Inhaled Nitric Oxide Helps Restore Transplanted Liver Function

SEATTLE, Aug. 23 -- Breathing nitric oxide during liver transplantation helps kick start the grafted organ, researchers reported.

Inhaling the gas during a liver graft inhibited hepatic ischemic-reperfusion injury and hastened return of function, John D. Lang Jr., M.D., of the University of Washington here, and Rakesh P. Patel, M.D., of the University of Alabama, and colleagues, reported online in the Journal of Clinical Investigation.

Ischemia-reperfusion injury in transplanted livers contributes to organ dysfunction and failure and is characterized in part by loss of nitric oxide produced by the liver, the researchers said.

Inhalation of nitric oxide is nontoxic and at high concentrations (80 ppm) has been found to inhibit reperfusion injury in extrapulmonary tissues, the investigators said.

In a prospective, blinded, placebo-controlled pilot study, patients (ages 30 to 67) were randomized to placebo (nitrogen) or 80 ppm of inhaled nitric oxide (10 in each group) during the surgery only.

After induction of anesthesia and achieving stable hemodynamic status, blood was drawn and was followed by either placebo (nitrogen) or nitric oxide gas inhalation. Inhalation continued until one hour after reperfusion. Subsequent blood tests tracked the progress of reperfusion.

Wedge biopsies from the right lobe of the donor liver were collected before reperfusion and an hour after reperfusion.

When results were adjusted for cold ischemia time and sex, inhaled nitric oxide significantly decreased the length of hospital stays by approximately 10% (1.24 days on average).

Evaluation of serum transaminases (alanine transaminase, aspartate aminotransferase) and coagulation times (prothrombin time, partial thromboplastin time), indicated that nitric oxide improved the rate at which liver function was restored.

In addition, the researchers reported that although nitric oxide did not significantly affect changes in inflammatory markers in liver tissue one hour after reperfusion, the gas significantly lowered hepatocyte apoptosis.

It is possible, they said, that limiting the second liver biopsy to one hour after reperfusion may not have allowed assessment of all potential effects of nitric oxide on inflammation (specifically cytokine release) and necrotic cell death.

Evaluation of circulating nitric oxide metabolites indicated that of all possible candidates an increase in blood nitrite levels was a most likely mediator of the beneficial extrapulmonary effects of inhaled nitric oxide.

Circulating nitrite concentrations were significantly increased in patients inhaling nitric oxide, suggesting that metabolism of this anion across the microcirculation is a dynamic process that may result in nitric oxide generation.

Importantly, the researchers said, nitric oxide was well tolerated and did not result in any undesirable changes in cardiopulmonary performance, caused no direct toxicity, and did not predispose patients to secondary toxicities associated with pulmonary complications or infection.

In addition to limiting the second liver biopsy to an hour after reperfusion, and other possibly inappropriate indices, the main limitation of the current study, the researchers said, was its small size, suggesting that a larger trial is still required.