NIHR Blood and Transplant Research Unit, Newcastle University and Cambridge University, Newcastle upon Tyne, UK.
Newcastle University, Newcastle-upon-Tyne, UK.
Cochrane Database Syst Rev. 2023 Sep 12;9(9):CD014685. doi: 10.1002/14651858.CD014685.pub2.
Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The increasing prevalence of these conditions drives demand and necessitates the increasing use of donated livers which have traditionally been considered suboptimal. Several novel machine perfusion preservation technologies have been developed, which attempt to ameliorate some of the deleterious effects of ischaemia reperfusion injury. Machine perfusion technology aims to improve organ quality, thereby improving outcomes in recipients of suboptimal livers when compared to traditional static cold storage (SCS; ice box).
To evaluate the effects of different methods of machine perfusion (including hypothermic oxygenated machine perfusion (HOPE), normothermic machine perfusion (NMP), controlled oxygenated rewarming, and normothermic regional perfusion) versus each other or versus static cold storage (SCS) in people undergoing liver transplantation.
We used standard, extensive Cochrane search methods. The latest search date was 10 January 2023.
We included randomised clinical trials which compared different methods of machine perfusion, either with each other or with SCS. Studies comparing HOPE via both hepatic artery and portal vein, or via portal vein only, were grouped. The protocol detailed that we also planned to include quasi-randomised studies to assess treatment harms.
We used standard Cochrane methods. Our primary outcomes were 1. overall participant survival, 2. quality of life, and 3. serious adverse events. Secondary outcomes were 4. graft survival, 5. ischaemic biliary complications, 6. primary non-function of the graft, 7. early allograft function, 8. non-serious adverse events, 9. transplant utilisation, and 10. transaminase release during the first week post-transplant. We assessed bias using Cochrane's RoB 2 tool and used GRADE to assess certainty of evidence.
We included seven randomised trials (1024 transplant recipients from 1301 randomised/included livers). All trials were parallel two-group trials; four compared HOPE versus SCS, and three compared NMP versus SCS. No trials used normothermic regional perfusion. When compared with SCS, it was uncertain whether overall participant survival was improved with either HOPE (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.42 to 1.98; P = 0.81, I = 0%; 4 trials, 482 recipients; low-certainty evidence due to imprecision because of low number of events) or NMP (HR 1.08, 95% CI 0.31 to 3.80; P = 0.90; 1 trial, 222 recipients; very low-certainty evidence due to imprecision and risk of bias). No trials reported quality of life. When compared with SCS alone, HOPE was associated with improvement in the following clinically relevant outcomes: graft survival (HR 0.45, 95% CI 0.23 to 0.87; P = 0.02, I = 0%; 4 trials, 482 recipients; high-certainty evidence), serious adverse events in extended criteria DBD liver transplants (OR 0.45, 95% CI 0.22 to 0.91; P = 0.03, I = 0%; 2 trials, 156 participants; moderate-certainty evidence) and clinically significant ischaemic cholangiopathy in recipients of DCD livers (OR 0.31, 95% CI 0.11 to 0.92; P = 0.03; 1 trial, 156 recipients; high-certainty evidence). In contrast, NMP was not associated with improvement in any of these clinically relevant outcomes. NMP was associated with improved utilisation compared with SCS (one trial found a 50% lower rate of organ discard; P = 0.008), but the reasons underlying this effect are unknown. We identified 11 ongoing studies investigating machine perfusion technologies.
AUTHORS' CONCLUSIONS: In situations where the decision has been made to transplant a liver donated after circulatory death or donated following brain death, end-ischaemic HOPE will provide superior clinically relevant outcomes compared with SCS alone. Specifically, graft survival is improved (high-certainty evidence), serious adverse events are reduced (moderate-certainty evidence), and in donors after circulatory death, clinically relevant ischaemic biliary complications are reduced (high-certainty evidence). There is no good evidence that NMP has the same benefits over SCS in terms of these clinically relevant outcomes. NMP does appear to improve utilisation of grafts that would otherwise be discarded with SCS; however, the reasons for this, and whether this effect is specific to NMP, is not clear. Further studies into NMP viability criteria and utilisation, as well as head-to-head trials with other perfusion technologies are needed. In the setting of donation following circulatory death transplantation, further trials are needed to assess the effect of these ex situ machine perfusion methods against, or in combination with, normothermic regional perfusion.
肝移植是治疗终末期肝病和某些晚期肝癌或急性肝功能衰竭患者的唯一方法。这些疾病的发病率不断上升，导致需求增加，需要越来越多地使用传统上被认为不理想的捐赠肝脏。已经开发出几种新型机器灌注保存技术，试图改善缺血再灌注损伤的一些有害影响。机器灌注技术旨在改善器官质量，从而改善不理想肝脏接受者的预后，与传统的静态冷藏（SCS；冰盒）相比。
评估不同的机器灌注方法（包括低温氧合机器灌注（HOPE）、常温机器灌注（NMP）、控制性氧合复温以及常温区域灌注）之间的效果，以及与 SCS 相比，在接受肝移植的患者中。
我们使用了标准的、广泛的 Cochrane 检索方法。最新的搜索日期是 2023 年 1 月 10 日。
我们纳入了比较不同机器灌注方法的随机临床试验，无论是彼此之间还是与 SCS 进行比较。HOPE 通过肝动脉和门静脉或仅通过门静脉进行的研究被分组。该方案详细说明了我们还计划纳入准随机研究来评估治疗危害。
我们使用了标准的 Cochrane 方法。我们的主要结局是 1. 总体参与者生存率，2. 生活质量，和 3. 严重不良事件。次要结局是 4. 移植物存活率，5. 缺血性胆并发症，6. 移植物原发性无功能，7. 早期移植物功能，8. 非严重不良事件，9. 移植利用，和 10. 移植后第一周转氨酶释放。我们使用 Cochrane 的 RoB 2 工具评估偏倚，并使用 GRADE 评估证据确定性。
我们纳入了 7 项随机试验（来自 1301 例随机/纳入肝脏的 1024 例肝移植受者）。所有试验均为平行两组试验；四项比较 HOPE 与 SCS，三项比较 NMP 与 SCS。没有试验使用常温区域灌注。与 SCS 相比，HOPE 是否能提高总体参与者生存率尚不确定（风险比（HR）0.91，95%置信区间（CI）0.42 至 1.98；P = 0.81，I = 0%；4 项试验，482 例受者；由于事件数量少，结果不确定，因此证据确定性为低）或 NMP（HR 1.08，95%CI 0.31 至 3.80；P = 0.90；1 项试验，222 例受者；由于不精确和偏倚风险，证据确定性为极低）。没有试验报告生活质量。与单独的 SCS 相比，HOPE 与以下相关的临床相关结局改善相关：移植物存活率（HR 0.45，95%CI 0.23 至 0.87；P = 0.02，I = 0%；4 项试验，482 例受者；高确定性证据）、延长标准 DBD 肝移植中严重不良事件（OR 0.45，95%CI 0.22 至 0.91；P = 0.03，I = 0%；2 项试验，156 名参与者；中度确定性证据）和 DCD 供体肝接受者中临床显著缺血性胆管病（OR 0.31，95%CI 0.11 至 0.92；P = 0.03；1 项试验，156 例受者；高确定性证据）。相比之下，NMP 与这些临床相关结局的改善无关。与 SCS 相比，NMP 与移植利用率的提高相关（一项试验发现器官丢弃率降低了 50%；P = 0.008），但这一效应的原因尚不清楚。我们确定了 11 项正在进行的机器灌注技术研究。
在决定移植脑死亡后或循环死亡后捐赠的肝脏的情况下，与单独的 SCS 相比，结束时的低温 HOPE 将提供更好的临床相关结局。具体而言，移植物存活率得到改善（高确定性证据），严重不良事件减少（中度确定性证据），并且在循环死亡后供体中，临床相关缺血性胆管并发症减少（高确定性证据）。目前没有证据表明 NMP 在这些临床相关结局方面优于 SCS。NMP 似乎确实提高了 SCS 可能丢弃的移植物的利用率；然而，其原因尚不清楚，也不清楚这是否是 NMP 特有的。需要进一步研究 NMP 的可行性标准和利用率，以及与其他灌注技术的头对头试验。在循环死亡后移植的情况下，需要进一步的试验来评估这些离体机器灌注方法对或联合常温区域灌注的效果。
