Vasoplegia treatments: the past, the present, and the future

Abstract

Vasoplegia is a ubiquitous phenomenon in all advanced shock states, including septic, cardiogenic, hemorrhagic, and anaphylactic shock. Its pathophysiology is complex, involving various mechanisms in vascular smooth muscle cells such as G protein-coupled receptor desensitization (adrenoceptors, vasopressin 1 receptors, angiotensin type 1 receptors), alteration of second messenger pathways, critical illness-related corticosteroid insufficiency, and increased production of nitric oxide. This review, based on a critical appraisal of the literature, discusses the main current treatments and future approaches. Our improved understanding of these mechanisms is progressively changing our therapeutic approach to vasoplegia from a standardized to a personalized multimodal treatment with the prescription of several vasopressors. While norepinephrine is confirmed as first line therapy for the treatment of vasoplegia, the latest Surviving Sepsis Campaign guidelines also consider that the best therapeutic management of vascular hyporesponsiveness to vasopressors could be a combination of multiple vasopressors, including norepinephrine and early prescription of vasopressin. This new approach is seemingly justified by the need to limit adrenoceptor desensitization as well as sympathetic overactivation given its subsequent deleterious impacts on hemodynamics and inflammation. Finally, based on new pathophysiological data, two potential drugs, selepressin and angiotensin II, are currently being evaluated.

Keywords: Catecholamines; Circulatory failure; Septic shock; Vasoconstrictor agents; Vasoplegic syndrome.

Fig. 1

The principal mechanisms involved in the regulation of vascular tone during vasoplegia as well as treatment options at the central, cellular, and intracellular levels. Central level. Inflammatory triggers such as tumor necrosis factor α (TNF, interleukin (IL)-1 and IL-6 activate the neuro-immune system. This activation leads to norepinephrine, epinephrine, cortisol, vasopressin, and indirectly angiotensin II production in order to counteract vasoplegia. Overactivation of this system may be treated at this integrative level with α₂ agonists and selective β₁ blockers. Cellular level. G-protein-coupled receptors are predominantly involved in vascular smooth muscle cell contraction: α₁ adrenoceptors (α₁AR), vasopressin 1 receptors (V1R), and angiotensin type 1 receptors (AT-R1). These receptors activate phospholipase C (PLC) with generation of inositol 1,4,5 trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidyl inositol 4,5 bisphosphate (PiP₂). DAG stimulates protein kinase C (PKC), which in turn activates voltage-sensitive calcium channels, while IP3 activates sarcoplasmic reticulum calcium channels. α₁ARs increase intracellular calcium by receptor-operated calcium channels (ROCC) stimulation. Available treatments at this level are epinephrine, norepinephrine, dopamine, phenylephrine, selepressin, vasopressin (V1), and angiotensin II. Adrenomedullin primarily acts on endothelial cells. Intracellular level. Translocation of nuclear factor-κB (NF-κB) into the nucleus induces pro-inflammatory cytokine production. These cytokines enhance inducible nitric oxide synthase (iNOS) expression and overproduction of NO. This molecule activates cyclic guanosine monophosphate production as a mediator of vasodilation. Available treatments at this level are glucocorticoids (at different steps), β₁ blockade, and methylene blue. Vascular sensitive calcium channel (VSCC)