Dual aortic and portal perfusion at procurement prevents ischaemic‐type biliary lesions in liver transplantation when using octogenarian donors: a retrospective cohort study

Several risk factors for ischaemic‐type biliary lesions (ITBL) after liver transplantation (LT) have been identified, but the role of portal vein perfusion at graft procurement is still unclear. This was a prospective study on double aortic and portal perfusion (DP) of liver grafts stratified by donor's decade (<60 yo; 60–69 yo; 70–79 yo and ≥80 yo) versus similar historical cohorts of primary, adult grafts procured with single aortic perfusion (SP) only. The primary study aim was to assess the role of DP on the incidence of ITBL. There was no difference in the incidence of overall biliary complications according to procurement technique for recipients of grafts <80 years. A higher incidence of ITBL was observed for patients receiving grafts ≥80 years and perfused through the aorta only (1.9 vs. 13.4%; P = 0.008). When analysing octogenarian grafts, donor male gender (HR = 6.4; P = 0.001), haemodynamic instability (HR = 4.9; P = 0.008), and type‐2 diabetes mellitus (DM2) (HR = 3.0; P = 0.03) were all independent risk factors for ITBL, while double perfusion at procurement (HR = 0.1; P = 0.04) and longer donor intensive care unit (ICU) stay (HR = 0.7; P = 0.04) were protective factors. Dual aortic and portal perfusion has the potential to reduce post‐transplant ITBL incidence for recipients of octogenarian donor grafts. Larger series are needed to confirm this preliminary experience.     

Causes and consequences of ischemic-type biliary lesions after liver transplantation

Biliary complications are a major source of morbidity, graft loss, and even mortality after liver transplantation. The most troublesome are the so-called ischemic-type biliary lesions (ITBL), with an incidence varying between 5% and 15%. ITBL is a radiological diagnosis, characterized by intrahepatic strictures and dilatations on a cholangiogram, in the absence of hepatic artery thrombosis. Several risk factors for ITBL have been identified, strongly suggesting a multifactorial origin. The main categories of risk factors for ITBL include ischemia-related injury; immunologically induced injury; and cytotoxic injury, induced by bile salts. However, in many cases no specific risk factor can be identified. Ischemia-related injury comprises prolonged ischemic times and disturbance in blood flow through the peribiliary vascular plexus. Immunological injury is assumed to be a risk factor based on the relationship of ITBL with ABO incompatibility, polymorphism in genes coding for chemokines, and pre-existing immunologically mediated diseases such as primary sclerosing cholangitis and autoimmune hepatitis. The clinical presentation of patients with ITBL is often not specific; symptoms may include fever, abdominal complaints, and increased cholestasis on liver function tests. Diagnosis is made by imaging studies of the bile ducts. Treatment starts with relieving the symptoms of cholestasis and dilatation by endoscopic retrograde cholangiopancreaticography (ERCP) or percutaneous transhepatic cholangiodrainage (PTCD), followed by stenting if possible. Eventually up to 50% of the patients with ITBL will require a retransplantation or may die. In selected patients, a retransplantation can be avoided or delayed by resection of the extra-hepatic bile ducts and construction of a hepaticojejunostomy. More research on the pathogenesis of ITBL is needed before more specific preventive or therapeutic strategies can be developed.     

Doppler ultrasonic evaluation of hepatic functional reserve]

Ultrasonic Doppler measurement of the blood flow in the portal vein and hepatic artery was conducted to evaluate the function and functional reserve of the liver in 146 patients with various forms of cholangitis combined with biliary cirrhosis and hepatic insufficiency. The functional reserve of the liver was judged by comparison of the basic blood flow on a fasting stomach with the blood flow after a functional histamine load. Five types of responses of the portal vein blood flow to the functional load according to the degree of disturbed hepatic function were revealed. Comparison of the flow of blood along the portal vein in healthy individuals with that in patients with diabetes mellitus and a formed splenorenal shunt showed that disconnection of the blood flow from the splenic vein has no effect on the flow of blood in the portal vein. The latter is regulated at the level of microcirculation in the liver, which is confirmed by the correlation between the blood flow in the portal vein and in the hepatic artery.     

Retrograde reperfusion via vena cava lowers the risk of initial nonfunction but increases the risk of ischemic-type biliary lesions in liver transplantation – a randomized clinical trial

Initial nonfunction (INF) and biliary complications such as ischemic-type biliary lesion (ITBL) remain two major complications in clinical orthotopic liver transplantation (OLT). The influence of ischemia and reperfusion injury (I/R) as a significant risk factor for both complications is widely unquestioned. A new reperfusion technique that reduces I/R injury should lead to a reduction in both INF and ITBL. One hundred and thirty two OLT patients were included in this study and randomized into two groups. Group A underwent standard reperfusion with anterograde simultaneous arterial and portal reperfusion and group B received retrograde reperfusion via the vena cava before sequential anterograde reperfusion of portal vein and hepatic artery. Serum transaminase level as a surrogate parameter for I/R injury and serum bilirubin level as a parameter for graft function were significantly reduced during the first week after OLT in group B. INF rate was 7.7% in group A and 0% in group B (P = 0.058). ITBL incidence was 4.55% in group A versus 12.3% in group B (P = 0.053). Retrograde reperfusion seemed to be beneficial for hepatocytes, but was detrimental for the biliary epithelium. The unexplained increased incidence of ITBL after retrograde reperfusion will be focus of further investigation.     

In vivo evaluation of an implantable portal pump system for augmenting liver perfusion

BACKGROUND: Increasing portal inflow in cirrhosis using a mechanical pump reduces portal venous pressure and improves liver function. A pump has been developed for portal vein implantation in human cirrhosis. This study describes the initial in vivo evaluation in a porcine model. METHODS: Five Large White pigs underwent laparotomy and exposure of the liver. Flow in the hepatic artery, portal vein and hepatic microcirculation was monitored continuously. Hepatic tissue oxygenation was measured by near-infrared spectroscopy. After baseline measurements the pump was inserted into the portal vein. Pump flow rate was then increased stepwise to 50 per cent over the baseline value for a period of 2 h. The pump was then stopped for 20 min and left in situ while continuing to collect systemic and hepatic haemodynamic data. The animal was killed and biopsies for histological examination were taken from the liver, small intestine and spleen. RESULTS: The baseline total hepatic blood flow was 626(39) ml/min; the hepatic artery supplied 18.4(2.1) per cent and the portal vein 81.6(2.1) per cent. The pump was inserted successfully in all animals without surgical complications. During surgical insertion of the pump, the temporary portal vein occlusion resulted in a significant rise in hepatic artery blood flow (22(3) per cent; P < 0.01 versus baseline). Portal vein flow was augmented by pumping; there was a significant correlation between the pump motor speed and portal vein flow (P < 0.0001). This inflow correlated directly with flow in the hepatic microcirculation and hepatic tissue oxygenation (P < 0.001). The pump ran satisfactorily throughout the study. Histological examination revealed no evidence of structural damage to the liver or ischaemic changes in the small intestine or spleen. CONCLUSION: It is technically possible and safe to insert an implantable pump in the portal vein. Portal venous blood flow can be increased up to 50 per cent with a resultant increase in flow in the hepatic microcirculation and hepatic oxygenation and without adverse effects on either hepatic or systemic haemodynamics.     

携带IL-13基因肝干细胞对冷缺血大鼠移植肝脏保护作用的研究

目的以基因工程干细胞治疗的方式来改善缺血-再灌注状况,使移植肝脏更好地耐受缺血-再灌注,以减少移植术后的并发症,延长移植器官存活期。方法利用已建立的Wistar大鼠冷缺血原位肝移植(OLT)模型,术中经受体大鼠门静脉输入IL-13基因修饰的或未修饰的肝卵圆细胞(HOC)即转染组和未转染组,分别于术后1、3、7及14d检测受体大鼠肝脏功能变化、组织学变化、胆管上皮细胞(BEC)的增殖情况、α-平滑肌肌动蛋白(α-SMA)的表达、肝组织中HO-1 mRNA的表达,并观察移植大鼠术后的存活情况。结果转入IL-13基因的HOC对冷保存损伤的肝脏有一定的保护作用;术后7d,肝移植组和未转染组的α-SMA表达较转染组明显(P0.05);术后3d,未转染组和转染组的BEC增殖指数明显低于肝移植组(P0.05)。转染组术后各时相点的HO-1 mRNA表达水平均明显高于相应时相点的其他各组的水平(P0.05);移植术中经门静脉输入HOC对缺血性胆管损伤所诱导的BEC增殖有一定的抑制作用,对BEC具有一定的保护作用;肝移植组生存率明显低于假手术组和转染组(P0.05)。结论IL-13的持续表达能促进术后移植肝内HO-1 mRNA的表达,这有利于对供肝的保护,有利于受体大鼠术后肝功能的恢复。促进HO-1 mRNA的表达是IL-13对BEC的具有保护作用的机理之一。     

Factors Predicting Ischemic-Type Biliary Lesions (ITBLs) After Liver Transplantation

Among biliary complications, ischemic-type biliary lesions (ITBLs) remain a major cause of morbidity in liver transplant recipients, significantly affecting the chance of survival of both patients and grafts. We retrospectively reviewed 10 years of prospectively collected donor and recipient data from April 2001 to April 2011. We evaluated the incidence of ITBL occurrence, exploring the possible predisposing factors, including donor and recipient data. Two hundred fifty-one grafts were harvested: 222 of them were transplanted at our institution, the remaining 29 (11.6%) discarded by our donor team as showing >40% macrovesicular steatosis. Mild-moderate (20%-40%) macrovesicular steatosis (P < .001) and cold ischemia time (P = .048) significantly increased the risk of ITBL, also as an independent risk factor after multivariate analysis.     

Hemodynamic and microcirculatory changes in the liver in experimental acute pancreatitis of dogs

To investigate the hemodynamic changes of the liver in acute pancreatitis the microcirculation of the liver, portal venous flow, hepatic artery blood flow, cardiac index were measured in 15 dogs with acute pancreatitis induced by autologous bile and trypsin injection into the main pancreatic duct during the experimental period for 5 hrs. The effect of protease inhibitor (PATM) in a dose of 3 mg/kg/kg/hr on those hemodynamic changes was investigated in another series of acute pancreatitis in dogs. In acute pancreatitis hepatic microcirculation decreased to 26 +/- 15 ml/min/100g at 5 hrs after onset of pancreatitis, portal venous flow and hepatic artery flow decreased to 86 +/- 16 ml/min and 66 +/- 30 ml/min at 5 hrs, respectively. The administration of PATM maintained the portal blood flow during the first 2 hrs and showed a trend of decreasing to 219 +/- 93 ml/min at 5 hrs. The hepatic microcirculation showed 77 +/- 25 ml/min/100g and 72 +/- 14 ml/min/100g at 1 and 2 hrs respectively and then decreased to 47 +/- 21 ml/min/100g at 5 hrs. We concluded hemodynamic and microcirculatory changes of the liver in acute pancreatitis was disturbed due to the decreased portal and hepatic artery flow, however, the administration of PATM has an effect of improvement of liver microcirculation.     

Symposium on portal hypertension and its complications: current management. Preoperative assessment and predictors of encephalopathy.

None of the preoperative predictors of encephalopathy proposed so far to evaluate the risk of portacaval shunting in cirrhotic patients has been of value. The authors have found, in preliminary studies, that measurement of the hepatic extraction of indocyanine green (ICG), which correlates highly with the "functional" portal blood supply, could be of prognostic value: cirrhotic patients with a near-normal value for ICG extraction often have encephalopathy after portacaval shunting whereas those with a low ICG extraction value seldom have encephalopathy. These preliminary data suggest that cirrhotic patients with markedly decreased ICG extraction have a lesser risk of encephalopathy since their portal blood supply is already shunted away from hepatocytes before the operation because of anatomic changes in the liver microcirculation.     

Measurement of the portal blood flow in man by continuous local thermodilution method: II. Portal hemodynamics before and after hepatectomy

We found that measurements of portal blood flow by continuous thermodilution were highly reproducible even after hepatectomy. Our subjects numbered 59 in all: In these patients having diseases of the liver and biliary tract, we studied portal hemodynamics during percutaneous transhepatic portography. Of these, 37 underwent hepatectomy. We chose 19 subjects from this group, and measured again both portal venous flow and portal venous pressure many times, continuing for 14 more days. In all 19 patients checked after hepatectomy, portal hemodynamics became hypodynamic, and this change was greater when the amount of liver resected was large. In 18 of these patients, hemodynamics started to improve after the 7th postoperative day. Changes in hemodynamics were not significantly different in patients with or without cirrhosis. In one patient who died of hepatic failure, the portal hypodynamic state did not improve. With this exception, in patients with major resections, portal venous flow per liver volume had increased after surgery and continued to increase. This was not true for patients with minor resections. Portal hemodynamics are important in the functioning and regeneration of the remaining liver, and it is necessary to understand and medically correct portal hemodynamics before and after hepatectomy.     

Incidence of and risk factors for ischemic-type biliary lesions following orthotopic liver transplantation

Ischemic-type biliary lesions (ITBL) account for a major part of patients' morbidity and mortality after orthotopic liver transplantation (OLT). The exact origin of this type of biliary complication remains unknown. This study retrospectively evaluated 1843 patients. Patients with primary sclerosing cholangitis were excluded from this study. The diagnosis of ITBL was established only when all other causes of destruction of the biliary tree were ruled out.  Donor age ( P  = 0.028) and cold ischemic time (CIT) ( P  = 0.002) were found to be significant risk factors for the development of ITBL.  Organs that were perfused with University of Wisconsin (UW) solution developed ITBL significantly more often than Histidine–Tryptophan–Ketoglutarate (HTK)-perfused organs ( P  = 0.036). The same applied to organs harvested externally and shipped to our center versus those that were procured locally by our harvest teams ( P  < 0.001). Pressure perfusion via the hepatic artery significantly reduced the risk of ITBL ( P  = 0.001). The only recipient factor that showed a significant influence was Child-Pugh score status C ( P  = 0.021). Immunologic factors had no significant impact on ITBL. The clinical consequences of this study for our institution have been the strict limitation of CIT to <10 h and the exclusive use of HTK solution. We further advocate that all organ procurement teams perform pressure perfusion on harvested organs.     

超声参数－造影剂到达时间成像在肝移植术后缺血性胆管炎中的诊断价值

目的探讨超声参数－造影剂到达时间成像(P-MFI)技术在肝移植术后缺血性胆管炎(ITBL)中的诊断价值。 方法回顾性分析2015年1月1日至2017年12月31日随访期间在中山大学附属第三医院确诊ITBL的25例肝移植受者(ITBL组)临床资料,选取同期肝移植术后随访中移植肝功能正常受者作为对照组(33例)。由2名分别具有8、2年腹部超声诊断经验的医师(医师1和医师2)采用双盲法,分别对所有病例进行超声造影及P-MFI诊断信心评分。采用成组t检验比较ITBL组与对照组年龄以及医师1和医师2对两组受者超声造影和P-MFI诊断信心评分。采用卡方检验或Fisher确切概率法比较两组受者性别、胆管吻合方式、原发病以及医师1和医师2对两组受者P-MFI诊断信心评分差异。采用Kappa检验评价医师1和医师2的诊断一致性。P<0.05为差异有统计学意义。 结果两组受者年龄、性别、胆管吻合方式和原发病等一般资料差异均无统计学差异(P均>0.05)。ITBL组和对照组受者平均P-MFI编辑时间分别为(8.2±1.8)s和(6.8±1.9)s,差异具有统计学意义(t＝－2.516,P<0.05)。对照组动脉首先显影,为红色;随后胆管壁与门静脉管壁显影(几乎为同一时段),胆管壁显影清晰,20例为黄绿色或绿色,9例为绿色和蓝色混合,4例为蓝色与紫色相间;最后为门静脉与肝实质显影,颜色多为蓝色和紫色。ITBL组动脉首先显影,为红色;随后门静脉和肝实质显影,门静脉壁为黄色或绿色,门静脉及肝实质为蓝色或蓝色与紫色相间;最后胆管壁显影,胆管壁显影较晚且不清晰,其中8例颜色充填较好,为绿色,4例为零星点状绿色,10例为稀疏深蓝或紫色,3例无颜色填充。医师1超声造影和P-MFI平均诊断信心评分分别为(4.4±0.5)分和(4.8±0.3)分,差异有统计学意义(t＝25.35,P<0.05)。ITBL组和对照组分别有22、5例P-MFI诊断信心评分高于超声造影,两组差异有统计学意义(χ²＝50.088,P<0.05)。医师2超声造影和P-MFI平均诊断信心评分分别为(4.2±0.6)分和(4.7±0.5)分,差异有统计学意义(t＝22.52,P<0.05);ITBL组和对照组分别有20、6例P-MFI诊断信心评分高于超声造影,两组差异有统计学意义(χ²＝40.798,P<0.05)。两位阅片者对于ITBL组和对照组受者评判一致性分别为较好和一般(Kappa值＝0.706和0.455)。 结论P-MFI技术可更直观、清晰显示胆管壁、肝脏血管及肝实质血流灌注情况,能为肝移植术后并发ITBL的诊断提供更丰富的信息,增强检查者的诊断信心。     

减少肝移植术后胆道缺血性损伤的临床路径

目的：针对肝移植术后并发症缺血性胆道损伤（ITBL）,试图建立区分各种导致ITBL的危险因素的临床路径,降低ITBL的发生率。方法：记录随访335例行原位肝移植术（OLT）病例的可能导致胆道缺血的危险因素,包括供肝热缺血时间、冷缺血时间、温缺血时间及供肝脂肪肝情况等。按照冷缺血时间分两组I：TBL组和正常组。比较其他危险因素在两组间的差别。结果：冷缺血时间控制〈8 h,正常组81例,ITBL组2例,热缺血时间差别有统计学意义（P=0.017）;8～12 h,正常组150例I,TBL组25例,胆道温缺血时间差异有统计意义（P=0.033）;〉12 h,正常组57例I,TBL组20例,供肝脂肪肝发生率差异有统计学意义（P〈0.05）。结论：为避免ITBL,冷缺血时间〈8 hI,TBL的发生率很低,只要控制好热缺血时间即可;冷缺血时间8~12 h,尽量将胆道温缺血时间控制在1 h左右;冷缺血时间〉12 h,对于有严重脂肪变的边缘供体可以考虑弃用。     

肝移植时代的门静脉高压治疗

胃食管静脉曲张出血是门静脉高压的常见并发症。药物和内窥镜治疗是静脉曲张的基础治疗。经颈静脉肝内门体静脉分流被推荐用于处理难治性或复发性胃食管静脉曲张出血。当患者存在危及生命的出血风险,而传统治疗风险较高、存在禁忌或效果不理想时,应选择肝移植治疗。传统治疗可以获得短期疗效,甚至可以较长时间稳定病情,但如果这些治疗导致门静...     

Hyperperfusion syndrome in small-for-size livers

BACKGROUND: Portal hyperperfusion in small-for-size livers might seriously impair postoperative liver regeneration. Using an experimental model, we investigated splenectomy as a measure to reduce portal blood flow and its impact on postoperative recovery following extended liver resection. METHOD: Wistar rats underwent partial (90%) hepatectomy with or without splenectomy under temporary inflow occlusion (30 min). In addition to 10-day survival rate, laser Doppler flowmetry of hepatic blood flow and fluorescence microscopic analysis of hepatic microcirculation were performed to assess the effect of splenectomy on initial microvascular reperfusion of liver remnants. RESULTS: While postischemic perfusion failure was comparable between both groups, portal blood flow was significantly reduced after simultaneous splenectomy (3.5+/-0.4 vs. 5.4+/-0.4 ml/min). Moreover, red blood cell velocity and volumetric blood flow were reduced in splenectomized animals. These animals experienced lower AST levels (421+/-36 vs. 574+/-73 U/l) and a significantly increased survival rate, reaching 6.6+/-1.3 vs 2.6+/-0.8 days. CONCLUSION: Simultaneous splenectomy significantly reduced the risk for postoperative hyperperfusion syndrome in small-for-size livers. Shear-stress-induced liver injury was diminished due to a significant reduction of portal venous blood flow, which positively influenced postoperative regeneration resulting in significantly higher survival.     

Left renal vein ligation for large splenorenal shunt during liver transplantation

Adequate hepatopetal portal vein blood flow is obligatory to ensure proper liver function after liver transplantation. Large collateral veins as shunts impair portal vein flow and even cause hepatofugal blood flow and portal steal syndrome. In particular, splenorenal shunts in liver transplant recipients can lead to allograft dysfunction and possible allograft loss or hepatic encephalopathy. Restoration of portal flow through left renal vein ligation (LRVL) is a treatment option, which is much easier compared to splenectomy, renoportal anastomosis and shunt closure, but bears the risk of moderate and temporary impairment of renal function. In addition, a patent portal vein is mandatory for LRVL. However, although LRVL has been reported to be an effective, safe and easy method to control portacaval shunts and increase hepatopetal flow in some studies, indications and safety are still not clear. In this review, we summarize existing studies on LRVL during liver transplantation.     

The effect of dobutamine on hepatic blood flow and oxygen supply-uptake ratio during enflurane nitrous oxide anesthesia in humans undergoing liver resection.

Liver surgery is often accompanied by hepatic hypoperfusion and hypoxia, and it is controversial whether catecholamines increase hepatic blood flow and oxygen supply. The effects of 3 micrograms.kg-1.min-1 dobutamine on hepatic circulation and oxygen balance were examined in patients anesthetized with enflurane, nitrous oxide, and oxygen for liver surgery. Dobutamine did not cause a significant increase in hepatic arterial blood flow. However, total hepatic blood flow and portal venous blood flow were increased, resulting in an increase in hepatic oxygen delivery (HDO2). The increase in HDO2 was not associated with an improvement of hepatic oxygen supply-uptake ratio, since hepatic oxygen uptake (HVO2) also increased. After hepatectomy, the increases in portal venous blood flow and HDO2 were not accompanied by an increase in HVO2. The stimulation of hepatocellular oxygen metabolism by dobutamine and depressed responsiveness of adrenoceptors on hepatocytes in which metabolism was already augmented are the likely explanation for the different reactions before and after hepatectomy.     

Ultrasound-Targeted Microbubble Cavitation During Machine Perfusion Reduces Microvascular Thrombi and Graft Injury in a Rat Liver Model of Donation After Circulatory Death

BackgroundIschemic cholangiopathy is a process of bile duct injury that might result from peribiliary vascular plexus (PBP) thrombosis and remains a dreaded complication in liver transplantation from donors after circulatory death (DCD). The aim of this study was to propose a mechanical method of clot destruction to clear microvascular thrombi in DCD livers before transplantation.MethodsSonothrombolysis (STL) is a process by which inertial cavitation of circulating microbubbles entering an ultrasound field create a high-energy shockwave at a microbubble-thrombus interface, causing mechanical clot destruction. The effectiveness of STL in DCD liver treatment remains unclear. We carried out STL treatment during normothermic, oxygenated, ex vivo machine perfusion (NMP), introducing microbubbles into the perfusate with the liver enveloped in an ultrasound field.ResultsThe STL livers showed reduction in hepatic arterial and PBP thrombus and decreases in hepatic arterial and portal venous flow resistance, reduced parenchymal injury as measured by aspartate transaminase release and oxygen consumption, and improved cholangiocyte function. Light and electron microscopy showed reduction of hepatic arterial and PBP thrombus in STL livers compared with controls and preserved hepatocyte structure, sinusoid endothelial morphology, and biliary epithelial microvilli.ConclusionIn this model, STL improved flow and functional measures in DCD livers undergoing NMP. These data suggest a novel therapeutic approach to treat PBP injury in DCD livers, which may ultimately increase the pool of grafts available to patients awaiting liver transplantation.     

The effects of a somatostatin analogue SMS 201-995 on hepatic haemodynamics in the cirrhotic rat

The effects of a somatostatin analogue, SMS 201-995 on hepatic haemodynamics were studied in rats with dimethylnitrosamine-induced cirrhosis. An intravenous infusion of 1, 2 or 4 micrograms kg-1 body wt h-1 SMS 201-995 produced a rapid and sustained decrease in portal pressure, portal venous flow and liver blood flow without significantly altering arterial blood pressure or pulse. The reductions in portal pressure, portal venous flow and liver blood were accompanied by an increase in splanchnic vascular resistance. Portal venous resistance was not affected. Subcutaneous injection of 2 micrograms kg-1 body wt SMS 201-995 produced a gradual decrease in portal pressure, the maximum reduction occurring 18 min after administration. This reduction in portal pressure was sustained for a further 20 min. The results suggest that SMS 201-995 may be of value in the control of bleeding oesophageal varices. Furthermore, the prolonged duration of action of SMS 201-995 following its subcutaneous administration suggests that the analogue may be useful in the long-term management of portal hypertension in patients with cirrhosis.