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.

Effects of inhaled nitric oxide for postoperative hypoxemia in acute type A aortic dissection: a retrospective observational study

“…A recent study on iNO-mediated prevention of bronchopulmonary dysplasia in Europe showed that iNO treatment may decrease several inflammatory and fibrotic factors in the lungs [22]. Preemptive iNO in human liver transplantation surgery led to clear anti-inflammatory effects in liver grafts which protected graft function, ameliorated pathological changes, and reduced postoperative morbidity [23]. In our study, we found no evidence of inflammation modulation since postoperative C-reactive protein levels were similar in the two groups.…”

Nitrite therapy prevents chlorine gas toxicity in rabbits

“…The rationale for this being that Cl 2 exposure results in endothelial dysfunction characterized by a loss of NO-bioavailability (15, 17) which would also predispose to inflammation and oxidative stress. NO-repletion therapies exist; the two most appreciated being inhaled NO administration or use of PDE-5 inhibitors (21, 37). However, the efficacy of these towards Cl 2 toxicity is unclear and with inhaled NO certainly, logistic and price constraints would likely preclude its administration in the field, in a mass casualty situation.…”

Strategies to increase nitric oxide signalling in cardiovascular disease

“…Although potentially unwanted side effects may occur through residual systemic bioactivity, this may in fact also be used therapeutically. Indeed, the delivery of systemic endocrine NO bioactivity through the inhalation of NO gas has been tested successfully in preclinical models of I-R injury 87 and in humans with liver ischaemia 88,89 . An overall reduced risk of brain injury has been observed in premature newborns with respiratory failure who received inhaled NO, which may be due to the existence of endocrine NO effects 9 .…”