A randomized clinical trial testing the anti-inflammatory effects of preemptive inhaled nitric oxide in human liver transplantation

John D. Lang, Alvin B. Smith, Angela Brandon, Kelley M. Bradley, Yuliang Liu, Wei Li, D. Ralph Crowe, Nirag C. Jhala, Richard C. Cross, Luc Frenette, Kenneth Martay, Youri L. Vater, Alexander A. Vitin, Gregory A. Dembo, Derek A. DuBay, J. Steven Bynon, Jeff M. Szychowski, Jorge D. Reyes, Jeffrey B. Halldorson, Stephen C. RayhillAndre A. Dick, Ramasamy Bakthavatsalam, Jared Brandenberger, Jo Ann Broeckel-Elrod, Laura Sissons-Ross, Terry Jordan, Lucinda Y. Chen, Arunotai Siriussawakul, Devin E. Eckhoff, Rakesh P. Patel

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Article numbere86053
JournalPloS one
Volume9
Issue number2
DOIs
StatePublished - Feb 12 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Lang, J. D., Smith, A. B., Brandon, A., Bradley, K. M., Liu, Y., Li, W., Crowe, D. R., Jhala, N. C., Cross, R. C., Frenette, L., Martay, K., Vater, Y. L., Vitin, A. A., Dembo, G. A., DuBay, D. A., Bynon, J. S., Szychowski, J. M., Reyes, J. D., Halldorson, J. B., ... Patel, R. P. (2014). A randomized clinical trial testing the anti-inflammatory effects of preemptive inhaled nitric oxide in human liver transplantation. PloS one, 9(2), [e86053]. https://doi.org/10.1371/journal.pone.0086053