{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T07:05:54Z","timestamp":1793862354167,"version":"4.6.1"},"reference-count":69,"publisher":"American Society for Clinical Investigation","issue":"23","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["P01HL108801"],"award-info":[{"award-number":["P01HL108801"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["KL2TR002385"],"award-info":[{"award-number":["KL2TR002385"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["K08GM102695"],"award-info":[{"award-number":["K08GM102695"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["K08HL130557"],"award-info":[{"award-number":["K08HL130557"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,12,6]]},"abstract":"<jats:p>\n                    <jats:bold>BACKGROUND.<\/jats:bold>\n                    Acute respiratory distress syndrome (ARDS) is a prevalent disease with significant mortality for which no effective pharmacologic therapy exists. Low-dose inhaled carbon monoxide (iCO) confers cytoprotection in preclinical models of sepsis and ARDS.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>METHODS.<\/jats:bold>\n                    We conducted a phase I dose escalation trial to assess feasibility and safety of low-dose iCO administration in patients with sepsis-induced ARDS. Twelve participants were randomized to iCO or placebo air 2:1 in two cohorts. Four subjects each were administered iCO (100 ppm in cohort 1 or 200 ppm in cohort 2) or placebo for 90 minutes for up to 5 consecutive days. Primary outcomes included the incidence of carboxyhemoglobin (COHb) level \u226510%, prespecified administration-associated adverse events (AEs), and severe adverse events (SAEs). Secondary endpoints included the accuracy of the Coburn-Forster-Kane (CFK) equation to predict COHb levels, biomarker levels, and clinical outcomes.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>RESULTS.<\/jats:bold>\n                    No participants exceeded a COHb level of 10%, and there were no administration-associated AEs or study-related SAEs. CO-treated participants had a significant increase in COHb (3.48% \u00b1 0.7% [cohort 1]; 4.9% \u00b1 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% \u00b1 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (\n                    <jats:italic>\n                      <jats:italic>\n                        R\n                        <jats:sup>2<\/jats:sup>\n                      <\/jats:italic>\n                    <\/jats:italic>\n                    = 0.9205;\n                    <jats:italic>\n                      <jats:italic>P<\/jats:italic>\n                    <\/jats:italic>\n                    &lt; 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>CONCLUSION.<\/jats:bold>\n                    Precise administration of low-dose iCO is feasible, well-tolerated, and appears to be safe in patients with sepsis-induced ARDS. Excellent agreement between predicted and observed COHb should ensure that COHb levels remain in the target range during future efficacy trials.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>TRIAL REGISTRATION.<\/jats:bold>\n                    ClinicalTrials.gov NCT02425579.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>FUNDING.<\/jats:bold>\n                    NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.124039","type":"journal-article","created":{"date-parts":[[2018,12,5]],"date-time":"2018-12-05T11:01:32Z","timestamp":1544007692000},"source":"Crossref","is-referenced-by-count":109,"title":["A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS"],"prefix":"10.1172","volume":"3","author":[{"given":"Laura E.","family":"Fredenburgh","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Perrella","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."},{"name":"Department of Pediatric Newborn Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Barragan-Bradford","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean R.","family":"Hess","sequence":"additional","affiliation":[{"name":"Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA."},{"name":"Department of Respiratory Care, Massachusetts General Hospital, Boston, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Peters","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen E.","family":"Welty-Wolf","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan D.","family":"Kraft","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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