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A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS
Journal article   Open access   Peer reviewed

A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS

Laura E. Fredenburgh, Mark A. Perrella, Diana Barragan-Bradford, Dean R. Hess, Elizabeth Peters, Karen E. Welty-Wolf, Bryan D. Kraft, R. Scott Harris, Rie Maurer, Kiichi Nakahira, …
JCI insight, Vol.3(23), 124039
12/06/2018
DOI: 10.1172/jci.insight.124039
PMID: 30518685
url
https://doi.org/10.1172/jci.insight.124039View
Published (Version of record) Open Access

Abstract

BACKGROUND. 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. METHODS. 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 ≥10%, 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. RESULTS. 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% ± 0.7% [cohort 1]; 4.9% ± 0.28% [cohort 2]) compared with placebo-treated subjects (1.97% ± 0.39%). The CFK equation was highly accurate at predicting COHb levels, particularly in cohort 2 (R2 = 0.9205; P < 0.0001). Circulating mitochondrial DNA levels were reduced in iCO-treated participants compared with placebo-treated subjects. CONCLUSION. 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. TRIAL REGISTRATION. ClinicalTrials.gov NCT02425579. FUNDING. NIH grants P01HL108801, KL2TR002385, K08HL130557, and K08GM102695. A randomized controlled trial to investigate the safety and feasibility of low-dose iCO administration in mechanically ventilated patients with sepsis-induced acute respiratory distress syndrome.

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