Lang John D, Smith Alvin B, Brandon Angela, Bradley Kelley M, Liu Yuliang, Li Wei, Crowe D Ralph, Jhala Nirag C, Cross Richard C, Frenette Luc, Martay Kenneth, Vater Youri L, Vitin Alexander A, Dembo Gregory A, Dubay Derek A, Bynon J Steven, Szychowski Jeff M, Reyes Jorge D, Halldorson Jeffrey B, Rayhill Stephen C, Dick Andre A, Bakthavatsalam Ramasamy, Brandenberger Jared, Broeckel-Elrod Jo Ann, Sissons-Ross Laura, Jordan Terry, Chen Lucinda Y, Siriussawakul Arunotai, Eckhoff Devin E, Patel Rakesh P
Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS One. 2014 Feb 12;9(2):e86053. doi: 10.1371/journal.pone.0086053. eCollection 2014.
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.
肝移植期间内皮型一氧化氮合酶衍生的一氧化氮（NO）生成减少会促进损伤。我们假设预先吸入一氧化氮（iNO）可改善同种异体移植物功能（主要目标）并减少移植后并发症（次要目标）。两个大学中心（A中心和B中心）的患者在肝移植手术阶段被随机分配接受安慰剂（每个中心n = 20）或iNO（80 ppm，每个中心n = 20）。在移植后长达9个月的设定间隔时间分析数据，并在组间进行比较。使用Mann-Whitney U检验、学生t检验、逻辑回归、重复测量方差分析和Cox比例风险模型检查患者特征和结果。进行了合并分析和按中心分层分析。B中心的终末期肝病模型（MELD）评分显著更高（22.5对19.5，p<0.0001），B中心的手术时间更长（7.7对4.5小时，p<0.001），B中心的热缺血时间更长（95.4对69.7分钟，p<0.0001）。未出现iNO引起的不良代谢或血液学影响。iNO通过肝功能测试改善了同种异体移植物功能（B中心，p<0.05；合并中心数据时谷丙转氨酶（ALT）的p<0.03），并在9个月时减少了并发症（A中心和B中心，p = 0.0062，比值比（OR）= 0.15，95%置信区间（CI）（0.04，0.59））。重症监护病房（ICU）住院时间（p = 0.47）和医院住院时间（p = 0.49）未减少。iNO增加了硝酸盐（p<0.001）、亚硝酸盐（p<0.001）和亚硝基血红蛋白（p<0.001）的浓度，推测亚硝酸盐为一种保护机制。每次移植的iNO平均成本为1020美元。iNO在一个中心是安全的且改善了同种异体移植物功能，在另一个中心有改善同种异体移植物功能的趋势。美国国立医学图书馆临床试验注册中心编号为00582010，网址如下：http://clinicaltrials.gov/show/NCT00582010 。
