PMID- 30518685
OWN - NLM
STAT- MEDLINE
DCOM- 20191125
LR  - 20221109
IS  - 2379-3708 (Electronic)
IS  - 2379-3708 (Linking)
VI  - 3
IP  - 23
DP  - 2018 Dec 6
TI  - A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS.
LID - 124039 [pii]
LID - 10.1172/jci.insight.124039 [doi]
LID - e124039
AB  - 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.
FAU - Fredenburgh, Laura E
AU  - Fredenburgh LE
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham 
      and Women's Hospital, Boston, Massachusetts, USA.
FAU - Perrella, Mark A
AU  - Perrella MA
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham 
      and Women's Hospital, Boston, Massachusetts, USA.
AD  - Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, 
      Massachusetts, USA.
FAU - Barragan-Bradford, Diana
AU  - Barragan-Bradford D
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham 
      and Women's Hospital, Boston, Massachusetts, USA.
FAU - Hess, Dean R
AU  - Hess DR
AD  - Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General 
      Hospital, Boston, Massachusetts, USA.
AD  - Department of Respiratory Care, Massachusetts General Hospital, Boston, 
      Massachusetts, USA.
FAU - Peters, Elizabeth
AU  - Peters E
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill 
      Cornell Medicine, New York, New York, USA.
FAU - Welty-Wolf, Karen E
AU  - Welty-Wolf KE
AD  - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of 
      Medicine, Duke University Medical Center, Durham, North Carolina, USA.
FAU - Kraft, Bryan D
AU  - Kraft BD
AD  - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of 
      Medicine, Duke University Medical Center, Durham, North Carolina, USA.
FAU - Harris, R Scott
AU  - Harris RS
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, 
      Massachusetts General Hospital, Boston, Massachusetts, USA.
FAU - Maurer, Rie
AU  - Maurer R
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
FAU - Nakahira, Kiichi
AU  - Nakahira K
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill 
      Cornell Medicine, New York, New York, USA.
FAU - Oromendia, Clara
AU  - Oromendia C
AD  - Department of Healthcare Policy and Research, Division of Biostatistics and 
      Epidemiology, Weill Cornell Medicine, New York, New York, USA.
FAU - Davies, John D
AU  - Davies JD
AD  - Department of Respiratory Care, Duke University Medical Center, Durham, North 
      Carolina, USA.
FAU - Higuera, Angelica
AU  - Higuera A
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham 
      and Women's Hospital, Boston, Massachusetts, USA.
FAU - Schiffer, Kristen T
AU  - Schiffer KT
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill 
      Cornell Medicine, New York, New York, USA.
FAU - Englert, Joshua A
AU  - Englert JA
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham 
      and Women's Hospital, Boston, Massachusetts, USA.
FAU - Dieffenbach, Paul B
AU  - Dieffenbach PB
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham 
      and Women's Hospital, Boston, Massachusetts, USA.
FAU - Berlin, David A
AU  - Berlin DA
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill 
      Cornell Medicine, New York, New York, USA.
FAU - Lagambina, Susan
AU  - Lagambina S
AD  - Department of Respiratory Care, Brigham and Women's Hospital, Boston, 
      Massachusetts, USA.
FAU - Bouthot, Mark
AU  - Bouthot M
AD  - Department of Respiratory Care, Brigham and Women's Hospital, Boston, 
      Massachusetts, USA.
FAU - Sullivan, Andrew I
AU  - Sullivan AI
AD  - Department of Respiratory Care, Brigham and Women's Hospital, Boston, 
      Massachusetts, USA.
FAU - Nuccio, Paul F
AU  - Nuccio PF
AD  - Department of Respiratory Care, Brigham and Women's Hospital, Boston, 
      Massachusetts, USA.
FAU - Kone, Mamary T
AU  - Kone MT
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, 
      Massachusetts General Hospital, Boston, Massachusetts, USA.
FAU - Malik, Mona J
AU  - Malik MJ
AD  - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of 
      Medicine, Duke University Medical Center, Durham, North Carolina, USA.
FAU - Porras, Maria Angelica Pabon
AU  - Porras MAP
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill 
      Cornell Medicine, New York, New York, USA.
FAU - Finkelsztein, Eli
AU  - Finkelsztein E
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill 
      Cornell Medicine, New York, New York, USA.
FAU - Winkler, Tilo
AU  - Winkler T
AD  - Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General 
      Hospital, Boston, Massachusetts, USA.
FAU - Hurwitz, Shelley
AU  - Hurwitz S
AD  - Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
FAU - Serhan, Charles N
AU  - Serhan CN
AD  - Center for Experimental Therapeutics and Reperfusion Injury, Department of 
      Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, 
      Boston, Massachusetts, USA.
FAU - Piantadosi, Claude A
AU  - Piantadosi CA
AD  - Division of Pulmonary, Allergy, and Critical Care Medicine, Department of 
      Medicine, Duke University Medical Center, Durham, North Carolina, USA.
FAU - Baron, Rebecca M
AU  - Baron RM
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham 
      and Women's Hospital, Boston, Massachusetts, USA.
FAU - Thompson, B Taylor
AU  - Thompson BT
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, 
      Massachusetts General Hospital, Boston, Massachusetts, USA.
FAU - Choi, Augustine Mk
AU  - Choi AM
AD  - Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill 
      Cornell Medicine, New York, New York, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT02425579
GR  - P01 HL108801/HL/NHLBI NIH HHS/United States
GR  - K08 GM102695/GM/NIGMS NIH HHS/United States
GR  - K08 HL143197/HL/NHLBI NIH HHS/United States
GR  - UL1 TR002384/TR/NCATS NIH HHS/United States
GR  - K08 HL130557/HL/NHLBI NIH HHS/United States
GR  - UL1 TR001102/TR/NCATS NIH HHS/United States
GR  - KL2 TR002385/TR/NCATS NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
DEP - 20181206
PL  - United States
TA  - JCI Insight
JT  - JCI insight
JID - 101676073
RN  - 0 (Biomarkers)
RN  - 0 (DNA, Mitochondrial)
RN  - 7U1EE4V452 (Carbon Monoxide)
RN  - 9061-29-4 (Carboxyhemoglobin)
SB  - IM
MH  - *Administration, Inhalation
MH  - Adult
MH  - Aged
MH  - Biomarkers/blood
MH  - Blood Gas Analysis
MH  - Carbon Monoxide/*administration & dosage
MH  - Carboxyhemoglobin
MH  - DNA, Mitochondrial
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Respiratory Distress Syndrome/*drug therapy
MH  - Respiratory Therapy/*methods
MH  - Sepsis/*drug therapy
PMC - PMC6328240
OTO - NOTNLM
OT  - Clinical Trials
OT  - Drug therapy
OT  - Pulmonology
OT  - Respiration
COIS- Conflict of interest: LEF has received clinical trial support for an unrelated 
      study from Asahi Kasei Pharma America (AKPA). DRH is a consultant for Philips 
      Respironics and Ventec Life Support; receives publishing royalties from Jones and 
      Bartlett, McGraw-Hill, and UpToDate; and is managing editor of Respiratory Care 
      (Daedalus Enterprises) and an inter-professional member of the Pulmonary Disease 
      Board of the American Board of Internal Medicine. BDK has received grants from 
      Karius Inc., Savara Pharmaceuticals, and Defense Advanced Research Projects 
      Agency, as well as personal fees from La Jolla Pharmaceutical Company. RSH is an 
      employee at Vertex Pharmaceuticals as of December 2017. JDD is a consultant for 
      Teleflex Medical. PFN has received personal fees from Third Pole Inc. CNS has 
      received personal fees from Corbus Pharmaceuticals, Inflammation Research 
      Foundation, and FASEB Journal, as well as grants from Solutex. CNS is an inventor 
      on patents related to resolvins and other pro-resolving mediators (both 
      composition of matter and use of) that are licensed by Partners-Brigham and 
      Women's Hospital (Partners-BWH) for clinical development. BTT has served as a 
      consultant on ARDS clinical trial design for Bayer, Boehringer Ingelheim, and 
      GlaxoSmithKline. AMKC is a cofounder of and SAB member for Proterris Inc. and 
      served as a consultant for Teva Pharmaceuticals. AMKC has a use patent on CO, 
      which belongs to University of Pittsburgh, Johns Hopkins University, Yale 
      University, and Proterris Inc.
EDAT- 2018/12/07 06:00
MHDA- 2019/11/26 06:00
PMCR- 2018/12/06
CRDT- 2018/12/07 06:00
PHST- 2018/08/06 00:00 [received]
PHST- 2018/10/29 00:00 [accepted]
PHST- 2018/12/07 06:00 [entrez]
PHST- 2018/12/07 06:00 [pubmed]
PHST- 2019/11/26 06:00 [medline]
PHST- 2018/12/06 00:00 [pmc-release]
AID - 124039 [pii]
AID - 10.1172/jci.insight.124039 [doi]
PST - epublish
SO  - JCI Insight. 2018 Dec 6;3(23):e124039. doi: 10.1172/jci.insight.124039.