Dysregulation of the renin-angiotensin system in septic shock: Mechanistic insights and application of angiotensin II in clinical management.

Synergistic physiologic mechanisms involving the renin-angiotensin system (RAS), the sympathetic nervous system, and the arginine-vasopressin system play an integral role in blood pressure homeostasis. A subset of patients with sepsis experience septic shock with attendant circulatory, cellular, and metabolic abnormalities. Septic shock is associated with increased mortality because of an inadequacy to maintain mean arterial blood pressure (MAP) despite volume resuscitation and the use of vasopressors. Vasodilatory shock raises the dose of vasopressors required to maintain a MAP of > 65 mm Hg. The diminished response to endogenous angiotensin II in sepsis-induced vasoplegia may be related to the aberrant RAS activation that stimulates a proinflammatory beneficial antibacterial response, increasing the secretion of proinflammatory cytokines that downregulate AT-1 receptors expression. Moreover, excessive systemic upregulation of nitric oxide synthase, stimulation of prostaglandin synthesis, and activation of ATP-sensitive potassium channels followed by reduced vascular entry of calcium ions are putative mechanisms in the reduced responsiveness to vasopressors. However, intravenous angiotensin II in catecholamine-resistant septic shock patients showed substantial evidence of raising the MAP to target hemodynamic levels, thus allowing time to treat underlying conditions. Nevertheless, evidence of catecholamine-sparing effect by adding angiotensin II, aimed at increasing the therapeutic index of vasopressor therapy, does not show an attenuation of end-organ damage. The use of angiotensin II in septic shock has not been evaluated in patients who are not catecholamine resistant. This, in conjunction with an evolving definition of catecholamine resistance, provides an opportunity for further evaluation of exogenous angiotensin II in septic shock.