Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis

Abstract

IntroductionMicrovascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis.MethodsWe studied 30 subjects with severe sepsis, and 10 healthy control subjects. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II concentration (Ang II). Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of thenar microvascular hemoglobin after five minutes of induced forearm ischemia. In so doing, we assessed bulk microvascular hemoglobin influx to the tissue during reactive hyperemia. We studied all subjects 24 hours after the development of organ failure. We studied a subset of 12 subjects at an additional timepoint, eight hours after recognition of organ failure (early sepsis).ResultsAfter 24 hours of resuscitation to clinically-defined endpoints of preload and arterial pressure, Ang II and PRA were elevated in septic subjects and the degree of elevation correlated negatively with the rate of microvascular reoxygenation during reactive hyperemia. Early RAS mediators correlated with microvascular dysfunction. Early Ang II also correlated with the extent of organ failure realized during the first day of sepsis.ConclusionsRAS is activated in clinical severe sepsis. Systemic RAS mediators correlate with measures of microvascular dysregulation and with organ failure.

Patterns of Use of Perioperative Angiotensin-Converting Enzyme Inhibitors in Coronary Artery Bypass Graft Surgery With Cardiopulmonary Bypass

“…38 These, together with activation of the sympathoadrenal and hemostatic pathways, may provide the groundwork for microvascular injury and organ dysfunction. 12,39 Thus, inhibition of ACE can mitigate angiotensin production and, importantly, may improve microcirculatory perfusion via the aforementioned mechanisms. 40,41 Additionally, ACEI added to cardioplegia solution has been shown to directly reduce ischemia/reperfusion injury, to reduce myocardial ACE activity, and to provide antiarrhythmic effects.…”

Angiotensin II in Septic Shock

“…The renin-angiotensin system in sepsis Activation of the RAS during sepsis is a well know phenomenon, observed in experimental [17] and clinical studies [18][19][20]. However, so far, most of our knowledge about the RAS system during septic shock has come from a few experimental studies performed with healthy rodents [17,[21][22][23][24][25][26], sheep [27,28] or pigs [7].…”

Does calcium channel blockade have a role in prevention of expression of sepsis in renal transplant recipients?

“…2 Pathological concentrations of the vasoconstrictor, angiotensin, can cause damage to the muscular layer of larger blood vessels and to the endothelium of smaller blood vessels. 3 The activation of an inflammation cascade inhibits expression of nitric oxide synthase; the loss of control of glucose disposal, which leads to oxidative stress, disrupts calcium/potassium vascular physiology; and the pressure-induced anatomical injury during uncontrolled hypertension results in loss of vascular integrity with impaired endothelial resistance to sepsis. 4,5 These mechanisms are operative in chronic loss of kidney function through injury to blood vessels, interstitial matrix, and renal tubules, resulting in decreased production of 1,25 (OH)2 D (calcitriol).…”