Vasoplegia Treatments: The Past, the Present, and the Future

Bruno Levy; Caroline Fritz; Elsa Tahon; Audrey Jacquot; Thomas Auchet; Antoine Kimmoun

Disclosures

Crit Care. 2018;22(52) 

In This Article

A Treatment-based Pathophysiological Approach to Vascular Hyporesponsiveness to Vasopressors

Here, we limit our description to the pathophysiological mechanisms involved in vascular hyporesponsiveness to vasopressors where treatments are currently available or soon will be. Thus, certain crucial mechanisms have been omitted, although they are described elsewhere in this series of articles on vasoplegia. The following three levels will be described: central (neuro-immune communication), cellular (G protein-coupled receptors (GPCRs)), and intracellular (alteration of second messenger pathways) (Figure 1).

Figure 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 (α 1 AR), 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 (PiP 2 ). 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)

Neuro-immune Communication

Shock states are primarily associated with a concomitant initial activation of the sympathetic system in the locus coeruleus and the hypothalamic pituitary-adrenal axis in the paraventricular nucleus by stimulation of baro- and chemoreceptors and inflammatory cytokines such as tumor necrosis factor (TNF)α, interleukin (IL)-1 and IL-6. These two systems are both co-activated such that activation of one also tends to activate the other. Consequences include the release of norepinephrine from sympathetic nerve extremities in lymphoid organs, epinephrine from the adrenal medulla, and cortisol from the adrenal cortex. Of note, vasopressin release is also under the control of baro- and chemoreceptors characterizing the autonomic system.[6] Moreover, vasopressin also increases the activation of the hypothalamic pituitary-adrenal axis.[7] Finally, vasopressin and angiotensin II interact synergistically at a peripheral level in vascular smooth muscle in order to increase calcium concentrations.[8] Together, all of these systems participate in the maintenance of vascular responsiveness, particularly during the initial stage of shock state.

Sustained activation of the sympathetic system is associated with dysautonomia, a syndrome characterized by loss of cardiovascular variability with inappropriate tachycardia, excessively elevated catecholamine levels with concomitant adrenoceptor desensitization, and pro-inflammatory states leading to poor outcome.[9] This triad participates in vascular hyporesponsiveness to vasopressors during shock states.

G-protein-coupled Receptors

The three major receptors (adrenergic, vasopressin 1 (V1), and angiotensin type 1 (AT1) receptors) involved in the regulation of vascular tone are GPCRs. During shock states, adrenergic, V1, and AT1 receptors undergo similar desensitization processes. Sustained agonist activation such as in the initial phase of shock is associated with phosphorylation of GPCRs by GPCR kinases (GRKs). This process appears to be activated early, even following transient agonist stimulation, and is a major cause of vascular hyporesponsiveness to the three major vasopressors. The decreasing affinity of α adrenergic receptors for various molecules such as endotoxin is known to enhance desensitization.[10] AT1 receptors are downregulated within the first hours after experimental septic shock. This process is associated with low blood pressure and low systemic vascular resistance.[11] However, others have also demonstrated that AT1 receptors are primarily downregulated, although not by their agonist but rather through deficient expression of the AT1 receptor-associated protein Arap1. Arap1 is known to enhance the transport of the AT1 receptor from endosomes to the plasma membrane.[12] Finally, V1 receptors appear to be less sensitive to agonistic stimulation due to low circulating concentrations of vasopressin in blood even during shock states.[7] After an initial increase in concentration at shock onset, a decrease in vasopressin plasma levels is most often observed.[13]

Alteration of Second Messenger Pathways

In addition to the desensitization process, other mechanisms are also highly involved in vascular hyporesponsiveness to vasopressors. For instance, expression of inducible nitric oxide synthase (iNOS) is enhanced during shock states in vascular smooth muscle cells (VSMCs) while NO production is increased a thousand-fold. Endotoxin and proinflammatory cytokines increase iNOS expression and NO production.[14] NO activates cyclic guanosine monophosphate (cGMP) production as well as calcium-sensitive potassium channels, potassium ATP channels, and myosin light chain phosphatase, all of which contribute to vasodilation.[15] Other mechanisms equally involved in vasodilatation include prostacyclin and cyclooxygenase 2 (COX2) pathways, although with no currently known positive therapeutic consequences.[16]

Critical illness-related corticosteroid insufficiency (CIRCI), which occurs in 50 % of septic shock patients, has a major impact on vascular hyporesponsiveness to vasopressors.[17] Involved mechanisms include insufficient synthesis of cortisol, tissue resistance to cortisol, and an excessive proinflammatory response. Injuries are observed at all levels of the hypothalamo-hypopituitary axis. Adrenocorticotropic hormone (ACTH) secretion may be impaired by shock-induced anatomical lesions of the pituitary axis.[18] It has also long been known that adrenal necrosis and/or hemorrhage may be due to shock state and particularly septic shock.[18] Tissue resistance has multifactorial causes involving, among others, downregulation of glucocorticoid receptor α at the tissue level and reduction of cortisol delivery to septic locations. Excessive proinflammatory secretion also impacts ACTH secretion. Thus, TNFα and IL-1, massively released during septic shock, downregulate ACTH and cortisol production.

Consequences of CIRCI on hemodynamic parameters during shock states are extensive with vascular hyporesponsiveness to phenylephrine and low blood pressure. Underlying mechanisms involve disinhibition of NF-κB with upregulation of iNOS responsible for NO over-production.

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