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

• Type of Material: Article
• Authors: Rinaldo Bellomo, University of Melbourne; Richard G. Wunderink, Northwestern University Feinberg School of Medicine; Harold Szerlip, Baylor University Medical Center at Dallas; Shane W. English, Ottawa Hospital Research Institute; Laurence Busse, Emory University; Adam M. Deane, Melbourne Medical School; Ashish Khanna, Emory University; Michael T. McCurdy, University of Maryland School of Medicine; Marlies Ostermann, Guy's and St Thomas' NHS Foundation Trust; Paul J. Young, Medical Research Institute of New Zealand; Damian R. Handisides, La Jolla Pharmaceutical Company; Lakhmir S. Chawla, La Jolla Pharmaceutical Company; George F. Tidmarsh, Stanford University School of Medicine; Timothy E. Albertson, University of California Davis
• Language: English
• Date: 2020-02-06
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13054-020-2733-x
• Title of Journal or Parent Work: Critical Care
• Volume: 24
• Issue: 1
• Start Page: 43
• End Page: 43
• Grant/Funding Information: The original study and the prespecified and post hoc analyses were funded by La Jolla Pharmaceutical Company. La Jolla Pharmaceutical Company was involved in the design of the study; the collection, analysis, and interpretation of data; and the writing of the manuscript.
• Keywords: Sepsis; Vasodilatory shock; Angiotensin I; Female; Angiotensin II; Humans; ACE dysfunction; ACE; Shock; Male; Catecholamines
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Radiology; Health Sciences, Pharmacology; Health Sciences, Health Care Management

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.