{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:24:14Z","timestamp":1792027454293,"version":"4.4.0"},"reference-count":27,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T00:00:00Z","timestamp":1760313600000},"content-version":"unspecified","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"University of Toronto - BHC Merit Award"},{"DOI":"10.13039\/100019711","name":"London Health Sciences Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100019711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013873","name":"Government of Ontario","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013873","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institute for Health Research","doi-asserted-by":"crossref","award":["447612"],"award-info":[{"award-number":["447612"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Sunnybrook Medical Services Alternative Funding Plan Association"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,9,10]]},"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Inhaled anaesthetics can be used in mechanically ventilated critically ill patients to provide sedation. This approach to sedation potentially improves patient and health system outcomes, but further supportive evidence is needed. The objective of the SAVE-ICU clinical trial is to compare the effectiveness of inhaled versus intravenous sedation in ventilated adults with acute hypoxaemic respiratory failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      SAVE-ICU is a multicentre, open-label, pragmatic, randomised controlled trial conducted in 15 intensive care units (ICUs) in Canada and the USA. Eligible patients include mechanically ventilated and sedated adults with acute hypoxemic respiratory failure from COVID-19 or non-COVID causes with PaO\n                      <jats:sub>2<\/jats:sub>\n                      \/F\n                      <jats:sub>I<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      ratio &lt;300\u2009mm Hg. Patients are excluded with a history of malignant hyperthermia, allergy to sedative agents, raised intracranial pressure, need for concomitant prostacyclin, low tidal volumes (&lt;200\u2009mL), one-lung ventilation or pneumonectomy, severe neuromuscular disorder (eg, amyotrophic lateral sclerosis, Guillain-Barr\u00e9 syndrome), pregnancy or moribund status (unlikely to survive &gt;12\u2009hour). A hierarchy of outcomes was identified at the time of trial design, as the trial was launched during the COVID-19 pandemic when study drug shortages, staffing challenges and healthcare system pressures were prevalent and there was a requirement for rapid evidence generation and implementation on this topic. The primary outcome and highest in the hierarchy is hospital mortality (requiring 758 participants). Secondary and lower hierarchical outcomes are ventilator-free days at day 30 (200 patients), quality of life at 3 months (144 participants) and ICU-free days at day 30 (128 participants). Additional secondary outcomes include median daily oxygenation at day 3 (PaO\n                      <jats:sub>2<\/jats:sub>\n                      \/F\n                      <jats:sub>I<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      ratio), need for adjunctive acute respiratory distress syndrome therapies (prone positioning, inhaled nitric oxide, paralysis with a neuromuscular blocking agent and extracorporeal membrane oxygenation) during ICU stay, days alive and free from delirium and coma at day 14, hospital-free days at day 60 and disability score at 3 months and 12\u2009months after enrolment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The protocol was approved by all hospital ethics committees and by Health Canada. Informed consent will be obtained from substitute decision makers or deferred consent (as permitted by site ethics board). Trial findings will be shared at the end of the study using peer-review publications, conference presentations and social media as part of the trial knowledge translation plan.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04415060\">NCT04415060<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2025-108441","type":"journal-article","created":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T16:16:04Z","timestamp":1760372164000},"page":"e108441","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Sedating with volatile anaesthetics for COVID-19 and non-COVID-19 acute hypoxaemic respiratory failure patients in ICU (SAVE-ICU): protocol for a randomised clinical trial"],"prefix":"10.1136","volume":"15","clinical-trial-number":[{"clinical-trial-number":"nct04415060","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04415060","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-1151","authenticated-orcid":false,"given":"Angela","family":"Jerath","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Sunnybrook Research Institute, Toronto, Ontario, Canada"},{"name":"Department of Anesthesiology and Pain Medicine, University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada"},{"name":"Sunnybrook Research Institute, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marat","family":"Slessarev","sequence":"additional","affiliation":[{"name":"Lawson Health Research Institute, London, Ontario, Canada"},{"name":"Medicine, Western University, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Martin","sequence":"additional","affiliation":[{"name":"Lawson Health Research Institute, London, Ontario, Canada"},{"name":"Medicine, Western University, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1323-0449","authenticated-orcid":false,"given":"Frederick","family":"D\u2019Aragon","sequence":"additional","affiliation":[{"name":"Anesthesiology, Universite de Sherbrooke Faculte de medecine et des sciences de la sante, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0310-0616","authenticated-orcid":false,"given":"Francois Martin","family":"Carrier","sequence":"additional","affiliation":[{"name":"Anesthesiology, Centre Hospitalier de l\u2019Universite de Montreal, Montreal, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janek","family":"Senaratne","sequence":"additional","affiliation":[{"name":"Grey Nuns Community Hospital, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary","family":"Meggison","sequence":"additional","affiliation":[{"name":"The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Hooper","sequence":"additional","affiliation":[{"name":"The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiorgos","family":"Alexandros Cavayas","sequence":"additional","affiliation":[{"name":"Hopital du Sacre-Coeur de Montreal, Montreal, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewan C","family":"Goligher","sequence":"additional","affiliation":[{"name":"Toronto General Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne J","family":"Couture","sequence":"additional","affiliation":[{"name":"IUCPQ-ULaval, Qu\u00e9bec City, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Randall","sequence":"additional","affiliation":[{"name":"Toronto Western Hospital, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roupen","family":"Hatzakorzian","sequence":"additional","affiliation":[{"name":"Royal Victoria Hospital, Montreal, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Jacka","sequence":"additional","affiliation":[{"name":"University of Alberta Hospital, Edmonton, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanine","family":"Wiener-Kronish","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongcong","family":"Xie","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruxandra L","family":"Pinto","sequence":"additional","affiliation":[{"name":"Sunnybrook Research Institute, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Cuthbertson","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada"},{"name":"Sunnybrook Research Institute, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,10,13]]},"reference":[{"key":"2025120415070357000_15.10.e108441.1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0291"},{"key":"2025120415070357000_15.10.e108441.2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000003299"},{"key":"2025120415070357000_15.10.e108441.3","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.bja.2023.05.004","article-title":"Effect of inhaled anaesthetics on cognitive and psychiatric outcomes in critically ill adults: a systematic review and meta-analysis","volume":"131","author":"Cuninghame","year":"2023","journal-title":"Br J Anaesth"},{"key":"2025120415070357000_15.10.e108441.4","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1007\/s00134-020-06154-8","article-title":"Inhalational volatile-based sedation for COVID-19 pneumonia and ARDS","volume":"46","author":"Jerath","year":"2020","journal-title":"Intensive Care Med"},{"key":"2025120415070357000_15.10.e108441.5","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1097\/ALN.0000000000004994","article-title":"Volatile Anesthetic Sedation for Critically Ill Patients","volume":"141","author":"O\u2019Gara","year":"2024","journal-title":"Anesthesiology"},{"key":"2025120415070357000_15.10.e108441.6","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201604-0686OC"},{"key":"2025120415070357000_15.10.e108441.7","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000001634"},{"key":"2025120415070357000_15.10.e108441.8","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1016\/S2213-2600(21)00323-4","article-title":"Inhaled isoflurane via the anaesthetic conserving device versus propofol for sedation of invasively ventilated patients in intensive care units in Germany and Slovenia: an open-label, phase 3, randomised controlled, non-inferiority trial","volume":"9","author":"Meiser","year":"2021","journal-title":"Lancet Respir Med"},{"key":"2025120415070357000_15.10.e108441.9","doi-asserted-by":"crossref","DOI":"10.1186\/s13063-015-1083-5","article-title":"The use of volatile anesthetic agents for long-term critical care sedation (VALTS): study protocol for a pilot randomized controlled trial","volume":"16","author":"Jerath","year":"2015","journal-title":"Trials"},{"key":"2025120415070357000_15.10.e108441.10","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1053\/j.jvca.2017.12.035","article-title":"Opportunity Knocks? The Expansion of Volatile Agent Use in New Clinical Settings","volume":"32","author":"Jerath","year":"2018","journal-title":"J Cardiothorac Vasc Anesth"},{"key":"2025120415070357000_15.10.e108441.11","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000000938"},{"key":"2025120415070357000_15.10.e108441.12","article-title":"Inhaled Volatiles for Status Asthmaticus, Epilepsy, and Difficult Sedation in Adult ICU and PICU: A Systematic Review","volume":"6","author":"Gorsky","year":"2024","journal-title":"Crit Care Explor"},{"key":"2025120415070357000_15.10.e108441.13","doi-asserted-by":"publisher","DOI":"10.1097\/EJA.0b013e32835f0aa5"},{"key":"2025120415070357000_15.10.e108441.14","doi-asserted-by":"publisher","DOI":"10.1097\/aln.0000000000000742"},{"key":"2025120415070357000_15.10.e108441.15","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-016-4429-x"},{"key":"2025120415070357000_15.10.e108441.16","doi-asserted-by":"publisher","DOI":"10.1097\/EJA.0000000000000252"},{"key":"2025120415070357000_15.10.e108441.17","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1001\/jama.2025.3169","article-title":"Inhaled Sedation in Acute Respiratory Distress Syndrome: The SESAR Randomized Clinical Trial","volume":"333","author":"Jabaudon","year":"2025","journal-title":"JAMA"},{"key":"2025120415070357000_15.10.e108441.18","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-158-3-201302050-00583"},{"key":"2025120415070357000_15.10.e108441.19","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1901686"},{"key":"2025120415070357000_15.10.e108441.20","doi-asserted-by":"crossref","DOI":"10.1186\/s40560-016-0178-8","article-title":"One-year resource utilisation, costs and quality of life in patients with acute respiratory distress syndrome (ARDS): secondary analysis of a randomised controlled trial","volume":"4","author":"Marti","year":"2016","journal-title":"J Intensive Care"},{"key":"2025120415070357000_15.10.e108441.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jval.2018.02.007"},{"key":"2025120415070357000_15.10.e108441.22","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201901-0109OC"},{"key":"2025120415070357000_15.10.e108441.23","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215554"},{"key":"2025120415070357000_15.10.e108441.24","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201810-2050CP"},{"key":"2025120415070357000_15.10.e108441.25","doi-asserted-by":"crossref","DOI":"10.1186\/s13063-018-2885-z","article-title":"Superiority and non-inferiority: two sides of the same coin?","volume":"19","author":"Dunn","year":"2018","journal-title":"Trials"},{"key":"2025120415070357000_15.10.e108441.26","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107039"},{"key":"2025120415070357000_15.10.e108441.27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1510063"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2025-108441","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T23:10:57Z","timestamp":1764889857000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2025-108441"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10]]},"references-count":27,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10,13]]},"published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1136\/bmjopen-2025-108441"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2025-108441","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"value":"2044-6055","type":"print"},{"value":"2044-6055","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10]]}}}