Terlipressin use and respiratory failure in patients with hepatorenal syndrome type 1 and severe acute-on-chronic liver failur

Summary

Background: Previous studies suggested increased mortality in patients with hepatorenal syndrome type 1 (HRS1) and advanced acute-on-chronic liver failure (ACLF). Aim: To assess mortality and respiratory failure (RF) in patients with HRS1 and ACLF treated with terlipressin.

背景:以前的研究表明1型肝肾综合征(HRS1)和晚期慢加急性肝衰竭(ACLF)患者的死亡率增加。目的:评估特利加压素治疗HRS1和ACLF患者的死亡率和呼吸衰竭(RF)。

Methods: In the CONFIRM study, we randomised 299 patients with HRS1 2:1 to terlipressin or placebo, both with albumin. At enrolment, all patients were assessed for organ failure (OF) using a validated ACLF grading system. Post hoc analyses assessed the effects of terlipressin vs. placebo on the incidence of RF and 90-day mortality.

方法:在CONFIRM研究中，我们将299例HRS1 2:1患者随机分为特利加压素组或安慰剂组，两者均使用白蛋白。在登记时，所有患者都使用有效的ACLF分级系统进行器官衰竭(OF)评估。事后分析评估了特利加压素与安慰剂相比对RF发生率和90天死亡率的影响。

Results: The incidence of RF with terlipressin (n = 200) was 9.4% in patients with grades 1–2 ACLF, and 30% with grade 3 ACLF (p = 0.0002); no such difference was observed in placebo-treated patients (n = 99) (6.2% grades 1–2 vs. 0% grade 3 ACLF, p > 0.05). RF incidence between terlipressin and placebo in patients with grade 3 ACLF was significant (p = 0.01). Baseline predictors of RF with terlipressin were INR (p = 0.011), mean arterial pressure (p = 0.037), and SpO2 (p = 0.014). Prior albumin as a continuous variable was not a predictor of RF. 90-day survival between terlipressin and placebo arms was similar for grades 1–2 ACLF (55.5% and 56.6%, respectively), but lower for grade 3 ACLF (27.55% vs. 50.0%) (p = 0.122), mainly related to RF.

结果:在1-2级ACLF患者中，特利加压素治疗的RF发生率为9.4%，在3级ACLF患者中为30%(p = 0.0002)；在安慰剂治疗的患者中没有观察到这种差异(n = 99) (6.2%的1-2级对0%的3级ACLF，p > 0.05)。在3级ACLF患者中，特利加压素和安慰剂之间的RF发生率显著(p = 0.01)。特利加压素治疗RF的基线预测因子为INR (p = 0.011)、平均动脉压(p = 0.037)和SpO2 (p = 0.014)。既往白蛋白作为连续变量不是RF的预测因子。对于1-2级ACLF，特利加压素组和安慰剂组之间的90天生存率相似(分别为55.5%和56.6%)，但对于3级ACLF较低(27.55%比50.0%) (p = 0.122)，主要与RF有关。

Conclusion: Terlipressin should be used with caution in patients with HRS1 and grade 3 ACLF. Patients with hypoxaemia are at increased risk of RF and mortality.

结论:特利加压素在HRS1和3级ACLF患者中应谨慎使用。低氧血症患者患RF和死亡的风险增加。

1.INTRODUCTION

Hepatorenal syndrome type 1 (HRS1) is a severe complication of liver cirrhosis with ascites. It is a special form of acute kidney injury (AKI), defined as an acute rise in serum creatinine (sCr) to ≥2.5 mg/ dl in less than 2 weeks when all other known causes of AKI have been excluded,1 associated with poor survival of a few weeks if left untreated.2 One of the major pathophysiological mechanisms involved in the development of HRS1 is splanchnic and systemic vasodilatation leading to paradoxical renal vasoconstriction.3 Therefore, the mainstay of treatment for HRS1 is the use of systemic and/or splanchnic vasoconstrictors.4 Terlipressin is the most widely used splanchnic vasoconstrictor for the treatment of HRS1 worldwide.5 The recent publication of the results of the CONFIRM trial (Clini calTrials.gov identifier: NCT02770716),6 which assessed the effects of terlipressin versus placebo, both with albumin, in the treatment of HRS1 in cirrhosis and ascites, reported an increased incidence of respiratory failure in patients who received terlipressin, but not in those who received placebo. The incidence of respiratory failure appeared to be most common among very ill patients, especially those with high-grade acute-on-chronic liver failure (ACLF). ACLF is a newly recognised syndrome that is observed in patients with chronic liver disease with or without cirrhosis that is associated with the potential for multiple organ failure and high short-term mortality within 4 weeks.7 The European Association for the Study of the Liver (EASL) defines ACLF by the number of organ failures in any of six organ systems as described by the modified Chronic Liver Failure-Sequential Organ Failure Assessment (CLIFSOFA) score.8 The ACLF severity is then graded according to the number of organ failures.8 ACLF is common in patients with HRS1. In addition to liver and kidney failures, non-hepatic organ dysfunction has been described in patients with AKI.9,10 Furthermore, the occurrence of grade 1 ACLF, which all patients with HRS1 have, confers a higher risk for subsequent higher grade ACLF development when compared with patients who have never developed ACLF.11 The use of terlipressin, which increases the systemic vascular resistance and cardiac afterload, may affect cardiac and respiratory function, especially in cirrhotic patients with advanced ACLF and who may have underlying cirrhotic cardiomyopathy. In this post-hoc analysis of the CONFIRM trial, we aimed to evaluate mortality in patients with HRS1 and baseline grade 3 ACLF versus grades 1–2 ACLF and identify risk factors for the development of respiratory failure with terlipressin use.

介绍：肝肾综合征1型(HRS1)是肝硬化腹水的严重并发症。它是急性肾损伤(AKI)的一种特殊形式，定义为在排除AKI的所有其他已知原因后，血清肌酐(sCr)在不到2周内急性升高至≥2.5 mg/ dl，1如果不进行治疗，则生存期只有几周。2 HR S1发展过程中涉及的主要病理生理机制之一是内脏和全身血管扩张，导致反常的肾血管收缩。3因此， HRS1的主要治疗方法是使用全身和/或内脏血管收缩剂。4特利加压素是世界范围内治疗HRS1最广泛使用的内脏血管收缩剂。5最近发表的CONFIRM试验结果(临床calTrials.gov标识符:NCT 02770716)6评估了特利加压素与安慰剂(均含白蛋白)在治疗肝硬化和腹水的HRS1中的效果，报告了接受特利加压素的患者呼吸衰竭发生率增加，但接受安慰剂的患者呼吸衰竭发生率没有增加。 呼吸衰竭的发生率似乎在重病患者中最为常见，尤其是那些重度慢加急性肝衰竭的患者(ACLF)。ACLF是一种新发现的综合征，在伴有或不伴有肝硬化的慢性肝病患者中观察到，与多器官衰竭的可能性和4周内的高短期死亡率相关。7欧洲肝脏研究协会(EASL)根据六个器官系统中任何一个器官系统的器官衰竭数量来定义ACLF，如修改的慢性肝功能衰竭-顺序器官衰竭评估(CLIFSOFA)评分所述。8 ACLF严重程度根据器官衰竭数量进行分级。8 ACLF常见于HRS1患者。除了肝和肾功能衰竭，AKI患者还出现了非肝器官功能障碍。9，10此外，与从未出现ACLF的患者相比，所有HRS1患者均出现1级ACLF，这增加了随后出现更高级别ACLF的风险。11使用特利加压素会增加全身血管阻力和心脏后负荷，可能会影响心脏和呼吸功能，尤其是在患有晚期ACLF和可能患有潜在肝硬化心肌病的肝硬化患者中。在CONFIRM试验的事后分析中，我们旨在评估HRS1和基线3级ACLF与1-2级ACLF患者的死亡率，并确定使用特利加压素发生呼吸衰竭的风险因素。

2 | PATIENTS AND METHODS

The protocol for the CONFIRM double-blind placebo-controlled trial has previously been published.6 In brief, patients who were at least 18 years of age, with cirrhosis, ascites, and rapidly progressive renal failure, with an sCr doubling to at least 2.25 mg/dl within 14 days who showed minimal response with ≤20% reduction in sCr after at least 48 h of diuretic withdrawal and plasma volume expansion with albumin, were included. Patients were excluded if they had an sCr of >7.0 mg/dl, one or more large volume paracenteses of ≥4 L within 2 days of randomisation, presence of shock, or sepsis and/or uncontrolled bacterial infection. Once enrolled, patients were randomly assigned to receive in 2:1 ratio of terlipressin or placebo 1 mg every 6 h by slow intravenous bolus injections under close observation. If sCr reduction was less than 30% from the baseline value on day 4, after a minimum of 10 doses of study drug, the dose could be increased to 2 mg every 6 h, except in patients with coronary artery disease, circulatory overload, pulmonary edema, or bronchospasm. Dose resumption was permitted after interruption for adverse events (AEs) except for cardiac or mesenteric ischemia, for which treatment was permanently discontinued. Patients were recommended to receive concomitant albumin at a dose of 20–40 gm/day as clinically indicated.

Patients were assessed for the presence of ACLF at study entry as described by the EASL-CLIF criteria.8 All patients had minimum grade 1 ACLF, because all had an sCr of ≥2 mg/dl due to the presence of HRS1. Grade 2 and 3 ACLF represented two and three organ failures, respectively.8 Patients were divided into those with grades 1–2 versus grade 3 ACLF and compared. Patients were monitored for AEs up to 7 days and serious adverse events (SAEs) up to 30 days after completion of treatment. The primary efficacy end point of the CONFIRM study was verified HRS reversal, defined as the percentage of patients with two consecutive sCr values no greater than 1.5 mg/dl at least 2 h apart, while on treatment (up to 24 h after the last dose) by Day 14 or discharge, and remaining alive without renal replacement therapy for at least 10 days. The end points of this study were the development of respiratory failure as an SAE (using the terms “acute respiratory failure” or “respiratory failure”) as reported by study site principal investigators, and mortality up to 90 days post treatment.

CONFIRM双盲安慰剂对照试验的方案之前已经公布。6简而言之，纳入了至少18岁、患有肝硬化、腹水和快速进展性肾衰竭、sCr在14天内翻倍至至少2.25 mg/dl的患者，这些患者在停用利尿剂和使用白蛋白进行血浆扩容至少48小时后，sCr降低≤20%的反应最小。如果患者的血肌酐> 7.0 mg/dl，在随机分组后2天内进行了一次或多次≥4 L的大容量穿刺，出现休克、败血症和/或未控制的细菌感染，则排除患者。一旦入选，患者被随机分配接受2:1比例的特利加压素或安慰剂，每6小时在密切观察下缓慢静脉推注1 mg。如果在第4天sCr降低低于基线值的30%，则在最少10剂研究药物后，剂量可增加至每6小时2 mg，除非患者患有冠状动脉疾病、循环超负荷、肺水肿或支气管痉挛。在因不良事件(AE)而中断治疗后，允许恢复剂量，但心脏或肠系膜缺血除外，因为心脏或肠系膜缺血导致治疗永久中断。根据临床指征，建议患者接受20-40克/天的伴随白蛋白。

按照EASL-CLIF标准的描述，在研究开始时对患者是否存在ACLF进行评估。8所有患者都有最低1级ACLF，因为由于存在HRS1，所有患者的sCr都≥2 mg/dl。2级和3级ACLF分别代表两个和三个器官衰竭。8名患者被分为1-2级和3级ACLF并进行比较。在治疗完成后，对患者进行最长7天的AE和最长30天的严重不良事件(SAE)监测。CONFIRM研究的主要疗效终点为经证实的HRS逆转，定义为在第14天或出院前接受治疗(最后一次给药后24小时内)且在没有肾脏替代治疗的情况下存活至少10天的患者中，两次连续sCr值间隔至少2小时不超过1.5 mg/dl的患者百分比。本研究的终点是研究中心主要研究者报告的作为严重不良事件(使用术语“急性呼吸衰竭”或“呼吸衰竭”)的呼吸衰竭的发展，以及治疗后90天内的死亡率。

2.1 | Statistical analysis

Continuous data were compared using a t-test. Binary and categorical data were analysed using a Cochran–Mantel–Haenszel (CMH) chi-square test, chi-square test, or a Fisher Exact test as follows: a CMH chi-square test stratified by qualifying sCr (less than 3.4 mg/ dl or at least 3.4 mg/dl) and pre-enrolment large volume paracentesis (at least one single event of at least 4 L or less than 4 L within 3 to 14 days before randomisation) if the number of events per cell and the number of expected events per cell were at least 5. If the expected cell counts were less than 5, an unstratified chi-square test was used instead of the CMH test. If the number of events per cell was less than 5, then a Fisher Exact test was used. Overall survival up to 90 days, defined as the days that each subject survived from the day of randomisation, was analysed using a two-sample log rank test. Predictors of respiratory failure were determined by first evaluating which baseline parameters were significant in univariate logistic regression models for respiratory failure. Then multivariate logistic regression with stepwise selection was used to determine the final significant baseline parameters. To assess competing risks, cumulative incidence function (CIF) estimates of the marginal probability for each competing event (cause-specific hazards of death or transplant) were calculated using Gray’s test.12

使用t检验比较连续数据。使用Cochran–Mantel–Haenszel(CMH)卡方检验、卡方检验或Fisher精确检验对二进制和分类数据进行分析，如下所示:如果每个细胞的事件数和每个细胞的预期事件数至少为5，则通过限定sCr(小于3.4 mg/ dl或至少3.4 mg/dl)和预登记大容量穿刺术(随机化前3至14天内至少一次至少4 L或小于4 L的单个事件)进行CMH卡方检验分层。如果预期的细胞计数小于5，则使用非分层卡方检验代替CMH检验。如果每个细胞的事件数小于5，则使用Fisher精确检验。使用双样本对数秩检验分析了最长90天的总生存期(定义为每个受试者从随机分组之日起存活的天数)。通过首先评估哪些基线参数在呼吸衰竭的单变量逻辑回归模型中有意义来确定呼吸衰竭的预测因子。然后使用逐步选择的多变量逻辑回归来确定最终的显著基线参数。为了评估竞争风险，使用格雷检验计算了每个竞争事件(死亡或移植的特定原因风险)边际概率的累积发生率函数(CIF)估计值。12

3 | RESULTS

Between July 13, 2016 and July 24, 2019, 300 patients with HRS1 were enrolled into the CONFIRM trial, with 199 patients randomly assigned to receive terlipressin and 101 patients to receive placebo. At study entry, all patients had renal failure as defined by the EASLCLIF-SOFA score and therefore had at least grade 1 ACLF, and no patient had circulatory failure because these were excluded for enrolment. Similar distribution of ACLF grades was observed between the terlipressin and placebo groups, grade 1: n = 99 or 49.5% for terlipressin and n = 41 or 41.4% for placebo; grade 2: n = 61 or 30.5% for terlipressin and n = 40 or 40.4% for placebo; grade 3: n = 40 or 20.0% for terlipressin and n = 18 or 18.2% for placebo. Table 1 shows patient demographics, vital signs, and laboratory data at study entry between the various subgroups.

2016年7月13日至2019年7月24日期间，300名HRS1患者参加了CONFIRM试验，其中199名患者随机分配接受特利加压素，101名患者接受安慰剂。在研究开始时，所有患者都患有由EASLCLIF-SOFA评分定义的肾衰竭，因此至少具有1级ACLF，并且没有患者患有循环衰竭，因为这些患者被排除入组。在特利加压素组和安慰剂组之间观察到相似的ACLF分级分布，1级:特利加压素组n = 99或49.5%，安慰剂组n = 41或41.4%；2级:特利加压素组n = 61或30.5%，安慰剂组n = 40或40.4%；3级:特利加压素组n = 40或20.0%，安慰剂组n = 18或18.2%。表1显示了不同亚组之间的患者人口统计数据、生命体征和实验室数据。

3.1 | Types of organ failure

The prevalence of various organ failures at baseline is shown in Table 1. All patients had renal failure at entry into the study. The next most common organ failure was liver failure, followed by coagulation failure, cerebral failure, and respiratory failure. The number of patients improving from baseline ACLF grade 3 to ACLF grade 0, 1, or 2 with treatment was similar between the terlipressin and placebo groups (Table S1). One of the secondary end points of the CONFIRM study was reversal of HRS, defined as any serum creatinine level of 1.5 mg/dl or less; this was observed in 36.2% of patients who received terlipressin, and 16.8% of patients who received placebo (p < 0.001) at the end of treatment.6 When patients were separated into grades 1–2 and grade 3 ACLF subgroups, there was a significant difference in the rates of HRS reversal in the grades 1–2 ACLF versus the grade 3 ACLF subgroup (p = 0.0007; Figure 1). The use of terlipressin was only able to achieve an increased HRS reversal rate versus placebo in the grades 1–2 ACLF subgroup (p = 0.0002), but this was not observed in the grade 3 ACLF subgroup (Figure 1).

器官衰竭的类型

各种器官衰竭的基线患病率如表1所示。所有患者在进入研究时都有肾衰竭。下一个最常见的器官衰竭是肝功能衰竭，其次是凝血功能衰竭，脑功能衰竭和呼吸衰竭。特利加压素组和安慰剂组通过治疗从基线ACLF 3级改善至ACLF 0、1或2级的患者人数相似(S1表)。CONFIRM研究的次要终点之一是HRS逆转，定义为任何血清肌酐水平为1.5 mg/dl或更低；在治疗结束时，接受特利加压素治疗的患者中有36.2%出现这种情况，接受安慰剂治疗的患者中有16.8%出现这种情况(p < 0.001)。6当患者被分为1-2级和3级ACLF亚组时，1-2级ACLF亚组与3级ACLF亚组的HRS逆转率存在显著差异(p = 0.0007图1)。与安慰剂相比，使用特利加压素只能在1-2级ACLF亚组中增加HRS逆转率(p = 0.0002)，但在3级ACLF亚组中没有观察到这种情况(图1)。

3.2 | Respiratory failure

Respiratory (lung) failure as defined by EASL-CLIF-SOFA score criteria8 was found at baseline in five (2.5%) patients who received terlipressin and in three (3.0%) patients who received placebo (Table 1). At the end of treatment, in the terlipressin group, there were significantly more patients (n = 16, 8.0%) who developed respiratory failure as defined by EASL-CLIF-SOFA score criteria, when compared with baseline (p = 0.023); in the placebo group, there was no difference in the number of patients with respiratory failure defined by EASL-CLIF-SOFA score criteria at the end of treatment compared with baseline (Figure 2A). Respiratory failure during treatment and follow-up periods was reported as AEs or SAEs by the study investigators; based on individual patient review, there were no clinically meaningful differences between the characteristics of patients with reported “acute respiratory failure” versus “respiratory failure.” Accordingly, the two safety terms were combined and are referred to in this paper as “respiratory failure.” The incidence of respiratory failure as reported by study investigators up to 30 days post treatment for both study groups, separated by patients with grades 1–2 ACLF versus grade 3 ACLF groups, is shown in Figure 2B. Within the terlipressin group, a significantly greater number of patients with grade 3 ACLF developed respiratory failure (n = 12/40, 30%) compared with those patients with grades 1–2 ACLF (n = 15/160, 9.4%, p = 0.002). Among those in the grade 3 ACLF subgroup, there were significantly more patients who received terlipressin and developed respiratory failure (n = 12/40, 30%), when compared with those who received placebo (n = 0/18, 0%, p = 0.01; Figure 2B). There was also a significantly greater number of deaths up to 30 days post treatment attributed to respiratory failure among patients with grade 3 ACLF who received terlipressin (n = 9/40, 22.5%) versus placebo (n = 0/18, 0%, p = 0.05; Figure 2C). The time to onset of, and time to death from, respiratory failure was approximately 5 to 7 days and 14 days, respectively, in both treatment groups. Based on individual patient review, a history of recent, baseline, or treatment-emergent dyspnea, pneumonia/ aspiration pneumonia, grade 3 or increasing hepatic encephalopathy, or upper gastrointestinal haemorrhage was present in most patients who developed respiratory failure in both treatment groups.

呼吸衰竭

根据EASL-CLIF-索法评分标准8定义的呼吸(肺)衰竭在基线时发现于5名(2.5%)接受特利加压素治疗的患者和3名(3.0%)接受安慰剂治疗的患者(表1)。在治疗结束时，与基线相比，特利加压素组出现EASL-CLIF-索法评分标准定义的呼吸衰竭的患者显著增多(n = 16，8.0%)(p = 0.023)；在安慰剂组，与基线相比，治疗结束时EASL-CLIF-索法评分标准定义的呼吸衰竭患者人数没有差异(图2A)。研究调查人员将治疗和随访期间的呼吸衰竭报告为AE或SAEs根据对单个患者的回顾，报告的“急性呼吸衰竭”与“呼吸衰竭”患者的特征之间没有临床意义上的差异因此，这两个安全术语被合并在一起，在本文中称为“呼吸衰竭”两个研究组的研究人员在治疗后30天内报告的呼吸衰竭发生率，按1-2级ACLF和3级ACLF患者分组，如图2B所示。在特利加压素组中，3级ACLF患者发生呼吸衰竭的人数(n = 12/40，30%)明显多于1-2级ACLF患者(n = 15/160，9.4%，p = 0.002)。在3级ACLF亚组中，与接受安慰剂的患者相比，接受特利加压素治疗并发生呼吸衰竭的患者明显更多(n = 12/40，30%)，p = 0.01图2B)。在接受特利加压素治疗的3级ACLF患者中，治疗后30天内因呼吸衰竭死亡的人数显著高于安慰剂组(n = 0/18，0%，p = 0.05图2C)。在两个治疗组中，呼吸衰竭的发病时间和死亡时间分别约为5-7天和14天。根据对单个患者的审查，两个治疗组中大多数出现呼吸衰竭的患者都有近期、基线或治疗中出现的呼吸困难、肺炎/吸入性肺炎、3级或加重的肝性脑病或上消化道出血的病史。

3.3 | Predictors of respiratory failure

Among various baseline characteristics, univariate logistic regression analysis identified baseline grade 1–2 versus grade 3 ACLF as a significant predictor of respiratory failure among patients who received terlipressin (intent-to-treat population; p = 0.002), but not for those who received placebo (Table S2). When multivariate logistic regression analysis was done using all significant univariate results, we found that baseline international normalised ratio (INR), mean arterial pressure (MAP), and pulse oximeter oxygen saturation (SpO2) were significant predictors of respiratory failure among patients who received terlipressin (Table 2). Prior albumin as a continuous variable was not a predictor of respiratory failure in the CONFIRM study.No predictors were identified for the placebo population. Because some cases of respiratory failure were associated with volume overload, the amount of albumin given before study enrolment was further assessed by determining the incidence of respiratory failure in the terlipressin and placebo groups by quartiles of albumin amounts given before enrolment into the study (Table 3).This analysis did not indicate a clear relationship between the incidence of respiratory failure and the amount of albumin prior to terlipressin or placebo administration. Similarly, prior albumin as a continuous variable was not a predictor of respiratory failure in the terlipressin or placebo groups (Table S3).

呼吸衰竭的预测因素

在各种基线特征中，单变量logistic回归分析确定基线1-2级与3级ACLF是接受特利加压素治疗的患者中呼吸衰竭的重要预测因素(意向性治疗人群；p = 0.002)，但对于接受安慰剂的患者没有影响(表S2)。当使用所有显著的单变量结果进行多变量逻辑回归分析时，我们发现基线国际标准化比值(INR)、平均动脉压(MAP)和脉搏血氧饱和度(SpO2)是接受特利加压素治疗的患者呼吸衰竭的显著预测因子(表2)。在CONFIRM研究中，既往白蛋白作为连续变量不是呼吸衰竭的预测因子。安慰剂组没有发现预测因素。因为一些呼吸衰竭病例与容量超负荷有关，所以通过确定特利加压素组和安慰剂组的呼吸衰竭发生率，进一步评估了研究招募前给予的白蛋白量(表3)。该分析没有表明在使用特利加压素或安慰剂之前，呼吸衰竭的发生率和白蛋白的量之间有明确的关系。类似地，在特利加压素组或安慰剂组中，既往白蛋白作为连续变量不是呼吸衰竭的预测因子(表S3)。

3.4 | Mortality At the end of the 90-day follow-up after completion of treatment, there were 101 deaths (50.8%) in the terlipressin group and 45 deaths (44.6%) in the placebo group. Although the overall and transplantfree survival does not differ between the terlipressin and placebogroups,6 subcategories of ACLF grades were used to assess mortality given that there were increased deaths from respiratory failure in patients with grade 3 ACLF who received terlipressin. Figure 3 shows that there was no difference in mortality between the terlipressin and placebo subgroups in those patients with grades 1–2 ACLF. However, in the terlipressin group, mortality was significantly higher in patients with grade 3 ACLF versus those with grades 1–2 ACLF (p < 0.001; Figure 3). Overall survival to 90 days in patients with baseline ACLF grade 1a (kidney failure-HRS only) was similar in the terlipressin and placebo groups, p = 0.7183 (Figure S1). Competing risk analysis indicated that in patients with baseline ACLF grade 3, there was a significant difference in the CIF estimates for the competing events of transplant or death for terlipressin compared to placebo (Gray’s p = 0.039); for patients with ACLF < grade 3, there was no significant impact of treatment on CIF estimates for those competing events (Gray’s p = 0.780) (Figures S2 and S3). Time to transplant by baseline ACLF grade was similar between treatment groups (Table S4).

死亡率

在治疗完成后的90天随访结束时，特利加压素组有101例死亡(50.8%)，安慰剂组有45例死亡(44.6%)。尽管特利加压素组和安慰剂组的总生存率和无移植生存率没有差异，但考虑到接受特利加压素治疗的3级ACLF患者呼吸衰竭死亡增加，ACLF分级的6个亚类被用于评估死亡率。图3显示，在1-2级ACLF患者中，特利加压素亚组和安慰剂亚组的死亡率没有差异。然而，在特利加压素组，3级ACLF患者的死亡率明显高于1-2级ACLF患者(p < 0.001图3)。特利加压素组和安慰剂组中基线ACLF 1a级(肾衰竭-仅HRS)患者的90天总生存期相似，p = 0.7183(图S1)。竞争风险分析表明，在基线CIF级患者中，特利加压素与安慰剂相比，移植或死亡竞争事件的CIF估计值存在显著差异(格雷p = 0.039)；对于ACLF < 3级的患者，治疗对这些竞争事件的CIF估计值没有显著影响(格雷的p = 0.780)(图S2和S3)。治疗组之间的基线ACLF分级移植时间相似(表S4)。

3.5 | Other adverse events

Although respiratory failure was the most common SAE reported in patients with grade 3 versus grades 1–2 ACLF in the terlipressin group, there was less of an imbalance between terlipressin and placebo treatment for other reported SAEs. In patients with grade 3 ACLF, multiple organ dysfunction syndrome and sepsis appeared to be slightly more common in the terlipressin group, with hepatic failure and alcoholic cirrhosis being more commonly reported in the placebo group; these trends were present for both overall SAEs reported as well as AEs leading to death (see Tables S5 and S6).

3.5 |其他不良事件

虽然呼吸衰竭是特利加压素组3级ACLF患者与1-2级患者相比最常见的SAE，但特利加压素与安慰剂治疗之间的不平衡在其他报告的SAE中较少。在3级ACLF患者中，多器官功能障碍综合征和脓毒症似乎在特利加压素组中更常见，而在安慰剂组中肝功能衰竭和酒精性肝硬化更常见；这些趋势出现在报告的总体SAE和导致死亡的AE中(见表S5和S6)。

4 | DISCUSSION

The results of this retrospective study, utilising data from the largest randomised, placebo-controlled study for the evaluation of terlipressin treatment for HRS1, expand on our previous report that terlipressin is more effective than placebo in improving renal function but is associated with SAEs, including respiratory failure.6 Our findings comport with previous publications indicating that terlipressin, when used for the treatment of HRS1, is associated with decreased overall survival in patients with grade 3 ACLF13 and provide placebo-controlled data that this is mainly related to respiratory failure in this subpopulation of patients; survival in patients with grades 1–2 ACLF treated with terlipressin is similar to that for placebo. Patients with grade 3 ACLF treated with terlipressin are at an increased risk of developing respiratory failure compared with those treated with placebo. Higher baseline INR, MAP, and a lower baseline SpO2 are risk factors for the development of respiratory failure with terlipressin therapy. This latter observation suggests that pre-existing, or treatment-emergent hypoxaemia and pulmonary dysfunction identifies a population of patients who may be particularly at risk for developing respiratory failure with terlipressin. Careful monitoring for the development of circulatory overload, assessment of baseline or treatment-emergent impaired oxygenation with SpO2 monitoring, and avoiding excessive use of albumin infusions appear to be important strategies that are likely to be valuable to mitigate the development of respiratory failure in patients with HRS1 treated with terlipressin. Terlipressin, a vasopressin analogue, has been shown to be effective in the management of HRS1 in cirrhosis.6,14–16 Although ischemic side effects have been uncommonly, but regularly observed in patients receiving terlipressin,17 respiratory failure as a complication of terlipressin has not been commonly reported or characterised. In a Cochrane systematic review in 2012, circulatory overload and respiratory distress or acidosis was briefly reported in seven and three patients, respectively, based on two small studies that formed part of the review.17 In the CONFIRM study and this more detailed analysis, respiratory failure is reported as an important potential AE for terlipressin. This is likely related in part to the fact that the CONFIRM study was the largest clinical trial in patients with HRS1 with a rigorous safety assessment and the greatest number of patients exposed to terlipressin, with terlipressin dosing and duration of treatment (approximately 6 days) similar to previous terlipressin studies.15,16 Although there were safety signals from prior studies, the larger CONFIRM study has allowed a more meaningful description of the incidence and impact of respiratory failure with terlipressin, particularly in patients with advanced disease or grade 3 ACLF. The effects of terlipressin on cardiopulmonary hemodynamics are complicated and the precise mechanisms leading to respiratory failure in patients with cirrhosis and HRS1 who receive terlipressin are unclear. Terlipressin is known to have differential effects on pulmonary versus the systemic hemodynamics.18 In patients with cirrhosis but without underlying portopulmonary hypertension or cardiac disease, a single dose of 2 mg of intravenous terlipressin was noted to induce an increase in pulmonary arterial pressure; in contrast, in patients with cirrhosis and pulmonary hypertension, the same single dose is associated with a decrease in pulmonary arterial pressure.18 A 2 mg dose of terlipressin has been shown to decrease heart rate and lead to a reduction in cardiac output.19 It is likely that the combined effects of terlipressin on cardiac function and pulmonary hemodynamics lead to congestion in the pulmonary circulation and hypoxaemia in some patients. In a study reassessing four cohorts of patients with HRS1 who received terlipressin within previous trials,13 while no cases of respiratory failure were specifically reported, 20 of 241 patients had a reported side effect of circulatory overload, suggesting the cardiopulmonary effects of terlipressin may contribute to, or be exacerbated by, volume overload in these patients. The observation of a trend for an increased incidence of respiratory failure among the patients who received an increasing dose of albumin prior to receiving terlipressin (Table 3) further suggests that volume overload from the albumin could unmask the cardiac and pulmonary effects of terlipressin. In summary, patients with decompensated cirrhosis may have compromised respiratory function at baseline. Terlipressin, by increasing cardiac afterload and effective circulating volume, may affect cardiac systolic and diastolic function, leading to compromised pulmonary function, particularly in the setting of fluid overload.18,20 In addition to the direct cardiopulmonary effects of terlipressin, the increased incidence of respiratory failure in patients with grade 3 ACLF are likely in part related to the existence of underlying severe ACLF. Cirrhosis is known to be an inflammatory state; the more advanced the cirrhosis, the more severe the extent of inflammation.21 In patients with high grades of ACLF, measurements of various inflammatory cytokines and chemokines suggest that the inflammation is very intense and associated with mitochondrial dysfunction and altered microcirculation.22 This hyperinflammatory state ultimately impairs the host immune defence mechanisms, rendering patients with ACLF more vulnerable to secondary infections, increased organ dysfunction, and increased mortality. It is not unexpected that organ failures such as respiratory failure would be more common in patients with grade 3 ACLF even in the absence of terlipressin, possibly related to excessive damage -associated molecular patterns (DAMPS) that fuel an inflammatory cascade that can initiate or perpetuate other organ dysfunction.23 In patients with grade 3 ACLF, the combined cardiac suppressive and pulmonary arterial hypertensive effects of terlipressin in some patients, together with volume overload related to excess albumin, creates “a perfect storm” for respiratory failure to develop within a hyperinflammatory state. It has been suggested that the use of terlipressin for the treatment of HRS in cirrhosis be avoided in patients with grade 3 ACLF, especially those patients with baseline predictors; this is also the group of patients who are less likely to respond with reversal of HRS (Figure 1).12 As observed in this patient population, multiple organ failures with a high grade of ACLF may be providing a constant source of pro-inflammatory cytokines, which perpetuate renal injury rendering patients unresponsive to terlipressin-related improved renal hemodynamics.13,24 However, a small number of patients with high-grade ACLF do respond to terlipressin with reversal of HRS1.25 Accordingly, it may be reasonable to carefully start terlipressin treatment in highly selected patients with HRS and advanced ACLF, if they do not have competing cardiopulmonary comorbidities and recent hypoxaemia and in whom liver transplantation may not be an option.25 Particularly, careful monitoring for the development of respiratory failure in this group of patients would be important; a detailed discussion with the patient and their family of the riskbenefits of terlipressin treatment in this setting are strongly suggested. ACLF is a dynamic event, which can improve with treatment. It has been suggested that terlipressin be administered in these selected patients for 3 days, especially in patients who are young, with vigilant monitoring for signs of improvement or deterioration.25 Otherwise, treatment options for these patients are very limited, especially if liver transplantation is not available. In conclusion, the use of terlipressin, together with albumin, in the treatment of HRS1 with cirrhosis can lead to the development of respiratory failure. This is especially true in patients with advanced grade 3 ACLF. All patients receiving terlipressin need to be monitored closely for the development of respiratory failure; excessive use of albumin should be avoided. Future studies should focus on elucidating the precise mechanisms involved in the development of respiratory failure associated with terlipressin treatment, the inflammatory components that may be active, treatment algorithms to mitigate adverse events, and the evaluation of new treatments for these severely ill patients.

4 |讨论

本回顾性研究的结果，利用了评估特利加压素治疗HRS1的最大随机、安慰剂对照研究的数据，扩展了我们以前的报告，即特利加压素在改善肾功能方面比安慰剂更有效，但与SAE有关，包括呼吸衰竭。6我们的研究结果与以前的出版物一致，表明特利加压素用于治疗HRS1时，与3级ACLF13患者的总生存率下降有关，并提供了安慰剂对照数据，表明这主要与该亚群患者的呼吸衰竭有关；接受特利加压素治疗的1-2级ACLF患者的存活率与安慰剂相似。与接受安慰剂治疗的患者相比，接受特利加压素治疗的3级ACLF患者发生呼吸衰竭的风险增加。较高的基线INR、MAP和较低的基线SpO2是特利加压素治疗发生呼吸衰竭的危险因素。后一项观察表明，预先存在的或治疗中出现的低氧血症和肺功能障碍可确定一群患者，他们可能特别容易因特利加压素而发生呼吸衰竭。仔细监测循环超负荷的发展，用SpO2监测评估基线或治疗中出现的氧合作用受损，以及避免过度使用白蛋白输注似乎是重要的策略，可能对减轻用特利加压素治疗的HRS1患者呼吸衰竭的发展有价值。特力加压素是一种血管加压素类似物，已被证明可有效治疗肝硬化患者的HRS1，14–16尽管缺血性副作用并不常见，但在接受特力加压素治疗的患者中经常观察到，17呼吸衰竭作为特力加压素的并发症尚未被普遍报道或描述。在2012年的Cochrane系统综述中，根据构成该综述一部分的两项小型研究，分别有7名和3名患者简要报告了循环超负荷和呼吸窘迫或酸中毒。17在CONFIRM研究和更详细的分析中，呼吸衰竭被报告为特利加压素的一个重要潜在不良事件。这可能部分与以下事实有关:CONFIRM研究是针对HRS1患者的最大规模临床试验，具有严格的安全性评估，暴露于特利加压素的患者数量最多，特利加压素剂量和治疗持续时间(约6天)与之前的特利加压素研究相似。15，16尽管之前的研究存在安全性信号，但更大规模的CONFIRM研究对特利加压素呼吸衰竭的发生率和影响进行了更有意义的描述，特别是在晚期疾病或3级ACLF患者中。特利加压素对心肺血流动力学的影响是复杂的，导致接受特利加压素治疗的肝硬化和HRS1患者呼吸衰竭的确切机制尚不清楚。众所周知，特利加压素对肺部和全身血液动力学有不同的影响。18在没有潜在门静脉肺动脉高压或心脏病的肝硬化患者中，单剂量2 mg静脉注射特利加压素可导致肺动脉压升高；相比之下，在肝硬化和肺动脉高压患者中，相同的单剂量与肺动脉压下降有关。18 2mg剂量的特利加压素已被证明可降低心率并导致心输出量减少。19特利加压素对心脏功能和肺血流动力学的综合作用可能会导致某些患者的肺循环充血和低氧血症。在一项对之前试验中接受特利加压素治疗的HRS1患者的四个队列进行重新评估的研究中，13虽然没有具体报告呼吸衰竭的病例，但241名患者中有20名报告了循环超负荷的副作用，这表明特利加压素的心肺效应可能会导致这些患者的容量超负荷，或因容量超负荷而加剧。观察到在接受特利加压素治疗前增加白蛋白剂量的患者中呼吸衰竭发生率增加的趋势(表3 ),进一步表明白蛋白的容量超负荷可能暴露特利加压素的心脏和肺效应。总之，失代偿期肝硬化患者在基线时呼吸功能可能受损。特利加压素通过增加心脏后负荷和有效循环量，可能会影响心脏的收缩和舒张功能，导致肺功能受损，尤其是在液体超负荷的情况下。18，20除了特利加压素的直接心肺效应外，3级ACLF患者呼吸衰竭发病率的增加可能部分与潜在的严重ACLF的存在有关。已知肝硬化是一种炎症状态；肝硬化越严重，炎症的程度就越严重。21在高度ACLF患者中，各种炎症细胞因子和趋化因子的测量结果表明，炎症非常严重，并与线粒体功能障碍和微循环改变有关。22这种过度炎症状态最终会损害宿主免疫防御机制，使ACLF患者更容易继发感染，器官功能障碍增加，死亡率增加。即使在没有特利加压素的情况下，器官衰竭(如呼吸衰竭)在3级ACLF患者中也更常见，这并不意外，可能与过度损伤相关分子模式(DAMPS)有关，这些分子模式会引发炎症级联反应，从而引发或延续其他器官功能障碍。23在3级ACLF患者中，特利加压素在某些患者中的心脏抑制和肺动脉高血压联合作用，以及与过量白蛋白相关的容量超负荷，为呼吸衰竭在高炎症状态下的发展创造了“完美风暴”。有人建议，在3级ACLF患者中，尤其是那些有基线预测指标的患者中，应避免使用特利加压素治疗肝硬化HRS这也是不太可能对HRS逆转产生反应的患者群体(图1)。12正如在该患者群体中观察到的，高度ACLF的多器官衰竭可能是促炎细胞因子的持续来源，其使肾损伤永久化，使患者对特利加压素相关的肾血流动力学改善无反应。13，24然而，少数高度ACLF患者确实对特利加压素产生反应，HRS1逆转。25因此， 对于高度选择的HRS和晚期ACLF患者，如果他们没有竞争性心肺合并症和近期低氧血症，并且肝移植可能不是一种选择，谨慎开始特利加压素治疗可能是合理的。25特别是，仔细监测这组患者呼吸衰竭的发展非常重要； 强烈建议与患者及其家人详细讨论在这种情况下使用特利加压素治疗的风险和益处。ACLF是一个动态事件，可以通过治疗来改善。有人建议对这些选定的患者使用特利加压素3天，尤其是年轻患者，同时警惕监测病情改善或恶化的迹象。25否则，这些患者的治疗选择非常有限，尤其是在无法进行肝移植的情况下。总之，联合应用特利加压素和白蛋白治疗合并肝硬化的HRS1可导致呼吸衰竭。这在晚期3级ACLF患者中尤其如此。所有接受特利加压素治疗的患者需要密切监测呼吸衰竭的发展；应避免过量使用白蛋白。未来的研究应侧重于阐明特利加压素治疗相关的呼吸衰竭发展的确切机制、可能活跃的炎症成分、减轻不良事件的治疗算法以及对这些重症患者的新治疗的评估。