Definitions and pathophysiology of vasoplegic shock

Abstract

Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition.

Keywords: Shock; Vasoplegia.

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Figures

Fig. 1

The relationship between tone in resistance vessels, under conditions of equal cardiac output, and the systemic blood pressure—preserved vasomotor tone leading to normotension and loss of vasomotor tone leading to hypotension

Fig. 2

The main clinical causes of vasoplegia (top) and how they are perceived to relate to underlying aetiologies (bottom)—i.e. sepsis is predominantly a response to PAMPS (pathogen-associated molecular patterns) compared to burns or polytrauma where DAMPS (damage-associated molecular patterns) are the major cause

Fig. 3

Endothelial and smooth muscle-mediated mechanisms of vascular dysfunction in shock. Hormonal and mechanical factors drive endothelial cell activation in the vasculature. Increased expression of the inducible isoform of nitric oxide synthase (iNOS) generates increased production of nitric oxide (NO) from arginine. NO directly reduces vascular tone through the activation of soluble guanylate cyclase, which catalyses the conversion of GTP to cyclic GMP. In addition, NO combines with oxygen free radicals (O2−) produced by dyfunctional mitochondria and a number of enzymes, including endothelial nitric oxide synthase (eNOS), NADPH and xanthine oxidase. The synthesised peroxynitrite also directly contributes to smooth muscle relaxation. Hydrogen sulphide (H2S) is synthesised from L-cysteine by cystathionine-β-synthase or cystathionine-γ-lyase (CBL). In shock, H2S reduces vascular tone through inhibition of mitochondrial function and activation of potassium channels. Arachidonic acid is converted to vasoactive prostaglandins via a two-step pathway involving cyclooxygenase (COX) isoforms and prostacyclin synthase (PGIS), which synthesises prostacyclin (PGI2). This in turn drives vasodilatation via the activation of stimulatory G-protein-coupled receptors (Gs), which promotes synthesis of cyclic AMP (AMP) from ATP by adenylate cyclase (AC). Thrombxane A2 (TXA2) is synthesised from the common intermediate PGH2 and plays a role in the regulation of vascular tone in shock states. In the smooth muscle, activation of protein kinase A (PKA) by a number of routes drives smooth muscle relaxation through potassium channel- and endoplasmic reticulum (ER)-mediated hyperpolarization and activation of myosin light chain kinase (MLCK). Glucogorticoids (G) activate glucocorticoid receptors (GR) through both classic and non-classic mechanisms to regulate vascular tone, a process that is impaired in a number of ways in shock. Changes in expression of adrenergic (α1) and vasopressin (VR) receptors and their circulating agonists impair the function of vascular smooth muscle in shock states