Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial

Kealy R Ham; David W Boldt; Michael T McCurdy; Laurence W Busse; Raphael Favory; Michelle N Gong; Ashish K Khanna; Stefan N Chock; Feng Zeng; Lakhmir S Chawla; George F Tidmarsh; Marlies Ostermann

doi:10.1186/s13613-019-0536-5

Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial

Ann Intensive Care. 2019 Jun 3;9(1):63. doi: 10.1186/s13613-019-0536-5.

Authors

Kealy R Ham¹, David W Boldt², Michael T McCurdy³, Laurence W Busse⁴, Raphael Favory^{5

6}, Michelle N Gong⁷, Ashish K Khanna⁸, Stefan N Chock⁹, Feng Zeng¹⁰, Lakhmir S Chawla¹⁰, George F Tidmarsh¹⁰, Marlies Ostermann¹¹

Affiliations

¹ Division of Critical Care Medicine, Regions Hospital, University of Minnesota, 640 Jackson Street, St. Paul, MN, 55101, USA. Kealy.R.Ham@HealthPartners.com.
² Division of Critical Care, Department of Anesthesiology, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
⁴ Department of Medicine, Emory University, Atlanta, GA, USA.
⁵ Critical Care Center, CHU Lille, Lille, France.
⁶ Lille Inflammation Research Center, University of Lille School of Medicine, Lille, France.
⁷ Department of Medicine, Montefiore Healthcare Center, Albert Einstein College of Medicine, Bronx, NY, USA.
⁸ Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest School of Medicine, Winston-Salem, NC & Outcomes Research Consortium, Cleveland, OH, USA.
⁹ Department of Surgery, Sunrise Hospital, Las Vegas, NV, USA.
¹⁰ La Jolla Pharmaceutical Company, San Diego, CA, USA.
¹¹ Department of Critical Care, Guy's and St. Thomas Hospital, King's College London, London, UK.

Abstract

Background: Early clinical data showed that some patients with vasodilatory shock are responsive to low doses of angiotensin II. The objective of this analysis was to compare clinical outcomes in patients requiring ≤ 5 ng kg^-1 min^-1 angiotensin II at 30 min (≤ 5 ng kg^-1 min^-1 subgroup) to maintain mean arterial pressure (MAP) ≥ 75 mmHg versus patients receiving > 5 ng kg^-1 min^-1 angiotensin II at 30 min (> 5 ng kg^-1 min^-1 subgroup). Data from angiotensin II-treated patients enrolled in the ATHOS-3 trial were used.

Results: The subgroup of patients whose angiotensin II dose was down-titrated from 20 ng kg^-1 min^-1 at treatment initiation to ≤ 5 ng kg^-1 min^-1 at 30 min (79/163) had significantly lower endogenous serum angiotensin II levels and norepinephrine-equivalent doses and significantly higher MAP versus the > 5 ng kg^-1 min^-1 subgroup (84/163). Patients in the ≤ 5 ng kg^-1 min^-1 subgroup were more likely to have a MAP response at 3 h versus those in the > 5 ng kg^-1 min^-1 subgroup (90% vs. 51%, respectively; odds ratio, 8.46 [95% CI 3.63-19.7], P < 0.001). Day 28 survival was also higher in the ≤ 5 ng kg^-1 min^-1 subgroup versus the > 5 ng kg^-1 min^-1 subgroup (59% vs. 33%, respectively; hazard ratio, 0.48 [95% CI 0.28-0.72], P = 0.0007); multivariate analyses supported the survival benefit in patients with lower angiotensin II levels. The ≤ 5 ng kg^-1 min^-1 subgroup had a more favorable safety profile and lower treatment discontinuation rate than the > 5 ng kg^-1 min^-1 subgroup.

Conclusions: This prespecified analysis showed that down-titration to ≤ 5 ng kg^-1 min^-1 angiotensin II at 30 min is an early predictor of favorable clinical outcomes which may be related to relative angiotensin II insufficiency.

Keywords: Angiotensin II; Dose response; Hypotension; Septic shock; Shock.