Capillary leak and endothelial permeability in critically ill patients: a current overview

Abstract

Capillary leak syndrome (CLS) represents a phenotype of increased fluid extravasation, resulting in intravascular hypovolemia, extravascular edema formation and ultimately hypoperfusion. While endothelial permeability is an evolutionary preserved physiological process needed to sustain life, excessive fluid leak-often caused by systemic inflammation-can have detrimental effects on patients' outcomes. This article delves into the current understanding of CLS pathophysiology, diagnosis and potential treatments. Systemic inflammation leading to a compromise of endothelial cell interactions through various signaling cues (e.g., the angiopoietin-Tie2 pathway), and shedding of the glycocalyx collectively contribute to the manifestation of CLS. Capillary permeability subsequently leads to the seepage of protein-rich fluid into the interstitial space. Recent insights into the importance of the sub-glycocalyx space and preserving lymphatic flow are highlighted for an in-depth understanding. While no established diagnostic criteria exist and CLS is frequently diagnosed by clinical characteristics only, we highlight more objective serological and (non)-invasive measurements that hint towards a CLS phenotype. While currently available treatment options are limited, we further review understanding of fluid resuscitation and experimental approaches to target endothelial permeability. Despite the improved understanding of CLS pathophysiology, efforts are needed to develop uniform diagnostic criteria, associate clinical consequences to these criteria, and delineate treatment options.

Keywords: Angiopoietin-2; Capillary leak syndrome; Critical care; Endothelial permeability; Fluid balance.

Fig. 1

Pathophysiological understanding of selected features of capillary leak including inflammation-induced glycocalyx shedding with increased circulation serum glycocalyx markers (syndecan-1, heparan sulfate), as well as angiopoietin-2/Tie2 signaling leading to compromised inter-endothelial adhesion

Fig. 2

Diagnostic approach to capillary leak syndrome (CLS): both serological markers related to glycocalyx shedding and vascular barrier signaling, as well as the vascular leak index can hint towards a CLS phenotype. More nuanced diagnostic approaches comprise bioelectrical impedance analysis (BIA), transpulmonary thermodilution (TPTD), PiCCO™ (pulse index continuous cardiac output), and intravital microscopy

Fig. 3

Phases of capillary leak with increased vascular permeability on the left leading to distinct clinical manifestation and necessitating aggressive treatment strategies, while the recovery phase on the right consists of stabilizing and optimizing the fluid status with de-resuscitation