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

Rinaldo Bellomo, Richard G Wunderink, Harold Szerlip, Shane W English, Laurence W Busse, Adam M Deane, Ashish K Khanna, Michael T McCurdy, Marlies Ostermann, Paul J Young, Damian R Handisides, Lakhmir S Chawla, George F Tidmarsh, Timothy E Albertson, Rinaldo Bellomo, Richard G Wunderink, Harold Szerlip, Shane W English, Laurence W Busse, Adam M Deane, Ashish K Khanna, Michael T McCurdy, Marlies Ostermann, Paul J Young, Damian R Handisides, Lakhmir S Chawla, George F Tidmarsh, Timothy E Albertson

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.

Keywords: ACE; ACE dysfunction; Angiotensin I; Angiotensin II; Sepsis; Vasodilatory shock.

Conflict of interest statement

Rinaldo Bellomo, Richard G. Wunderink, Ashish K. Khanna, Marlies Ostermann, and Paul J. Young have nothing to disclose.

Harold Szerlip received personal fees from La Jolla Pharmaceutical Company during the conduct of the study.

Shane W. English’s research center (Ottawa Hospital Research Institute) received per-patient reimbursement from La Jolla Pharmaceutical company for research coordinator time.

Laurence W. Busse has received consulting fees from La Jolla Pharmaceutical Company.

Adam M. Deane’s employer at the time of study (Royal Adelaide Hospital) received per-patient reimbursement to the institution from La Jolla Pharmaceutical Company for research coordinator time.

Michael T. McCurdy has served on the speakers’ bureau for La Jolla Pharmaceutical Company.

Damian R. Handisides and Lakhmir S. Chawla are employees of La Jolla Pharmaceutical Company and own stock.

George F. Tidmarsh was an employee of La Jolla Pharmaceutical Company at the time of the analysis and owns stock.

Timothy E. Albertson received institutional research funding during the conduct of the study and speaking honoraria after the conduct of the study from La Jolla Pharmaceutical Company.

Figures

Fig. 1
Fig. 1
Survival to day 28 by baseline ratio of angiotensin I/II (ANG angiotensin, CI confidence interval, Est estimate

References

    1. Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, et al. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med. 2014;40(12):1795–1715. doi: 10.1007/s00134-014-3525-z.
    1. Vincent JL, De Backer D. Circulatory shock. New Engl J Med. 2013;369(18):1726–1734. doi: 10.1056/NEJMra1208943.
    1. Sakr Y, Reinhart K, Vincent JL, Sprung CL, Moreno R, Ranieri VM, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) study. Crit Care Med. 2006;34(3):589–597. doi: 10.1097/01.CCM.0000201896.45809.E3.
    1. Bassi E, Park M, Azevedo LC. Therapeutic strategies for high-dose vasopressor-dependent shock. Crit Care Res Pract. 2013;2013:654708.
    1. Standl T, Annecke T, Cascorbi I, Heller AR, Sabashnikov A, Teske W. The nomenclature, definition and distinction of types of shock. Dtsch Arztebl Int. 2018;115(45):757–768.
    1. Leone M, Asfar P, Radermacher P, Vincent JL, Martin C. Optimizing mean arterial pressure in septic shock: a critical reappraisal of the literature. Crit Care. 2015;19:101. doi: 10.1186/s13054-015-0794-z.
    1. Davis AL, Carcillo JA, Aneja RK, Deymann AJ, Lin JC, Nguyen TC, et al. American College of Critical Care Medicine clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock. Crit Care Med. 2017;45(6):1061–1093. doi: 10.1097/CCM.0000000000002425.
    1. Howell MD, Davis AM. Management of sepsis and septic shock. JAMA. 2017;317(8):847–848. doi: 10.1001/jama.2017.0131.
    1. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304–377. doi: 10.1007/s00134-017-4683-6.
    1. Avni T, Lador A, Lev S, Leibovici L, Paul M, Grossman A. Vasopressors for the treatment of septic shock: systematic review and meta-analysis. PLoS One. 2015;10(8):e0129305. doi: 10.1371/journal.pone.0129305.
    1. Schmittinger CA, Torgersen C, Luckner G, Schroder DC, Lorenz I, Dunser MW. Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study. Intensive Care Med. 2012;38(6):950–958. doi: 10.1007/s00134-012-2531-2.
    1. Brown SM, Lanspa MJ, Jones JP, Kuttler KG, Li Y, Carlson R, et al. Survival after shock requiring high-dose vasopressor therapy. Chest. 2013;143(3):664–671. doi: 10.1378/chest.12-1106.
    1. Auchet T, Regnier MA, Girerd N, Levy B. Outcome of patients with septic shock and high-dose vasopressor therapy. Ann Intensive Care. 2017;7(1):43. doi: 10.1186/s13613-017-0261-x.
    1. Brand DA, Patrick PA, Berger JT, Ibrahim M, Matela A, Upadhyay S, Spiegler P. Intensity of vasopressor therapy for septic shock and the risk of in-hospital death. J Pain Symptom Manag. 2017;53(5):938–943. doi: 10.1016/j.jpainsymman.2016.12.333.
    1. Luque M, Martin P, Martell N, Fernandez C, Brosnihan KB, Ferrario CM. Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension. J Hypertens. 1996;14(6):799–805. doi: 10.1097/00004872-199606000-00017.
    1. Azizi M, Chatellier G, Guyene TT, Murieta-Geoffroy D, Menard J. Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives. Circulation. 1995;92(4):825–834. doi: 10.1161/01.CIR.92.4.825.
    1. Zhang W, Chen X, Huang L, Lu N, Zhou L, Wu G, Chen Y. Severe sepsis: low expression of the renin-angiotensin system is associated with poor prognosis. Exp Ther Med. 2014;7(5):1342–1348. doi: 10.3892/etm.2014.1566.
    1. Rice CL, Kohler JP, Casey L, Szidon JP, Daise M, Moss GS. Angiotensin-converting enzyme (ACE) in sepsis. Circ Shock. 1983;11(1):59–63.
    1. Orfanos SE, Armaganidis A, Glynos C, et al. Pulmonary capillary endothelium-bound angiotensin-converting enzyme activity in acute lung injury. Circulation. 2000;102(16):2011–2018. doi: 10.1161/01.CIR.102.16.2011.
    1. Chawla LS, Busse LW, Brasha-Mitchell E, Alotaibi Z. The use of angiotensin II in distributive shock. Crit Care. 2016;20(1):137. doi: 10.1186/s13054-016-1306-5.
    1. Giapreza (angiotensin II) injection for intravenous infusion [package insert]. San Diego, CA: La Jolla Pharmaceutical Company; 2017.
    1. Chawla LS, Russell JA, Bagshaw SM, Shaw AD, Goldstein SL, Fink MP, Tidmarsh GF. Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3): protocol for a phase III, double-blind, randomised controlled trial. Crit Care Resusc. 2017;19(1):43–49.
    1. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419–430. doi: 10.1056/NEJMoa1704154.
    1. Kistler E, Li J, Mazor R, Munoz D, Aletti F, Santamaria M. ACE inhibition by circulating peptides formed de novo in experimental hemorrhagic shock. Crit Care Med. 2016;44(12):120. doi: 10.1097/01.ccm.0000508851.99369.fa.
    1. Saijonmaa O, Nyman T, Fyhrquist F. Downregulation of angiotensin-converting enzyme by tumor necrosis factor-alpha and interleukin-1beta in cultured human endothelial cells. J Vasc Res. 2001;38(4):370–378. doi: 10.1159/000051068.
    1. Dou XM, Cheng HJ, Meng L, Zhou LL, Ke YH, Liu LP, Li YM. Correlations between ACE single nucleotide polymorphisms and prognosis of patients with septic shock. Biosci Rep. 2017;37(2). 10.1042/BSR20170145.
    1. Yende S, Quasney MW, Tolley EA, Wunderink RG. Clinical relevance of angiotensin-converting enzyme gene polymorphisms to predict risk of mechanical ventilation after coronary artery bypass graft surgery. Crit Care Med. 2004;32(4):922–927. doi: 10.1097/01.CCM.0000119427.02721.85.
    1. Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, Campagnole-Santos MJ. The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1-7) Physiol Rev. 2018;98(1):505–553. doi: 10.1152/physrev.00023.2016.
    1. Reddy R, Asante I, Liu S, Parikh P, Liebler J, Borok Z, et al. Circulating angiotensin peptides levels in acute respiratory distress syndrome correlate with clinical outcomes: a pilot study. PLoS One. 2019;14(3):e0213096. doi: 10.1371/journal.pone.0213096.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner