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. Graphical Abstract

Hypersensitive blood vessels in Clarkson disease

“…Massive vascular permeability leading to systemic edema, hypoproteinemia, and hypotensive shock, denoted capillary leak syndrome (CLS), can be a sequela to sepsis, trauma, or other severe conditions ( 1 ). A distinct subgroup named idiopathic systemic CLS (ISCLS), or Clarkson syndrome, was identified by Bayard D. Clarkson in the 1960s.…”

Managing sepsis and septic shock in an endothelial glycocalyx-friendly way: from the viewpoint of surviving sepsis campaign guidelines

“…The derangement of the glycocalyx is associated with organ dysfunction and high mortality in sepsis [ 18 ]. A disrupted glycocalyx results in capillary leak syndrome (CLS) in sepsis, manifesting as an excessive fluid shift from the intravascular to the extravascular space and resulting in intravascular hypovolemia, interstitial edema, and tissue hypoperfusion [ 19 ]. Disruption of the glycocalyx also exposes adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and P-selectin (Fig.…”

“…The simultaneous presence of systemic edema, hypovolemia, and hemodynamic instability in various critically ill patients is referred to as CLS. CLS is known to be associated with delayed extubation, longer time in the ICU, and a higher chance of prolonged dependence on vasoactive medication [ 19 ]. To date, there is neither an established definition nor standardized diagnostic criteria for this condition.…”

“…To date, there is neither an established definition nor standardized diagnostic criteria for this condition. Wollborn et al [ 19 ] aimed to identify common characteristics of CLS in different types of critically ill patients. Since the impairment of vascular endothelial cells, especially the glycocalyx damage, is deeply involved in the pathogenesis of CLS, they utilized a range of techniques, such as assay of serum biomarkers (angiopoietin-2, syndecan-1, intracellular adhesion molecule-1, lactate, and interleukin-6), intravital microscopic observation, and non-invasive bioelectrical impedance analysis.…”