Angiotensin I and angiotensin II concentrations and their ratio in catecholamine-resistant vasodilatory shock

Abstract

Background: In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. Methods: We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes. Results: Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P < 0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P < 0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P < 0.0001), lower ANG II levels (P < 0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P < 0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses. Conclusions: Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction. Trial registration: ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Angiotensin II infusion in COVID-19-associated vasodilatory shock: a case series

“…This represents the first experience with ANGII in COVID-19-associated vasodilatory shock and with ANGII as primary vasopressor in humans. The findings are consistent with those of a previous trial and subsequent subgroup [2] and ANG I/II ratio-related analyses [3]. They suggest the absence of early physiologically harm and improved oxygenation with ANG II.…”

“…ANGII may be logical in this setting. It specifically assists patients recently exposed to angiotensin-converting enzyme inhibitors [2,3] and increases the internalization and downregulation of angiotensinconverting enzyme 2 [4], the receptor for COVID-19. Its use may also inform the debate about the risks and benefits of angiotensin receptor blockers in COVID-19-infected patients [5].…”

Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial

“…We found that serum renin concentrations were significantly elevated in most patients with CRVS and that they were positively and significantly associated with angiotensin I concentrations and angiotensin I/II ratios. This ratio, a surrogate for ACE activity, has previously been reported to be associated with increased mortality risk in CRVS ( 16 ). As with those patients having elevated angiotensin I/II ratios, patients with serum renin concentrations above the study population median had a significantly increased risk of mortality.…”

“…If this were true, high renin concentrations would potentially identify patients most likely to benefit from angiotensin II therapy ( 13 – 15 ). In support of this theory, high ratios of angiotensin I to angiotensin II correlate with negative outcomes in such patients ( 16 ). Moreover, in a study of patients with sepsis, reduced angiotensin II and ACE concentrations outperformed established illness-severity scores in predicting outcomes ( 17 ).…”

The Effect of Angiotensin II Infusion on Markers of Organ Function in Invasively Ventilated COVID-19 Patients

“…In a phase III double blind randomized trial, ANG II as rescue vasopressor improved blood pressure in such vasodilatory shock [6], increased survival in patients with a high angiotensin I/II ratio [7] and in those with a high renin level . [8]. Moreover, in patients receiving renal replacement therapy (RRT) at randomization, ANG II increased the likelihood of recovery to RRT independence [9].…”