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

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.

PMID: 38103056
PMCID: PMC10725390
DOI: 10.1186/s13613-023-01227-5

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

Daniel E Leisman et al. Ann Intensive Care. 2023.

. 2023 Dec 16;13(1):128.

doi: 10.1186/s13613-023-01227-5.

Authors

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.

PMID: 38103056
PMCID: PMC10725390
DOI: 10.1186/s13613-023-01227-5

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.

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Conflict of interest statement

DEL, AMD, KRH, and RB declare no competing interests. DRH, CDA, and TNH are employees of Innoviva Specialty Therapeutics, of which La Jolla Pharmaceutical Company (LJPC) is a subsidiary. LSC declares that he was formerly an employee of LJPC. TEA received consulting fees from LJPC. LWB served on the Speaker’s Bureau for LJPC and received consulting fees from LJPC. DWB served on the Speaker’s Bureau for LJPC and received consulting fees from LJPC. MNG received NIH and CDC grants for research unrelated to this study, fees for serving on scientific advisory panel for Philips Healthcare and Endpoint for advice on AI and personalized approach to sepsis, and previously received funding from LJPC for the conduct of the Athos-3 trial. AKK served on the Speaker’s Bureau for LJPC, received consulting fees from LJPC, and received research grant funding from La Jolla Pharmaceutical Company for the ATHOS-3 study and through the Wake Forest Center for Hypertension and Vascular Research for RAAS in septic shock. MTM served on the Speaker’s Bureau for LJPC. MO declares that her institution received research funding from LJPC. BTT declares that during a portion of this research, the author had a financial interest in Direct Biologics, a developer and manufacturer of regenerative biologic products, including an investigational treatment of COVID-19 associated ARDS. These interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies. JTT received research grant support and institutional funding from LJPC.

Figures

**Fig. 1**
Respiratory Measures Over Time for Angiotensin-II versus Placebo. Displays respiratory variables over time by treatment group. Black indicates the placebo group, pink the Ang-II group. Error bars display the SEM. Asterisks display the p-value for the between-treatment group difference at the indicated timepoint, adjusted for the baseline value, from the regression model as follows: *p < 0.05; **p < 0.01; ***p < 0.001. Hashmarks show the within-treatment difference versus the baseline as follows: ^#p < 0.05; ^##p < 0.01; ^###p < 0.001. *Ang-II* angiotensin-II, *PEEP* positive end-expiratory pressure, *mAwP* mean airway pressure, *SEM* standard error of the mean

**Fig. 2**
Cardiovascular support measures over time for angiotensin-II versus placebo. Displays the hourly total vasopressor dose in norepinephrine equivalents and mean arterial pressure over time by treatment group. Black curves show the placebo group. Pink curves show the Ang-II group. Error bars display the SEM. *Ang-II* angiotensin-II, *SEM* standard error of the mean

**Fig. 3**
P:F over time by treatment group and vasopressor support level. Left graphs display the predicted P:F over time by treatment group at varying vasopressor dose levels from the longitudinal mixed-effects repeated measures models. Circle markers with solid lines display model estimates for the placebo group. Triangle markers with dashed lines, the angiotensin-II group. Colors are used to display the vasopressor dose: light blue = 0.10 mcg/kg/min; dark blue = 0.25 mcg/kg/min; purple = 0.50 mcg/kg/min; black = 0.75 mcg/kg/min. Right graphs show the model effect size for angiotensin-II treatment (purple triangles) and NED (blue squares) at each time point. Error bars indicate the 95%CIs. The model estimates for both variables are tabulated with 95%CIs and p-values at the bottom of the figure. *Ang-II* angiotensin-II, *NED* norepinephrine equivalent dose, *P:F* PaO₂/FiO₂ ratio, *95%CI* 95% confidence interval, *NED*_Total total vasopressor dose in NED, *NED*_Catechol total catecholamine dose in NED

See this image and copyright information in PMC

References

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

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

Authors

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