Ashish Khanna1, Shane W English1, Xueyuan S Wang1, Kealy Ham1, James Tumlin1, Harold Szerlip1, Laurence W Busse1, Laith Altaweel1, Timothy E Albertson1, Caleb Mackey1, Michael T McCurdy1, David W Boldt1, Stefan Chock1, Paul J Young1, Kenneth Krell1, Richard G Wunderink1, Marlies Ostermann1, Raghavan Murugan1, Michelle N Gong1, Rakshit Panwar1, Johanna Hästbacka1, Raphael Favory1, Balasubramanian Venkatesh1, B Taylor Thompson1, Rinaldo Bellomo1, Jeffrey Jensen1, Stew Kroll1, Lakhmir S Chawla1, George F Tidmarsh1, Adam M Deane1. 1. From Anesthesiology Institute, Center for Critical Care and Department of Outcomes Research, Cleveland Clinic, Cleveland (A.K.); the Department of Medicine (Critical Care), University of Ottawa, and the Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa (S.W.E.); Division of Critical Care Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC (X.S.W.); Regions Hospital, St. Paul, MN (K.H.); University of Tennessee College of Medicine, Chattanooga (J.T.); the Division of Nephrology, Baylor University Medical Center, Dallas (H.S.); the Department of Medicine, Emory University School of Medicine, Atlanta (L.W.B.); Inova Medical Center, Falls Church, VA (L.A.); the Department of Internal Medicine, University of California Davis School of Medicine, Sacramento (T.E.A.), the Division of Critical Care, Department of Anesthesiology, University of California Los Angeles, Los Angeles (D.W.B.), and La Jolla Pharmaceutical Company, San Diego (J.J., S.K., L.S.C., G.F.T.) - all in California; the Department of Pulmonary and Critical Care Medicine, Riverside Methodist Hospital, Columbus, OH (C.M.); the Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore (M.T.M.); the Department of Surgery, Sunrise Hospital, Las Vegas (S.C.); Intensive Care Unit, Wellington Hospital, and Medical Research Institute of New Zealand, Wellington, New Zealand (P.J.Y.); the Division of Critical Care, Department of Medicine, Eastern Idaho Regional Medical Center, Idaho Falls (K.K.); the Department of Medicine, Pulmonary and Critical Care, Northwestern University Feinberg School of Medicine, Chicago (R.G.W.); the Department of Critical Care and Nephrology, King's College London, Guy's and St. Thomas' Hospital, London (M.O.); the Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh (R.M.); the Department of Medicine, Albert Einstein College of Medicine, and the Division of Critical Care Medicine, Montefiore Medical Center, Bronx, NY (M.N.G.); John Hunter Hospital, New Lambton Heights, and School of Medicine and Public Health, University of Newcastle, Callaghan, NSW (R.P.), the Department of Intensive Care, Wesley Hospital and Princess Alexandra Hospital, University of Queensland, St Lucia (B.V.), and School of Medicine, University of Melbourne, Parkville (R.B.), and the Intensive Care Unit, the Royal Melbourne Hospital, University of Melbourne (A.M.D.), Melbourne, VIC - all in Australia; the Division of Intensive Care Medicine, Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Helsinki and Helsinki University Hospital, Helsinki (J.H.); INSERM UMR 995 LIRIC (Lille Inflammation Research Center), Centre Hospitalier Universitaire Lille, Critical Care Center and University of Lille School of Medicine, Lille, France (R.F.); and the Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (B.T.T.).
Abstract
BACKGROUND: Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS: We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS: A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 receivedangiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). CONCLUSIONS:Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843 .).
RCT Entities:
BACKGROUND: Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS: We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 μg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS: A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). CONCLUSIONS:Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843 .).
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