human albumin (1)and 63–69 ml of pentastarch, a synthetic colloid (2).

At higher levels of Pc, more filtration occurs with crystalloids compared to colloids, resulting in more efficient filling of the intravascular compartment with colloids.

The interstitial COP is not a major determinant of filtered volume

The interstitial COP is higher than originally assumed and plays very little role in determining the filtration rate. The main driver of filtration is the transendothelial hydrostatic pressure difference and the difference in COP between the plasma and the sub-glycocalyx layer.

Under most circumstances, there is no reabsorption of fluid from the interstitium to the capillaries

According to the Starling principle, fluid is filtered from the arterial end of capillaries and reabsorbed from the venous end. However, under most circumstances, there is no reabsorption of fluid from the interstitium to the capillaries. On the contrary, the filtered fluid is absorbed by the lymphatic system. Reabsorption of fluid back into the capillaries does not occur because the driving force for filtration, Pc, is higher than the forces that oppose filtration [Pis + (πc – πis)] throughout the capillary system.

Pc > Pis + (πc – πis)

Transient fluid reabsorption of about 500 ml may occur from the interstitium to the capillaries, for about 15–30 min after a sudden decrease in Pc. This may occur due to rapid loss of intravascular volume, for instance, from hemorrhage. However, equilibrium is reached after a transient phase of reabsorption, followed by continued filtration.

In clinical practice, this implies that the administration of colloids does not result in reabsorption of fluid from the interstitium back into the intravascular compartment; resolution of tissue edema does not happen with colloid use. On the contrary, if the glycocalyx is damaged, colloids may leak out from the capillaries and worsen edema.

Measures that may protect the glycocalyx

Several studies have shown improved clinical outcomes when a higher ratio of fresh frozen plasma to packed red cells is administered during major transfusion (3). A more liberal use of fresh frozen plasma may thus help preserve the glycocalyx following major transfusion. Adverse clinical outcomes associated with overzealous fluid resuscitation have emerged from many recent trials (4,5). Hypervolemia due to aggressive resuscitation may lead to damage to the glycocalyx and increased vascular permeability. There has been an intense debate on the optimal degree of glycemic control among critically ill patients (6,7). Avoidance of hyperglycemia may be one of the important strategies that may preserve the glycocalyx. Hydrocortisone may preserve the glycocalyx by attenuating possible damage by inflammatory mediators, especially TNF-alpha (8). It is possible that the purported clinical benefits observed with corticosteroid use in sepsis may be related to a favorable effect on the glycocalyx. Volatile anesthetic agents, especially sevoflurane may conserve the glycocalyx in post-ischemic coronary artery beds and improve coronary flow (9).

The bottom line

• The presumed superiority of colloid resuscitation based on the Starling principle is a flawed concept.
• In critically ill patients, the glycocalyx layer suffers damage, leading to leakage of both colloids and crystalloids.
• Transendothelial filtration of fluid occurs to a similar extent with both crystalloids and colloids at normal or low capillary pressures.
• Filtration occurs throughout the capillary bed; reabsorption does not occur except transiently following acute hypovolemia.
• Reabsorption of fluid from the interstitium to the intravascular compartment and resolution of edema does not occur with the infusion of colloids.
• Maintenance of normovolemia and normoglycemia may protect the glycocalyx; hydrocortisone may attenuate damage to the glycocalyx in septic patients. The glycocalyx-preserving effect of fresh frozen plasma during major transfusion needs further investigation.

 

References

1. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004 May 27;350(22):2247–56.
2. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008 Jan 10;358(2):125–39.
3. Gonzalez EA, Moore FA, Holcomb JB, Miller CC, Kozar RA, Todd SR, et al. Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma. 2007 Jan;62(1):112–9.
4. Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, et al. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med. 2011 Jun 30;364(26):2483–95.
5. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564–75.
6. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive Insulin Therapy in Critically Ill Patients. N Engl J Med. 2001 Nov 8;345(19):1359–67.
7. Intensive versus Conventional Glucose Control in Critically Ill Patients. N Engl J Med. 2009 Mar 26;360(13):1283–97.
8. Chappell D, Hofmann-Kiefer K, Jacob M, Rehm M, Briegel J, Welsch U, et al. TNF-alpha induced shedding of the endothelial glycocalyx is prevented by hydrocortisone and antithrombin. Basic Res Cardiol. 2009 Jan;104(1):78–89.
9. Annecke T, Chappell D, Chen C, Jacob M, Welsch U, Sommerhoff CP, et al. Sevoflurane preserves the endothelial glycocalyx against ischaemia-reperfusion injury. Br J Anaesth. 2010 Apr;104(4):414–21.