title: A randomized clinical trial testing the anti-inflammatory effects of preemptive inhaled nitric oxide in human liver transplantation.
abstract: Decreases in endothelial nitric oxide synthase derived nitric oxide (NO) production during liver transplantation promotes injury. We hypothesized that preemptive inhaled NO (iNO) would improve allograft function (primary) and reduce complications post-transplantation (secondary). Patients at two university centers (Center A and B) were randomized to receive placebo (n = 20/center) or iNO (80 ppm, n = 20/center) during the operative phase of liver transplantation. Data were analyzed at set intervals for up to 9-months post-transplantation and compared between groups. Patient characteristics and outcomes were examined with the Mann-Whitney U test, Student t-test, logistic regression, repeated measures ANOVA, and Cox proportional hazards models. Combined and site stratified analyses were performed. MELD scores were significantly higher at Center B (22.5 vs. 19.5, p<0.0001), surgical times were greater at Center B (7.7 vs. 4.5 hrs, p<0.001) and warm ischemia times were greater at Center B (95.4 vs. 69.7 min, p<0.0001). No adverse metabolic or hematologic effects from iNO occurred. iNO enhanced allograft function indexed by liver function tests (Center B, p<0.05; and p<0.03 for ALT with center data combined) and reduced complications at 9-months (Center A and B, p = 0.0062, OR = 0.15, 95% CI (0.04, 0.59)). ICU (p = 0.47) and hospital length of stay (p = 0.49) were not decreased. iNO increased concentrations of nitrate (p<0.001), nitrite (p<0.001) and nitrosylhemoglobin (p<0.001), with nitrite being postulated as a protective mechanism. Mean costs of iNO were $1,020 per transplant. iNO was safe and improved allograft function at one center and trended toward improving allograft function at the other. ClinicalTrials.gov with registry number 00582010 and the following URL:http://clinicaltrials.gov/show/NCT00582010.
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Lang
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Alvin B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Brandon
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Kelley M
authors.initials: KM
authors.lastname: Bradley
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary-pancreatic Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: D Ralph
authors.initials: DR
authors.lastname: Crowe
authors.affiliation: Department of Pathology and Laboratory Medicine, Ruth and Raymond Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Nirag C
authors.initials: NC
authors.lastname: Jhala
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Cross
authors.affiliation: Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Luc
authors.initials: L
authors.lastname: Frenette
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Martay
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Youri L
authors.initials: YL
authors.lastname: Vater
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vitin
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Dembo
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Dubay
authors.affiliation: Department of Surgery, Division of Immunology and Organ Transplantation, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.
authors.forename: J Steven
authors.initials: JS
authors.lastname: Bynon
authors.affiliation: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jeff M
authors.initials: JM
authors.lastname: Szychowski
authors.affiliation: Department of Surgery, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Reyes
authors.affiliation: Department of Surgery, University of California San Diego Health Care System, San Diego, California, United States of America.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Halldorson
authors.affiliation: Department of Surgery, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Rayhill
authors.affiliation: Department of Surgery, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Andre A
authors.initials: AA
authors.lastname: Dick
authors.affiliation: Department of Surgery, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Ramasamy
authors.initials: R
authors.lastname: Bakthavatsalam
authors.affiliation: Department of Surgery, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Jared
authors.initials: J
authors.lastname: Brandenberger
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Broeckel-Elrod
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Sissons-Ross
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Terry
authors.initials: T
authors.lastname: Jordan
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Lucinda Y
authors.initials: LY
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Arunotai
authors.initials: A
authors.lastname: Siriussawakul
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Devin E
authors.initials: DE
authors.lastname: Eckhoff
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Rakesh P
authors.initials: RP
authors.lastname: Patel
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D000704:Analysis of Variance; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D015331:Cohort Studies; D017707:Erythrocyte Transfusion; D005260:Female; D017048:Health Care Costs; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D007362:Intensive Care Units; D007902:Length of Stay; D017093:Liver Failure / Q000601:surgery*; D016031:Liver Transplantation / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000191:economics; D017713:Platelet Transfusion; D016016:Proportional Hazards Models; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D009569:Nitric Oxide