Definitions and pathophysiology of vasoplegic shock.

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

Understanding the controversy over the identity of EDRF

Thirteen years after its discovery, there is still controversy over the chemical identity of endothelium-derived relaxing factor (EDRF). Although pharmacological and chemical evidence indicates that EDRF is nitric oxide, other candidates, including S-nitrosocysteine, dinitrosyl-iron-cysteine complex, nitroxyl and hydroxylamine, have been proposed to account for the vasorelaxant properties of EDRF. Such diverse compounds should differ in their stability and in reactivity with oxyhaemoglobin and with redox-active nucleophiles such as thiols. Here we use a bioassay to compare the pharmacodynamic profiles of these and other compounds with those of nitric oxide and EDRF. We find that some S-nitrosothiols, dinitrosyl-iron-cysteine complex, sodium nitroxyl and hydroxylamine can be eliminated as candidates as they are more stable than EDRF and less susceptible to inhibition by oxyhaemoglobin. Co-infusion of cysteine revealed major differences between the remaining candidates because it reduced the effect of authentic nitric oxide and EDRF on the bioassay tissues but enhanced the survival of S-nitrosocysteine and S-nitrosocysteamine. Our results further support the evidence that EDRF, the pharmacological entity described by Furchgott and Zawadzki, is nitric oxide