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

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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 PaO ₂/FiO ₂-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 cmH ₂O/mmHg at hour-48 with angiotensin-II versus − 0.4 cmH ₂O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH ₂O/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).

Supplementary Information

The online version contains supplementary material available at 10.1186/s13613-023-01227-5.

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Most cited references 47

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Acute respiratory distress syndrome: the Berlin Definition.

V Ranieri, Gordon D Rubenfeld, B Taylor Thompson … (2013)

The acute respiratory distress syndrome (ARDS) was defined in 1994 by the American-European Consensus Conference (AECC); since then, issues regarding the reliability and validity of this definition have emerged. Using a consensus process, a panel of experts convened in 2011 (an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic Society and the Society of Critical Care Medicine) developed the Berlin Definition, focusing on feasibility, reliability, validity, and objective evaluation of its performance. A draft definition proposed 3 mutually exclusive categories of ARDS based on degree of hypoxemia: mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg), and severe (PaO2/FIO2 ≤ 100 mm Hg) and 4 ancillary variables for severe ARDS: radiographic severity, respiratory system compliance (≤40 mL/cm H2O), positive end-expiratory pressure (≥10 cm H2O), and corrected expired volume per minute (≥10 L/min). The draft Berlin Definition was empirically evaluated using patient-level meta-analysis of 4188 patients with ARDS from 4 multicenter clinical data sets and 269 patients with ARDS from 3 single-center data sets containing physiologic information. The 4 ancillary variables did not contribute to the predictive validity of severe ARDS for mortality and were removed from the definition. Using the Berlin Definition, stages of mild, moderate, and severe ARDS were associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; P < .001) and increased median duration of mechanical ventilation in survivors (5 days; interquartile [IQR], 2-11; 7 days; IQR, 4-14; and 9 days; IQR, 5-17, respectively; P < .001). Compared with the AECC definition, the final Berlin Definition had better predictive validity for mortality, with an area under the receiver operating curve of 0.577 (95% CI, 0.561-0.593) vs 0.536 (95% CI, 0.520-0.553; P < .001). This updated and revised Berlin Definition for ARDS addresses a number of the limitations of the AECC definition. The approach of combining consensus discussions with empirical evaluation may serve as a model to create more accurate, evidence-based, critical illness syndrome definitions and to better inform clinical care, research, and health services planning.

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Angiotensin-converting enzyme 2 protects from severe acute lung failure

Yumiko Imai, Keiji Kuba, Shuan Rao … (2005)

Drug hope for SARS The SARS (severe acute respiratory syndrome) epidemic of 2003 caused almost 800 deaths, many of them due to acute respiratory distress syndrome (ARDS) as a complication. There are no effective drugs available for treating ARDS, but new work in mice suggests that ACE2 (angiotensin-converting enzyme 2) might be an option. ACE2 can protect mice from lung injury in an ARDS-like syndrome, whereas other components of the renin–angiotensin system for controlling blood pressure and salt balance actually make the condition worse. ACE2 is expressed in the healthy lung but downregulated by lung injury and it was shown recently (Nature 426, 450–454; 2003) to be a receptor for the SARS coronavirus. Supplementary information The online version of this article (doi:10.1038/nature03712) contains supplementary material, which is available to authorized users.

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Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial

Lee AL Poole, Alan Davidson, Kate McGuigan … (2018)

Precision medicine approaches that target patients on the basis of disease subtype have transformed treatment approaches to cancer, asthma, and other heterogeneous syndromes. Two distinct subphenotypes of acute respiratory distress syndrome (ARDS) have been identified in three US-based clinical trials, and these subphenotypes respond differently to positive end-expiratory pressure and fluid management. We aimed to investigate whether these subphenotypes exist in non-US patient populations and respond differently to pharmacotherapies.

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Author and article information

Contributors

Daniel E. Leisman:

ORCID: http://orcid.org/0000-0001-9670-9425

dleisman@mgh.harvard.edu

Journal

Journal ID (nlm-ta): Ann Intensive Care

Journal ID (iso-abbrev): Ann Intensive Care

Title: Annals of Intensive Care

Publisher: Springer International Publishing (Cham )

ISSN (Electronic): 2110-5820

Publication date (Electronic): 16 December 2023

Publication date PMC-release: 16 December 2023

Publication date Collection: 2023

Volume: 13

Electronic Location Identifier: 128

Affiliations

[1 ]Department of Medicine, Massachusetts General Hospital, ( https://ror.org/002pd6e78) 55 Fruit St., GRB 7-730, Boston, MA 02114 USA

[2 ]Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, ( https://ror.org/002pd6e78) Boston, MA USA

[3 ]Innoviva Specialty Therapeutics, Waltham, MA USA

[4 ]GRID grid.416792.f, Department of Medicine, , Veterans Affairs Medical Center, ; San Diego, CA USA

[5 ]GRID grid.27860.3b, ISNI 0000 0004 1936 9684, Departments of Medicine, Emergency Medicine and Anesthesiology, School of Medicine, , UC Davis, ; Sacramento, CA USA

[6 ]Department of Medicine, Emory University, ( https://ror.org/03czfpz43) Atlanta, GA USA

[7 ]Emory Critical Care Center, Emory Healthcare, ( https://ror.org/00yksxf10) Atlanta, GA USA

[8 ]GRID grid.19006.3e, ISNI 0000 0000 9632 6718, Division of Critical Care, Department of Anesthesiology and Perioperative Medicine, , University of California, Los Angeles, ; Los Angeles, CA USA

[9 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Medicine and Radiology, Royal Melbourne Hospital, , The University of Melbourne, Melbourne Medical School, ; Parkville, Australia

[10 ]GRID grid.251993.5, ISNI 0000000121791997, 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, ( https://ror.org/03zzw1w08) Phoenix, AZ USA

[12 ]GRID grid.241167.7, ISNI 0000 0001 2185 3318, 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, ( https://ror.org/041w69847) Cleveland, OH USA

[15 ]Department of Critical Care, King’s College London, Guy’s & St Thomas’ Hospital, ( https://ror.org/0220mzb33) London, UK

[16 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Division of Pulmonary and Critical Care Medicine, Department of Medicine, , University of Maryland School of Medicine, ; Baltimore, MD USA

[17 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Department of Emergency Medicine, , University of Maryland School of Medicine, ; Baltimore, MD USA

[18 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Medicine, , Harvard Medical School, ; Boston, MA USA

[19 ]Renal Division, Department of Medicine, Emory University Medical Center, Emory University, ( https://ror.org/03czfpz43) Atlanta, GA USA

[20 ]GRID grid.1002.3, ISNI 0000 0004 1936 7857, Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine, , Monash University, ; Melbourne, Australia

[21 ]GRID grid.414094.c, ISNI 0000 0001 0162 7225, Department of Critical Care, Melbourne Medical School, , University of Melbourne, Austin Hospital, ; Melbourne, Australia

[22 ]Data Analytics Research and Evaluation (DARE) Centre, Austin Hospital, ( https://ror.org/010mv7n52) Melbourne, Australia

[23 ]Department of Intensive Care Medicine, Austin Hospital, ( https://ror.org/010mv7n52) Melbourne, Australia

[24 ]GRID grid.489411.1, ISNI 0000 0004 5905 1670, 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, ( https://ror.org/005bvs909) Melbourne, VIC Australia

Author information

Daniel E. Leisman http://orcid.org/0000-0001-9670-9425

Article

Publisher ID: 1227

DOI: 10.1186/s13613-023-01227-5

PMC ID: 10725390

PubMed ID: 38103056

SO-VID: 6591e01c-aa8c-469a-8338-407bbd76dfdf

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 7 August 2023

Date accepted : 10 December 2023

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issue-copyright-statement © La Société de Réanimation de Langue Francaise = The French Society of Intensive Care (SRLF) 2023

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: angiotensin ii,renin–angiotensin system,ards,norepinephrine,shock,septic

Data availability:

ScienceOpen disciplines: Emergency medicine & Trauma

Keywords: angiotensin ii, renin–angiotensin system, ards, norepinephrine, shock, septic

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

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Irish Journal of Paramedicine

Most cited references 47

Acute respiratory distress syndrome: the Berlin Definition.

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial

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