Severe sepsis: Low expression of the renin-angiotensin system is associated with poor prognosis

Abstract

Severe sepsis has a high fatality rate, but no clinical indices for prognosis have been established. In recent years, the renin-angiotensin system (RAS) has received considerable attention. However, clinical data on RAS are inconsistent. Therefore, the aim of the present study was to assess the significance of RAS in the prognosis of sepsis. Blood samples were collected from patients, who met the diagnostic criteria of severe sepsis, on day 1 (D1) and 3 (D3). For each sample, the levels of angiotensin II (AngII), angiotensin-converting enzyme (ACE) and additional indices were measured. Patients were monitored for 28 days. On the D1 of inclusion, the average Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 22.2 and the Sepsis-related Organ Failure Assessment (SOFA) score was 6.1. Logistic regression analysis revealed that mortality-associated variables included the APACHE II score on D1, the SOFA score on D1, high lactic acid levels on D3 and low AngII and ACE levels on D1 and D3. AngII levels (<86.1 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 77.3% for predicting mortality. ACE levels (<39.2 ng/ml) on D1 had a sensitivity of 88.2% and specificity of 72.7% for predicting mortality. These two indices were better than the APACHE II and SOFA scores. Therefore, low expression levels of AngII and ACE are valuable in predicting the mortality of patients with severe sepsis.

Classic and Nonclassic Renin-Angiotensin Systems in the Critically Ill

“…Ang II and renin levels are increased in the context of sepsis and significantly associated with severity of disease. 1,6,75 Serum ACE concentration in patients with pulmonary sepsis were lower than in healthy volunteers, with reduced levels associated with increased mortality. 6,76 In line with our understanding of Ang II effects, recent data strongly suggest that exogenous Ang II infusion decreases vasopressor dose requirements in patients with vasodilatory shock, mirroring the physiologic effects of endogenous Ang II: increase in sympathetic tone, endogenous catecholamine and vasopressin release, and direct stimulation of vascular smooth muscle cells.…”

“…1,6,75 Serum ACE concentration in patients with pulmonary sepsis were lower than in healthy volunteers, with reduced levels associated with increased mortality. 6,76 In line with our understanding of Ang II effects, recent data strongly suggest that exogenous Ang II infusion decreases vasopressor dose requirements in patients with vasodilatory shock, mirroring the physiologic effects of endogenous Ang II: increase in sympathetic tone, endogenous catecholamine and vasopressin release, and direct stimulation of vascular smooth muscle cells. 2 During sepsis, Ang II upregulation may induce ROS generation and endothelial structural changes, both being pivotal physiologic responses to infection, yet also central in the pathogenesis of its most severe presentation, namely septic shock, where they become oxidative stress and endothelial dysfunction.…”

“…44 It is a potent cardioprotective antifibrotic agent that binds the AT 2 R. 44,45 Angiotensin-Converting Enzyme 2 ACE2 is the pivotal enzyme of the nonclassic RAS. 10 ACE2 is transmembrane monocarboxypeptidase that converts Ang II into Ang (1-7) and Ang I into Ang (1)(2)(3)(4)(5)(6)(7)(8)(9). ACE2 was simultaneously discovered by 2 independent groups, using 2 complementary DNA libraries (heart and lymphoma).…”

“…Modulation of RAS is central in the intensive care unit spectrum of diseases (eg, hemodynamic failure) and is associated with patient outcomes. [1][2][3][4][5][6][7] The RASs are enzymatic cascades implicating sequential peptide cleavage, leading to angiotensin generation by angiotensin-converting enzymes (ACEs). 8 RAS also modulates inflammation and immune responses.…”

Angiotensin in Critical Care

“…The natural role of the RAS is to preserve volume status and arterial blood pressure, thereby maintaining the systemic circulation and also the microcirculation. In sepsis, both over-and under-stimulation of the RAS have been reported in patients [20][21][22][23][24][25]. The capacity of ACE and the functionality of angiotensin receptors are key factors that determine whether hemodynamic stability can be achieved and maintained.…”