Operative Surgical Group,Branch of Surgery of Chinese Medical Association Transplantation Group,Branch of Surgery of Chinese Medical Association

ABSTRACT With the dawn of organ donation after a citizen's death in China,the use of split-liver transplantation(SLT)can effectively increase the source of donor liver,reduce the waiting time for organ transplantation in patients,and particularly solve the problem of organ shortage in children.In recent years,many transplantation centers have been performing SLT to varying degrees and efficacy.At the current stage,the experiences of countries with advanced transplantation techniques should be used to establish an SLT consensus that is suitable for China to further increase the ratio and efficacy of SLT.In this paper,we combined expert experiences to generate an SLT expert consensus that included donor and donor liver evaluation,recipient selection criteria,donor and recipient matching,selection of splitting form and tools,blood vessels and bile ducts dissection and allocation,perioperative management of SLT,and organ allocation.

Keywords:Split-liver transplantation (SLT)Organ donation after citizen's death Graft-to-recipient weight ratio (GRWR)Anatomical variation Hepatic steatosis Model for end-stage liver disease (MELD)

1.Introduction

In the 1980s,Bismuth and Houssin1reduced the size of transplanted livers,thus enabling the possibility for adult donor livers to be used for children.In 1988,Pichlmayret al.2transplanted one donor liver to two recipients(one child and one adult)and completed the world's first split-liver transplantation (SLT).In the same year,Bismuthet al.3completedthefirstfullleft/fullrightSLTandthe recipients were two adult patients.The use of SLT and living donor liver transplantation (LDLT) has decreased mortality in the pediatric waitlist from 40%inthe 20th century to 10%atpresent.Additionally,mortality for older children had decreased to 5%.4As SLT techniques progresses and matures,its efficacy in experienced transplantation centers is close to that for whole liver transplantation.5－7In 2015,liver transplantation in China entered the age of donor liver source from organ donation after a citizen's death.Many domestic transplantation centers have been performing SLT to varying degrees and efficacy.8At the current stage,the mature experiences of countries with advanced transplantation techniques should be used to establish an SLT consensus that is suitable for China to further increase the ratio and efficacy of SLT.

2.Donor and donor liver evaluation

2.1.Evaluation of general condition of donors

Donor livers from organ donation after a citizen's death can undergo injuries of varying severities from different causes before donation; hence,the functional graft size (FGS) is lower than that of the actual volume.9The quality requirements for donor liver splitting are higher and transplant centers around the world have different donor selection criteria.10Table1 shows the general condition requirements for SLT donors.The splitting method and donor liver quality criteria can be appropriate to relax depending on the condition of the donor and recipient to expand the source of donor livers.

2.2.Donor liver anatomical and volume evaluation

After preliminary screening based on the donor's general condition and confirmation of donor for liver splitting,abdominal colored ultrasound,contrast-enhanced ultrasound,or upper abdominal enhanced computed tomography (CT) scan should be performed to evaluate the anatomical status of the hepatic artery,portal vein,and hepatic vein.When the required conditions aremet,three-dimensional reconstruction can be conducted to accurately understand the condition of the donor liver.As magnetic resonance imaging (MRI) evaluation is a long and difficult process to be completed for donors in a critical condition,it is not recommended as a routine examination.

Table1 General condition requirements for split-liver transplantation donors.

2.2.1.Hepatic artery evaluation

With the improvement of microsurgical techniques,common variations of hepatic artery are no longer contraindications for donor liver splitting.However,preoperative imaging examination combined with intraoperative examination are required to understand the anatomical condition of the hepatic artery so that a surgery plan can be formulated before splitting,anastomosis,and reconstruction.11

2.2.2.Portal vein evaluation

Compared with the hepatic artery,there are lesser variations in the portal vein.However,rare portal vein variations may be a contraindication for SLT(Fig.1).12,13The main principles are as follows:(i) anatomical variations at one side of the donor liver that will affect the portal vein blood supply at the other side after splitting should be avoided;(ii)multiple portal vein orifices after splitting at one side of the donor liver should be avoided; (iii) avoid splitting such that portal vein reconstruction difficulty is not higher on any side of the donor liver.This procedure shortens the cold ischemia time and reduces the incidence of postoperative complications.

2.2.3.Bile duct evaluation

As variations in bile duct are common,the anatomical status of bile ducts should be understood first before splitting the liver parenchyma.Ifin situsplitting is performed,then the common bile duct should be first dissected during surgery by excising the common bile duct at the upper margin of the pancreas for direct imaging,and cholangiography such as that performed in LDLT is not required.Ifex situsplitting is performed,then cholangiography is first performed while preparing the donor liver to understand the bile duct anatomy as soon as possible to determine the bile duct splitting and reconstruction methods.Fusion of the bile duct draining the right liver with the left hepatic duct is the most common;fusion of the right posterior branch with the left hepatic duct accounts for 22% of variants; and fusion of the right anterior branch with the left hepatic duct accounts for 6%of variants.These variants are not contraindications for splitting when the donor liver bile duct can be precisely dissected (Fig.2) and the sites of bile duct splitting need to be accurately determined during cholangiography.14The main principle is a position for bile duct dissection should be present so that there is sufficient bile drainage in both sides of the graft.At the same time,reconstruction of multiple complex branches should be avoided as much as possible.

2.2.4.Hepatic vein evaluation

The hepatic vein is crucial as an anatomical landmark while determining the splitting method and splitting plane.For SLT involving the left lateral lobe (LLL,segments II + III) and the extended right lobe (eRL,segments I + IV－VIII),the anatomical characteristics of the left hepatic vein and its confluence with the middle hepatic vein should be determined.Attention should be directed toward anatomical variations such as the fusion of the hepatic vein from the segment II or III with the middle hepatic vein or inferior vena cava.Protection should be ensured during dissection.For full left and full right SLT,the anatomical characteristics of the middle hepatic vein should be understood and the diameter of hepatic veins of the segments IV,V,and VIII along with their fusion type with the middle hepatic vein should be determined.

2.2.5.Liver volume evaluation

CT three-dimensional reconstruction imaging can be used to determine the donor liver volume of the two to-be-split parts of the graft.The donor liver volume can also be estimated based on the liver volume formula.15,16Generally,the graft-to-recipient weight ratio (GRWR) and standard liver volume (SLV) are used as the basic criteria for matching donors and recipients.

2.3.Donor liver quality evaluation

2.3.1.Hepatic steatosis

It is an independent risk factor that affects the early prognosis of SLT.There are diverse evaluation methods,such as preoperative ultrasound,CT scans,inspection by an organ procurement surgeon,and pathology examinations.The ratio of hepatic steatosis can be accurately obtained from pathology findings to differentiate between microvesicular or macrovesicular steatosis.Hence,pathology examination remains the gold standard for determining steatosis.It is recommended that the samples be obtained via preoperative liver biopsy or during organ harvesting via frozen section pathology tests for confirmation on the suspicion of steatosis.Steatosis in the donor liver should not exceed 10% for SLT.

2.3.2.Liver fibrosis and liver stiffness

Only non-fibrotic donor livers (pathological grade of S0) are allowed for SLT.Therefore,the liver tissue samples must be obtained from the suspected cases for pathology tests.The severity of liver fibrosis can also be determined from non-invasive ultrasound or MRI elastography.However,MRI has weak operability and is complex for donor evaluation.Ultrasound elastography can be used to detect liver stiffness,which indirectly reflects the degree of liver fibrosis and edema of the donor liver.The liver stiffness requirement for splitting is ＜7 kPa.

3.Recipient selection criteria and donor and recipient matching principles

SLT is safe when the known risk factors are avoided.The recommended recipient selection criteria and donor/recipient matching principles are as follows:(i)adult recipient GRWR ＞1.2%and pediatric recipient GRWR of 2－4%;17,18(ii)pediatric recipient weight ＞6 kg;19(iii)no history of complex upper abdominal surgery;(iv)liver retransplantation is a relative contraindication for SLT and is only considered for good-quality donor livers;(v)critically ill recipients should have a score of ＜30 on both the model for end-stage liver disease (MELD) score for adults and the pediatric end-stage liver disease (PELD) score for children;20(vi) for emergency liver transplant recipients,whole liver transplantation is preferred in principle.If there are one adult and one pediatric emergency liver transplant recipients,then SLT can be considered for good-quality livers; (vii) severe portal hypertension recipients should be carefully selected to avoid postoperative hyperperfusion injury in the graft and small-for-size syndrome;(viii)recipients with significant portosystemic shunt should be carefully selected to prevent insufficient perfusion of the transplanted liver due to postoperative shunting and the seventh-day syndrome.

4.Splitting form and instrument selection

4.1.Selection between in situ or ex situ splitting

It is recommended that multicenter collaboration must be strengthened for donor liver splitting to increase the proportion ofin situsplitting.This process will decrease the cold ischemia time and result in better wound hemostasis,thereby improving the quality of the splitting grafts.Duringin situsplitting,there should be an active cooperation with the coordinator,surgical staff,anesthesiologist,and other organ harvesting teams to reduce intraoperative bleeding,shorten the length of surgery,and avoid affecting other organs to be harvested,such as the heart,lungs,and kidneys.21Whenin situsplitting cannot be performed due to the donor's condition or organ harvesting hospital,a proper coordination among various departments participating in splitting should be ensured so that the donor liver is harvested,transported,gone throughex situsplitting,and transplanted in an efficient and orderly manner to decrease the cold ischemia time and increase efficacy.

4.2.Splitting form

Conventional splitting forms include typical splitting form and full left/right liver splitting.22,23Conventional splitting divides the donor liver into the LLL (segments II + III) and the eRL (segments I+IV－VIII).This splitting form is mainly used for the combination of one adult and one pediatric recipient.Full left/right liver splitting divides the donor liver into a left hemiliver (segments I－IV) and right hemiliver (segments V－VIII).This splitting form can be used for two weight-matched adult patients.This form can also be used for two weight-matched pediatric patients with pediatric donor livers.

When splitting into the left and right hemilivers,the splitting plane should be determined strictly according to the route of the middle hepatic vein and anatomical characteristics to ensure a smooth reflux in the left and right hemilivers.With regards to the middle hepatic vein allocation,the middle hepatic vein can be fully split for the left and right hemilivers or the middle hepatic vein can be retained in the left hemiliver,whereas the middle hepatic vein branches in segments V and VIII of the right hemiliver are reconstructed.The splitting form for the donor liver is selected based on the conditions of the donor and recipients.

4.3.Splitting instruments

Forin situsplitting,many tools used for segmenting the liver parenchyma that are currently used in the liver surgery can be used.These tools include the ultrasonic knife,cavitron ultrasonic surgical aspirator(CUSA),water jet,and LigaSure.The tools selected should be based on the surgeon's habit and the surgical instruments that he/she is most familiar with should be used for splitting.Forex situsplitting,it is recommended that CUSA+bipolar electrocoagulation be used for donor liver splitting to decrease wound bleeding after reperfusion.

5.Dissection and allocation of blood vessels and bile ducts

The dissection and allocation of blood vessels and bile ducts in SLT require a comprehensive consideration of hepatic blood supply after splitting,relative integrity of bile ducts,and the difficulty of surgical reconstruction to avoid postoperative technique-related complications.5,24

5.1.Hepatic artery

As there are different variants of the hepatic artery,25the hepatic artery splitting form for SLT is first determined by the type of artery followed by the hepatic artery diameter.The hepatic artery trunk is allocated to the side where the vascular diameter is small and there is difficult reconstruction.Right livers from adult donors are mostly transplanted to adults.To match the artery diameter,the artery trunk is mostly retained in the right liver.In contrast,the left hepatic artery is thinner and smaller in children donor liver.Therefore,it is recommended that the artery trunk be retained in the left graft.The middle hepatic artery mainly provides blood to the left hemiliver,particularly the left medial lobe.Therefore,the middle hepatic artery and left hepatic artery are usually retained in the LLL or left hemiliver during splitting.If the middle hepatic artery arises from the left hepatic artery,then direct anastomosis of the common trunk can be conducted after partial dissection at the origin of the left hepatic artery.If there is no common trunk between the two arteries and no direct communicating branch (after splitting,heparin solution can be used for testing or backflow can be tested in the middle hepatic artery after anastomosis of the left hepatic artery),then the two arteries must be anastomosed respectively.

During artery anastomosis,the artery bifurcation should be cut into vascular sleeves as much as possible.This procedure can decrease the incidence of complications such as arterial anastomotic stenosis and thrombosis.As only the left hepatic artery is retained for the LLL,no artery bifurcation can be used to create vascular sleeves for anastomosis.It is recommended that fine anastomosis be conducted under a high-powered magnifying lens or microscope.

5.2.Portal vein

The allocation of the portal vein is simpler than that of the hepatic artery.A classical method is to retain the portal vein trunk in the eRL when the portal vein left branch is retained in the LLL.During splitting,attention should be directed toward the protection of the portal vein branch at the caudate lobe to avoid injury.For full left/right liver splitting,allocation should be based on the characteristics of the recipients’ portal veins.Whether the portal vein trunk should be retained in the left or right hemiliver should be decided based on the portal vein lengths of the donor and recipient,degree of diameter matching,and reconstruction difficulty.

5.3.Hepatic vein

In the classical splitting form,the middle hepatic vein,right hepatic vein,and vena cava trunk are retained in the eRL,whereas the left hepatic vein is retained in the LLL.After the defect caused by splitting the left hepatic vein at the vena cava is repaired using the donor iliac vein patches,an intact vena cava can be obtained.During anastomosis,the modified piggyback or classical techniques can be used similar to the whole liver to reconstruct the outflow tract.

In full left/right liver splitting,the allocation of the middle hepatic vein and vena cava is determined based on the condition of the donor and recipient.15,26The left/right liver splitting form is mainly used in two adult recipients or two pediatric recipients of a pediatric donor liver.The weight of the selected recipients is lower and the right liver can basically satisfy the GRWR requirements.However,the left liver usually has a problem of insufficient GRWR.Generally,there are two splitting methods for full left/right liver splitting:(i)similar to the adult right hemiliver LDLT,the middle hepatic vein trunk and vena cava are retained in the left hemiliver,whereas the hepatic vein branches in the segments V and VIII are retained for the right hemiliver for angioplasty and reconstruction.(ii) The middle hepatic vein is fully split.This method can maximally retain backflow in the hepatic vein at the splitting plane of the left and right hemilivers,and more functional liver volume can be obtained.After complete splitting of the middle hepatic vein,the iliac blood vessel of the donor can be used to reconstruct the middle hepatic veins in both the hemilivers.Classical or piggyback methods can be used for reconstruction in the part of the graft that retained the inferior vena cava,whereas the piggyback method is used to reconstruct an outflow tract in the part of the graft in which the inferior vena cava was not retained.

5.4.Bile ducts

The site of bile duct splitting should be determined based on the splitting form.In the classical splitting form,the left hepatic duct are split at its site of fusion with the common hepatic duct and the common hepatic duct is retained at the eRL.In full left/right liver splitting,the diameter,length,and anastomotic difficulty of the donors'and recipients’ bile ducts are used for bile duct allocation.The common hepatic duct and the common bile duct can be retained in the left hemiliver or right hemiliver.Additionally,the retention of bile duct trunk should be the same as that of the artery trunk to prevent disruption to the arterial blood supply to the extrahepatic bile duct,resulting in biliary complications.27

6.Perioperative management of SLT

SLT perioperative management basic principles are generally the same as for whole liver transplantation.Under the premise that suitable recipients are selected,attention should be directed toward the following areas:(i) focus on the regulation of coagulation function in the recipient during surgery to avoid wound hemorrhage due to coagulation disorder after reperfusion; (ii) low central venous pressure should be maintained when intraoperative hemodynamics are stable to facilitate backflow in the donor liver;(iii) the postoperative management team should be familiar with the donor liver splitting and reconstruction methods,and employ different imaging techniques to actively monitor and manage the SLT-related vascular and biliary complications;(iv)attention should be directed toward monitoring and controlling of small-for-size syndrome.

7.Organ allocation

SLT development should be encouraged for the effective expansion of the source of grafts and decrease the waiting time in recipients,so that more patients,particularly pediatric patients,can be benefited.28If the donor satisfies the aforementioned basic requirements,then SLT evaluation can be prioritized to decide whether SLT is suitable.At present,organ allocation principles are based on the MELD or PELD scores,and patients with higher scores are prioritized for organ transplantation.One good organ can be directly given to one patient with a high MELD score.Usually,SLT is not recommended for patients with overly high MELD scores.We recommend that donor livers that can be split should be assigned a higher priority so that it can be first allocated to two recipients undergoing SLT.If the liver cannot be split,then it should enter MELD scorebased allocation.

8.Summary

As the dawn of donor liver source from cadaver organ donation after citizens’ death approaches in China,the use of SLT can effectively increase the source of donor liver and solve the problem of organ shortage for children in particular.The careful assessment of the donor and donor liver function,precise preoperative planning,the selection of suitable donors and recipients,and precise surgical procedures should be performed to improve the efficacy of SLT.At the same time,active adjustments should be made to the organ allocation policies and multicenter collaboration should be strengthened to promote the stable development of SLT in a safe and normative manner.

Authors’ contributions

Guihua Chen,Kefeng Dou,and Yang Yang were as the main person in charge of the consensus.Shuhong Yi and Qing Yang were the writing authors of the manuscript.Other experts participated in consensus discussion and suggestions.All authors read and approved the final manuscript.

Authors’ information

Drafting committee chairpersons:Guihua Chen (The Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,China.E-mail address:chgh1955@263.net),Kefeng Dou (Xijing Hospital of Air Force Medical University,Xi'an,China.E-mail address:doukef@fmmu.edu.cn),and Yang Yang(The Third Affiliated Hospital of Sun Yat-sen University,Guangzhou,China.E-mail address:yysysu@163.com).

Drafting committee members:Wentao Wang(West China Hospital of Sichuan University),Zhengxin Wang (Affiliated Huashan Hospital of Fudan University),Jing Wang(The Third Affiliated Hospital of Sun Yat-sen University),Jiandong Wang (Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine),Jizhou Wang(The First Affiliated Hospital of University of Science and Technology of China),Bo Wang(Xijing Hospital of Air Force Medical University),Yinan Deng (The Third Affiliated Hospital of Sun Yatsen University),Shichun Lu (The General Hospital of the People’s Liberation Army),Xiaomin Lu(Union Hospital Affiliated with Tongji Medical College of Huazhong University of Science and Technology),Jianxin Ye(The First Affiliated Hospital of Fujian Medical University),Qifa Ye(Zhongnan Hospital of Wuhan University),Guoyue Lu (The First Hospital of Jilin University),Yu Lu (The First Affiliated Hospital of Xi’an Jiaotong University),Anlong Zhu (The First Affiliated Hospital of Harbin Medical University),Zhijun Zhu(Beijing Friendship Hospital,Capital Medical University),Jiye Zhu(Peking University People’s Hospital),Jie Ren (The Third Affiliated Hospital of Sun Yat-sen University),Yan Zhuang(Peking University First Hospital),Li Zhuang(Shulan Hospital),Jun Liu(Shandong Provincial Hospital),Chao Liu (The Second Affiliated Hospital of Zhengzhou University),Lei Liu (The Third People’s Hospital of Shenzhen),Jiaze An (Xijing Hospital of Air Force Medical University),Xuyong Sun(303 Hospital of People’s Liberation Army),Sheng Yan (The First Affiliated Hospital,Zhejiang University School of Medicine),Xiangqian Su(Beijing Cancer Hospital),Xilin Du(Tangdu Hospital of Air Force Medical University),Weimin Li (The second Affiliated Hospital of Chinese PLA General Hospital),Li Li(The First Hospital of Kunming),Ning Li(Beijing Youan Hospital,Capital Medical University),Yousheng Li (Nanjing General Hospital of Nanjing Military Command),Hua Li (The Third Affiliated Hospital of Sun Yat-sen University),Guogang Li (The Second Affiliated Hospital,Zhejiang University School of Medicine),Yang Yang (The Third Affiliated Hospital of Sun Yat-sen University),Jianqing Yang (Liuzhou People’s Hospital),Qing Yang (The Third Affiliated Hospital of Sun Yat-sen University),Jiayin Yang (West China Hospital of Sichuan University),Yijun Yang (Hainan General Hospital),Jun Shi(The First Affiliated Hospital of Nanchang University),Zhongjun Wu(The First Affiliated Hospital of Chongqing Medical University),Jian Wu(The First Affiliated Hospital,Zhejiang University School of Medicine),Dequan Wu (The Second Affiliated Hospital of Harbin Medical University),Xiaoshun He (The First Affiliated Hospital of Sun Yat-sen University),Genshu Wang(The Third Affiliated Hospital of Sun Yat-sen University),Zhongyang Shen(Tianjin First Central Hospital),Boyong Shen(Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine),Wu Song (The First Affiliated Hospital of Sun Yat-sen University),Jinghai Song(Beijing Hospital),Taiping Zhang(Peking Union Medical College Hospital),Tong Zhang(The Third Affiliated Hospital of Sun Yat-sen University),Yingcai Zhang (The Third Affiliated Hospital of Sun Yat-sen University),Xuewen Zhang(Shaanxi University of Chinese Medicine),Bingyuan Zhang(The Affiliated Hospital of Qingdao University),Leida Zhang(The Southwest Hospital of Army Medical University),Weiqi Lu(Zhongshan Hospital,Fudan University),Yifa Chen(Tongji Hospital,Tongji Medical College,Huazhong University of Science&Technology),Zheng Chen (The Second Affiliated Hospital of Guangzhou Medical University),Guihua Chen (The Third Affiliated Hospital of Sun Yat-sen University),Xinguo Chen (The Third Medical Centre of Chinese PLA General Hospital),Dong Shang (The First Affiliated Hospital of Dalian Medical University),Shuhong Yi(The Third Affiliated Hospital of Sun Yat-sen University),Huimin Yi (The Third Affiliated Hospital of Sun Yat-sen University),Gangjian Lo (The Third Affiliated Hospital of Sun Yat-sen University),Jian Zhou(Zhongshan Hospital,Fudan University),Yunzhao Zhao (Jinling Clinical College of Nanjing Medical University),Hongchuan Zhao(The First Affiliated Hospital of Anhui Medical University),Jia Yao(The Third Affiliated Hospital of Sun Yat-sen University),Qiang He(Beijing Chao-yang Hospital,Capital Medical University),Mingming Nie(Changhai Hospital of Shanghai),Guangming Li(Beijing Youan Hospital,Capital Medical University),Yijun Xia (Inner Mongolia People’s Hospital),Qiang Xia (Renji Hospital,Shanghai Jiao Tong University School of Medicine),Jianmin Qian (Affiliated Huashan Hospital of Fudan University),Jie Gao (Peking University People’s Hospital),Wenzhi Guo (The First Affiliated Hospital of Zhengzhou University),Hui Tang (The Third Affiliated Hospital of Sun Yat-sen University),Kaishan Tao (Xijing Hospital of Air Force Medical University),Hua Huang(Fudan University Shanghai Cancer Center),Liping Cao (The Second Affiliated Hospital,Zhejiang University School of Medicine),Jie Cao(Renji Hospital,Shanghai Jiao Tong University School of Medicine),Chengze Wei(307 Hospital of People’s Liberation Army),Zhihai Peng(Shanghai General Hospital),Kuirong Jiang (Jiangsu Province Hospital),Ziqing Hei (The Third Affiliated Hospital of Sun Yat-sen University),Zhiren Fu (Shanghai Changzheng Hospital),Hao Wen (The First Affiliated Hospital of Xinjiang Medical University),Zhengjun Qiu (Shanghai General Hospital),Zuojun Zhen (The First People’s Hospital of Foshan),Binsheng Fu(The Third Affiliated Hospital of Sun Yat-sen University),Kefeng Dou (Xijing Hospital of Air Force Medical University),Jian Dou(The Third Hospital of Hebei Medical University),Jianqiang Cai(Cancer Hospital Chinese Academy of Medical Sciences),and Wenlong Zhai (The First Affiliated Hospital of Zhengzhou University).

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported by the National 13th 5-year Plan Major Science and Technology Research Project (2017ZX10203205-006-001); National Key Research and Development Program of China(2017YFA0104304); National Natural Science Foundation of China(81570593,81670601,81770648,81870449,81972286); Natural Science Foundation of Guangdong Province (2015A030312013,2016A030313224,2017A030311034);Science and Technology Planning Project of Guangdong Province (2017B020209004,20169013,2017B030314027); Guangzhou Science and Technology Planning Project (2014Y2-00200,201604020001,201508020262,201400000001-3,201607010024).