Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock

Daniel E Leisman; Damian R Handisides; Lakhmir S Chawla; Timothy E Albertson; Laurence W Busse; David W Boldt; Adam M Deane; Michelle N Gong; Kealy R Ham; Ashish K Khanna; Marlies Ostermann; Michael T McCurdy; B Taylor Thompson; James S Tumlin; Christopher D Adams; Tony N Hodges; Rinaldo Bellomo

doi:10.1186/s13613-023-01227-5

Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock

Ann Intensive Care. 2023 Dec 16;13(1):128. doi: 10.1186/s13613-023-01227-5.

Authors

Daniel E Leisman^{1

2}, Damian R Handisides³, Lakhmir S Chawla⁴, Timothy E Albertson⁵, Laurence W Busse^{6

7}, David W Boldt⁸, Adam M Deane⁹, Michelle N Gong¹⁰, Kealy R Ham¹¹, Ashish K Khanna^{12

13

14}, Marlies Ostermann¹⁵, Michael T McCurdy^{16

17}, B Taylor Thompson¹⁸, James S Tumlin¹⁹, Christopher D Adams³, Tony N Hodges³, Rinaldo Bellomo^{20

21

22

23

24

25}

Affiliations

¹ Department of Medicine, Massachusetts General Hospital, 55 Fruit St., GRB 7-730, Boston, MA, 02114, USA. dleisman@mgh.harvard.edu.
² Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA. dleisman@mgh.harvard.edu.
³ Innoviva Specialty Therapeutics, Waltham, MA, USA.
⁴ Department of Medicine, Veterans Affairs Medical Center, San Diego, CA, USA.
⁵ Departments of Medicine, Emergency Medicine and Anesthesiology, School of Medicine, UC Davis, Sacramento, CA, USA.
⁶ Department of Medicine, Emory University, Atlanta, GA, USA.
⁷ Emory Critical Care Center, Emory Healthcare, Atlanta, GA, USA.
⁸ Division of Critical Care, Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Department of Medicine and Radiology, Royal Melbourne Hospital, The University of Melbourne, Melbourne Medical School, Parkville, Australia.
¹⁰ Division of Critical Care Medicine, Division of Pulmonary Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
¹¹ Department of Critical Care, Mayo Clinic, Phoenix, AZ, USA.
¹² Department of Anesthesiology, Section On Critical Care Medicine, Wake Forest University School of Medicine, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
¹³ Perioperative Outcomes and Informatics Collaborative (POIC), Winston-Salem, NC, USA.
¹⁴ Outcomes Research Consortium, Cleveland, OH, USA.
¹⁵ Department of Critical Care, King's College London, Guy's & St Thomas' Hospital, London, UK.
¹⁶ Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁷ Department of Emergency Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
¹⁸ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁹ Renal Division, Department of Medicine, Emory University Medical Center, Emory University, Atlanta, GA, USA.
²⁰ Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
²¹ Department of Critical Care, Melbourne Medical School, University of Melbourne, Austin Hospital, Melbourne, Australia.
²² Data Analytics Research and Evaluation (DARE) Centre, Austin Hospital, Melbourne, Australia.
²³ Department of Intensive Care Medicine, Austin Hospital, Melbourne, Australia.
²⁴ The Australian and New Zealand Intensive Care Society (ANZICS) Centre for Outcome and Resource Evaluation (CORE), Melbourne, Australia.
²⁵ Intensive Care Unit, Royal Melbourne Hospital, Melbourne, VIC, Australia.

Abstract

Background: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS.

Methods: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO₂/FiO₂-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality.

Results: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2-161.5], p = 0.0028). Similarly, oxygenation index decreased by - 6.0 cmH₂O/mmHg at hour-48 with angiotensin-II versus - 0.4 cmH₂O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH₂O/mmHg, [95%CI - 8.6 to - 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5-47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group.

Conclusions: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock.

Trial registration: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Keywords: ARDS; Angiotensin II; Norepinephrine; Renin–angiotensin system; Septic; Shock.

Associated data

ClinicalTrials.gov/NCT02338843