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Outcomes in patients with vasodilatory shock and renal replacement therapy treated with intravenous angiotensin II James A. Tumlin, MD; Raghavan Murugan, MD, MS, FRCP, FCCM; Adam M. Deane, MD, PhD; Marlies Ostermann, MD, PhD; Laurence W. Busse, MD; Kealy R. Ham, MD; Kianoush?Kashani, MD, MSc; Harold M. Szerlip, MD; John R. Prowle, MD, MA, MB, BChir, MSc, FFICM, FRCP; Azra?Bihorac, MD, MS, FCCM, FASN; Kevin W. Finkel, MD, FACP, FASN, FCCM; Alexander?Zarbock, MD; Lui G. Forni MD, MB, PhD; Shannan J. Lynch, PhD; Jeff Jensen, BS; Stew Kroll, MA; Lakhmir?S. Chawla, MD; George?F.?Tidmarsh, MD, PhD; Rinaldo Bellomo, MD, MBBS, FRACP, FCICM, FAAHMSSupplemental Digital Content 1List of Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Investigators and Study SitesThe lead investigators at each site are shown in bold.InvestigatorsSite1Harold Szerlip, MD; Michael Foreman, MD; John Garrett, MD; Brandon Rabeler, MD; Adan Mora Jr, MDBaylor University Medical Center, Dallas, TX2Bruce Friedman, MD; Joseph Shaver, MDJoseph M. Still Research Foundation, Augusta, GA3Laurence W. Busse, MD; Laith Altaweel, MD; Jason Vourlekis, MD; Svetolik Djurkovic, MD; Sarah Anderson, BA; Samer Tanveer, MSW; Swathi Ramesh, MPH; Jing Wang, PhD; Christopher King, MD; Tricia Brannan, MHMP, BSN, RN; Shu Zhen, RN, BSN; Karlie Smith, RN; Courtney Southard, MPHInova Fairfax Hospital, Fall Church, VA4Richard G. Wunderink, MD; Mark Landmeier, MD; Rishi Raj, MD; Raj Shah, MD; Susan Russell, MD; Curtis Weiss, MD, MS; Northwestern University Feinberg School of Medicine, Chicago, IL5James Tumlin, MD; Claude Galphin, MD; Christopher Poole, MD; Sibaji Shome, MD; John Gunter Jr, MDUniversity of Tennessee, Chattanooga, TN6Raghavan Murugan, MD; David Huang, MD, MPH; Scott Gunn, MD; Hyung Kim, MD, PhD; Jonathan Elmer, MD, MS; Bradley Molyneaux, MD, PhD; Matthew Neal, MD; Chethan Puttarajappa, MD; Clifton Callaway, MD, PhD; Ali?Al-Khafaji, MD, MPH; University of Pittsburgh Medical Center, Pittsburgh, PA7Azra Bihorac, MD; William Smith, MD; Gregory Janelle, MD; Peggy White, MDUniversity of Florida, Gainesville, FL8Xueyuan Wang, MD; J. Mauricio Del Rio, MD; Ehimemen Iboaya, MD; Mashael Al-Hegelan, MD; Amanda Jimenez, DODuke University Medical Center, Durham, NC9Kevin Chung, MD; Jeremy Pamplin, MD; Leopoldo Cancio, MD; Ian Driscoll, MD; John Graybill, MD; Edward McCann, MD, MSc; Valerie Sams, MD; Julie Rizzo, MAJ, MC; Matthew Rowan, PhD, MFS; Craig Ainsworth, MDU.S. Army Military Medical Center, Fort Sam Houston,TX10Kianoush Kashani, MD; Nathan Smischney, MD; Vivek Iyer, MD, MPHMayo Clinic, Rochester, MN11Stefan Chock, MD; Heidi Kabler, MD; Sheri Stucke, PhD, APN; Kathleen Campos, APRN; Brenda Pratt, APRN; Elliot Shin, MD, MS; Matthew Johnson, MD, MMS; Christopher Richardson, MD; Christopher Fisher, MD; Allan MacIntyre, DO; Kitae Kim, MDSunrise Hospital, Las Vegas, NV12Daniel Feinstein, MD; Douglas McQuaid, MD; Murali Ramaswamy, MD; Paul Hoffman, RN, NP; Rahul Desai, PAC; Carly Rivet, MD, MPH; Wesam Yacoub, MDMoses Cone Health, Greensboro, NC13Ashish Khanna, MD; Daniel Sessler, MD; Silvia Perez Protto, MD; Roshni Sreedharan, MD; Jia Liu, MD; Sabry Ayad, MD; Brett Elo, DO; Chiedozie Udeh, MD; R. Duncan Hite, MD; Abhijit Duggal, MD, MPH, MS; Tarik Hanane, MD; Praneeta Chodavarapu, MD; Partha Saha, MD; Yehoshua Schacham, MD; Huseyin Oguz Yilmaz, MDThe Cleveland Clinic Foundation, Cleveland, OH14Kealy Ham, MD; David Dries, MSE, MD; Tenbit Emiru, MD, PhD; Michael Brogan, MD; Bruce Bennett, MDRegions Hospital, St. Paul, MN15H. Bryant Nguyen, MD; David Bland, MBBS, BSc; Paresh Giri, MD; Vi Dinh, MD; Kanwaljeet Maken, MD; Laren Tan, MDLoma Linda University Medical Center, Loma Linda, CA16Timothy Albertson, MD; Brian Morrissey, MD; Hugh Black, MD; Christian Sandrock, MD, MPH; Christian Sebat, DOUniversity of California, Davis, CA17Peter Hou, MD; Gyorgy Frendl, MD, PhD; Derek Guanaga, BA; Matthew Long, BA; Jesse Loughlin, BA; Sean Gemunden, BS; Raghu Seethla, MD; Sujatha Pentakota, MD; Reza Askari, MD; Imoigele Aisiku, MD, MSCRBrigham and Women's Hospital, Boston, MA18David Boldt, MD; Sumit Singh, MD; Vadim Gudzenko, MD; Joseph Meltzer, MD; Steven Chang, MD, PhD; Rajan Saggar, MD; Igor Barjaktarevic, MD; William Edwards, MD; Daniel Rolston, MD, MSUniversity of California, Los Angeles, CA19Michelle Gong, MD; S. Jean Hsieh, MD; Aluko Hope, MD; Graciela Soto, MD, MS; Hayley Gershengorn, MD; Nida Qadir, MD; Kristina Kordesch, RN, NP; Muneer Bhatt, PAC; Brittany Gary, MD; Tina Chen, MD; Lawrence Lee, PhD, PA-C; Chao-Ping Wu, MD; Jorge Ataucuri-Vargas, MD; Cassidy Dahn, MDMontefiore Medical Center, Moses Division, Bronx, NY20Firas Koura, MD; Lori Akers, APRN; Michael Raichel, DOKentucky Lung Clinic, Hazard, KY21Shravan Kethireddy, MD; Abraham Layon, MD; Kay Blyler, BSN, RN; Renee Weller, BSN, RN; Linda Bagnata, BSN, RN; Molly Herring, DO; Trudy Snyder, ASN; Michele Mitchell, BSN, RN; Sudheer Penupolu, MD; Zachariah Nealy, MD; Jonathan Perez, MD; Kenneth Snell, MDGeisinger Medical Center, Danville, PA22Matthias Merkel, MD; Miriam Treggiari, MD, PhD, MPHOregon Health & Science University, Portland, OR23Kenneth Krell, MD; Amy Thornley, MSN, ACNP-BC; John Miller, MD, PhDEastern Idaho Regional Medical Center, Idaho Falls, ID24Chris Naum, MD; Rajat Kapoor, MD; Timothy Pohlman, MD; Michael Duncan, MD; Heather Adams, BSN, RN; Erin Turk, BSN, RN; Tessa Oakes, BSN, RN; Katherine Hashmi, BSN, RN; Debra Broach, MSN, RN; Anne-Marie Thorp, BSN, RN; Terri Strickland, BSN, RN; Betty Logan, BSN, RN; Ronda McNamee, BSN, RN; Jean Nash, BSN, RN; Tonya Isaacs, BSN, RN; Caroline Lynn, MSN, RNMethodist Hospital, Indiana University, Indianapolis, IN25Paula Ferrada, MD; Rahul Anand, MD; Jonathan DeAntonio, MD; Stefan Leichtle, MDVirginia Commonwealth University, Richmond, VA26Michelle Gong, MD; S. Jean Hsieh, MD; Aluko Hope, MD; Graciela Soto, MD, MS; Hayley Gershengorn, MD; Nida Qadir, MD; Kristina Kordesch, RN, NP; Muneer Bhatt, PAC; Brittany Gary, MD; Tina Chen, MD; Lawrence Lee, PhD, PA-C; Chao-Ping Wu, MD; Jorge Ataucuri-Vargas, MD; Cassidy Dahn, MDMontefiore Medical Center, Weiler Division, Bronx, NY27Aaron Strumwasser, MD; Daniel Grabo, MD; Damon Clark, MD; Subarna Biswas, MDKeck Hospital, University of Southern California, Los?Angeles, CA28Rita Pechulis, MD; Daniel Schwed-Lustgarten, MD; Traci Eichelberger, BSN, RN; Denise Knittle, BSN, RN; Jennifer Strow, DO; Leslie Baga, BSN, RN, MSCRA; Sagan Loburak, BSN, RN; Jean Novak, BA, MT; Dorthea Watson, DO; Hugh Marsh, RN; Shannon Hoffman-Huffaker, RN, MSN; Jennifer Rovella, DO; Jason Laskosky, PharmD, BCPSLehigh Valley Health Network, Allentown, PA29Ashish Khanna, MD; Daniel Sessler, MD; Silvia Perez-Protto, MD; Roshni Sreedharan, MD; Jia Liu, MD; Sabry Ayad, MD; Brett Elo, DO; Chiedozie Udeh, MBBS, MHEcon; Duncan Hite, MD; Abhijit Duggal, MD, MPH, MS; Tarik Hanane, MD; Praneeta Chodavrapu, MD; Partha Saha, MD; Yehoshua Schacham, MD; Huseyin Oguz Yilmaz, MDThe Cleveland Clinic Foundation - Fairview Hospital, Cleveland, OH30Claude Galphin, MD; Michael Harper, MD; James Tumlin, MD; David Rice, MDSoutheast Renal Research Institute / Memorial Hospital, Chattanooga, TN31Michael McCurdy, MD; Daniel Haase, MD; Darin M. Zimmermann, MDUniversity of Maryland School of Medicine, Baltimore, MD 32Matthew Prekker, MD, MPH; James Leatherman, MD; Sumanth Ambur, MD; Joshua Huelster, MD; Katherine Jacoby, MD; Kenneth Dodd, MD; Eduardo Soto, MDHennepin County Medical Center, Minneapolis, MN33Aaron Strumwasser, MD; Daniel Grabo, MD; Damon Clark, MD; Subarna Biswas, MDLos Angeles County + University of Southern California Medical Center, Los Angeles, CA34Caleb Mackey, MD; Ian Baird, MD; Edward Cordasco Jr, DO; Brian Zeno, MD; Simrit Bhullar, DO; Heather Lee, MSN, RN, CNP; David Rudinsky, DO; Kevin Swiatek, DORiverside Methodist Hospital, Columbus, OH35Prem Kandiah, MD; Ram Subramaniam, MD; Cedric Pimentel, MD; Ofer Sadan, MD, PhD; Alley Killian, PharmDEmory University, Atlanta, GA36Rinaldo Bellomo, MDAustin Hospital, Heidelberg, VIC, Australia37James Walsham, MBChB; Anand Krishnan, MDPrincess Alexandra Hospital, Brisbane, QLD, Australia38Geoffrey Dobb, MBBS; Soumya Ray, MBBS; Andrew Chapman, MBBS; Robert McNamara, MBBS; Alexander Bennett, MBBS; Timothy Bowles, MBBS; Steven Webb, MBBSRoyal Perth Hospital, Perth, WA, Australia39Shailesh Bihari, MBBS; Andrew Bersten, MBBSFlinders Medical Centre, Bedford Park, SA, Australia40Brent Richards, MBChB; James Winearls, MBBS; David Pearson, MA, MB BChirGold Coast University Hospital, Southport, QLD, Australia41Adam Deane, MBBS; Marianne Chapman, BMBS, PhD; Benjamin Reddi, MA, MBChB, PhD; Hao Wong, MBBS; Nikki Yeo, MBChB; Yasmine Abdelhamid, MBBSRoyal Adelaide Hospital, Adelaide, SA, Australia42Andrew Davies, MBBS; Ravindranath Tiruvoipati, MBBS, MSFrankston Hospital, Frankston, VIC, Australia43Edward Litton, MBChB; Adrian Regli, MD; Christopher Allen, MBBS; Bart De Keulenaer, MDFiona Stanley Hospital, Murdoch, WA, Australia44David Cooper, MBChBRoyal Hobart Hospital, Hobart, TAS, Australia45Frank Van Haren, MD, PhD; Sean Chan, BMed; Manoj Singh, MBBS; Sumeet Rai, MBBSCanberra Hospital, Canberra, ACT, Australia46Naomi Diel, MBBS; Simon Finfer, MBBS; Pierre Janin, MD; Anthony Delaney, MBBS; Wade Stedman, MBBS; Oliver Flower, MBBSRoyal North Shore Hospital, Sydney, NSW, Australia47Jeremy Cohen, MBBS; Jeffrey Lipman, MBBChRoyal Brisbane and Women's Hospital, Herston, QLD, Australia48Balasubramanian Venkatesh, MD; Angeline Reid, MBBS; Denzil Gill, MBChB; Jeremy Cohen, MBBS, PhDThe Wesley Hospital and Wesley Medical Research, Auchenflower, QLD, Australia49Ian Seppelt, MBBSNepean Hospital, Kingswood, NSW, Australia50Christopher MacIsaac, MBBS; Thomas Rechnitzer, MBBS; James Anstey, MBBS; Shyamala Sriram, MBBSRoyal Melbourne Hospital, Parkville, VIC, Australia51Rakshit Panwar, MBBS; Cynthia Bierl, MBBS; Eduardo Martinez, MD; Ken Havill, MBBS; Robert O'Connor, MBBS; Philippa Jamieson, MBBSJohn Hunter Hospital, New Lambton Heights, NSW, Australia52Paul Young, MBChB; Christopher Poynter, MBChB; Peter Hicks, MBBS; Shawn Sturland, MBBS; Ben Barry, MBBS; Richard Dinsdale, MBChB; Alexander Psirides, MBBS; Robert Ure, MBChBWellington Hospital, Wellington, New Zealand53Colin McArthur, MBChB; Gillian Bishop, MBChB; Craig Hourigan, MBChB; Leslie Galler, MBChB; Rex Smith, MBChB; Stephen Streat, MBChB; Paul Gardiner, MBChB; Kerry Benson-Cooper, MBChB; Andrew Van der Poll, MBChB; Kari-Jussi Pullinen, MDAuckland City Hospital, Auckland, New Zealand54David Zygun, MD; R. T. Noel Gibney, MBChB; Constantine Karvellas, MD; Michael Meier, MDUniversity of Alberta Hospital, Edmonton, AB, Canada55John Boyd, MD; Najib Ayas, MD; Adam Peets, MD; Demetrios Sirounis, MD; Keith Walley, MDSt Paul’s Hospital, Vancouver, BC, Canada56Shane W. English, MD, FRCPC, MSc; Giuseppe Pagliarello, MD; Andrew Seely, MD; Lauralyn McIntyre, MD; Gwynne Jones, MDUniversity of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada57John Muscedere, MD; J. Gordon Boyd, MD; Suzanne Bridge, MD; Christine D'Arsigny, MD; John Drover, MD; Jason Erb, MD; Imelda Galvin, MD; Paul Heffernan, MD; Daniel Howes, MD; Roy Ilan, MD; David Maslove, MD; David Messenger, MD; Christopher Parker, MD; Stephanie Sibley, MDKingston General Hospital, Kingston, ON, Canada58Christopher Doig, MD; Selena Au, MSc, MD; Carla Chrusch, MSc, MD; John Kortbeek, MD; Paul McBeth, MASc, MD; Juan Posadas-Calleja, MD; Amanada Des Ordons, MD; Bryan Yipp, MSc, MDRockyview General Hospital, Calgary, AB, Canada59Gordon Wood, MD; Daniel Ovakim, MDVictoria General Hospital, Victoria, BC, Canada60Shane W. English, MD; Giuseppe Pagliarello, MD; Andrew Seely, MD; Lauralyn McIntyre, MD; Gwynne Jones, MDUniversity of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada61Johanna H?stbacka, MD, PhD; Ville Pettil?, MD, PhD; Erika Wilkman, DDS, MD, PhD; Suvi Vaara, MD, PhD; Minna B?cklund, MD, PhD; Markus Skrifvars, MD, PhD; Miia Valkonen, MD, PhD; Marjatta Okkonen, MD, PhD; Pekka Jakkula, MD; Ilmar Efendijev, MDHelsinki University Central Hospital, Helsinki, Finland62Sari Karlsson, MD, PhD; Anne Kuitunen, MD, PhD; Ville Jalkanen, MD; Annukka Vahtera, MD; Jaakko L?ngsj?, MD, PhD; Sanna Hoppu, MD, PhDTampere University Hospital, Tampere, Finland63Mika Valtonen, MD; Jussi Heiro, MD; Olli Arola, MD; Outi Inkinen, MD; Mikko J?rvisalo, MD, PhD; Riikka Takala, MD, PhD; Kimmo Kaskinoro, MD, PhD; Juha Gr?nlund, MD, PhDTurku University Hospital, Turku, Finland64John Prowle, MD; Chris Kirwan, MD; Parjam Zolfaghari, MBBS, PhD; Rupert Pearse, MD; Andrew Leitch, MA, MBBS; Russell Hewson, MD; Michael O'Dwyer, PhD; Michael O’Connor, MD; Ryan Haines, MBBSRoyal London Hospital, London, UK65Catherine Snelson, MBChB; Tony Whitehouse, MD; Phillip Pemberton, MBChBQueen Elizabeth Hospital, Birmingham, UK66Jonathan Wilkinson, MBChB; Matthew Outram, MBBS; Livia Malanjum, MBChB; Rae Webster, MBChB, LLB, MBA; David Welburn Popple, MBBS; Christopher Leng, MBBS; Jonathan Hardwick, MDNorthampton General Hospital, Northampton, UK67Andrew Gratrix, MBChB; James Pettit, MbChB; Elanchezzian Balakumar, MBBS; Ian Smith, MBBS; Dale Ventour, MBBSHull Royal Infirmary, Hull, UK68Marlies Ostermann, MD; Duncan Wyncoll, MBBS; Manu Shankar-Hari, MD, PhD; Luigi Camporota, MD, PhD; Catherine McKenzie, PhDKing’s College London, St. Thomas Hospital, London, UK69Gavin Perkins, MD; Joyce Yeung, MBChB, PhD; James Turner, MBChB; Neil Crooks, MBBS; Anna Dennis, MBBSBirmingham Heartlands Hospital, Birmingham, UK70Ingeborg Welters, MD; Richard Wenstone, MBChB; Jonathan Walker, MBChB; Leon Cloherty, MBChBRoyal Liverpool Hospital, Liverpool, UK71Jeremy Bewley, MBChBBristol Royal Infirmary, Bristol, UK72Jean Dellamonica, MDCHU Nice, Nice, France73Saad Nseir, MD, PhD; Geoffrey Ledoux, MD; Roland Lawson, MD; Sophie Six, MD; Thierry Onimus, MD; Sébastien Préau, MD, PhD; Mercè Jourdain, MD, PhD; Emilie Gury-Duburcq, MD; Laurent Robriquet, MD, PhD; Anahita Rouzé, MD; Juliette Masse, MD; Ahmed El Kalioubie, MD, PhD; Benoit Voisin, MD; Emmanuelle Jaillette, MD; Erika Parmentier, MD; Anne-Sophie Moreau, MD; Julien Poissy, MD, PhD; Duburcq Thibault, MD; Maxime Granier, MD; Patrick Girardie, MD; Lea Satre-Buisson, MDHospital Roger Salengro, CHRU de Lille, Lille, France74Hugo Van Aken, MD, PhD; Alexander Zarbock, MD; Melanie Meersch, MDUniversity Hospital Münster, Münster, Germany75Jacques Creteur, MD; Serge Brimioulle, MD, PhD; David Grimaldi, MD, PhDErasme University Hospital, Brussels, BelgiumATHOS-3 Study CommitteesProtocol CommitteeLakhmir S. Chawla, MDLa Jolla Pharmaceutical Company, San Diego, CASean Bagshaw, MD, MSc, FRCPCUniversity of Alberta, Edmonton, AB, CanadaMitchell P. Fink, MDDavid Geffen School of Medicine, University of California, Los Angeles, CAStuart L. Goldstein, MDCincinnati Children's Hospital Medical Center, Cincinnati, OHAndrew Shaw, MB, FRCA.Vanderbilt University Medical Center, Nashville, TNJames Russell, MDUniversity of British Columbia, Vancouver, BC, CanadaGeorge Tidmarsh, MD, PhDLa Jolla Pharmaceutical Company, San?Diego, CAExecutive/Steering/Writing CommitteeRinaldo Bellomo, MDThe University of Melbourne, Melbourne, AustraliaAshish Khanna, MDCleveland Clinic, Cleveland, OHLaurence W. Busse, MDEmory University School of Medicine, Atlanta, GAMarlies Ostermann, MD, PhDKing’s College London, London, UKLakhmir S. Chawla, MDLa Jolla Pharmaceutical Company, San Diego, CAB. Taylor Thompson, MDHarvard Medical School, Boston, MAShane W. English, MD, MScUniversity of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, CanadaPaul Young, MBChB, PhDMedical Research Institute of New Zealand, Wellington, New ZealandAdam M. Deane, MDUniversity of Melbourne, AustraliaData and Safety Monitoring BoardJames Russell, MD (Chair)University of British Columbia, Vancouver, BC, CanadaJoel Singer, PhDUniversity of British Columbia, Vancouver, BC, CanadaSean Bagshaw, MD, MSc, FRCPCUniversity of Alberta, Edmonton, AB, CanadaRationale for ATHOS-3 Study Design Despite recent advancements in critical care, mortality in the intensive care unit due to shock remains unacceptably high (>?50%) (1). Substantial evidence exists that maintaining an adequate mean arterial pressure (MAP) is important to outcomes; even a short exposure to hypotension (defined as MAP <?55?mmHg) may lead to increases in complications such as acute kidney injury and myocardial damage (2). The human body leverages three main regulatory systems to maintain blood pressure: the sympathetic nervous system, arginine-vasopressin, and the renin-angiotensin system. Clinicians currently only have two categories of therapeutic agents available for the management of hypotension, specifically catecholamines and vasopressin. Catecholamines and vasopressin are familiar and well-characterized vasopressors, but have significant side effects at high doses. Patients receiving high doses of vasopressors (>?0.2?ug/kg/min of norepinephrine or the equivalent) are at an increased mortality risk of >?50% (3, 4). In order to defend an appropriate MAP, clinicians are often faced with the undesirable trade-off of higher toxicities due to escalating doses of catecholamines or vasopressin. Angiotensin II has been studied previously in only a single randomized controlled trial of 20?patients (ATHOS-1). ATHOS-3 was designed to meet the Food and Drug Administration (FDA) approval requirements of safety and efficacy. A study design in which the MAP target remained 65 to 75 mmHg once angiotensin II was added would have necessitated a reduction in the background vasopressor dose. This reduction in background vasopressor would have offset potential toxicity and not yielded a clear examination of the safety profile of the new agent. Likewise, using an active comparator would not have allowed a clear determination of the vasopressor activity nor a clear determination of the safety of angiotensin II. The placebo-controlled study design in which the MAP was allowed to rise for the first three hours was therefore chosen to clearly define the potency and safety of angiotensin II.The study design built in two major endpoints within the first 48 hours:?The first three hours was a ‘vasopressor’ trial to test the hypothesis that angiotensin II can raise blood pressure in patients with severe vasodilatory shock already on a high dose of background vasopressors. This is important, as available data clearly show that even a short period of hypotension may lead to worse outcomes. The main utility for angiotensin II is as a vasopressor and it was essential to clearly delineate its safety and vasopressor potency.The second phase of the trial was a more typical vasopressor study design wherein a new vasopressor is introduced, the clinical MAP target is maintained, and catecholamines are titrated down to estimate the effect on blood pressure. This portion of the study, which mimicked “realworld” practice, allowed the clinicians to use their clinical judgment regarding how to best leverage three different drugs in the management of hypotension.In summary, the study design allowed for a clear assessment of safety and incorporated two key metrics of a vasopressor performance: capacity to raise blood pressure and a potency assessment as compared with catecholamine dosing. Inclusion and Exclusion Criteria from ATHOS-3 Study ProtocolEach patient must meet all of the following inclusion criteria to be enrolled in the study:Adult patients ≥?18 years of age with catecholamine-resistance hypotension, defined as those who require a total sum catecholamine dose of >?0.2 ?g/kg/min (see Table 1 for conversion to norepinephrine equivalent) for a minimum of 6 hours and a maximum of 48 hours, to MAP between 55 to 70 mmHg. Patients are required to have central venous access and an arterial line present, and these are expected to remain present for at least the initial 48 hours of study.Patients are required to have an indwelling urinary catheter present, and it is expected to remain present for at least the initial 48 hours of study. Patients must have received at least 25 mL/kg of crystalloid or colloid equivalent over the previous 24hour period, and be adequately volume resuscitated in the opinion of the treating investigator.Patients must have clinical features of high-output shock by meeting one of the following criteria:Central venous oxygen saturation (ScvO2) > 70% (either by oximetry catheter or by central venous blood gas) and central venous pressure (CVP) > 8 mmHg. ORCardiac Index > 2.3 L/min/m2.Patient must meet 5a or 5b to be eligible.Patient or legal surrogate is willing and able to provide written informed consent and comply with all protocol requirements.Patients meeting any of the following exclusion criteria are not to be enrolled in the study:Patients who are < 18 years of age.Any patient with burns covering > 20% of total body surface area. Patients with a Cardiovascular Sepsis-related Organ Failure Assessement (SOFA) score ≤ 3.Patients diagnosed with acute occlusive coronary syndrome requiring intervention.Patients on veno-arterial (VA) extracorporeal membrane oxygenations (ECMO).Patients who have been on ECMO for less than 12 hours. Patients in liver failure with a Model for End-Stage Liver Disease (MELD) score of ≥ 30.Patients with a history of asthma or who are currently experiencing bronchospasm requiring the use of inhaled bronchodilators, if not mechanically ventilated. Patients with acute mesenteric ischemia or a history of mesenteric ischemic. Patients with a history of, presence of, or highly-suspected of having an aortic dissection or abdominal aortic aneurysm.Patients requiring more than 500 mg daily of hydrocortisone or equivalent glucocorticoid medication as a standing dose. Patients with Raynaud’s phenomenon, systemic sclerosis ,or vasospastic disease.Patients with an expected lifespan of < 12 hours.Patients with active bleeding AND an anticipated need (within 48 hours of initiation of the study) for transfusion of > 4 units of packed red blood cells.Patients with active bleeding AND hemoglobin < 7g/dL or any other condition that would contraindicate serial blood sampling.Patients with an absolute neutrophil count of < 1000 cells/mm3.Patients with a known allergy to mannitol.Patients who are current participating in another interventional clinical trial.Patients who are known to be pregnant at the time of screening.Supplemental Table 1. Conversion to norepinephrine equivalentDrugDoseNorepinephrine Equivalent Dose (g/kg/min)Epinephrine a0.1 g/kg/min0.1Norepinephrine a0.1 g/kg/min0.1Dopamine a15 g/kg/min0.1Phenylephrine b1.0 g/kg/min0.1Vasopressin0.04 U/min0.1The conversion scale was developed based on the cardiovascular Sequential Organ Failure Assessment scorea and the medical literatureb (5,6). Vasopressin equivalence to norepinephrine was developed with the use of the Vasopressin and Septic Shock Trial data set (by JAR) (7). Supplemental Table 2. Site enrollment by country (modified intent-to-treat population)CountryPatients Enrolled – n (%)RegionUSA200 (62.3)North AmericaAustralia43 (13.4)AustralasiaCanada36 (11.2)North AmericaUnited Kingdom18 (5.6)Western EuropeNew Zealand9 (2.8)AustralasiaFinland7 (2.2)Western EuropeFrance6 (1.9)Western EuropeBelgium1 (0.3)Western EuropeGermany1 (0.3)Western EuropeTotal321Supplemental Table 3. Titration schema: hour 0 through hour 3 (binding)Current MAP mmHgInitial Study Drug Doseng/kg/minStudy Drug Titration IntervalminStudy Drug Dose Titrationng/kg/minStudy Drug Maximal Doseng/kg/minStudy Drug Minimal Doseng/kg/min≤ 59205Increase to 80 a then by increments of 202002.560-742015Increase by 102002.575-84N/A15Maintain dose2002.5≥ 85N/A5Decrease by 10 b2002.5 cN/A=not applicable (such patients are not eligible for study participation); MAP=mean arterial pressure.aDosing may be modified by consensus opinion of the data safety monitoring board to as low as 60 ng/kg/min and as high as 120 ng/kg/min if deemed necessary for safety purposes.bOnce a dose of 10 ng/kg/min has been reached, study drug may be further reduced by halving each titration until the minimum dose is achieved. cDosing may be modified to as low as 1.25 ng/kg/min for those patients considered “hyper-responders”, ie, MAP remains ≥?85?mmHg despite discontinuation of vasopressin and all catecholamines. Supplemental Table 4. Titration schema: hour 3 through hour 48 (nonbinding)Current MAPmmHgStudy Drug Titration IntervalminStudy Drug Dose Titrationng/kg/minStudy Drug Maximal Doseng/kg/minStudy Drug Minimal Doseng/kg/min≤ 595Increase to 40402.560-6415Increase by 10402.565-7015Maintain dose a402.5≥ 7015Decrease by 10 b402.5 cMAP=mean arterial pressure.aIf the sum of the norepinephrine + epinephrine dose is ≥?0.03 but <?0.1 ?g/kg/min, study drug dose should be maintained.bIf vasopressin is being used, vasopressin should be weaned off first. Then, titrate standard-of-care vasopressors until the sum of the norepinephrine + epinephrine dose is as low as 0.03 ?g/kg/min. cDosing may be modified to as low as 1.25 ng/kg/min for those patients considered “hyper-responders”, ie, MAP remains ≥?70 mmHg despite discontinuation of vasopressin and reduction of sum norepinephrine + epinephrine dose to as low as 0.03??g/kg/min. Supplemental Table 5. Summary of post-hoc analysis baseline demographics and disease characteristicsAcute Kidney Injury + Renal Replacement Therapy at Study Drug InitiationCharacteristicPlacebo(n = 60)Ang II(n = 45)All Patients(N = 105)pAgen = 60n = 45N = 105<?65 years - n (%)35 (58.3) 28 (62.2) 63 (60.0)≥ 65 years - n (%)25 (41.7) 17 (37.8) 42 (40.0)Median (IQR)62.0 (51.0-73.5)62.0 (50.0-72.0)62.0 (51.0-73.0).9613Sex - n (%)n = 60n = 45N = 105Male39 (65.0) 23 (51.1) 62 (59.0).1661Female21 (35.0)22 (48.9)43 (41.0)Ethnicity - n (%)n = 60n = 45N = 105Hispanic or Latino5 (8.3)3 (6.7)8 (7.6)1.0000Non-Hispanic or Latino55 (91.7)42 (93.3)97 (92.4)Race - n (%)n = 60n = 45N = 105White41 (68.3)35 (77.8)76 (72.4).3783Non-white19 (31.7)10 (22.2)29 (27.6)Black or African American12 (20.0)3 (6.7)15 (14.3)Asian5 (8.3)2 (4.4)7 (6.7)American Indian or Alaska Native01 (2.2)1 (1.0)Other2 (3.3)4 (8.9)6 (5.7)Baseline weight (kg)n = 60n = 45N = 105Median (IQR)93.1 (77.1-109.0)80.5 (73.0-100.0)88.9 (75.0-107.1).1718Baseline height (cm)n = 59n = 45N = 104Median (IQR)170.0 (165.0178.0)170.0 (160.0-178.0)170.0 (162.0178.0).5542Baseline body mass index (kg/m2)n = 59n = 45N = 104Median (IQR)31.4 (26.2-37.4)29.5 (25.2-34.4)30.5 (25.7-36.4).2299Geographic region - n (%)n = 60n = 45N = 105Australia/New Zealand6 (10.0)10 (22.2)16 (15.2).0497Europe4 (6.7)7 (15.6)11 (10.5)United States/Canada50 (83.3)28 (62.2)78 (74.3)Screening mean arterial pressure (mmHg)n = 60n = 45N = 105<?65 - n (%)29 (48.3)24 (53.3)53 (50.5).6945≥ 65 - n (%)31 (51.7)21 (46.7)52 (49.5)Median (IQR)65.4 (68.9-67.5)64.3 (62.3-68.2)54.7 (62.2-67.7).5687Baseline mean arterial pressure (mmHg)n = 60n = 45N = 105<?65 - n (%)25 (41.7)18 (40.0) 43 (41.0)1.0000≥ 65 - n (%)35 (58.3) 27 (60.0) 62 (59.0)Median (IQR)65.7 (61.2-67.9)65.7 (63.0-69.0)65.7 (62.3-68.0).1706Baseline APACHE II scoren = 60n = 45N = 105≤?30 - n (%)27 (45.0)21 (46.7) 48 (45.7).640831-40 - n (%)28 (46.7) 18 (40.0)46 (43.8)≥ 41 - n (%)5 (8.3)6 (13.3) 11 (10.5)Median (IQR)31.5 (27-38)32.0 (24-37)32.0 (26-38).6176Baseline albumin (g/dL)n = 60n = 41N = 101Median (IQR)2.3 (1.9-2.8)2.3 (2.0-2.7)2.3 (1.9-2.8).6523Baseline ScvO2 (%)n = 60n= 45N = 105Median (IQR)76.0 (72.0-82.2)76.0 (73.0-82.0)76.0 (72.2-82.0).7791Baseline central venous pressure (mmHg)n = 44n = 34N = 78Median (IQR)13.0 (10-18)13.0 (10-16)13.0 (10-18).8045Baseline cardiac index (L/min/m2)n = 28n = 23N = 51Median (IQR)3.2 (2.5-3.8)3.2 (2.7-4.0)3.2 (2.6-3.9).8795Baseline MELD scoren = 60n = 45N = 105<?30 - n (%)44 (73.3)37 (82.2)81 (77.1).3509≥ 30 - n (%)16 (26.7)8 (17.8)24 (22.9)Median (IQR)25.5 (23-30)23.0 (19-28)25.0 (22-29).0095Exposure to angiotensin-converting enzyme inhibitors - n (%)n = 60n = 45N = 105No53 (88.3)40 (88.9)93 (88.6)1.0000Yes7 (11.7)5 (11.1)12 (11.4)Exposure to angiotensin receptor blockers - n (%)n = 60n = 45N = 105No57 (95.0)39 (86.7)96 (91.4).1673Yes3 (5.0)6 (13.3)9 (8.6)Chest x-ray finding of acute respiratory distress syndrome - n (%)n = 60n =44N = 104No33 (55.0)28 (63.6)61 (58.7).4242Yes27 (45.0)16 (36.4)43 (41.3)Medical history of sepsis - n (%)n = 60n = 45N = 105No8 (13.3)7 (15.6)15 (14.3).7837Yes52 (86.7)38 (84.4)90 (85.7)Cause of shock - n (%)n = 60n = 45N = 105Sepsis52 (86.7)38 (84.4)90 (85.7)Not applicableOther/potentially sepsis5 (8.3)4 (8.9)9 (8.6)Vasoplegia0 (0.0)2 (4.4)2 (1.9)Pancreatitis1 (1.7)0 (0.0)1 (1.0)Other2 (3.3)1 (2.2)3 (2.9)Vasopressin use during 6?h prior to randomization - n (%)n = 60n = 45N = 105No10 (16.7)14 (31.1)24 (22.9).1019Yes50 (83.3)31 (68.9)81 (77.1)Average NED dose during 6?h prior to randomization (μg/kg/min)n = 60n = 45N = 105Median (IQR)0.51 (0.36-0.78)0.38 (0.31-0.50)0.42 (0.33-0.70).0135Baseline NED dose (μg/kg/min)n = 60n = 45N = 105<?0.2 - n (%)1 (1.7)5 (11.1)6 (5.7).0263≥ 0.2 - <?0.35 - n (%)18 (30.0)15 (33.3)33 (31.4)≥ 0.35 - <?0.50 - n (%)12 (20.0)14 (31.1)26 (24.8)≥ 0.50 - n (%)29 (48.3)11 (24.4)40 (38.1)Median (IQR)0.46 (0.32-0.79)0.36 (0.23-0.49)0.42 (0.28-0.69).0194Baseline angiotensin I (pg/mL)n = 52n = 43N = 95< 72.3 - n (%)11 (21.2)8 (18.6)19 (20.0)72.3 - < 253 - n (%)13 (25.0)11 (25.6)24 (25.3)253 - < 676 - n (%)15 (28.8)14 (32.6)29 (30.5)≥ 676 - n (%)13 (25.0)10 (23.3)23 (24.2)Median (IQR)286.0 (90.8674.5)271.0 (121.0-533.0)271.0 (95.2-653.0).7649Baseline angiotensin II (pg/mL)n = 50n = 41N = 91< 23.85 - n (%)17 (34.0)7 (17.1)24 (26.4)23.85 - < 83.75 - n (%)13 (26.0)9 (22.0)22 (24.2)83.75 - < 299.50 - n (%)7 (14.0)13 (31.7)20 (22.0)≥ 299.50 - n (%)13 (26.0)12 (29.3)25 (27.5)Median (IQR)55.1(15.2-305.0)116.0(35.8-346.0)72.8(20.7-342.0).1079Baseline angiotensin I/II ration = 50n = 41N = 91≥ 1.63 - n (%)33 (66.0)19 (46.3)52 (57.1)< 1.63 - n (%)17 (34.0)22 (53.7)39 (42.9)Median (IQR)3.6 (1.1-10.2)1.6 (0.8-4.2)2.2 (1.0-7.4).0253Ang II=angiotensin II; APACHE II=Acute Physiology and Chronic Health Evaluation II; IQR=interquartile range; MELD=Model End-stage Liver Disease; NED=norepinephrine equivalent dose; SD=standard deviation.Supplemental Table 6. Mean arterial pressure baseline to hour 3Placebo(n = 60)Ang II(n = 45)All Patients(N = 105)BaselineMean (SD)63.7 (6.49)65.9 (5.15)Median (range)65.7 (43.3-74.5)65.7 (55.0-78.3)p.0600 aAverage hour 0-3Mean (SD)66.7 (9.22)76.8 (8.05)Median (range)66.9 (43.1-86.7)78.3 (59.0-97.5)p< .001aChange from baselineMean (SD)3.0 (6.17)10.8 (6.86)Median (range)2.2 (-6.6-18.7)11.8 (-6.2-32.5)p< .001aAng II=angiotensin II; SD=standard deviation.a Two-sample t-test of Ang II compared to placebo.Supplemental Table 7. Mean norepinephrine equivalent dose (μg/kg/min)Placebo(n = 60)Ang II(n = 45)All Patients(N = 105)BaselineMean (SD)0.65 (0.617)0.49 (0.454)0.59 (0.556)Median (range)0.46 (0.13-3.80)0.36 (0.15-2.58)0.42 (0.13-3.80)Average hour 0-3Mean (SD)0.67 (0.667)0.47 (0.462)0.59 (0.594)Median (range)0.48 (0.13-4.46)0.33 (0.01-2.58)0.41 (0.01-4.46)Change from baselineMean (SD)0.02 (0.119)-0.02 (0.063)0.00 (0.101)Median (range)0.00 (-0.25-0.66)0.00 (-0.26-0.13)0.00 (-0.26-0.66)p0.65 (0.617)0.49 (0.454).0199 aAng II=angiotensin II; SD=standard deviation.a Two-sample t-test of Ang II compared to placebo.Supplemental Figure 1. Survival probability through day 28 in patients with no history of end-stage renal disease that initiated renal replacement therapy after study drug initiation. There was no statistically significant difference (p = .6201) on survival through Day?28 between the angiotensin II (LJPC-501) group (n = 28) and the placebo group (n = 22). Supplemental Figure 2. Cumulative incidence of discontinuation of renal replacement therapy through day 7 in patients with no history of endstage renal disease that initiated renal replacement therapy (dialysis) after study drug initiation. There was no statistically significant difference (p = .7745) in the cumulative incidence of renal replacement therapy discontinuation by the end of day 7 between the angiotensin II (LJPC-501) group (n = 28) and the placebo group (n = 22).Supplement Figure 3. Mean (Standard Error) of Mean Arterial Pressure by Hour in patients with no history of end-stage renal disease that initiated renal replacement therapy after study drug initiation.? Mean arterial pressure (mmHg) is shown from initiation of angiotensin II (LJPC-501) or placebo through hour 48 by study group.? By hour 3, the angiotensin II (LJPC-501) group (n?=?28) achieved a significantly (p?<?.001) greater mean arterial pressure response than the placebo group (n = 22). Supplemental Figure 4. Cumulative incidence of time to discontinuation of vasopressor(s) through day 7 accounting for death as a competing risk . Subjects with death prior to day 7 are censored at day 7. There was no significant difference between the angiotensin?II and placebo groups (p = .113).Supplemental Figure 5. Cumulative incidence of time to discontinuation of ventilation through 7 day accounting for death as a competing risk. Subjects with death prior to day 7 are censored at day 7. The adjustment showed a significant difference between the angiotensin II and placebo groups (p = .015).References1.Sviri S, Hashoul J, Stav I, et al: Does high-dose vasopressor therapy in medical intensive care patients indicate what we already suspect? J Crit Care 2014; 29:157-1602.Walsh M, Devereaux PJ, Garg AX, et al: Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology 2013; 119:507-5153.Brown SM, Lanspa MJ, Jones JP, et al: Survival after shock requiring high-dose vasopressor therapy. Chest 2013; 143:664-6714.Mayr FB, Yende S, Angus DC: Epidemiology of severe sepsis. Virulence 2014; 5:4-115.Vincent JL, Moreno R, Takala J, et al: The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22:707-7106.Chawla LS, Russell JA, Bagshaw SM, et al: Angiotensin II for the Treatment of High-Output Shock?3 (ATHOS-3): protocol for a phase III, double-blind, randomised controlled trial. Crit?Care?Resusc 2017; 19:43-497.Russell JA, Walley KR, Singer J, et al: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877-887 ................
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