Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside

Abstract

Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside Abstract Purpose: To delineate some of the characteristics of septic vascular hypotension, to assess the most commonly cited and reported underlying mechanisms of vascular hyporesponsiveness to vasoconstrictors in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Methods: Source data were obtained from a PubMed search of the medical literature with the following MeSH terms: Muscle, smooth, vascular/ physiopathology; hypotension/etiology; shock/physiopathology; vasodilation/physiology; shock/therapy; vasoconstrictor agents. Results: Nitric oxide (NO) and peroxynitrite are crucial components implicated in vasoplegia and vascular hyporeactivity. Vascular ATP-sensitive and calcium-activated potassium channels are activated during shock and participate in hypotension. In addition, shock state is characterized by inappropriately low plasma glucocorticoid and vasopressin concentrations, a dysfunction and desensitization of alpha-receptors, and an inactivation of catecholamines by oxidation. Numerous other mechanisms have been individualized in animal models, the great majority of which involve NO: MEK1/2-ERK1/2 pathway, H 2 S, hyperglycemia, and cytoskeleton dysregulation associated with decreased actin expression. Conclusions: Many therapeutic approaches have proven their efficiency in animal models, especially therapies directed against one particular compound, but have otherwise failed when used in human shock. Nevertheless, high doses of catecholamines, vasopressin and terlipressin, hydrocortisone, activated protein C, and non-specific shock treatment have demonstrated a partial efficiency in reversing sepsis-induced hypotension.

Role of miR-124 and miR-141 in the regulation of vascular reactivity and the relationship to RhoA and Rac1 after hemorrhage and hypoxia

“…Alteration of the expressions of miR-124 and miR-141 with their overexpressed plasmids and antisenses abolished the damage to hypoxia-induced vascular contractile response. This finding provides a new basis on which to treat hypoxia or shock-induced vascular hyporeactivity, the key complication of many critical illnesses such severe trauma, shock, sepsis, multiple organ dysfunction syndrome, and others (11,12). Nevertheless, whether other miRNAs that changed after hypoxia are involved in the regulation of hypoxia-induced vascular contractile dysfunction needs further investigation.…”

Ghrelin-mediated sympathoinhibition and suppression of inflammation in sepsis

“…Proinflammatory cytokines, released by norepinephrine stimulation of ␣ 2A -adrenergic receptor, lead to overproduction of nitric oxide. Nitric oxide contributes to vasoplegia and loss of mean arterial pressure in the late stages of shock (46), requiring vasopressor support. Thus, sympathoinhibition in early sepsis may be beneficial in arresting some of the late developments of the sepsis-shock cascade.…”

How much excess fluid impairs outcome of sepsis?

“…One reason for these findings is that patients presenting with respiratory failure and/or shock have more pronounced "dysregulated host response to infection" (as per sepsis definition) [14]. Consequently, they may more frequently have excessive vasodilatation and vascular hyporesponsiveness [15], mitochondrial dysfunction [16], global myocardial depression [16], and increased vascular permeability [17]. Therefore, there are penalties for under-and over-resuscitating leading to an increased risk of organ ischemia/hypoxia and organ edema, respectively [5] (Fig.…”