Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation
John D. Lang Jr., … , Devin E. Eckhoff, Rakesh P. Patel
John D. Lang Jr., … , Devin E. Eckhoff, Rakesh P. Patel
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2583-2591. https://doi.org/10.1172/JCI31892.
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Research Article Transplantation

Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation

Abstract

Ischemia/reperfusion (IR) injury in transplanted livers contributes to organ dysfunction and failure and is characterized in part by loss of NO bioavailability. Inhalation of NO is nontoxic and at high concentrations (80 ppm) inhibits IR injury in extrapulmonary tissues. In this prospective, blinded, placebo-controlled study, we evaluated the hypothesis that administration of inhaled NO (iNO; 80 ppm) to patients undergoing orthotopic liver transplantation inhibits hepatic IR injury, resulting in improved liver function. Patients were randomized to receive either placebo or iNO (n = 10 per group) during the operative period only. When results were adjusted for cold ischemia time and sex, iNO significantly decreased hospital length of stay, and evaluation of serum transaminases (alanine transaminase, aspartate aminotransferase) and coagulation times (prothrombin time, partial thromboplastin time) indicated that iNO improved the rate at which liver function was restored after transplantation. iNO did not significantly affect changes in inflammatory markers in liver tissue 1 hour after reperfusion but significantly lowered hepatocyte apoptosis. Evaluation of circulating NO metabolites indicated that the most likely candidate transducer of extrapulmonary effects of iNO was nitrite. In summary, this study supports the clinical use of iNO as an extrapulmonary therapeutic to improve organ function following transplantation.

Authors

John D. Lang Jr., Xinjun Teng, Phillip Chumley, Jack H. Crawford, T. Scott Isbell, Balu K. Chacko, Yuliang Liu, Nirag Jhala, D. Ralph Crowe, Alvin B. Smith, Richard C. Cross, Luc Frenette, Eric E. Kelley, Diana W. Wilhite, Cheryl R. Hall, Grier P. Page, Michael B. Fallon, J. Steven Bynon, Devin E. Eckhoff, Rakesh P. Patel

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Figure 1

iNO therapy and human liver transplantation.

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iNO therapy and human liver transplantation. (A) Experimental protocol f...
(A) Experimental protocol for administering placebo or iNO to patients and sample (blood and liver biopsy) collection. (B) Methemoglobin (metHb) levels as a function of blood draw. #P ≤ 0.001 for corresponding placebo versus iNO measurements by unpaired t test. (C) Volume of platelets transfused during surgery #P ≤ 0.05. (D and E) Average percent decrease in PT and PTT after surgery. Data are normalized to coagulation times measured immediately (<1 hour) after surgery and were 26.7 ± 1.4 seconds (placebo) and 34.4 ± 2.5 seconds (iNO) for PT and 54.6 ± 7.3 seconds (placebo) and 70.2 ± 6.5 seconds (iNO) for PTT. (F and G) Average percent decrease in serum ALT and AST levels after surgery. Data were normalized to ALT and AST levels measured immediately (<1 hour) after surgery and were 601.8 ± 145.4 U/l (placebo) and 689.3 ± 149.5 U/l (iNO) for ALT and 922.1 ± 228.7 U/l (placebo) and 940.9 ± 211.3 U/l (iNO) for AST. For data in panels D–G, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 for corresponding placebo versus iNO measurements. (H) Cox analysis of patient hospital length of stay. P = 0.034 adjusted for sex and cold ischemic time. Filled squares: placebo; filled circles: iNO.