University of Groningen. Technical aspects of liver transplantation Polak, Wojciech Grzegorz

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1 University of Groningen Technical aspects of liver transplantation Polak, Wojciech Grzegorz IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2008 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Polak, W. G. (2008). Technical aspects of liver transplantation s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Technical Aspects Of Liver Transplantation Wojciech G. Polak

3 Paranimfen: Egbert Sieders Akihiko Soyama Cover image by Hynek Mergental W.G. Polak 2008 Lay-out and printing by: Gildeprint Drukkerijen, Enschede

4 RIJKSUNIVERSITEIT GRONINGEN TECHNICAL ASPECTS OF LIVER TRANSPLANTATION Proefschrift ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 18 juni 2008 om uur door Wojciech Grzegorz Polak geboren op 22 mei 1967 te Wroclaw, Polen

5 Promotores: Prof.dr. M.J.H. Slooff Prof.dr. R.J. Porte Copromotores: Dr. P.M.J.G. Peeters Dr. K.P. de Jong Beoordelingscommissie: Prof.dr. J. Lerut Prof.dr. O.T. Terpstra Prof.dr. H.J. Verkade ISBN:

6 CONTENTS Chapter 1 General introduction and outline of the thesis 7 Chapter 2 The evolution of surgical techniques in liver transplantation - 11 a review. Submitted for publication Chapter 3 Analysis of differences in outcome of two European liver 55 transplant centers. Transpl Int 2006; 19: Chapter 4 Liver transplantation with preservation of the inferior vena cava. 75 A comparison of conventional and piggyback techniques in adults. Clin Transplant 2004: 18: Chapter 5 End-to-side caval anastomosis in adult piggyback liver 93 transplantation. Clin Transplant 2006; 20: Chapter 6 The sequence of revascularization in liver transplantation: 111 it does make a difference. Liver Transplantation 2006; 12: Chapter 7 Sequential and simultaneous revascularization in adult 121 piggyback orthotopic liver transplantation. Liver Transplantation 2005; 11: Chapter 8 The outcome of primary liver transplantation from deceased 135 donors in children with body weight 10 kg. Clin Transplant 2008; 22: Chapter 9 Summary, conclusions and recommendations 155 Chapter 10 Sammenvatting, conclusies en toekomstig onderzoek 163

7 Acknowledgements 171 Curriculum vitae 175

8 CHAPTER 1 GENERAL INTRODUCTION AND OUTLINE OF THE THESIS

9 8 Chapter 1 INTRODUCTION Liver transplantation is nowadays an accepted modality for the treatment of patients with variety of acute and chronic liver failure and unresectable hepatic tumours. The surgical technique has evolved considerably over the years. Despite of this liver transplantation remains still a formidable operation. Not only is the liver the largest organ in the body, but in most instances it is also fibrotic or cirrhotic due to underlying disease. This process has several consequences relevant for the liver transplant operation. Due to the loss of functioning hepatocytes the clotting becomes disturbed. Moreover, the loss of functioning hepatocytes leads to cachexia due to deficient metabolic processes and wound healing capacity is diminished. Also other organ system may get involved like the kidneys, lungs and heart, leading to hepatorenal and hepatopulmonary syndromes, and cirrhotic cardiomyopathy respectively. This in turn may influence the operability of such patients. Additional to these functional disturbances the fibrotic process in the diseased liver leads to portal hypertension with its sequelae as encephalopathy, ascites, secondary bacterial peritonitis, oesophageal varices, and hypersplenism with thrombocytopenia. In patients with cholangitis or hepatitis the inflammatory process may invoke adhesions around the liver with ingrowth of collaterals, becoming congested due to portal hypertension. The same may occure after operations preceding the transplantation procedure. Removal of such a diseased organ in such patients and under such circumstances needs special techniques and expertise. Replacing the organ by a new liver graft may seem in principle a straightforward operation needing only a new viable graft and reconstruction of the afferent and efferent vessels and biliary tract. However, the implantation also has its pitfalls. The quality of the new graft can vary ranging from a graft providing immediate function to delayed function or even no function at all. As a consequence dysfunctional grafts require an urgent retransplantation. During the donor procedure, the graft, its parenchyma or vasculature may be damaged. Especially when this is not reported this may lead to severe complications like bleeding, infarctions or necrosis of the bile ducts. Damage to the donor vessels or bile ducts can only be corrected by reconstructions which in turn might have their own complications. The recipient vessels might not be suitable for vascular anastomoses like in case of partial or complete portal vein thrombosis or tiny or sclerotic hepatic arteries. Also the recipient biliary tract may be unsuitable for reconstruction of the biliary contuity. All this needs to be recognized and taken care off in order to finish the procedure successfully.

10 General introduction and outline of the thesis 9 Selected technical aspects of this complicated operation, as liver transplantation is, and their influences on outcome are the subject of this thesis. AIM The specific aim of this thesis is to analyse the impact of selected technical aspects of the liver transplantation and analyse the effects of these adaptations on the outcome of liver transplantation performed in the University Medical Center Groningen. OUTLINES OF THE THESIS The aim of Chapter 2 is to give a general overview of the evolution of surgical techniques in liver transplantation and their impact on the outcome. Chapter 3 reports an open comparison between the results of two distinct European liver transplant centers differing in case volume and experience. The aim of this chapter is to investigate whether there are differences in outcome in terms of patient and graft survival and morbidity and to identify the causes of such differences in order to take measures to improve the outcome. In Chapter 4 the Groningen experience with two techniques of liver transplantation, the conventional technique and piggyback technique is analysed. The purpose of this analysis is comparison of the outcome in terms of survival, morbidity, mortality and liver function as well as operative characteristics in order to find out if one of these techniques is superior over the other. Chapter 5 describes an end-to-side technique of caval anastomosis without the routine use of temporary portocaval shunt in adult full-size piggyback liver transplantation. The aim of this part is to analyse the results of this technique particularly in terms of outcome and complications specific to this technique. In Chapter 6 current techniques of revascularization of the liver graft are reviewed and discussed. The aim of Chapter 7 is to analyse if there are any differences in outcome of liver transplantation when two reperfusion protocols are used, a sequential one with first portal vein reperfusion followed by arterial reperfusion and a simultaneous reperfusion protocol. As outcome parameters were taken patient and graft survival, intraoperative blood loss, morbidity and post transplant liver function.

11 10 Chapter 1 Finally, Chapter 8 describes single center experience in pediatric liver transplantation in children with body weight equal or below 10 kg. The aim of this chapter is to analyse the outcome in terms of patient and graft survival in order to find factors affecting the outcome. The thesis is concluded by summary and future perspectives in Chapter 9. Finally, Chapter 10 contains the Dutch translation of Chapter 9.

12 CHAPTER 2 THE EVOLUTION OF SURGICAL TECHNIQUES IN LIVER TRANSPLANTATION - A REVIEW Polak WG, Peeters PMJG, Slooff MJH Submitted for publication

13 12 Chapter 2 ABSTRACT Currently, liver transplantation (LT) is an accepted method of treatment of end-stage liver disease, metabolic diseases with their primary defect in the liver and unresectable primary liver tumors. Surgical techniques in liver transplantation have evolved considerably over the past 40 years. The developments have led to a safer procedure for the recipient reflected by continuously improving survival figures after LT. Also the new techniques offer the possibility of tailoring the operation to the needs and condition of the recipient as in partial grafting or in different revascularization techniques, or in techniques of biliary reconstructions. Additionally the new techniques such as split LT, domino transplantation and LRLT have also brought about an increase in the available grafts. In this review the evolution of surgical techniques in LT over the past 40 years and their contribution to the current results are discussed.

14 INTRODUCTION The evolution of surgical techniques in liver transplantation - a review 13 Currently, liver transplantation (LT) is an accepted method of treatment of end-stage liver disease, metabolic diseases with their primary defect in the liver and unresectable primary liver tumors. The first attempt of LT in humans was done by Thomas Starzl at the University of Colorado in Denver, in The recipient was a three-years-old boy with biliary atresia. The child died during transplantation, because of coagulopathy and bleeding. After several unsuccessful LTs in Denver, Boston and Paris, a voluntary worldwide moratorium discouraged liver transplantation until On July 23, 1967 Thomas Starzl performed the first successful LT. The recipient was 19-month-old girl with hepatocellular carcinoma 5. One year later, Sir Roy Calne successfully launched LT in Cambridge, UK 6. Despite the fact that at least the operation seemed to be feasible, LT remained an experimental procedure until 1983 due to its low one year survival rate, which at that time was around 30% 7,8. In that year a National Institute of Health Consensus Development was held in Washington DC. Based on the experiences from four liver transplant centers in Pittsburgh (US), Cambridge (UK), Hannover (Germany) and Groningen (the Netherlands) a consensus document was published stating that LT could be recognized as an accepted method of treatment for patients with end-stage liver disease 9. By that time the first improved one year survival rate approaching 60% were reported 10. From the first successful LT until now many details of the surgical technique of LT have been improved and adopted in order to achieve a superior outcome. Currently, one year patient survival after LT is about 85-90% and long-term survival is about 70% 11,12. In this review the evolution of surgical techniques in LT over the past 40 years and their contribution to the current results are discussed. IMPLANTATION TECHNIQUES Conventional LT In the early days of LT, the technique in which the native liver is removed together with the retrohepatic part of the inferior vena cava (IVC) and orthotopically replaced by a donor liver including the IVC with supra- and infrahepatic IVC anastomoses, was the standard technique of LT 13. This technique is called the conventional technique and it was exclusively used until the early 1980 s. The results of the procedure improved over

15 14 Chapter 2 the years from the poor survival during the early days to 60% one year survival reported in the early 1980 s 10. The conventional technique requires temporary cross-clamping of the IVC and portal vein (PV) with important hemodynamic consequences as reduced back-flow to the heart, congestion in the caval and splanchic bed as well as a reduction of renal function. The congestion leads to increased bleeding during hepatectomy. To solve this problems a veno-venous by-pass (VVB) was introduced in the mid 1980 s Venous-venous by-pass The first clinical attempts with a passive by-pass from the IVC to the superior vena cava via the internal jugular vein were often complicated by fatal pulmonary embolism due to clotting in the plastic cannulae 1. To avoid thrombotic complications Calne et al. introduced a femoro-femoral partial cardiopulmonary bypass with a pump oxygenator. This provided the wanted hemodynamic stability 16. However, the need for systemic heparinisation often led to uncontrolled bleeding. In 1983 Griffith et al. introduced a VVB with the use of centrifugal pump and heparin coated cannulae 14. Shaw described the first LT with this type of VVB without the need of systemic heparinization 15. As shown by several studies the benefits of the VVB include: (1) reduction of hemodynamic instability in the anhepatic phase; (2) preservation of renal function; (3) reduction of blood loss and (4) prevention of portal and systemic cogestion 15,17,18. The complication rate of the VVB varies between 10-30% 19. The most common complications include wound infection, hematoma, lymphocoele, deep vein thrombosis, and nerve injuries and they are associated with the insertion of cannulae Severe complications as hypothermia, bleeding complications as a result of hemolysis and platelet depletion or pulmonary embolism can be life-threatening Additionally, the use of the VVB is associated with higher costs. Over time modifications of the standard VVB were introduced in order to simplify its use and reduce complications. In the presence of porto-caval or mesenterico-caval shunts single-limb bypass from the IVC was used 26. Also cannulation of the PV was replaced in some centers by cannulation of the inferior mesenteric vein 27. A percutaneous technique for establishing the VVB for femoral and axillary cannula was introduced in 1994 by Oken et al. to reduce complications due to the dissection in the axilla and in the groin 28. A prospective randomized study showed that this percutaneous technique shortens operative time, provides better shunt flow and is associated with a lower complication rate in comparison to the open technique 29.

16 The evolution of surgical techniques in liver transplantation - a review 15 Despite the advantages of the VVB several centers reported excellent results of LT without the VVB and recommended to use it selectively The development of an alternative graft implantation technique technique with preservation of the IVC, the so called piggyback technique ultimately made the VVB redundant. Piggyback technique In the piggyback technique in the contrast to the conventional technique the native IVC remains in situ during hepatectomy. To achieve this, the native liver is dissected from the IVC. Although this technique was already used in the pioneering period of clinical LT in Denver (US) and Cambridge (UK), it was popularized by Tzakis et al. in ,6,34. In the original report of Tzakis piggyback LT was still performed with the use of a VVB [34]. Venous outflow reconstruction was done between the suprahepatic end of the donor IVC and a common orifice created of two or three hepatic veins (left and middle hepatic vein or right and middle hepatic vein). This is the classical piggyback technique 34. Currently, the piggyback technique is the dominating one in LT and it is feasible in most of the cases Several studies, including one randomized trial compared the results of the conventional technique and the piggyback technique. The results of these studies showed shorter operation time, shorter warm ischemia time, shorter anhepatic phase, reduction of blood loss and reduction of the cost of the procedure in favour of the piggyback technique Modifications of the piggyback technique The Achilles heel of the piggyback technique is the venous outflow reconstruction. Many reports about outflow problems are published, showing a frequency of outflow complications of % 43,44. This includes major graft congestion, caval stenosis or thrombosis, acute and chronic Budd-Chiari syndrome, and torsion or stenosis of caval anastomosis. Belghitti et al. described a side-to-side anastomosis between donor and recipient IVC without the routine use of VVB 45. In this modification both supra- and infrahepatic end of the donor IVC is closed and the anastomosis is created between two new incisions, one made on the recipient IVC and another on the donor IVC. Cherqui et al. introduced another venous outflow reconstruction. He enlarged the common orifice of

17 16 Chapter 2 three hepatic veins by the caudal incision on the anterior wall of the recipient IVC and anastomosed it with the suprahepatic end of the donor IVC (end-to-side anastomosis) 46. This technique was further modified by closing all hepatic veins and creating an anastomosis between a new incision on the anterior wall of recipient IVC and a V-shape incision on the donor IVC 47,48. In some particular situations leading to a short suprahepatic IVC cuff such as in domino liver transplantation or in case of outflow complications after piggyback implantation some authors advocated the use of the infrahepatic cavo-caval anastomosis 49,50. All these modifications of venous outflow reconstruction were meant to improve the venous outflow from the graft and to reduce outflow complications. There are few studies comparing different techniques of venous outflow reconstruction in piggyback LT 44,51,52. A French retrospective, multicenter study showed that the classical piggyback technique was associated with a higher bleeding complication from the caval anastomosis as well as with a higher incidence of Budd-Chiari syndrome in comparison to the side-to-side or end-to-side cavocavostomy 44. In contrast, the result of a prospective study from Belgium demonstrated that although the classical piggyback technique was associated with a higher incidence of bleeding complications compared to the side-to-side technique, all outflow complications occurred only in the latter technique 51. In a recent study Cescon et al. compared three types of orifices used for caval anastomosis in classical piggyback LT and he found that a cuff of left and middle hepatic veins with a >1 cm transversal cavoplasty was associated with the lowest rate of complications related to caval anastomosis (stenosis, thrombosis or kinking) 52. Temporary portocaval shunt (TPCS) As an alternative to the VVB authors recommended the use of a TPCS with the piggyback technique in order to provide better hemodynamic stability and decompress the splanchic area during the anhepatic phase 53,54. A prospective randomized trial assessing the use of TPCS in piggy-back LT demonstrated improvement of hemodynamic status, reduction of intraoperative transfusion requirements and preservation of renal function 55. Molmenti et al. reported good results with a novel technique facilitating TPCS when a direct shunt could not be created 56,57. Either a donor iliac vein or plastic cannula was used to bridge the distance between portal vein and the IVC. In contrast, several reports demonstrated that excellent results with piggyback LT are feasible without a TPCS 41,47,58. The TPCS probably has its own indication field in patients tending to hemodynamic

18 The evolution of surgical techniques in liver transplantation - a review 17 instability, patients with a difficult hepatectomy (i.e. large caudate lobe) or patients with few portosystemic collaterals. Pre-reperfusion flushing and IVC venting Liver grafts need to be flushed before reperfusion to prevent air emboli and to remove toxic products from the graft after the preservation period. If too high concentration of vasoactive substances and potassium enters the systematic circulation after reperfusion it may cause a variety of hemodynamic changes ranging from arrhythmias, hypotension to cardiac arrest, known as postreperfusion syndrome 59. This syndrome occurs in approximately 30% of all transplant patients 59,60. Flushing solutions Ringer s solution has been the most common flushing solution since the early years of LT 3. However, experimental as well as clinical studies showed that rinsing with cold Ringer s solution causes endothelial cell swelling, cellular rounding, protrusion of cells into the sinusoidal space, which can be deleterious for graft function 61,62. Therefore, some centers replaced Ringer s solution with other flushing solutions as saline, serum albumin, plasmanate (serum substitute), Carolina Rinse Solution or autologous blood 60,63,64. In a randomized prospective study Adam et al. investigated two flushing protocols, one with Ringer s lactate and another with human albumin 63. The results of this study showed that the degree of hepatocellular injury was significantly lower in grafts flushed with human albumin probably due to their protective effects as oxygen radicals scavenger and by the maintenance of normal oncotic pressure. Bachmann et al. compared in a prospective randomized trial three different flushing protocols using human albumin, Carolina Rinse solution and blood 64. In this study Carolina Rinse Solution proved to prevent reperfusion injury and improve graft function compared to human albumin and blood, which is explained by protection of sinusoidal endothelial cells and decreased activation of Kupfer cells. In all aforementioned studies the liver graft was flushed when the caval anastomosis was made and subsequently it was reperfused. The liver is not uniformly rinsed by this technique 65,66. Therefore, toxic products such as potassium can still enter the systematic circulation after recirculation in too high concentration. To prevent this some authors proposed additional flush with portal or arterial blood and the use of vena cava venting.

19 18 Chapter 2 IVC venting The technique of additional flushing with portal blood was already mentioned in the late 1970s by Wall et al., however in his report only the first 100 ml of portal blood reperfusing the graft was discarded 67. This technique was refreshed by Fukuzawa et al., who showed that additional flush with 500 ml of portal blood was associated with better early graft function, better hemodynamic stability and smaller shifts in serum potassium compared to Ringer s solution alone 60. Additionally, Fukuzawa et al. proposed IVC venting with a catheter placed through the infrahepatic anastomosis, which allowed the external drainage of the effluent before the caval clamp was released. Another study showed also that portal blood flush alone together with IVC venting prior to reperfusion was sufficient and optimized graft function without risk of hyperkalemia 68. The advantage of IVC venting was shown in a prospective study by Brems et al. 69. He showed that graft flushing with crystalloid solution and afterwards portal blood with IVC venting resulted in stable serum potassium and lower rate of postreperfusion syndrome in comparison to the technique without IVC venting. However, different results were obtained in two other studies. In a randomized study, Millis et al. compared four different flushing techniques with a solution of Ringer s lactate and serum albumin: initial portal flush with or without IVC venting, and initial arterial flush with or without IVC venting 70. In both groups with IVC venting additional flush with 500 ml portal blood was performed. He did not find any differences in postoperative graft function between the four groups, however the lowest incidence of postreperfusion syndrome was observed in the group of portal flush without IVC venting. Similarly, in a more recent retrospective study comparing two flushing techniques, portal vein flush with Ringer s without IVC venting and portal blood flush with IVC venting, the authors demonstrated that the first technique was associated with better hemodynamic recovery, higher lactate clearance and better early postoperative graft function compared to the second one 71. Based on the available data it seems that flushing alone provides inadequate cleaning of the liver with increased possibility of an unwanted high potassium influx in the systematic circulation. Addition of venting seems to be more effective with lower chances of deleterious effects after reperfusion. The debate about which solution is superior for flushing is still not definitely concluded.

20 The evolution of surgical techniques in liver transplantation - a review 19 REVASCULARIZATION PROTOCOLS During the first attempts of LT in humans the liver grafts were reperfused first via hepatic artery 5. Nowadays, the most commonly used sequence of revascularization is initial reperfusion via the PV (initial portal reperfusion IPR) and subsequent reconstruction of the hepatic artery. This order is based on the experience from liver surgery that portal blood flow alone can provide adequate hepatocellular function 72. However, IPR increases the risk of warm ischemic damage to the bile ducts, which depend solely on arterial blood supply. Due to the increasing incidence of ischemic biliary complications the order of revascularization protocols during LT became subject of investigation. Sequential revascularization Sequential revascularization techniques can start either in anterograde fashion via PV or hepatic artery (HA), or in retrograde fashion via the inferior vena cava (IVC) (retrograde reperfusion). Several authors advocated the use of sequential revascularization with arterial blood first (initial arterial reperfusion IAR) In a prospective randomized study, Durcef et al. showed more stable hemodynamics, better graft reperfusion and lower peak value of serum aspartate aminotranferase in patients with IAR compared to patients with IPR 73. The result of a recent prospective, randomized study comparing hemodynamic profile and tissue oxygenation during IPR and IAR showed in contrast to the previous study that IPR offers better graft perfusion and metabolic function than IAR 74. Due to the larger blood volume IPR causes an acute increase in pulmonary vascular load, which can be detrimental in patients with pulmonary hypertension or cardiomyopathy. IAR, therefore may be indicated in patients with poor pulmonary and cardiac reserve. In another study, Noun et al. demonstrated that IAR provides better graft reperfusion and lower requirements of blood transfusion as well as shorter postreperfusion fase in comparison to IPR 75. However, no differences in postoperative aspartate aminotransferase, bile flow and early vascular and biliary complications were observed between these two revascularization protocols. Similar results were obtained by Sadler et al., who showed no differences in the postoperative liver function, intraoperative blood products use and 30-day and 1-year mortality between IPR and IAR 76.

21 20 Chapter 2 Retrograde reperfusion A new technique of retrograde reperfusion via the IVC followed by subsequent anterograde reperfusion via PV has recently been proposed 77. In this technique the vascular clamp on the IVC is removed immediately after completing the IVC anastomosis, allowing retrograde reperfusion while the PV anastomosis is being constructed. The rationale for this technique is that it shortens the warm ischemia time (WIT) and efficiently removes perfusion fluid from the graft before anterograde blood flow is reestablished. The results of a recent prospective, randomized clinical trial comparing retrograde revascularization with simultaneous revascularization demonstrated significantly reduction of serum transaminases and bilirubin levels in the first week posttransplantation as well as lower incidence of primary non-function and initial poor function in the retrograde reperfused grafts compared to simultaneously reperfused grafts 78. However, this novel technique of reperfusion was associated with a higher incidence of ischemic-type biliary lesions (ITBL). Simultaneous revascularization In the simultaneous revascularization the liver graft is reperfused simultaneously via PV and HA. The motivation for this approach is the same as for the IAR: to reduce the incidence of biliary complications 79. An additional advantage of simultaneous reperfusion is that, in case of a problem with one of the two anastomoses, this can be repaired without completely interrupting blood flow to the graft. The disadvantage of simultaneous revascularization is prolongation of the WIT and the anhepatic phase, which can be detrimental to postoperative graft function, survival and morbidity 80,81. Two retrospective studies compared IPR with simultaneous reperfusion 79,82. No differences were found in patient and graft survival rates and the incidence of primary nonfunction between both techniques of reperfusion. However, simultaneously reperfused grafts showed significantly lower incidence of biliary complications. In contrast to these studies, the results of a recent retrospective study showed no differences in patient and graft survival, morbidity rates, incidence and severity of acute rejection, recuperation of liver function, or the incidence of ITBL, when comparing IPR versus simultaneous reperfusion 83. From the data published to date it is clear that further randomized studies are needed to prove the exact value of each revascularization technique. So far IPR remains the main technique of revascularization, except for specific conditions, where IAR or simultaneous revascularization can be used. The role of retrograde revascularization remains to be established.

22 The evolution of surgical techniques in liver transplantation - a review 21 TECHNIQUES OF VASCULAR RECONSTRUCTIONS Portal vein reconstruction PV reconstruction is usually performed in end-to-end fashion. It is very important to prevent stenosis in the portal anastomosis in order to avoid portal hypertension 84. To achieve this goal different techniques can be used. Starzl et al. proposed a so called growth factor, which allows portal anastomosis to distend to its maximal diameter after releasing a clamp from the PV and estabilishing portal flow 85. To increase this effect it is helpful to clamp the donor PV for a short period as described by Calleja et al. 86. In cases with a size discrepancy between donor and recipient PV (pediatric LT, partial grafts) or PV hypoplasia the reconstruction of the PV vein can be challenging and requires special techniques. The same is true for portal vein thrombosis. Size mismatch or hypoplasia of the native PV The size mismatch between donor and recipient PV is frequently located at the smaller recipient side. In such cases the donor PV can be anastomosed to a branch patch of left and right recipient PV or even to the branch patch of recipient PV and coronary vein 87. If this is not possible such as in hypoplastic PV, an incision on the ventral side of the native PV over the full length of the narrowing enlarges the opening on the PV 88. This defect can be covered by a patch or if not too ong covered by the end-to-end anastomosis. If the donor PV is long enough, the narrow or hypoplastic recipient portal vein can be resected and the anastomosis is made at the level of the confluence of splenic and superior mesenteric vein 88. If the donor PV is too short an interposition graft fashioned from the donor iliac vein can be used 88,89. Portal vein thrombosis PV thrombosis used to be an absolute contraindication for LT. However, several groups started to perform eversion thrombectomy in case of PV thrombosis with a success rate of 95% and one-year patient survival above 80% If PV thrombosis is not only restricted to the PV, but involves the portal confluence, there is necessary to use a jump-graft with a donor iliac vein between recipient superior mesenteric vein and donor PV 93,94. All recipients after thrombectomy of the PV as well as after a jumpgraft reconstruction require anticoagulation therapy to prevent recurrent thrombosis 95,96. However, the 5-year patient survival in patients with PV reconstruction for massive

23 22 Chapter 2 PV thrombosis is still inferior compared to the patients without it 97. In case of massive portal system thrombosis special, so called salvage revascularization techniques were introduced. Cavoportal hemitransposition was proposed by Tzakis et al. in cases where no portal inflow could be achieved 98. In this technique the infrahepatic part of the recipient IVC is ligated and the donor PV is anastomosed to the recipient IVC 98,99. Sheil et al. described another salvage technique; renoportal anastomosis 100. This technique is preferably used in patients with preexistent patent distal splenorenal shunt either spontaneous or after shunt surgery 101. A recent meta-analysis of cavoportal hemitransposition and renoportal anastomosis showed a high postoperative complication rate in this procedures and an actuarial patient survival of 74% 102. Arterialization of the portal vein is the third technique used to provide adequate portal blood inflow 103. In this technique, the graft receives blood inflow to the portal vein from the aorta via an iliac conduit or from the common hepatic artery 104,105. The experiences with this technique are still limited and modest results are reported 105. The ultimate refugium in cases where no portal flow can be established is multivisceral organ transplantation. However, so far one and five year patient survival of 65% and 49% are reported 106. Portal hyperpefusion A particular complication of partial LT is the small-for-size-syndrome. This syndrome can range from mild hepatic dysfunction with hyperbilirubinemia to the graft failure leading to retransplantation or death. The problem occurs when a too small for size graft receives all native portal inflow. Increased portal flow results in the subsequent reduction of hepatic arterial inflow by the so-called hepatic arterial buffer response, which can increase the risk for hepatic artery thrombosis (HAT) and ITBL 107. The most important measure to prevent this syndrome is adequate size matching based on volume measurements 108. Surgically portal hyperperfusion can be reduced either by splenic artery ligation combined with portal vein banding or by partial portosystemic shunting as reported by the Ghent group 109.

24 ARTERIAL RECONSTRUCTION The evolution of surgical techniques in liver transplantation - a review 23 Standard arterial reconstruction To avoid early HAT, which ultimately requires retransplantation, a patent arterial anastomosis is mandatory. The preferred method for standard arterial reconstruction is a direct anastomosis between donor and recipient HA in end-to-end fashion. Whenever possible it should be done with Carrel patches on donor and recipient side, as arterial anastomoses without patches was found to be associated with a significantly higher incidence of HAT 110,111. In order to further decrease the incidence of HAT a branch-patch technique was introduced 112. In this technique the arterial anastomosis is performed between bifurcations of the donor and recipient artery (i.e. bifurcation of the proper HA to the left and right HA or bifurcation of the common HA to the proper HA and the gastroduodenal artery) 113,114. Unsuitable recipient artery In some cases the standard arterial anastomosis cannot be made because of unsuitable recipient arteries due to stenosis, thrombosis, atherosclerosis, intimal dissection or other pathology. In order to overcome these problems alternative methods of arterial reconstruction have been developed. One of these methods is the use of an arterial conduit from the donor iliac artery directly to the aorta 115,116. The conduit can be anastomosed either to the infrarenal or to supratruncal aorta If the donor iliac artery is not available some authors recommended use of saphenous vein, autologous radial artery or donor superior mesenteric artery (SMA) as the conduit for arterial revascularization The use of cryopreserved grafts as the conduit has been abandoned, because of the high complication rate (stenosis, aneurysm formation) 123. Two studies indicated that use of donor arterial conduits was associated with excellent long term outcomes 124,125. However, several other studies confirmed that independently of the site of anastomosis, the use of conduits significantly increases the risk of HAT, especially in the later posttransplant period Therefore, other authors recommended direct anastomosis between an aortic Carrel patch of the donor celiac axis to the recipient supratruncal aorta or use the recipient s splenic artery for arterial reconstruction with the similar results as the standard anastomosis 119,130,131. The arterial inflow from the recipient side may be compromised by celiac trunk compression by the arcuate ligament. This can be diagnosed intraoperatively either

25 24 Chapter 2 by pressure or flow measurements and it can be solved by cleavage of the ligament 132,133. When there is still low arterial inflow, an arterial conduit directly to the aorta is recommended. Size discrepancy and multiple arteries Partial grafting and living donor liver transplantation (LDLT) brought new challenges for arterial reconstruction with newer techniques and instruments. In order to overcome size discrepancies between donor and recipient HA the Kyoto group recommended several techniques for arterial reconstruction 134. In case of a small caliber difference an undersized artery is cut obliquely or by fish-mouth method, whereas in a case of a marked diameter difference a funnelization technique is preferred. In the fish-mouth method two longitudinal contralateral (180 apart) incisions are made on the undersized artery, whereas in the funnelization technique the caliber of the oversized artery is reduced gradually with vascular sutures. Testa et al. adopted the fish-mouth technique 135. The arteriotomy is performed on the posterior wall of donor artery and on the arterior wall of the recipient artery (mirror incision). Then the back wall is sutured first from the inside with the running suture followed by running suture on the anterior wall, which prevents turnover of the anastomosed arteries. Okazaki et al. introduced the double-needle microsuture technique to avoid the intimal dissection due to turning over the microclamps on the anastomosed arteries 136. In this technique the back wall of the anastomosis is suture first with the use of double needle microsuture allowing the optimal adaptation of the intima. The double-needle technique is especially useful for arteries in which the tunica intima is separated from tunica media. In a substantial number of donor livers (24-32%) variant arterial anatomy is present 132,137,138. The presence of aberrant arterial anatomy was found to be a risk factor for arterial injuries during liver procurement with subsequently increased risk for HAT after LT 139. If an accessory artery is present it usually has to be reconstructed on the back-table prior to implantation. Depending of the length and size of the accessory HA it can be reinserted to the stump of splenic artery or gastroduodenal artery, or in case of accessory right HA from the SMA a fold-over technique can be used in which the anastomosis between patches of SMA and celiac trunk is made with a subsequent anastomosis of the distal end of splenic artery to the recipient artery 140. The presence of multiple arteries posed another problem for arterial reconstruction in LDLT. It is not always necessary to reconstruct all arteries, as sometimes the reconstruction

26 The evolution of surgical techniques in liver transplantation - a review 25 of the dominant artery is sufficient when a pulsatile back-bleeding from the stumps of other artery/arteries is confirmed. In the absence of such backflow all arteries need to be reconstructed 141,142. Marcos et al. demonstrated in a recent report of arterial reconstruction in adult right lobe LDLT excellent results with a novel technique using an Y extension graft or a reversed extension bifurcated graft from the recipient proper HA with its bifurcation 143. All aforementioned microsurgical techniques are routinely performed with the use of either surgical loupes or a surgical microscope, which substantially decreased the number of arterial complications 144,145. Although meticulous arterial reconstruction and introduction of microsurgical techniques were recommended by pioneers of LT, the development of partial liver grafts and especially LDLT established a place for microsurgical techniques in LT 7. BILIARY ANASTOMOSIS The biliary anastomosis is called the Achilles heel of LT, because biliary and biliary related complications are the most common source of morbidity and mortality after LT 146,147. Depending on the definition and diagnostics as well as type of the liver graft the reported incidence of biliary complications varies from 7-38% During the first human LT a loop cholecystojejunostomy with ligation of the donor common bile duct was used 5. Many different types of bilio-digestive anastomoses such as a loop cholecystojejunostomy, Roux-en-Y cholecystojejunostomy and cholecystoduodenostomy have been used over the years 7,8, All this techniques were abandoned because of a high rate of biliary complications (obstructions and leakage), which were mostly related to obstruction of the cystic duct, the locus minoris resistentiae of those techniques. Currently, two main techniques of biliary tract reconstruction are used: choledochocholedochostomy (CDC) and Roux-en-Y hepatico-/choledochojejunostomy. The choice of the technique depends mostly on the recipient s bile duct status. Duct-to-duct anastomosis The first experiences with choledochocholedochostomy (CDC) were discouraging 7,158. The CDC was associated with a high incidence of bile leak often due to ischemia of the common bile duct. The role of the common bile duct vascularization was not realized yet. However, after a pivotal report of Terblanche in 1983 clarifying the importance of

27 26 Chapter 2 the vascularization of the common bile duct, and its relevance for bile duct anastomosis the results of CDC substantially improved 147,156,160,161. If the recipient s bile duct is normal the CDC is preferable, as it creates physiological bile flow to the duodenum with preservation of the sphincter of Oddi function, it allows endoscopic diagnostics and interventions, and it avoids intestinal contamination of the bile ducts 161,162. It can be done in end-to-end or side-to-side fashion The side-to-side technique seems to offer greater technical feasibility and easier reconstruction in the presence of major discrepancy between donor and recipient bile duct, whereas the endto-end technique doesn t require long bile ducts for anastomosis and it reported to be safer in case of large choledochal varices 151. A prospective randomized trial comparing end-to-end versus side-to-side biliary showed no differences in the outcome and the incidence of biliary complication proving that both techniques are equally effective 163. Another prospective randomized trial comparing interrupted and continuous suture in CDC, showed no differences between both suture types with respect to the incidence of leaks and strictures 164. A new technique of end-to-end CDC using vascular staples was proposed recently by Thomas et al In this study tissue everting clips were compared to a conventional handsewn technique showing no differences in biliary complications between both techniques. Hepaticojejunostomy/choledochojejunostomy The only bilo-digestive anastomosis, which routinely found a place in LT was the Rouxen-Y hepaticojejunostomy or choledochojejunostomy 147,156. Both techniques are indicated when the recipient bile duct is abnormal due to the underlying disease (primary sclerosing cholangitis, cystic fibrosis) or absent as in biliary atresia. Also when the distance between donor and recipient bile duct is too large one of these techniques should be used in order to avoid traction on the anastomosis. Taking into account blood supply of the bile ducts, hepaticojejunostomy as a high bilodigestive anastomosis provides better conditions for preventing biliary strictures than choledochojejunostomy 166,167. A randomized trial comparing CDC with hepaticojejunostomy is not sensible, because both techniques have their own indication field. In retrospective series both techniques demonstrated similar outcome, however increased bacterial and fungal colonization of biliary tract, bile leakage and biliary strictures were more common when Roux-en-Y hepatico-/choledochojejunostomy was used 146,156,168,169.

28 The evolution of surgical techniques in liver transplantation - a review 27 Although choledochoduodenostomy has almost been abandoned as a technique of biliary reconstruction, it can play a role as an alternative or a rescue technique on rare occasions. Such as in patients with difficult access due to previous operations or patients with a relatively short bowel due to previous resections or in patients with primary sclerosing cholangitis 170. Biliary drainage The possible benefits of the use of biliary drainage include monitoring of bile production, decompression of the biliary tract and easy radiological access. On the other hand, the use of biliary drainage needs an additional opening in the recipient bile duct with a risk of exit site leakage and complications after biliary drain removal [ 168 ]. Moreover, a biliary drain is a foreign body and it may cause partial obstruction by dislodgement, it may increase bile sludge and stone formation, as well as risk for cholangitis 171. It also needs to be present for 6-12 weeks after transplantation often to the patients discomfort. To avoid complications associated with the use of biliary drainage several authors proposed some technical modifications Sawyer et al. used a polypropelene drainage catheter introduced through the stump of cystic duct instead of standard T-tube, showing significant reduction of tube-related complications, but not the frequency of other biliary complications 172. Internal stenting was used by other authors 173,174. Johnson et al. recommended use of double-j catheter as an internal stent as a safe alternative to standard T-tube 173. Other centres proposed a modified technique of T-tube removal with radiological placing of a temporary catheter at the time of T-drain removal or using the T-tube itself as a drain under fluoroscopy guidance at the level of the former entrance place in the common bile duct 175,176. The results of two prospective randomized studies comparing the use of a T-tube in CDC did not show any benefits of the use of the T-tube 177,178. In a French multicenter study patients with the CDC over the T-tube had a significantly higher biliary complications rate (33.3% vs 15.5%) compared to the patients without the T-tube 177. This was mostly due to T-tube related complications. The results of the second study showed that the use of a T-tube was associated with a significantly higher number of septic complications 178. In a prospective randomized trial Bawa et al. compared CDC with and without using polyvinyl internal stent 174. He found that patient with an internal biliary stent had a significantly higher bilary complications rate compared to patients without biliary stenting. Additionally, the use of T-tube was associated with significantly higher cost as it was shown first in a retrospective study and then confirmed by results

29 28 Chapter 2 of randomized trial 179,180. In summary the progress in biliary reconstruction was related to the recognition of the importance of the arterial circulation of the bile ducts, which made a safe use of CDC possible. Duct-to-duct anastomosis without routine use of biliary stenting is a preferable technique of biliary reconstruction in LT. If it is not possible the hepaticojejunostomy is an equivalent alternative. PARTIAL LIVER TRANSPLANTATION Extended waiting time and an unacceptable high mortality on the waiting list for LT in children as a result of scarcity of pediatric donors were obvious reasons for searching new techniques to obtain suitable grafts for this specific age group. Reduced-size liver transplantation The first reduced-size liver transplantation was performed in Denver in 1975, however this case was not reported until description of a new technique for reducing adult donor livers to a left lateral liver graft in 1984 by Bismuth in Paris and by Broelsch in Hannover These techniques were rapidly implemented by several major pediatric transplant centers 184,185. The results of reduced-size LT were equal to the results of full-size LT and waiting time and mortality on the waiting list for children were significantly reduced 186,187. As a logical consequence of these favorable results of partial grafts and the fact that for that purpose adult livers were withdrawn from the adult donor pool, the emergence of the split liver technique became a fact 188. Split liver transplantation Split LT was first performed by Pichlmayr in Hannover and Bismuth in Paris in ,190. The technique of liver splitting allows the division of the adult donor liver together with its vascular and biliary structures into two functional grafts, which can be transplanted into two recipients. Usually grafts were split in a left or left lateral liver for a child and a right lobe graft for an adult recipient. The application of split LT was subject to important adaptations over the years. Two important items emerged after the initial experiences Firstly, applying the technique in an emergency situation should be done with caution and secondly donor

30 The evolution of surgical techniques in liver transplantation - a review 29 livers eligible for splitting should fulfill certain selection criteria as formulated by Ville de Goyet 196. These criteria include: donors less that 45 years old, hemodynamically stable, low or mild inotropic support, normal or slightly altered liver tests, less then five days in the intensive care unit and normal macroscopic aspect at procurement. Only when such conditions are met the results of split LT are equal to whole liver grafting 197,198. A major debate in split LT concerned the subject of in situ or ex-situ splitting In the beginning the liver splitting was usually performed ex-situ, which means that the whole liver was procured and subsequently divided into two grafts on the back-table 202. Rogiers et al. proposed a new technique, in which the liver is splitted during organ procurement in the heart-beating donor 203. This technique was developed from left lateral segmentectomy for living donation. The main advantage of the in-situ technique is a shorter WIT, better hemostasis and lower rate of biliary complications 199,204. However, this technique significantly prolongs the time of organ procurement and it might cause hemodynamic instability during the donor procedure. Also procurement teams may outstand their welcome in donor hospitals due to the prolonged operation times. So far from the available literature there is no consensus which technique is superior as both techniques demonstrate similar patient and graft survival compared to whole liver grafting 200,201,204. In a retrospective study, Rayes et al. compared exsitu and in-situ splitting techniques with respect to patient and graft survival 205. He found that the in-situ technique provided significantly higher one-year graft survival in pediatric recipients compared to the ex-situ technique. However, this difference did not translate in higher one-year patient survival in pediatric recipients. Moreover, there were no differences in one-year patient and graft survival in adult recipients between both techniques. Nowadays split LT can be regarded as a routine procedure in experienced centers. The application of this technique however is still developing. Although liver splitting is used to be performed in adult donor livers Cescon et al. recently reported also excellent results of split LT from pediatric donors below 40 kg 206. Until 2005 only grafts from stable heart-beating donors were considered for splitting. However, recently Muiesan et al. reported the first experiences with split and reducedsize liver transplantation from non-heart beating donors 207. Due to the increasing shortage of donor grafts especially for adults the technique of left/ right splitting of a graft for two adults re-emerged The value of this technique is currently under evaluation in experienced centers, as left lobe grafts in adult recipients had inferior outcome in the past

31 30 Chapter 2 Recently, left lateral graft procurement was further developed to create monosegmental grafts and therefore facilitating LT in very small children Living donor liver transplantatation (LDLT) Evolution of surgical techniques related to partial LT as well as the continuing shortage of deceased donors led to the development of LDLT. Initially it was developed for pediatric recipients as the mortality rate in children awaiting LT was high. The first attempts were performed by Raia et al. in 1988 and The first successful LDLT was reported in 1990 by Strong et al., who transplanted a left lateral segment from a mother to her 17-months-old son with biliary atresia 219. Since then many centers, especially in Japan where liver grafts from deceased donors were not available, further developed LDLT 220. LDLT for pediatric recipients turned out to be a great success, as patient and graft survival was comparable and in most centers superior to that in split and reduced size LT and even in whole LT 12, At the same time it appeared a relatively safe procedure for the donor, with a complications rate of 15-20% as reported in large series and a mortality rate of between 0.1% and 0.4% The excellent results of LDLT in children together with increasing waiting time for adult patients with malignant liver tumors prompted the use of living donor liver grafts also for adults 227. First left lobe grafts were used 228. However, the volume of the left liver lobe seemed not sufficient for adults and small-for-size syndrome appeared to be a frequent complication as well as the results were not satisfactory 222,229. Nowadays left lobes are only used for small adults or older adolescents, or they are used in a dual graft setting 228,230,231. Therefore, right lobe grafting is the most applied technique for LDLT in adults. The long-term results of LDLT for adults are nowadays approaching those of whole LT. However, the rate of biliary complications is high 12, Additionally, morbidity in living donors of right liver lobes is significantly higher than morbidity after living donation for pediatric recipients The techniques of LT with living donor grafts are in essence the same as for implantation of partial grafts from deceased donors. However, vascular and biliary reconstructions are often more complex due to multiple vessels or ducts. Except for an adequate graft size match in LDLT, good venous drainage of the anterior sector of the right liver lobe was found to be extremely important for postoperative liver function 237. Many different approaches have been adopted to avoid venous congestion of the anterior sector. These include reconstruction of the hepatic veins of segment V and VIII into the recipient IVC using an interposition vein graft or a routine inclusion of the middle hepatic vein in the

32 The evolution of surgical techniques in liver transplantation - a review 31 graft In LDLT the same techniques of biliary reconstructions can be used as in LT from deceased donors. Roux-en-Y hepaticojejunostomy has been standard biliary reconstruction in pediatric LDLT, however recently duct-to-duct reconstruction is used more frequently, especially in adult LDLT In case of multiple bile ducts if they are close to each other they can be unified into a single orifice (ductoplasty) before anastomosis OTHER LIVER TRANSPLANTATION TECHNIQUES Domino liver transplantation (DLT) The concept of DLT was first developed during the international workshop in liver transplantation for familial amyloidosis polyneuropathy in Stockholm in Two years later Furtado performed the first successful DLT in Portugal 247. This technique is possible in patients with a primary genetic defect restricted to the liver with secondary debilitating extrahepatic manifestations in vital organs such as kidneys, heart and brain. In order to stop the progression of the disease the liver needs to be replaced 248. This liver is suitable for donation to another patient with liver failure, because it takes one or two decades, before the disease becomes symptomatic in a recipient Therefore, such domino livers are given to elderly patients or patients with a malignant disease in the liver 250. The advantage for the domino recipients is that they can get a graft in earlier course of their disease. Familial amyloid polyneuropathy is a classical example of the disease, where domino LT can be used. The results of DLT are rewarding. Furtado et al. reported one-year patients survival of 70% and 60% 3-year survival, however a recent report Yamamoto et al. showed 1- year and 5-year patient survival of 95% and 92% in recipients transplanted in the last decade Domino donation evolved over the years. In the early years the liver was implanted with the native IVC, while nowadays the domino liver is harvested without the IVC This requires reconstruction of the suprahepatic caval vein cuff for piggyback implantation 255,256. The advantage of leaving the native IVC in situ is the improved hemodynamic stability in these already hemodynamic compromised patients. Azoulay et al. reported also split LT from domino livers from patients with familial amyloid polyneuropathy 257.

33 32 Chapter 2 Auxiliary liver transplantation (ALT) In the early days of LT the risks of the recipient hepatectomy were appreciated. This caused an interest in ALT, in which the native liver remained in place and a new graft was transplanted in a heterotopic position. This is the so called heterotopic auxiliary LT. The first successful heterotopic auxiliary LT was reported by Fortner et al. in 1970, however the long-term results were disappointing and inferior to orthotopic LT 258,259. The main reasons for this were technical complications due to a high venous outflow pressure, portal vein flow diversion as well as the high risks for the development of hepatocellular carcinoma in the native liver. As showed in a recent case-control study comparing the results ALT and orthotopic LT, ALT can not be an alternative for orthotopic LT for chronic liver disease due to the inferior long-term outcome 260. Therefore, the technique of heterotopic auxiliary LT has been abandoned for chronic liver diseases. Terpstra et al. reintroduced the concept of heterotopic ALT for acute liver failure 261. It based on the fact that after recuperation of the native liver the auxiliary graft could be removed. This elegant concept was shown to be viable. However, it gained no support in the transplant community, because of technical problems implied by portal vein thrombosis and graft dysfunction, which led to the inferior patient survival compared to orthotopic LT. To solve this problem in a recent report Ringers et al. described a new technique of ALT in which dissection of the recipient hepatoduodenal ligament is avoided 262. In this technique end-to-end anastomose was performed between donor portal vein and recipient left renal vein, hepatic artery was anastomosed to the aorta using an iliac arterial graft conduit and the bile duct was anastomosed to the stomach. In 1991 Gubernatis et al. introduced a new technique of ALT for fulminant hepatic failure, in which part of the native liver was removed and a partial liver graft was implanted orthotopically (auxiliary partial orthotopic LT) 263. The technique of auxiliary partial orthotopic LT tried to avoid the disadvantages of ALT while keeping the idea of a temporary auxiliary graft. Several studies except for one from Japan reported favorable outcome after auxiliary orthotopic LT for fulminant hepatic failure, however it was associated with a higher postoperative morbidity As shown in one study it should be offered only for patients with high chances of liver regeneration 265. Auxiliary orthotopic liver transplantation was also performed with good results for metabolic liver disorders that cause life-threatening extrahepatic complications as for example Crigler-Najjar syndrome type The rationale for this treatment is to provide sufficient liver mass to correct the metabolic disorder while keeping the majority of the native liver.

34 The evolution of surgical techniques in liver transplantation - a review 33 An interesting variant of auxiliary orthotopic LT was developed in Japan to overcome small-for-size syndrome in LRLT 274. First, a left hemihepatectomy is performed in the recipient with subsequent implantation of the left lobe from the living donor. The right part of the native liver is kept in place until sufficient graft regeneration. Subsequently the remaining native liver is removed during a second-stage operation. Although conceptually promising, the ALT plays a minimal role in the treatment of patients with acute or chronic liver failure mostly because of the high complications rate, its complexity as well as the fact that orthotopic LT remains a gold standard of the treatment. SUMMARY Surgical techniques in liver transplantation have evolved considerably over the past 40 years. The developments have led to a safer procedure for the recipient reflected by continuously improving survival figures after LT. Also the new techniques offer the possibility of tailoring the operation to the needs and condition of the recipient as in partial grafting or in different revascularization techniques, or in techniques of biliary reconstructions. Additionally the new techniques such as split LT, domino transplantation and LRLT have also brought about an increase in the available grafts. REFERENCES 1. Starzl TE, Marchioro TL, Von Kaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the liver in humans. Surg Gynecol Obstet 1963;117: Moore FD, Birtch AG, Dagher F, Veith F, Krisher JA, Order SE et al. Immunosuppression and vascular insufficiency in liver transplantation. Ann N Y Acad Sci 1964;120: Demirleau J, Noureddine M, Vignes C, Prawerman A, Reziciner S, Larraud P et al.tentative d homogreffe hepatique. [Attempted hepatic homograft.] Mem Acad Chir (Paris) 1964;90: Starzl TE, Marchioro TL, Rowlands DT Jr, Kirkpatrick CH, Wilson WE, Rifkind D et al. Immunosuppression after experimental and clinical homotransplantation of the liver. Ann Surg 1964;160:

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36 The evolution of surgical techniques in liver transplantation - a review Chari RS, Gan TJ, Robertson KM, Bass K, Camargo CA, Greig PD et al. Venovenous bypass in adult orthotopic liver transplantation: routine or selective use? J Am Coll Surg 1998;186: Budd JM, Isaac JL, Bennett J, Freeman JW. Morbidity and mortality associated with largebore percutaneous venovenous bypass cannulation for 312 orthotopic liver transplantations. Liver Transpl 2001;7: Katirji MB. Brachial plexus injury following liver transplantation. Neurology 1989;39: Eleborg L, Sallander S, Tollemar J. Minimal hemolytic effect of veno-venous bypass during liver transplantation. Transpl Int 1991;4: Navalgund AA, Kang Y, Sarner JB, Jahr JS, Gieraerts R. Massive pulmonary thromboembolism during liver transplantation. Anesth Analg 1988; 67: Khoury GF, Kaufmann RD, Musich JA. Hypothermia related to the use of venovenous bypass during liver transplantation. Eur J Anesthesiol 1990;7: Khoury GF, Mann ME, Porot MJ, Abdul-Rasool IH, Busuttil RW. Air embolism associated with veno-venous bypass during orthotopic liver transplantation. Anesthesiology 1987;67: Stegall MD, Mandell S, Karrer F, Kam I. Liver transplantation without venovenous bypass. Transplant Proc 1995;27: Slooff MJ, Bams JL, Sluiter WJ, Klompmaker IJ, Hesselink EJ, Verwer R. A modified cannulation technique for veno-venous bypass during orthotopic liver transplantation. Transplant Proc 1989;21: Oken AC, Frank SM, Merritt WT, Fair J, Klein A, Burdick J et al. A new percutaneous technique for establishing venous bypass access in orthotopic liver transplantation. J Cardiothorac Vasc Anesth 1994;8: Tisone G, Mercadante E, Dauri M, Colella D, Anselmo A, Romagnoli J et al. Surgical versus percutaneous technique for veno-venous bypass during orthotopic liver transplantation: a prospective randomized study. Transplant Proc 1999;31: Wall WJ, Grant DR, Duff JH, Kutt JL, Ghent CN, Bloch MS. Liver transplantation without venous bypass. Transplantation 1987;43: Grande L, Rimola A, Cugat E, Alvarez L, Garcia-Valdecasas JC, Taura P, Beltran J et al.. Effect of venovenous bypass on perioperative renal function in liver transplantation: results of a randomized, controlled trial. Hepatology 1996;23: Johnson MW, Powelson JA, Auchincloss H Jr, Delmonico FL, Cosimi AB. Selective use of veno-venous bypass in orthotopic liver transplantation. Clin Transplant 1996;10:181-5.

37 36 Chapter Kuo PC, Alfrey EJ, Garcia G, Haddow G, Dafoe DC. Orthotopic liver transplantation with selective use of venovenous bypass. Am J Surg 1995;170: Tzakis A, Todo S, Starzl TE. Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 1989:210: Fleitas MG, Casanova D, Martino E, Maestre JM, Herrera L, Hernanz F et al. Could the piggyback operation in liver transplantation be routinely used? Arch Surg 1994;129: Belghiti J, Ettorre GM, Durand F, Sommacale D, Sauvanet A, Jerius JT et al. Feasibility and limits of caval-flow preservation during liver transplantation. Liver Transpl 2001; 7: Lerut J, Ciccarelli O, Roggen F, Laterre PF, Danse E, Goffette P et al. Cavocaval adult liver transplantation and retransplantation without veno-venous bypass and without portocaval shunting: a prospective feasibility study in adult liver transplantation. Transplantation 2003,75: Gonzalez FX, Garcia-Valdecasas JC, Grande L, Pacheco JL, Cugat E, Fuster J et al.. Vena cava vascular reconstruction during orthotopic liver transplantation: a comparative study. Liver Transpl Surg 1998:4: Hosein Shokouh-Amiri M, Osama Gaber A, Bagous WA, Grewal HP, Hathaway DK, Vera SR et al. Choice of surgical technique influences perioperative outcomes in liver transplantation Ann Surg 2002:231: Jovine E, Mazziotti A, Grazi GL, Ercolani G, Masetti M, Morganti M et al. Piggy-back versus conventional technique in liver transplantation: report of a randomized trial. Transpl Int 1997:10: Lerut JP, Molle G, Donataccio M, De Kock M, Ciccarelli O, et al. Cavocaval liver transplantation without venovenous bypass and without temporary portocaval shunting: the ideal technique for adult liver grafting? Transpl Int 1997:10: Miyamoto S, Polak WG, Geuken E, Peeters PM, de Jong KP, Porte RJ et al. Liver transplantation with preservation of the inferior vena cava. A comparison of conventional and piggyback techniques in adults. Clin Transplant 2004;18: Parrilla P, Sanchez-Bueno F, Figueras J, Jaurrieta E, Mir J, Margarit C et al. Analysis of the complications of the piggy-back technique in 1,112 liver transplants. Transplantation 1999;67: Navarro F, Le Moine MC, Fabre JM, Belghiti J, Cherqui D, Adam R et al. Specific vascular complications of orthotopic liver transplantation with preservation of the retrohepatic vena cava: review of 1361 cases. Transplantation 1999;68: Belghiti J, Panis Y, Sauvanet A, Gayet B, Fekete F. A new technique of side to side caval anastomosis during orthotopic hepatic transplantation without inferior vena caval occlusion. Surg Gynecol Obstet 1992:175:

38 The evolution of surgical techniques in liver transplantation - a review Cherqui D, Lauzet JY, Rotman N, Duvoux C, Dhumeaux D, Julien M et al. Orthotopic liver transplantation with preservation of the caval and portal flows. Technique and results in 62 cases. Transplantation 1994:58: Polak WG, Nemes BA, Miyamoto S, Peeters PM, de Jong KP, Porte RJ, Slooff MJ. End-to-side caval anastomosis in adult piggyback liver transplantation. Clin Transplant 2006;20: Dasgupta D, Sharpe J, Prasad KR, Asthana S, Toogood GJ, Pollard SG et al. Triangular and self-triangulating cavocavostomy for orthotopic liver transplantation without posterior suture lines: a modified surgical technique. Transpl Int 2006;19: Merenda R, Gerunda GE, Neri D, Barbazza F, Di Marzio E, Bruttocao A et al. Infrahepatic terminolateral cavo-cavostomy as a rescue technique in complicated modified piggyback liver transplantation. J Am Coll Surg 1997;185: Nishida S, Pinna A, Verzaro R, Levi D, Kato T, Nery JR et al. Domino liver transplantation with end-to-side infrahepatic vena cavocavostomy. J Am Coll Surg 2001;192: Hesse UJ, Berrevoet F, Torisi R, Pattyn P, Mortier E, Decruyenaere J et al. Hepato-venous reconstruction in orthotopic liver transplantation with preservation of the recipients inferior vena cava and veno-venous bypass. Langenbeck s Arch Surg 2000;385: Cescon M, Grazi GL, Varotti G, Ravaioli M, Ercolani G, Gardini A et al. Venous outflow reconstructions with the piggyback technique in liver transplantation: a single-center experience of 431 cases. Transpl Int 2005;18: Tzakis AG, Reyes J, Nour B, Marino IR, Todo S, Starzl TE. Temporary end to side portacaval shunt in orthotopic hepatic transplantation in humans. Surg Gynecol Obstet 1993:176: Belghiti J, Noun R, Sauvanet A. Temporary portocaval anastomosis with preservation of caval flow during orthotopic liver transplantation. Am J Surg 1995;169: Figueras J, Llado L, Ramos E, Jaurrieta E, Rafecas A, Fabregat J et al. Temporary portocaval shunt during liver transplantation with vena cava preservation. Results of a prospective randomized study. Liver Transpl 2001;7: Molmenti EP, Marsh JW, Molmenti H, Reyes J, Fung JJ. Modified temporary end-to-side portocaval shunt in liver and small bowel transplantation. Pediatr Transplant 2001;5: Molmenti EP, Marsh JW, Fung JJ, Casavilla FA. Rapid temporary portosystemic bypass. Dig Dis Sci 2002;47: Muscari F, Suc B, Aguirre J, Di Mauro GL, Bloom E, Duffas JP et al. Orthotopic liver transplantation with vena cava preservation in cirrhotic patients: is systematic temporary portacaval anastomosis a justified procedure? Transplant Proc 2005;37:

39 38 Chapter Aggarwal S, Kang Y, Freeman JA, Fortunato FL, Pinsky MR. Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation. Transplant Proc 1987;19(4 Suppl 3): Fukuzawa K, Schwartz ME, Acarli K, Katz E, Gabrielson G, Gettes M et al. Flushing with autologous blood improves intraoperative hemodynamic stability and early graft function in clinical hepatic transplantation. J Am Coll Surg 1994;178: Gao WS, Takei Y, Marzi I, Lindert KA, Caldwell-Kenkel JC, Currin RT et al. Carolina rinse solution--a new strategy to increase survival time after orthotopic liver transplantation in the rat. Transplantation 1991;52: Bachmann S, Caldwell-Kenkel JC, Currin RT, Tanaka Y, Takei Y, Marzi I et al. Ultrastructural correlates of liver graft failure from storage injury: studies of graft protection by Carolina rinse solution and pentoxifylline. Transplant Proc 1993;25: Adam R, Astarcioglu I, Castaing D, Bismuth H. Ringer s lactate vs serum albumin as a flush solution for UW preserved liver grafts: results of a prospective randomized study. Transplant Proc 1991;23: Bachmann S, Bechstein WO, Keck H, Lemmens HP, Brandes N, John AK et al. Pilot study: Carolina Rinse Solution improves graft function after orthotopic liver transplantation in humans. Transplant Proc 1997;29: Paulsen AW, Valek TR, Ramsay M, Swygert T, Klintmalm G. Determination of an adequate flush volume for removal of preservation fluid prior to revascularization of the donor liver. Transplant Proc 1989; 21: Fukuzawa K, Schwartz ME, Emre S, Miller CM. The effect of allograft flushing with portal blood on the reperfusion syndrome and graft function in clinical liver transplantation. Hepatology 1991;14:52A. 67. Wall WJ, Calne RY, Herbertson BM, Baker PG, Smith DP, Underwood J et al. Simple hypothermic preservation for transporting human livers long distances for transplantation. Report of 12 cases. Transplantation 1977;23: Emre S, Schwartz ME, Mor E, Kishikawa K, Yagmur O, Thiese N et al. Obviation of prereperfusion rinsing and decrease in reservation/reperfusion injury in liver transplantation by portal blood flushing. Transplantation 1994;57: Brems JJ, Takiff H, McHutchison J, Collins D, Biermann LA, Pockros P. Systemic versus nonsystemic reperfusion of the transplanted liver. Transplantation 1993;55: Millis JM, Melinek J, Csete M, Imagawa DK, Olthoff KM, Neelankanta G et al. Randomized controlled trial to evaluate flush and reperfusion techniques in liver transplantation. Transplantation 1997;63:

40 The evolution of surgical techniques in liver transplantation - a review Gruttadauria S, Cintorino D, Musumeci A, Arcadipane A, Burgio G, Clarizia S et al. Comparison of two different techniques of reperfusion in adult orthotopic liver transplantation. Clin Transplant 2006;20: Rosenberg PM, Friedman LS. The liver in circulatory failure. In: Schiff ER, Sorrel MF, Maddrey WS (eds). Schiff s diseases of the liver. Lippincott Williams & Wilkins Publishers; 2002: Ducerf C, Mechet I, Landry JL, DeLaRoche E, Berthoux N, Bourdeix O et al. Hemodynamic profiles during piggyback liver grafts using arterial or portal revascularization. J Am Coll Surg 2000;190: Moreno C, Sabaté A, Figueras J, Camprubí I, Dalmau A, Fabregat J et l. Hemodynamic profile and tissular oxygenation in orthotopic liver transplantation: Influence of hepatic artery or portal vein revascularization of the graft. Liver Transpl 2006;12: Noun R, Sauvanet A, Belghiti J. Appraisal of the order of revascularization in human liver grafting: a controlled study. J Am Coll Surg 1997;185: Sadler KM, Walsh TS, Garden OJ, Lee A. Comparison of hepatic artery and portal vein reperfusion during orthotopic liver transplantation. Transplantation 2001;72: Kniepeiss D, Iberer F, Grasser B, Schaffellner S, Stadlbauer V, Tscheliessnigg KH. A single-center experience with retrograde reperfusion in liver transplantation. Transpl Int 2003;16: Heidenhain C, Heise M, Jonas S, Ben-Asseur M, Puhl G, Mittler J et al. P. 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. Transpl Int 2006;19: Sankary HN, McChesney L, Frye E, Cohn S, Foster P, Williams J. A simple modification in operative technique can reduce the incidence of nonanastomotic biliary strictures after orthotopic liver transplantation. Hepatology 1995;21: Piratvisuth T, Tredger JM, Hayllar KA, Williams R. Contribution of true cold and rewarming ischemia times to factors determining outcome after orthotopic liver transplantation. Liver Transpl Surg 1995;1: Platz KP, Mueller AR, Schafer C, Jahns S, Guckelberger O, Neuhaus P. Influence of warm ischemia time on initial graft function in human liver transplantation. Transplant Proc 1997;29: Massarollo PC, Mies S, Raia S. Simultaneous arterial and portal revascularization in liver transplantation. Transplant Proc 1998;30: Polak WG, Miyamoto S, Nemes BA, Peeters PM, de Jong KP, Porte RJ et al. Sequential and simultaneous revascularization in adult orthotopic piggyback liver transplantation. Liver Transpl 2005: 11:

41 40 Chapter Scantlebury VP, Zajko AB, Esquivel CO, Marino IR, Starzl TE. Successful reconstruction of late portal vein stenosis after hepatic transplantation. Arch Surg 1989;124: Starzl TE, Iwatsuki S, Shaw BW Jr. A growth factor in fine vascular anastomoses. Surg Gynecol Obstet 1984;159: Calleja IJ, Polo JR, Garci a-sabrido JL, Ferreiroa JP, Valdecantos E. Two-clamp method to avoid portal anastomotic stenosis in liver transplantation. Am J Surg 1993; 165: Tanaka K, Uemoto S, Tokunaga Y, Fujita S, Sano K, Nishizawa T et al. Surgical techniques and innovations in living related liver transplantation. Ann Surg 1993;217: Marwan IK, Fawzy AT, Egawa H, Inomata Y, Uemoto S, Asonuma K et al. Innovative techniques for and results of portal vein reconstruction in living-related liver transplantation. Surgery 1999;125: Mitchell A, John PR, Mayer DA, Mirza DF, Buckels JA, De Ville De Goyet J. Improved technique of portal vein reconstruction in pediatric liver transplant recipients with portal vein hypoplasia. Transplantation 2002;73: Molmenti EP, Roodhouse TW, Molmenti H, Jaiswal K, Jung G, Marubashi S et al. Thrombendvenectomy for organized portal vein thrombosis at the time of liver transplantation. Ann Surg 2002;235: Dumortier J, Czyglik O, Poncet G, Blanchet MC, Boucaud C, Henry L et al. Eversion thrombectomy for portal vein thrombosis during liver transplantation. Am J Transplant 2002;2: Robles R, Fernandez JA, Hernandez Q, Mara n C, Rami rez P, Sanchez-Bueno F et al. Eversion thromboendovenectomy in organized portal vein thrombosis during liver transplantation. Clin Transplant 2004;18: Shaked A, Busuttil RW. Liver transplantation in patients with portal vein thrombosis and central portacaval shunts. Ann Surg 1991;214: Lerut JP, Mazza D, van Leeuw V, Laterre PF, Donataccio M, de Ville de Goyet J, Van Beers B, Bourlier P, Goffette P, Puttemans T, Otte JB. Adult liver transplantation and abnormalities of splanchnic veins: experience in 53 patients. Transpl Int 1997;10: Tzakis A, Todo S, Stieber A, Starzl TE. Venous jump grafts for liver transplantation in patients with portal vein thrombosis. Transplantation 1989; 48: Moreno Gonzalez E, Garci a Garci a I, Gomez Sanz R, Gonzalez-Pinto I, Loinaz Segurola C, Jimenez Romero C. Liver transplantation in patients with thrombosis of the portal, splenic or superior mesenteric vein. Br J Surg. 1993;80: Yerdel MA, Gunson B, Mirza D, Karayalcin K, Olliff S, Buckels J et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 2000;69:

42 The evolution of surgical techniques in liver transplantation - a review Tzakis AG, Kirkegaard P, Pinna AD, Jovine E, Misiakos EP, Maziotti A et al.. Liver transplantation with cavoportal hemitransposition in the presence of diffuse portal vein thrombosis. Transplantation 1998;65: Selvaggi G, Weppler D, Nishida S, Moon J, Levi D, Kato T et al. Ten-year experience in portocaval hemitransposition for liver transplantation in the presence of portal vein thrombosis. Am J Transplant 2007;7: Sheil AG, Stephen MS, Chui AK, Ling J, Bookallil MJ. A liver transplantation technique in a patient with a thrombosed portal vein and a functioning renal-lieno shunt. Clin Transplant 1997;11: Kato T, Levi DM, DeFaria W, Nishida S, Tzakis AG. Liver transplantation with renoportal anastomosis after distal splenorenal shunt. Arch Surg 2000; 135: Paskonis M, Jurgaitis J, Mehrabi A, Kashfi A, Fonouni H, Strupas K et al. Surgical strategies for liver transplantation in the case of portal vein thrombosis--current role of cavoportal hemitransposition and renoportal anastomosis. Clin Transplant 2006;20: Troisi R, Kerremans I, Mortier E, Defreyne L, Hesse UJ, de Hemptinne B. Arterialization of the portal vein in pediatric liver transplantation. A report of two cases. Transpl Int 1998;11: Charco R, Margarit C, Lopez-Talavera JC, Hidalgo E, Castells L, Allende H et al. Outcome and hepatic hemodynamics in liver transplant patients with portal vein arterialization. Am J Transplant 2001;1: Settmacher U, Stange B, Schaser KD, Puhl G, Glanemann M, Steinmuller T et al. Primary permanent arterialization of the portal vein in liver transplantation. Transpl Int 2003;16: Tzakis AG, Kato T, Levi DM, Defaria W, Selvaggi G, Weppler D et al. 100 multivisceral transplants at a single center. Ann Surg 2005;242: Bolognesi M, Sacerdoti D, Bombonato G, Merkel C, Sartori G, Merenda R et al. Change in portal flow after liver transplantation: effect on hepatic arterial resistance indices and role of spleen size. Hepatology 2002;35: Kiuchi T, Tanaka K, Ito T, Oike F, Ogura Y, Fujimoto Y et al. Small-for-size graft in living donor liver transplantation: how far should we go? Liver Transpl 2003;9:S Troisi R, de Hemptinne B. Clinical relevance of adapting portal vein flow in living donor liver transplantation in adult patients. Liver Transpl 2003;9:S Merion RM, Burtch GD, Ham JM, Turcotte JG, Campbell DA. The hepatic artery in liver transplantation. Transplantation 1989;48: Quinones-Baldrich WJ, Memsic L, Ramming K, Hiatt J, Busuttil RW. Branch patch for arterialization of hepatic grafts. Surg Gynecol Obstet 1986;162:

43 42 Chapter Kalayoglu M, Belzer FO. A new technique for arterialization of the hepatic graft. Surg Gynecol Obstet 1987;164: Busuttil RW, Colonna JO 2nd, Hiatt JR, Brems JJ, el Khoury G, Goldstein LI et al. The first 100 liver transplants at UCLA. Ann Surg 1987;206: Meneu-Diaz JC, Moreno-Gonzalez E, Garcia Garcia I, Jimenez Romero C, Loinaz Segurola C, Gomez Sanz R et al. Hepatic allograft arterialization by means of the gastroduodenal bifurcation (branch patch) as a prognostic factor. Transplantation 2004;77: Starzl TE, Halgrimson CG, Koep LJ, Weil R 3rd, Taylor PD. Vascular homografts from cadaveric organ donors. Surg Gynecol Obstet. 1979;149: Shaw BW Jr, Iwatsuki S, Starzl TE. Alternative methods of arterialization of the hepatic graft. Surg Gynecol Obstet 1984;159: Goldstein RM, Secrest CL, Klintmalm GB, Husberg BS. Problematic vascular reconstruction in liver transplantation. Part I. Arterial. Surgery 1990;107: Stewart MT, Millikan WJ Jr, Henderson JM, Galloway JR, Dodson TF. Proximal abdominal graft for arterialization during hepatic transplantation. Surg Gynecol Obstet 1989;169: Shaked AA, Takiff H, Busuttil RW. The use of the supraceliac aorta for hepatic arterial revascularization in transplantation of the liver. Surg Gynecol Obstet 1991;173: Garcia-Valdecasas JC, Grande L, Rimola A, Fuster J, Lacy A, Visa J. The use of the saphenous vein for arterial reconstruction in orthotopic liver transplant. Transplant Proc 1990;22: Rogers J, Chavin KD, Kratz JM, Mohamed HK, Lin A, Baillie GM et al. Use of autologous radial artery for revascularization of hepatic artery thrombosis after orthotopic liver transplantation: case report and review of indications and options for urgent hepatic artery reconstruction. Liver Transpl 2001;7: Muiesan P, Rela M, Heaton ND. Use of cadaveric superior mesenteric artery as interpositional vascular graft in orthotopic liver transplantation. Br J Surg 2001;88: Kuang AA, Renz JF, Ferrell LD, Ring EJ, Rosenthal P, Lim RC et al. Failure patterns of cryopreserved vein grafts in liver transplantation. Transplantation. 1996;62: Cappadonna CR, Johnson LB, Lu AD, Kuo PC. Outcome of extra-anatomic vascular reconstruction in orthotopic liver transplantation. Am J Surg 2001;182: Zamboni F, Franchello A, Ricchiuti A, Fop F, Rizzetto M, Salizzoni M. Use of arterial conduit as an alternative technique in arterial revascularization during orthotopic liver transplantation. Dig Liver Dis 2002;34:122-6.

44 The evolution of surgical techniques in liver transplantation - a review Muralidharan V, Imber C, Leelaudomlipi S, Gunson BK, Buckels JA, Mirza DF et al. Arterial conduits for hepatic artery revascularisation in adult liver transplantation. Transpl Int 2004;7: Del Gaudio M, Grazi GL, Ercolani G, Ravaioli M, Varotti G, Cescon M et al. Outcome of hepatic artery reconstruction in liver transplantation with an iliac arterial interposition graft. Clin Transplant 2005;19: Stange BJ, Glanemann M, Nuessler NC, Settmacher U, Steinmuller T, Neuhaus P. Hepatic artery thrombosis after adult liver transplantation. Liver Transpl 2003;9: Silva MA, Jambulingam PS, Gunson BK, Mayer D, Buckels JA, Mirza DF et al. Hepatic artery thrombosis following orthotopic liver transplantation: a 10-year experience from a single centre in the United Kingdom. Liver Transpl 2006;12: Cherqui D, Riff Y, Rotman N, Julien M, Fagniez PL. The recipient splenic artery for arterialization in orthotopic liver transplantation. Am J Surg. 1994; 167: Figueras J, Pares D, Aranda H, Rafecas A, Fabregat J, Torras J et al. Results of using the recipient s splenic artery for arterial reconstruction in liver transplantation in 23 patients. Transplantation 1997;64: Settmacher U, Haase R, Heise M, Bechstein WO, Neuhaus P. Variations of surgical reconstruction in liver transplantation depending on vasculature. Langenbecks Arch Surg 1999;384: Fukuzawa K, Schwartz ME, Katz E, Mor E, Emre S, Acarli K et al. The arcuate ligament syndrome in liver transplantation. Transplantation 1993;56: Inomoto T, Nishizawa F, Sasaki H, Terajima H, Shirakata Y, Miyamoto S et al. Experiences of 120 microsurgical reconstructions of hepatic artery in living related liver transplantation. Surgery 1996;119: Testa G, Losanoff JE, Gangemi A, Benedetti E. Excellent outcome using an alternative technique for arterial reconstruction in living-related liver transplant: sphenoid anastomosis. Transpl Int 2007; 20: Okazaki M, Asato H, Takushima A, Nakatsuka T, Sarukawa S, Inoue K, Harii K, Sugawara Y, Makuuchi M. Hepatic artery reconstruction with double-needle microsuture in living-donor liver transplantation. Liver Transpl 2006; 12: Hiatt JR, Gabbay J, Busuttil RW. Surgical anatomy of the hepatic arteries in 1000 cases. Ann Surg 1994;220: Gruttadauria S, Foglieni CS, Doria C, Luca A, Lauro A, Marino IR. The hepatic artery in liver transplantation and surgery: vascular anomalies in 701 cases. Clin Transplant 2001;15:

45 44 Chapter Nijkamp DM, Slooff MJ, van der Hilst CS, Ijtsma AJ, de Jong KP, Peeters PM et al. Surgical injuries of postmortem donor livers: incidence and impact on outcome after adult liver transplantation. Liver Transpl 2006;12: Gordon RD, Shaw BW Jr, Iwatsuki S, Todo S, Starzl TE. A simplified technique for revascularization of homografts of the liver with a variant right hepatic artery from the superior mesenteric artery. Surg Gynecol Obstet 1985;160: Ikegami T, Kawasaki S, Matsunami H, Hashikura Y, Nakazawa Y, Miyagawa S et al. Should all hepatic arterial branches be reconstructed in living-related liver transplantation? Surgery 1996;119: Takatsuki M, Chiang YC, Lin TS, Wang CC, Concejero A, Lin CC et al. Anatomical and technical aspects of hepatic artery reconstruction in living donor liver transplantation. Surgery 2006;140: Marcos A, Killackey M, Orloff MS, Mieles L, Bozorgzadeh A, Tan HP. Hepatic arterial reconstruction in 95 adult right lobe living donor liver transplants: evolution of anastomotic technique. Liver Transpl 2003;9: Mori K, Nagata I, Yamagata S, Sasaki H, Nishizawa F, Takada Y et al. The introduction of microvascular surgery to hepatic artery reconstruction in living-donor liver transplantation- -its surgical advantages compared with conventional procedures. Transplantation 1992;54: Shackleton CR, Goss JA, Swenson K, Colquhoun SD, Seu P, Kinkhabwala MM et al. The impact of microsurgical hepatic arterial reconstruction on the outcome of liver transplantation for congenital biliary atresia. Am J Surg 1997; 173: Stratta RJ, Wood RP, Langnas AN, Hollins RR, Bruder KJ, Donovan JP et al. Diagnosis and treatment of biliary tract complications after orthotopic liver transplantation. Surgery 1989;106: Greif F, Bronsther OL, Van Thiel DH, Casavilla A, Iwatsuki S, Tzakis A et al. The incidence, timing, and management of biliary tract complications after orthotopic liver transplantation. Ann Surg 1994;219: Lerut JP, Gordon RD, Iwatsuki S, Starzl TE. Human orthotopic liver transplantation: surgical aspects in 393 consecutive grafts. Transplant Proc 1988;20(1 Suppl 1): Klein AS, Savader S, Burdick JF, Fair J, Mitchell M, Colombani P et al. Reduction of morbidity and mortality from biliary complications after liver transplantation. Hepatology 1991; 14: Heffron TG, Emond JC, Whitington PF, Thistlethwaite JR Jr, Stevens L, Piper J et al. Biliary complications in pediatric liver transplantation. A comparison of reduced-size and whole grafts. Transplantation 1992;53:391-5.

46 The evolution of surgical techniques in liver transplantation - a review Neuhaus P, Blumhardt G, Bechstein WO, Steffen R, Platz KP, Keck H. Technique and results of biliary reconstruction using side-to-side choledochocholedochostomy in 300 orthotopic liver transplants. Ann Surg 1994;219: Chardot C, Candinas D, Mirza D, Gunson B, Davison S, Murphy MS et al. Biliary complications after paediatric liver transplantation: Birmingham s experience. Transpl Int 1995;8: Cronin DC 2nd, Alonso EM, Piper JB, Newell KA, Bruce DS, Woodle ES et al. Biliary complications in living donor liver transplantation. Transplant Proc 1997;29: Egawa H, Uemoto S, Inomata Y, Shapiro AM, Asonuma K, Kiuchi T et al. Biliary complications in pediatric living related liver transplantation. Surgery 1998;124: Buis CI, Verdonk RC, Van der Jagt EJ, van der Hilst CS, Slooff MJ, Haagsma EB et al. Nonanastomotic biliary strictures after liver transplantation, part 1: Radiological features and risk factors for early vs. late presentation. Liver Transpl 2007;13: Colonna JO 2nd, Shaked A, Gomes AS, Colquhoun SD, Jurim O, McDiarmid SV et al. Biliary strictures complicating liver transplantation. Incidence, pathogenesis, management, and outcome. Ann Surg 1992;216: Calne RY. A new technique for biliary drainage in orthotopic liver transplantation utilizing the gall bladder as a pedicle graft conduit between the donor and recipient common bile ducts. Ann Surg 1976;184: Calne RY, McMaster P, Portmann B, Wall WJ, Williams R. Observations on preservation, bile drainage and rejection in 64 human orthotopic liver allografts. Ann Surg 1977;186: Halff G, Todo S, Hall R, Starzl TE. Late complications with gallbladder conduit biliary reconstruction after liver transplantation. Transplantation 1989;48: Terblanche J, Allison HF, Northover JM. An ischemic basis for biliary strictures. Surgery 1983; 94: Krom RA, Kingma LM, Haagsma EB, Wesenhagen H, Slooff MJ, Gips CH. Choledochocholedochostomy, a relatively safe procedure in orthotopic liver transplantation. Surgery 1985;97: Rabkin JM, Orloff SL, Reed MH, Wheeler LJ, Corless CL, Benner KG et al. Biliary tract complications of side-to-side without T tube versus end-to-end with or without T tube choledochocholedochostomy in liver transplant recipients. Transplantation 1998;65: Davidson BR, Rai R, Kurzawinski TR, Selves L, Farouk M, Dooley JS et al. Prospective randomized trial of end-to-end versus side-to-side biliary reconstruction after orthotopic liver transplantation. Br J Surg 1999;86:

47 46 Chapter Castaldo ET, Pinson CW, Feurer ID, Wright JK, Gorden DL, Kelly BS et al. Continuous versus interrupted suture for end-to-end biliary anastomosis during liver transplantation gives equal results. Liver Transpl 2007;13: Thomas KT, Gorden DL, Chari RS, Wright JK, Feurer ID, Pinson CW. Biliary reconstruction using non-penetrating, tissue everting clips versus conventional sewn biliary anastomosis in liver transplantation. HPB 2006;8: Northover J, Terblanche J. Bile duct blood supply. Its importance in human liver transplantation. Transplantation 1978;26: Terblanche J, Worthley CS, Spence RA, Krige JE. High or low hepaticojejunostomy for bile duct strictures? Surgery 1990;108: O Connor TP, Lewis WD, Jenkins RL. Biliary tract complications after liver transplantation. Arch Surg 1995;130: Sossenheimer M, Slivka A, Carr-Locke D. Management of extrahepatic biliary disease after orthotopic liver transplantation: review of the literature and results of a multicenter survey. Endoscopy 1996;28: Schmitz V, Neumann UP, Puhl G, Tran ZV, Neuhaus P, Langrehr JM. Surgical complications and long-term outcome of different biliary reconstructions in liver transplantation for primary sclerosing cholangitis-choledochoduodenostomy versus choledochojejunostomy. Am J Transplant 2006;6: Ben-Ari Z, Neville L, Davidson B, Rolles K, Burroughs AK. Infection rates with and without T-tube splintage of common bile duct anastomosis in liver transplantation. Transpl Int 1998;11: Sawyer RG, Punch JD. Incidence and management of biliary complications after 291 liver transplants following the introduction of transcystic stenting. Transplantation 1998;66: Johnson MW, Thompson P, Meehan A, Odell P, Salm MJ, Gerber DA et al. Internal biliary stenting in orthotopic liver transplantation. Liver Transpl 2000;6: Bawa SM, Mathew A, Krishnan H, Minford E, Talbot D, Mirza DF et al. Biliary reconstruction with or without an internal biliary stent in orthotopic liver transplantation: a prospective randomised trial. Transpl Int 1998;11 Suppl 1: S Goodwin SC, Bittner CA, Patel MC, Noronha MA, Chao K, Sayre JW. Technique for reduction of bile peritonitis after T-tube removal in liver transplant patients. J Vasc Interv Radiol 1998;9: Urbani L, Campatelli A, Romagnoli J, Catalano G, Sartoni G, Costa A et al. T-tube removal after liver transplantation: a new technique that reduces biliary complications. Transplantation 2002;74:410-3.

48 The evolution of surgical techniques in liver transplantation - a review Scatton O, Meunier B, Cherqui D, Boillot O, Sauvanet A, Boudjema K et al. Randomized trial of choledochocholedochostomy with or without a T tube in orthotopic liver transplantation. Ann Surg 2001;233: Vougas V, Rela M, Gane E, Muiesan P, Melendez HV, Williams R et al. A prospective randomised trial of bile duct reconstruction at liver transplantation: T tube or no T tube? Transpl Int 1996;9: Shimoda M, Saab S, Morrisey M, Ghobrial RM, Farmer DG, Chen P et al. A cost-effectiveness analysis of biliary anastomosis with or without T-tube after orthotopic liver transplantation. Am J Transplant 2001;1: Amador A, Charco R, Marti J, Navasa M, Rimola A, Calatayud D et al. Clinical trial on the cost-effectiveness of T-tube use in an established deceased donor liver transplantation program. Clin Transplant 2007;21: Starzl Te. Demetris AJ: Liver transplantation: A 31 year perspective. Chicago, Year Book, 1990: Bismuth H, Houssin D. Reduced-sized orthotopic liver graft in hepatic transplantation in children. Surgery 1984;95: Broelsch CE, Neuhaus P, Burdelski M, et al. Orthotope transplantation von lebersegmenten bei kleinkindern mit gallengangsatresien. Orthotopic transplantation of hepatic segments in infants with biliary atresia. In Koslowski L, ed. Chirurgisches Forun 84 F. Experim U. Klimische Forschung Hrsg. Berlin/Heidelberg: Springer, Otte JB, de Ville de Goyet J, Sokal E, Alberti D, Moulin D, de Hemptinne B et al. Size reduction of the donor liver is a safe way to alleviate the shortage of size-matched organs in pediatric liver transplantation. Ann Surg 1990;211: Emond JC, Whitington PF, Thistlethwaite JR, Alonso EM, Broelsch CE. Reduced-size orthotopic liver transplantation: use in the management of children with chronic liver disease. Hepatology 1989;10: de Ville de Goyet J, Hausleithner V, Reding R, Lerut J, Janssen M, Otte JB. Impact of innovative techniques on the waiting list and results in pediatric liver transplantation. Transplantation 1993;56: Langnas AN, Marujo WC, Inagaki M, Stratta RJ, Wood RP, Shaw BW Jr. The results of reduced-size liver transplantation, including split livers, in patients with end-stage liver disease. Transplantation 1992;53: Slooff MJ. Reduced size liver transplantation, split liver transplantation, and living related liver transplantation in relation to the donor organ shortage. Transpl Int 1995;8: Pichlmayr R, Ringe B, Gubernatis G, Hauss J, Bunzendahl H. Transplantation of a donor liver to 2 recipients (splitting transplantation)- a new method in the further development of segmental liver transplantation. Langenbecks Arch Chir 1988;373:

49 48 Chapter Bismuth H, Morino M, Castaing D, Gillon MC, Descorps Declere A, Saliba F et al. Emergency orthotopic liver transplantation in two patients using one donor liver. Br J Surg 1989;76: Broelsch CE, Emond JC, Whitington PF, Thistlethwaite JR, Baker AL, Lichtor JL. Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Ann Surg 1990;212: Azoulay D, Astarcioglu I, Bismuth H, Castaing D, Majno P, Adam R et al. Split-liver transplantation. The Paul Brousse policy. Ann Surg 1996;224: Kalayoglu M, D Alessandro AM, Knechtle SJ, Hoffmann RM, Pirsch JD, Judd RH et al. Preliminary experience with split liver transplantation. J Am Coll Surg 1996;182: Rela M, Vougas V, Muiesan P, Vilca-Melendez H, Smyrniotis V, Gibbs P et al. Split liver transplantation: King s College Hospital experience. Ann Surg 1998;227: Sieders E, Peeters PM, TenVergert EM, Bijleveld CM, de Jong KP, Zwaveling JH et al. Analysis of survival and morbidity after pediatric liver transplantation with full-size and technicalvariant grafts. Transplantation 1999;68: de Ville de Goyet J : Technique for ex situ cadaveric liver division. In : Rogiers X, Bismuth H, Busuttil RW, Broering DC, Azoulay D. eds. Split Liver Transplantation. Darmstadt : Springer; 2002: Wilms C, Walter J, Kaptein M, Mueller L, Lenk C, Sterneck M et al.. Long-term outcome of split liver transplantation using right extended grafts in adulthood: A matched pair analysis. Ann Surg 2006;244: Cardillo M, De Fazio N, Pedotti P, De Feo T, Fassati LR, Mazzaferro V et al. Split and whole liver transplantation outcomes: a comparative cohort study. Liver Transpl 2006;12: Rogiers X, Malago M, Gawad K, Jauch KW, Olausson M, Knoefel WT et al. In situ splitting of cadaveric livers. The ultimate expansion of a limited donor pool. Ann Surg 1996;224: Noujaim HM, Gunson B, Mayer DA, Mirza DF, Buckels JA, Candinas D et al. Worth continuing doing ex situ liver graft splitting? A single-center analysis. Am J Transplant 2003;3: Goss JA, Yersiz H, Shackleton CR, Seu P, Smith CV, Markowitz JS et al. In situ splitting of the cadaveric liver for transplantation. Transplantation 1997;64: Otte JB, de Ville de Goyet J, Alberti D, Balladur P, de Hemptinne B. The concept and technique of the split liver in clinical transplantation. Surgery 1990;107: Rogiers X, Malago M, Habib N, Knoefel WT, Pothmann W, Burdelski M et al. In situ splitting of the liver in the heart-beating cadaveric organ donor for transplantation in two recipients. Transplantation 1995;59:

50 The evolution of surgical techniques in liver transplantation - a review Yersiz H, Renz JF, Farmer DG, Hisatake GM, McDiarmid SV, Busuttil RW. One hundred in situ split-liver transplantations: a single-center experience. Ann Surg 2003;238: Reyes J, Gerber D, Mazariegos GV, Casavilla A, Sindhi R, Bueno J et al. Split-liver transplantation: a comparison of ex vivo and in situ techniques. J Pediatr Surg 2000;35: Cescon M, Spada M, Colledan M, Torre G, Andorno E, Valente U et al. Feasibility and limits of split liver transplantation from pediatric donors: an italian multicenter experience. Ann Surg 2006;244: Muiesan P, Jassem W, Girlanda R, Steinberg R, Vilca-Melendez H, Mieli-Vergani G et al. Segmental liver transplantation from non-heart beating donors--an early experience with implications for the future. Am J Transplant 2006;6: Azoulay D, Castaing D, Adam R, Mimoz O, Bismuth H. Transplantation of three adult patients with one cadaveric graft: wait or innovate. Liver Transpl 2000;6: Sommacale D, Farges O, Ettorre GM, Lebigot P, Sauvanet A, Marty J et al. In situ split liver transplantation for two adult recipients. Transplantation 2000;69: Humar A, Ramcharan T, Sielaff TD, Kandaswamy R, Gruessner RW, Lake JR et al. Split liver transplantation for two adult recipients: an initial experience. Am J Transplant 2001;1: Kilic M, Seu P, Stribling RJ, Ghalib R, Goss JA. In situ splitting of the cadaveric liver for two adult recipients. Transplantation 2001;72: Yersiz H, Renz JF, Hisatake G, Reichert PR, Feduska NJ Jr, Lerner S et al. Technical and logistical considerations of in situ split-liver transplantation for two adults: Part I. Creation of left segment II, III, IV and right segment I, V-VIII grafts. Liver Transpl 2001;7: Azoulay D, Castaing D, Adam R, Savier E, Delvart V, Karam V et al. Split-liver transplantation for two adult recipients: feasibility and long-term outcomes. Ann Surg 2001;233: Colledan M, Segalin A, Andorno E, Corno V, Lucianetti A, Spada M et al. Modified splitting technique for liver transplantation in adult-sized recipients. Technique and preliminary results. Acta Chir Belg 2000;100: Strong R, Lynch S, Yamanaka J, Kawamoto S, Pillay P, Ong TH. Monosegmental liver transplantation. Surgery 1995;118: Mentha G, Belli D, Berner M, Rouge JC, Bugmann P, Morel P et al. Monosegmental liver transplantation from an adult to an infant. Transplantation 1996;62: Srinivasan P, Vilca-Melendez H, Muiesan P, Prachalias A, Heaton ND, Rela M. Liver transplantation with monosegments. Surgery 1999;126: Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet 1989;2:497.

51 50 Chapter Strong RW, Lynch SV, Ong TH, Matsunami H, Koido Y, Balderson GA. Successful liver transplantation from a living donor to her son. N Engl J Med 1990;322: Tanaka K, Uemoto S, Tokunaga Y, Fujita S, Sano K, Nishizawa T et al. Surgical techniques and innovations in living related liver transplantation. Ann Surg 1993;217: Emond JC, Heffron TG, Kortz EO, Gonzalez-Vallina R, Contis JC, Black DD et al. Improved results of living-related liver transplantation with routine application in a pediatric program. Transplantation 1993;55: Miller CM, Gondolesi GE, Florman S, Matsumoto C, Muñoz L, Yoshizumi T et al. One hundred nine living donor liver transplants in adults and children: a single-center experience. Ann Surg 2001;234: Roberts JP, Hulbert-Shearon TE, Merion RM, Wolfe RA, Port FK. Influence of graft type on outcomes after pediatric liver transplantation. Am J Transplant 2004;4: Bourdeaux C, Darwish A, Jamart J, Tri TT, Janssen M, Lerut J et al. Living-related versus deceased donor pediatric liver transplantation: a multivariate analysis of technical and immunological complications in 235 recipients. Am J Transplant 2007;7: Grewal HP, Thistlewaite JR Jr, Loss GE, Fisher JS, Cronin DC, Siegel CT et al. Complications in 100 living-liver donors. Ann Surg 1998;228: Fujita S, Kim ID, Uryuhara K, Asonuma K, Egawa H, Kiuchi T et al. Hepatic grafts from live donors: donor morbidity for 470 cases of live donation. Transpl Int 2000;13: Lo CM.Complications and long-term outcome of living liver donors: a survey of 1,508 cases in five Asian centers. Transplantation 2003;75(3 Suppl):S Kawasaki S, Makuuchi M, Matsunami H, Hashikura Y, Ikegami T, Nakazawa Y et al. Living related liver transplantation in adults. Ann Surg 1998; 227: Soejima Y, Shimada M, Suehiro T, Hiroshige S, Ninomiya M, Shiotani S, Harada N, Hideki I, Yonemura Y, Maehara Y. Outcome analysis in adult-to-adult living donor liver transplantation using the left lobe. Liver Transpl 2003;9: Lee S, Hwang S, Park K, Lee Y, Choi D, Ahn C et al. An adult-to-adult living donor liver transplant using dual left lobe grafts. Surgery 2001;129: Hwang S, Lee SG, Lee YJ, Sung KB, Park KM, Kim KH et al. Lessons learned from 1,000 living donor liver transplantations in a single center: how to make living donations safe. Liver Transpl 2006;12: Lo CM, Fan ST, Liu CL, Wei WI, Lo RJ, Lai CL, Chan JK, Ng IO, Fung A, Wong J. Adult-toadult living donor liver transplantation using extended right lobe grafts. Ann Surg 1997; 226:

52 The evolution of surgical techniques in liver transplantation - a review Thuluvath PJ, Yoo HY. Graft and patient survival after adult live donor liver transplantation compared to a matched cohort who received a deceased donor transplantation. Liver Transpl 2004;10: Olthoff KM, Merion RM, Ghobrial RM, Abecassis MM, Fair JH, Fisher RA et al. Outcomes of 385 adult-to-adult living donor liver transplant recipients: a report from the A2ALL Consortium. Ann Surg 2005;242: Morioka D, Egawa H, Kasahara M, Ito T, Haga H, Takada Y et al. Outcomes of adult-to-adult living donor liver transplantation: a single institution s experience with 335 consecutive cases. Ann Surg 2007;245: Ito T, Kiuchi T, Egawa H, Kaihara S, Oike F, Ogura Y et al. Surgery-related morbidity in living donors of right-lobe liver graft: lessons from the first 200 cases. Transplantation 2003;76: Marcos A, Orloff M, Mieles L, Olzinski AT, Renz JF, Sitzmann JV. Functional venous anatomy for right-lobe grafting and techniques to optimize outflow. Liver Transpl 2001;7: Sugawara Y, Makuuchi M, Sano K, Imamura H, Kaneko J, Ohkubo T et al. Vein reconstruction in modified right liver graft for living donor liver transplantation. Ann Surg 2003;237: Lee SG, Park KM, Hwang S, Kim KH, Choi DN, Joo SH et al. Modified right liver graft from a living donor to prevent congestion. Transplantation 2002; 74: Lo CM, Fan ST, Liu CL, Yong BH, Wong Y, Lau GK, Lai CL, Ng IO, Wong J. Lessons learned from one hundred right lobe living donor liver transplants. Ann Surg 2004;240: Egawa H, Inomata Y, Uemoto S, Asonuma K, Kiuchi T, Fujita S et al. Biliary anastomotic complications in 400 living related liver transplantations. World J Surg 2001;25: Liu CL, Lo CM, Chan SC, Fan ST. Safety of duct-to-duct biliary reconstruction in right-lobe live-donor liver transplantation without biliary drainage. Transplantation 2004;77: Shah SA, Grant DR, McGilvray ID, Greig PD, Selzner M, Lilly LB et al. Biliary strictures in 130 consecutive right lobe living donor liver transplant recipients: results of a Western center. Am J Transplant 2007;7: Kasahara M, Egawa H, Takada Y, Oike F, Sakamoto S, Kiuchi T et al. Biliary reconstruction in right lobe living-donor liver transplantation: Comparison of different techniques in 321 recipients. Ann Surg 2006;243: Fan ST, Lo CM, Liu CL, Tso WK, Wong J. Biliary reconstruction and complications of right lobe live donor liver transplantation. Ann Surg 2002;236:

53 52 Chapter Ericzon BG, Larsson M, Herlenius G, Wilczek HE; Familial Amyloidotic Polyneuropathy World Transplant Registry. Report from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR) and the Domino Liver Transplant Registry (DLTR). Amyloid 2003;10 Suppl 1: Furtado A, Tome L, Oliveira FJ, Furtado E, Viana J, Perdigoto R. Sequential liver transplantation. Transplant Proc 1997; 29: Khanna A, Hart M, Nyhan WL, Hassanein T, Panyard-Davis J, Barshop BA. Domino liver transplantation in maple syrup urine disease. Liver Transpl. 2006;12: Monteiro E, Perdigoto R, Furtado AL. Liver transplantation for familial amyloid polyneuropathy. Hepatogastroenterology 1998;45: Furtado AJ. Domino liver transplantation using FAP grafts. HUC experience -hopes and realities. Amyloid 2003;10 Suppl 1: Yamamoto S, Wilczek HE, Nowak G, Larsson M, Oksanen A, Iwata T et al. Liver transplantation for familial amyloidotic polyneuropathy (FAP): a single-center experience over 16 years. Am J Transplant 2007;7: Azoulay D, Samuel D, Castaing D, Adam R, Adams D, Said G et al. Domino liver transplants for metabolic disorders: experience with familial amyloidotic polyneuropathy. J Am Coll Surg 1999;189: Pacheco-Moreira LF, de Oliveira ME, Balbi E, da Silva AC, Miecznikowski R, de Faria LJ et al. A new technical option for domino liver transplantation. Liver Transpl 2003;9: Inomata Y, Zeledon ME, Asonuma K, Okajima H, Takeichi T, Ishiko T et al. Whole-liver graft without the retrohepatic inferior vena cava for sequential (domino) living donor liver transplantation. Am J Transplant 2007;7: Jabbour N, Gagandeep S, Genyk Y, Selby R, Mateo R. Caval preservation with reconstruction of the hepatic veins using caval-common iliac bifurcation graft for domino liver transplantation. Liver Transpl 2006;12: Mergental H, Gouw AS, Slooff MJ, de Jong KP. Venous outflow reconstruction with surgically reopened obliterated umbilical vein in domino liver transplantation. Liver Transpl 2007;13: Azoulay D, Castaing D, Adam R, Mimoz O, Bismuth H. Transplantation of three adult patients with one cadaveric graft: wait or innovate. Liver Transpl 2000;6: Absolon KB, Hagihara PF, Griffen WO Jr, Lillehei RC. Experimental and clinical heterotopic liver homotransplantation. Rev Int Hepatol. 1965;15: Fortner JG, Beattie EJ Jr, Shiu MH, Kawano N, Howland WS. Orthotopic and heterotopic liver homografts in man. Ann Surg 1970;172:23-32.

54 The evolution of surgical techniques in liver transplantation - a review de Rave S, Hansen BE, Groenland TH, Kazemier G, de Man RA, Metselaar HJ et al. Heterotopic vs. orthotopic liver transplantation for chronic liver disease: a case-control comparison of short-term and long-term outcomes. Liver Transpl 2005;11: Terpstra OT, Metselaar HJ, Hesselink EJ, de Rave S, Groenland TH, Stibbe J et al.. Auxiliary partial liver transplantation for acute and chronic liver disease. Transplant Proc 1990;22: Ringers J, Dubbeld J, Baranski AG, Coenraad M, Sarton E, Schaapherder AF et al. A novel technique for auxiliary partial liver transplantation with reno-portal anastomosis and avoidance of the hepatoduodenal ligament. Am J Transplant 2006;6: Gubernatis G, Pichlmayr R, Kemnitz J, Gratz K. Auxiliary partial orthotopic liver transplantation (APOLT) for fulminant hepatic failure: first successful case report. World J Surg 1991;15: van Hoek B, de Boer J, Boudjema K, Williams R, Corsmit O, Terpstra OT. Auxiliary versus orthotopic liver transplantation for acute liver failure. EURALT Study Group. European Auxiliary Liver Transplant Registry. J Hepatol 1999;30: Durand F, Belghiti J, Handra-Luca A, Francoz C, Sauvanet A, Marcellin P et al. Auxiliary liver transplantation for fulminant hepatitis B: results from a series of six patients with special emphasis on regeneration and recurrence of hepatitis B. Liver Transpl 2002;8: Chenard-Neu MP, Boudjema K, Bernuau J, Degott C, Belghiti J, Cherqui D et al. Auxiliary liver transplantation: regeneration of the native liver and outcome in 30 patients with fulminant hepatic failure--a multicenter European study. Hepatology 1996;23: Bismuth H, Azoulay D, Samuel D, Reynes M, Grimon G, Majno P et al. Auxiliary partial orthotopic liver transplantation for fulminant hepatitis. The Paul Brousse experience. Ann Surg 1996;224: Sudan DL, Shaw BW Jr, Fox IJ, Langnas AN. Long-term follow-up of auxiliary orthotopic liver transplantation for the treatment of fulminant hepatic failure. Surgery 1997;122: Azoulay D, Samuel D, Ichai P, Castaing D, Saliba F, Adam R et al. Auxiliary partial orthotopic versus standard orthotopic whole liver transplantation for acute liver failure: a reappraisal from a single center by a case-control study. Ann Surg 2001;234: Jaeck D, Boudjema K, Audet M, Chenard-Neu MP, Simeoni U et al. Auxiliary partial orthotopic liver transplantation (APOLT) in the treatment of acute liver failure. J Gastroenterol 2002;37 Suppl 13: Boudjema K, Bachellier P, Wolf P, Tempe JD, Jaeck D. Auxiliary liver transplantation and bioartificial bridging procedures in treatment of acute liver failure. World J Surg 2002;26:

55 54 Chapter Kasahara M, Takada Y, Egawa H, Fujimoto Y, Ogura Y, Ogawa K et al. Auxiliary partial orthotopic living donor liver transplantation: Kyoto University experience. Am J Transplant 2005;5: Rela M, Muiesan P, Vilca-Melendez H, Dhawan A, Baker A, Mieli-Vergani G, Heaton ND. Auxiliary partial orthotopic liver transplantation for Crigler-Najjar syndrome type I. Ann Surg 1999; 229: Inomata Y, Kiuchi T, Kim I, Uemoto S, Egawa H, Asonuma K, Fujita S, Hayashi M, Tanaka K. Auxiliary partial orthotopic living donor liver transplantation as an aid for small-for-size grafts in larger recipients. Transplantation 1999;67:

56 CHAPTER 3 ANALYSIS OF DIFFERENCES IN OUTCOME OF TWO EUROPEAN LIVER TRANSPLANT CENTERS Nemes B, Polak W, Ther G, Hendriks H, Kobori L, Porte RJ, Sarvary E, de Jong KP, Doros A, Gerlei Z, van den Berg AP, Fehervari I, Gorog D, Peeters PM, Jaray J, Slooff MJ Transplant International 2006; 19:

57 56 Chapter 3 ABSTRACT Authors analyzed the differences in the outcome of two European liver transplant centers differing in case volume and experience. The first was the Transplantation and Surgical Clinic, Semmelweis University, Budapest, Hungary (SEB) and the second the University Medical Center Groningen, Groningen, The Netherlands (UMCG). We investigated if such differences could be explained. The 1-, 3- and 5-year patient survival in the UMCG was 86%, 80%, and 77% compared with 65%, 56%, and 55% in SEB. Graft survival at the same time points was 79%, 71%, and 66% in the UMCG and 62%, 55%, and 53% in SEB. Significant differences were present regarding the donor and recipient age, diagnosis mix, disease severity and operation variables, preoperative transfusion rate, vascular complications, postoperative infection rate, and need for renal replacement. To determine factors correlating with survival, a separate uni- and multivariate analysis was performed in each center individually, between study parameters and patient survival. In both centers, perioperative red blood cell (RBC) transfusion rate was a significant predictor for patient survival. The difference in blood loss can be explained by different operation techniques and shorter operation time in SEB, with consequently less time spent on hemostasis. It was jointly concluded that measures to reduce blood loss by adapting the operation technique might lead to improved survival and reduced morbidity.

58 INTRODUCTION Analysis of differences in outcome of two European liver transplant centers 57 It is an established fact that centers performing liver transplantations have different outcomes in terms of patient and graft survival and morbidity. Such differences are most often related to center volume 1-3. However, conflicting evidence does exist regarding this relation of center volume and outcome in liver transplantation. Edwards et al. observed a higher mortality in centers performing 20 or fewer liver transplantations (OLT) per year 1. However, the relevance of the 20 OLTs, as cut-off point was debated 4. McMillan et al. reported no statistical differences in patient survival between a small-volume center, performing 122 OLTs in seven years and the patient survival of the national register 5. Seiler et al. also published a comparable patient survival in 60 patients over 6 years 6. The effect of center volume on outcome seems to decrease when experience is gained over time 7. Liver transplantation is a technically and logistically very complex procedure performed for a variety of diseases in often different types of patients. Thus far no studies are published analyzing why differences in center volume and experience lead to different outcomes. In order to clarify the effect of center volume and experience on outcome after liver transplantation, a study was performed in two distinct liver transplantation centers in Europe. The first centre (SEB; Transplantation and Surgical Clinic, Semmelweis University Budapest, Hungary) is a young center, started in 1995, with a limited experience and numbers, while the other centre UMCG (Dept. Hepatobiliary Surgery & Liver Transplantation, University Medical Center Groningen, The Netherlands) is one of the oldest in Europe, started in 1979, with consequently higher numbers and experience The aim of this study was to investigate whether there were differences in outcome in terms of patient and graft survival and morbidity and to identify the causes of such differences in order to take measures to improve the outcome. PATIENTS AND METHODS Study population In order to create homogenous groups, only primary, full size, adult liver transplantations (>16 years of age), performed between 1995 and 2002, were included. Combined organ transplantations (liver and kidney, liver and lung), and pediatric cases were excluded. During the eight-year study period 333 patients had an OLT in the UMCG, 251 adults

59 58 Chapter 3 and 88 children. Among the 251 adults four patients received a kidney and liver, four patients received partial liver grafts, and two patients received a combined liver and lung transplantation. Consequently, 241 adult, full-size liver transplant patients were included in the study for the UMCG. During the same period 134 patients underwent on OLT in SEB, 126 adults and eight children. Among the 126 adults two patients received a liver and kidney; there were neither partial liver transplantations nor combined lung and liver transplantations performed: the study group of SEB thus consisted of 124 adult patients. Patients were selected according to local selection protocols of the two centers which are published previously 9,11,12. For the purpose of the study the following recipient parameters were recorded. The Child-Pugh score, whether the patient had pre-olt upper abdominal surgery, the urgency code of the patient at the time of OLT and whether the patient had complications related to the liver disease 13,14. Encephalopathy and spontaneous bacterial peritonitis (SBP) was classified according to the definition given by A.T. Blei 15. Hepatorenal syndrome (HRS) in both centers was defined, as the creatinin clearance was less than 90 ml/min and/or signs of sodium and water retention. In both centers, ABO identical or compatible grafts from hemodinamically stable, brain death, and heart beating donors with normal or near normal liver function tests were used. In both centers organ retrieval was performed according to the technique described by Starzl et al. 16. For in situ perfusion of the liver either histidine-tryptophanketoglutarate solution (HTK) or University of Wisconsin solution (UW; adenosine) were used. Anaestesiological management In the UMCG total intravenous anesthesia (using sufentanil, midazolam, and vercuronium) with volume-controlled ventilation was provided 17. In SEB, the induction was performed with etomidate, fentanyl or alfentanyl and atracurium and maintained with fentanyl, isoflurane, atracurium and dopamine Both centers used aprotinine for reduction of fibrinolysis as described by Porte et al. 21. In SEB, aprotinine was used as a standard in the beginning. From 1999, it is used on demand, in selected cases. Pulmonary artery catheter was used in both center for hemodinamical monitoring, consisting of central venous pressure (CVP), mean arterial pressure (MAP), cardiac output (CO) and pulmonary capillary wedge pressure. There was a change in SEB after the 64th OLT: a transpulmonary thermodilution (PiCCO, COLD) was used to measure CVP, MAP, CO,

60 Analysis of differences in outcome of two European liver transplant centers 59 intrathoracal blood volume and extravascular lung water. Further, both center used the regular blood gas analysis. SEB also used the Tonocap (DATEX) for the evaluation of the regional perfusion of the gastric mucosa (PHI) 19. Thrombelastography (TEG) was used in both centers intraoperatively to assess the coagulation status 18,20,22. In the UMCG red blood cell (RBC) replacement was done to maintain a hematokrit between , while in SEB it was ,21. In the UMCG Cell Saver was used up till 1997 when substantial blood loss was anticipated 17. In SEB, the Cell Saver was used routinely after Hydroxyethyl starch (HAES) was used frequently in SEB intra- and postoperatively for volume support because it was necessary due to the more extended blood loss.. HAES was only used in UMCG less frequently in cases that needed urgent volume support. Operative technique In both centers, electrocautery and argon beam coagulation were used during the recipient hepatectomy. Hemoclips and transfiction sutures or ligatures were used for larger vessels. When appropriate, a running suture for the diaphragmatic attachment was often used after hepatectomy. If necessary Liostipt and/or Surgicel or, Gelaspon were used for small, diffuse, surface bleedings. Implantation was performed in both centers by the conventional technique described by Starzl as well as the piggyback technique 23,24. In the UMCG, all conventional OLTs were performed with a veno-venous bypass (VVB) while in SEB the VVB was used selectively in conventional OLT cases 18,25. In both centers, an end to end portal vein reconstruction, with a continuous suture and growth factor, was performed. In cases of complex arterial reconstructions, when the use of donor iliac conduits was needed, both infrarenal and supratruncal approaches were used in the UMCG; while in SEB exclusively infrarenal conduits were used. Reperfusion was either sequential (portal vein followed by the artery) or simultaneous in the UMCG, while in SEB only sequential reperfusion was used. In both centers, duct to duct or hepaticojejunostomies were performed for biliary reconstruction. In the UMCG, always over a stent, while biliary stents were abolished in SEB after In the UMCG in contrast to SEB, a needle jejunostomy was introduced at the end of the procedure for feeding and return of collected bile production. Post-operative management Initially, in both centers, selective bowel decontamination (SBD), together with parenteral antibiotics was used for infection prevention 26,27. However, SEB discontinued the use of

61 60 Chapter 3 SBD in 1997 and the UMCG in Parenteral antibiotics (amoxycillin + ciprofloxacin) were continued for 24 hours in the UMCG and 96 hours in SEB, based on earlier experience in SEB Herpes viral prophylaxis with acyclovir (200mgr qid) was used longer in SEB (12 weeks) compared with the UMCG (4 weeks). In case of a CMV positive donor liver in a CMV negative recipient, a pre-emptive treatment with oral ganciclovir was used from Day10 for 14 weeks in the UMCG, while Cytotec i.v (till from 2002), then per oral ganciclovir was used in SEB. Ganciclovir dosages depended on creatinin clearance. Rejection prevention was basically different between the centers. Tailored immunosuppression was used in the UMCG. For liver diseases of possible autoimmune origin (like AIH, PBC and PSC), a triple immunosuppressive schema was used containing cyclosporine, azathioprine and low dose prednisolon in the UMCG. For all other patients, a double therapy was introduced containing tacrolimus or cyclosporine and low dose steroid. In patients with impaired renal function IL-2 antibodies (basiliximab) were used for induction therapy instead of calcineurin inhibitors until the creatinin clearance was above 50 ml/min 31. A fixed scheme was used for all patients in the SEB containing cyclosporine, azathioprine - later mycophenolate-mophetile and methylprednisolon while tacrolimus was used only occasionally and as secondary choice in case of proven hepatitis C recurrence 18,32. Also, it appeared that cyclosporine levels were kept higher in SEB during the first 6 months: the target level was μg/ml in the SEB and up to 250 ug/ml in UMCG for the 1-2 weeks, diminishing to 200 ug/ml in SEB and to ug/ml in UMCG by the second month. In both centers a liver biopsy was the gold standard for the diagnosis of rejection. However, in the UMCG protocol as well as on demand biopsies were taken while in SEB only on-demand biopsies were taken 33,34. In both centers, the Banff criteria were applied for histological grading of rejections 35. Treatment of rejection depended in both centers on the grading of rejection and clinical signs. In general, grade I acute rejection was only treated in case of liver function tests abnormalities. Grade II and III rejections were always treated. Treatment of these acute rejections consisted of steroid boluses of 1-gram per 24 hours during three consecutive days. Steroid resistant rejections, proven by biopsies were treated with ATG in the UMCG, while with ATG or OKT3 in the SEB. Liver and kidney function were monitored on a daily basis with a decreasing frequency over time on both centers. Kidney failure after liver transplantation was defined if any type of renal replacement therapy was needed. Only slight differences in post-operative surveillance were present between the centers 36. Doppler ultrasonography was done on prefixed time points in both centers and on demand when liver function deteriorated.

62 Analysis of differences in outcome of two European liver transplant centers 61 In the framework of this study. the following outcome parameters and definition of study parameters were used for both centers. Outcome parameters Patient survival was defined as the time period between the first transplantation and patient death or the end date of the study (December 2002). Graft survival was defined as the time period between the first transplantation and graft loss caused either by patient death or graft failure needing a reolt or by the end date of the study period. Complications were assessed as the number of patients with complications and the median number of complications/patient. The same was recorded for reinterventions. A reintervention was defined as any surgical, endoscopic, or invasive radiological intervention during the study period. The incidence of infectious, bleeding, vascular and biliary complications was assessed within the first year after OLT. The definitions of these complications are published elsewhere and were the same in both centers 29,30,31,37,38. Study variables Donor variables analysed were age and duration (days) of stay on the intensive care. The following recipient variables were taken into account: diagnosis, age, gender and condition of the patient as measured by Child-Pugh scores and classes, whether patients had previous operations or not, whether complications of liver disease were present or not and urgency at time of transplantation. The following peri-operative variables were scored: the type of the operation (piggyback versus conventional), whether the VVB was used or not, whether a biliary drain was used or not, the type of the preservation solution, the transfusion rate of RBC and FFP units, and the amount (ml) of thrombocyte transfusion) as well as the amount of autologous blood (ml) given during the operation, stay on the intensive care unit (days) and the intubation period (days). Operation time was defined from the incision till the closure of abdomen, the cold ischemic time (CIT) from start of the cold perfusion in the donor till the liver is removed from ice for transplantation. The warm ischemic time (WIT) was the time between the liver is removed from ice till reperfusion via portal vein or arterial (if sequential) or portal and arterial (if simultaneous reperfusion). Statistics The data were evaluated by SPSS Survival data were computed by the Kaplan-

63 62 Chapter 3 Meier method and differences in survival assessed by the log-rank test. Differences of the study variables between the centers were assessed by the Student t-test or Mann- Whitney U-test (for continuous variables) or chi-square-test (if categorical variables). To analyze the impact of the study variables within each center, differences in categorical variables were analyzed with Kaplan-Meier survival curves. Whereas for continuous variables median values were assessed in groups of patients having survived and patients who had died after transplantation (independent student t-test). Continuous variables were tested in patients surviving the transplantation and those who died first with the Levene`s test for equality of variances for homogeneicity and subsequently with the two tailed independent sample Student t-test or Mann-Whitney U-test. To identify risk factors for survival variables having a statistical influence on patient/graft survival after univariate analysis were entered by a stepwise backward manner into a multivariate analysis (Cox-regression analysis). The level of significance was set at RESULTS Patient and graft survival in the two centers are significantly different as shown in Fig 1. Patient survival Graft survival 1,0 Kaplan-Meier p = 0,001 1,0 Kaplan Meier p =0,001,9,9,8,8,7,7,6,6,5 Center,5 Center Cum Survival,4,3,2,1 0, SEB AZG Cum Survival,4,3,2,1 0, SEB AZG Patient survival (years) Graft survival (years) Figure 1. Patient and graft survival.

64 Analysis of differences in outcome of two European liver transplant centers 63 One, 3- and 5- year patient survival in the UMCG was respectively 86%, 80% and 77% compared with 65, 56 and 55% in SEB (p= 0.001). Graft survival at the same time points was, respectively, 79%, 71% and 66% in the UMCG compared with 62%, 55% and 53% in SEB (P=0.0001). In the UMCG 51 (21%) patients died after OLT compared with 53 (43%) patients in SEB (P= ). In Table 1, the distribution of deaths over time is shown. Table 1. Distribution of deaths over time. Distribution of death UMCG (241) (%) SEB (124) (%) P 1-2 months 27 (11) 26 (21) months 6 (2.5) 10 (8) months 3 (1) 7 (6) >12 months 15 (6) 10 (8) NS NOTE: Categorical variables are presented as number (percentage). In SEB (26/124, 21%) compared with the UMCG (27/241, 11%) a (P=0.012) higher number of patients died during the first two months after OLT. The same was true for the remaining first year after OLT; an additional nine patients (4%) died in the UMCG compared with 17 (14%) in SEB (P=0.036). After one year, no differences in mortality was observed between both centers. The causes of death in the UMCG were: 13 multiorgan failure (MOF) (48%), five cardio- and cerebrovascular (18%), four tumour (15%) thre graft insufficiency (11%) and two hemorrhage (7.4%). Causes of death for SEB were 17 MOF (66%), three cardio-and cerebrovascular (12%), three tumour (12%), one graft insufficiency (4)%, two hemorrhage (8)%. The focus of MOF was different in both centers. It was abdominal 61%, in UMCG and 58% in SEB (NS), pulmonal 48% in UMCG and 30% in SEB, while biliary 9% in UMCG and 44% in SEB (P=0.007). Regarding post operative morbidity significant differences were observed between both centers (Table 2). Post operative bleeding rate, number of vascular complications, rate of kidney failure were significantly higher in SEB compared with UMCG. Acute rejections and CMV infections were all significantly higher in the UMCG than in SEB. In order to explain these differences, patient and donor demographics and operative variables were compared between both centers in Table 3.

65 64 Chapter 3 Table 2. Postoperative complications. UMCG (241) SEB (124) P Primary non function (PNF) 4 (2) 6 (5) 0.08 Postoperative bleeding 38 (16) 41 (33) Vascular complications (all) 14 (6) 15 (12) Biliary complications (all) 68 (28) 23 (18) Infectious complications 90 (37) 60 (48) Kidney failure after liver 39 (16) 40 (32) transplantation Acute rejection Chronic rejection 125 (52) 16 (7) 46 (37) 6(5) Cytomegalovirus infection 81 (34) 25 (20) Patients with complications 144(60) 76 (61) 0.89 No. of complication / patient 1 (0-6) 2 (0-7) Patients with reintervention 108 (45) 60 (48) 0.51 No. of reintervention/patients 1 (0-11) 1 (0-8) 0.52 NOTE: Continuous variables are presented as median (range) and categorical variables as number (percentage). Patients in the UMCG were significantly older than patients in SEB. Between both centers, significant differences existed concerning the diagnosis of liver diseases. The proportion of patients with parenchymal liver disease was higher in SEB compared with UMCG (P = 0.006). This was mainly caused by a higher proportion of patients with post hepatitis C cirrhosis in SEB. The proportion of patients with cholestatic (P = 0.05) and metabolic diseases (P = 0.003) were significantly higher in the UMCG than in SEB, whereas in SEB more patients were transplanted with tumors as primary indication for transplantation (P = 0.004). The majority of these tumors were primary (n=2) or secondary malignancies (n=3). Regarding disease severity, it appeared that the Child-Pugh score was not different between both centers. In the UMCG, a significantly higher proportion of patients had previous abdominal operations compared with SEB (P = 0.006) and more patients were transplanted on higher than normal urgency grades (Eurotransplant Urgency Code 2 or High Urgent Code) compared with SEB (P = 0.02). Donors for patients in the UMCG were significantly older than for SEB patients (P = ) and had stayed one day (median) longer on the ICU (P = ). All operative variables but warm ischemic time was significantly different between both centers. HTK was in more than half of the transplantations the preservation solution in SEB while in the UMCG only a minority of the grafts was preserved in HTK. The most applied operation technique in the UMCG was the piggyback technique while in SEB the conventional OLT was the dominant

66 Analysis of differences in outcome of two European liver transplant centers 65 technique. When the conventional technique was used the VVB was used always in the UMCG while in SEB in only 38 (47%) of the conventional cases. Biliary drains were only used in about a quarter of the patients in SEB while in the UMCG 71% of the patients were provided with a biliary drain. The transfusion rate (RBC/FFP/Thrombocytes) was significantly higher in SEB compared with UMCG. Both median CIT and duration of the operations were shorter in SEB compared with UMCG. Table 3. Recipient and Donor demographics and operation variables. UMCG (241) SEB(124) P Recipient gender Male/Female (ratio) 137 / 104 (57 / 43) 61 / 63 (49 / 51) 0.16 Recipient age 47 (17-68) 42 (16-62) Diagnosis Fulminant hepatic failure 17 (7) 8 (6) 0.60 Parenchymal 123 (51) 82 (66) Cholestatic diseases 66 (29) 23 (18) 0.05 Metabolic diseases 27 (12) 3 (3) Tumours as primary indication 1 (0,04) 6 (5) Miscellaneous 7 (3) 3 (2) 0.78 Disease severity Child-Pugh score 9 (5-15) 9 (5-14) 0.62 Disease related complications 125 (52) 67 (54) 0.80 Previous abdominal operations 84 (35) 26 (21) Number and % of HU patients 35 (15) 8 (6) 0.02 Donor Donor age (years) 45 (7-72) 38 (12-63) Donor stay on ICU (days) 2 (1-27) 1 (0-8) Operation variables Preservation fluid UW/HTK 231/10 (96/4) 55/69 (44/56) Operation: piggyback/conventional 149/92 (62 / 38) 43 / 80 (35 / 65) Use of VVB in conventional OLTs 90 (98) 38 (47) Biliary drain used 170 (71) 35 (28) Blood transfusion [units of red blood cells (RBC)] 5 (0-100) 12 (2-50) FFP transfusion (ml) 1350 ( ) 3400 ( ) Thrombocyte transfusion (ml) 92 (0-600) 200 (20-800) CIT (min) 575 ( ) 489 ( ) WIT (min) Total operation time (min) 54 (20-129) 570 ( ) 55 (27-107) 450 ( ) NOTE: Continuous variables are presented as median (range) and categorical variables as number (percentage). HU = high urgency; UW = University of Wisconsin solution; HTK =histidine-tryptophan-ketoglutarate solution

67 66 Chapter 3 In order to see which factors in each individual centers were determinants for survival, the impact on survival of the described study variables was also analyzed for both centers separately. Only variables with a significant difference in the univariate analysis were included in a stepwise multivariate analysis. For the UMCG: recipient age, acute hepatic failure vs cholestatic diseases, WIT, RBC, FFP-, and thrombocyte transfusion and for SEB: donor age, recipient previous upper abdominal operation and intraoperative blood transfusion. In both centers peri-operative RBC transfusion rate had a significant influence on patient survival. In the UMCG recipient age and in SEB previous upper abdominal operations appeared also to have significant impact on patient survival as well (Table 4). Table 4. Multivariate (Cox regression) analysis of study parameters in relation to survival. Variables ß (± SE) P UMCG Peroperative blood transfusion 1.05 (1.02±1.07) (units of RBC) Recipient age (years) 1.04 (1.01±1.06) SEB Donor age (years) 1.05 (1.02±1.09) Peroperative blood transfusion (units of RBC) 1.05 (1.01±1.09) Previous upper abdominal operation 0.45 (0.22±0.92) 0.03 DISCUSSION This is the first open comparison between the outcomes of two liver transplant centres reported in the literature. Comparing the results of the two centres performing such a complex procedure as liver transplantation is a hazardous undertaking. Indications, surgical techniques, immunosuppressive protocols, infection prevention and postoperative surveillance depend on local protocols and medical culture. Comparing the outcome of two centres might serve as an instrument to improve procedures and the outcome in both centres. Patients transplanted in the UMCG showed a significant higher patient survival compared with patients transplanted in SEB. In Table 1, it is shown that in SEB compared with the UMCG, a significantly higher number of patients died in the early phase after transplantation. This suggests that the lower patient survival might

68 Analysis of differences in outcome of two European liver transplant centers 67 be related to the different operative techniques and peri-operative care in both centers. Analyzing the difference in recipient, donor and operation characteristics (Table 3) revealed several differences between the centers. In order to investigate whether these differences were relevant, the relation between the study variables and patient survival were analyzed per centre in a uni- and multivariate manner (Table 4). In both centers, peroperative transfusion rate (RBC/FFP/Thrombocytes) is a predictor for patient survival. In the UMCG, it appeared that also recipient age was a significant predictive factor for patient survival and in SEB the fact whether the patients had previous operations. These latter two factors, however, are given facts and cannot be influenced at time of the actual transplantation procedure. RBC transfusion rate as a measure for peroperative blood loss is an established determinator for patient survival in liver transplantation 17,21,22,31,39,40,41. The RBC transfusion rate in SEB was significantly higher compared with the UMCG. It is unlikely that the mentioned difference in transfusion policy between both centers is the only explanation for the observed increased transfusion rate. The significant higher number of FFP and thrombocyte infusions in SEB support the assumption that the observed higher transfusion rate in this center is caused by a higher peroperative blood loss. When the operation related variables are analysed several relevant differences are present (Table 3). In SEB, the proportion of patients operated with the conventional implantation technique is higher compared with the UMCG (P = 0009). In the UMCG, more patients are transplanted with the so called piggy back technique. Several reports are available showing a decreased RBC transfusion rate when the piggy back technique is used for implantation 24,39,42. Another important contributing difference between both centres for the higher transfusion rate in SEB might have been the fact that in that center a significant proportion of patients had a conventional OLT done without a VVB (P = ). One of the reported advantages of the VVB is a reduction in peroperative blood loss and more hemodinamic stability 25,39, That higher blood loss in SEB as reflected by the higher RBC/FFP/Thrombocyte transfusion rate is important because it explains also the differences in post operative complications. In SEB, a significantly higher post operative bleeding rate, infectious complications and renal insufficiency was reported 46. Evidence in the literature points towards increased blood loss as the causative factor for such complications 39-42,47,48. As support for the observed impact of per-operative blood loss in SEB is the other finding that whether the patients had previous upper abdominal surgery or not had also a significant impact on survival in SEB. In such patients, dissection of adhesions with collaterals resulting from the portal

69 68 Chapter 3 hypertension can add to the amount of blood loss. In SEB, hydroxyethyl starch (HAES) was used intraoperatively and postoperatively as well 38. The bleeding tendency after OLT is a critical point. The role of HAES in the haemorheology is contradictory 49. Some reports declare that the administration of 6% HAES (200 kdal/06) in clinically relevant doses can even improve the microcirculation 50. Because of the acute bigger blood loss, the volume of intraoperative HAES infusion was higher than the recommended limit in some cases in SEB during the early phase of OLT program. Another contributing factor to the observed differences in per-operative blood loss is the time taken for meticulous haemostasis. The fact that in SEB the median duration of the operative procedure was two hours shorter (P = 0.001) compared with that in the UMCG, is explained by the fact that in the UMCG more time is spent on haemostasis especially during the explantation of the native liver. Several other differences between the centers might have contributed to the different outcome. In the UMCG, significantly more biliary complications occurred compared with SEB (0.043). This might be related to the use of a biliary drain, which was used more often in the UMCG. Evidence in the literature points towards an increased biliary complication rate when stents are used There is a higher number of biliary complications in UMCG, but their spectrum, origin, and severity were different compared with SEB. In UMCG, the main component of biliary complications (60%) was leakage after removal of the biliary drain, 6-12 weeks after OLT. In contrary, in SEB, the main component of biliary problems was the necrosis, which was associated to the increased rate of HAT In the UMCG, significantly more acute rejections were observed compared with SEB (P = 0.007). This could be explained by the milder immunosuppression scheme in the UMCG compared with SEB. The higher level of maintenance immunosuppression in SEB, however, might also have contributed to the higher infection rate and renal failure rate in the SEB patients. On the other hand, in the UMCG, more acute rejections occurred which needed to be treated. This could have caused the higher number of CMV infections in the UMCG. In conclusion; the difference in patient survival between both centres can for the greater part be explained by the difference in per operative RBC/FFP/Thrombocyte transfusion rate i.e. blood loss. It is conceivable that the difference in blood loss is explained by different operation techniques and style. Adaptation of these factors may lead to a decrease in transfusion rate with subsequent improvement of survival. Other observed differences such as immunosuppressive schemes and the use of biliary stents - although not predictive for survival - can add to the improvements in both centers. As a result

70 Analysis of differences in outcome of two European liver transplant centers 69 of this analysis measures have been taken in SEB to adapt the peri-operative protocols regarding hemostasis, prevention of HAT (low hematocrit and post operative thrombosis prophylaxis), and infection prevention. Thus far this has led to an improvement of one and two year patient survival of 80 and 76%, respectively, after 2002 ACKNOWLEDGEMENTS Hereby the authors wish to thank Ms. Anikó Maléth, Ms. Márta Lakatos and Ms. Irén Tenkes for their technical assistance and support in collecting the data. REFERENCES 1. Edwards EB, Roberts JP, McBridge MA, Schulak JA, Hunsicker LG. The effect of the volume of procedures at transplantation centres on mortality after liver transplantation. N Eng J Med 1999; 341: Axelrod DA, Guidinger MK, McCullough KP, Leichtman AB, Punch JD, Merion RM. Association of center volume with outcome after liver and kidney transplantation. Am J Transplant. 2004; 4: Birkmeyer JD, Siewers AE, Finlayson EV. Hospital volume and surgical mortality in the United States. N Engl J Med 2002; 346: Laks MP, Hillebrand DJ, Bettschart V. Volume of procedures at transplantation centers and mortality after liver transplantation. N Eng J Med 2000; 342: McMillan RW, Uppot R, Zibari GB, Aultman DF, Dies DF, McDonald JC. Can low volume liver transplant centers be successful? The Regional Transplant Center of Willis-Knighton & Louisiana State University Medical Center. The first liver transplants. J La State Med Soc 1999; 151: Seiler A, Renner EL, Schilling M, Rieder H, Reichen J, Bischoff P, Buchler MW. Liver transplantation in a small center: feasibility, efficacy and prospects. Chirurg 1997; 68: Belle SH, Detre KM. Beringer KC. The relationship between outcome of liver transplantation and experience in new centers.liver Transpl Surg. 1995;1: Perner F. Liver Transplantation in Hungary Orv Hetil 1996; 137(42 Suppl 1): 2358

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72 Analysis of differences in outcome of two European liver transplant centers Starzl TE, Marchioro TI, Vom Kadula HN et al. Homotransplantation of the liver in human. Surg Gynecol Obstet, 1963; 117: Miyamoto S, Polak WG, Geuken E et al.liver transplantation with preservation of the inferior vena cava. A comparison of conventional and piggyback techniques in adults. Clin Transplant. 2004;18: Slooff MJH, Bams JL, Sluiter WJ, Klompmaker IJ, Hesselink EJ, Verwer R, A modified cannulation technique for veno-venous bypass during orthotopic liver transplantation. Transplant Proc 1989; 21: Slooff MJ, Rosman C, Van der Waaij D. Selective decontamination of the digestive tract in hepatobiliary surgery: a concept. HPB Surg 1990; 2:1 27. Rosman C, Klompmaker IJ, Bonsel GJ, Bleichrodt RP, Arends JP, Slooff MJH. The efficacy of selective bowel decontamination as infection prevention after liver transplantation. Transplant Proc 1990; 22: Zwaveling JH Infection prophylaxis in liver transplantation. Crit Care Med 2003; 31: Gerlei Z, Galffy Z, Remport A, Kobori L. New challenges in liver and kidney transplantation. Mycoses 2002; 45 (Suppl 2): Jakics J, Galffy Z, Hernold L, Racz A, Perner F. [The use of teicoplanin for Grampositive infections in patients with kidney transplantation] Article in Hungarian Orv Hetil. 1996; 137: Hendriks HG, van der Meer J, de Wolf JT, Peeters PM, Porte RJ, de Jong K, et al..intraoperative blood transfusion requirement is the main determinant of early surgical re-intervention after orthotopic liver transplantation. Transpl Int. 2005; 17: Nemes B, Sárváry E, Kóbori L, Gerlei Zs, Patonai A, Perner F, Weszelits V, Járay J and Schaff Zs. Serum hepatitis C virus-ribonucleotide acid monitoring after liver transplantation. The Hungarian experience. Dig Liver Dis. 2005; 37: Klompmaker LJ, Gouw AS, Haagsma EB. Selective treatment of early acute rejection after liver transplantation: effects on liver, infection rate, and outcome. Transpl Int 1997; 10: Patonai A, Nemes B, Görög D, Kóbori L, Sótonyi P Jr, Fehérvári I, Weszelits V, Doros A, Dallos G, Schaff Z, Perner F. [Pathologic evaluation of orthotopic liver transplantation in Hungary]Orv Hetil 2001; 142: Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997; 25: Kok T, Slooff MJH, Thijn CJ, Peeters PMJG, Verwer R, Bijlefeld CMA et al. Routine Doppler ultrasound for the detection of clinically unsuspected vascular complications in early postoperative phase after orthotopic liver transplantation. Transpl Int. 1998; 11: 272

73 72 Chapter Zwaveling JH, Maring JK, Klompmaker J, Haagsma EB, Bottema JT, Laseur M, et al. Selective decontamination of the digestive tract to prevent postoperative infection: a randomized placebo-controlled trial in liver transplant patients. Crit Care Med 2002; 30: Nemes B, Sárváry E, Sótonyi P, Gerlei Z, Doros A, Gálffy Z et al. Factors in association with sepsis after liver transplantation: the Hungarian experience. Transplant Proc 2005; 37: Moreno-Gonzalez E, Meneu-Diaz JG, Fundora Y, Ortega P, Moreno Elola-Olaso A, Garcia Garcia I et al. Advantages of the piggyback technique on intraoperative transfusion, fluid consumption, and vasoactive drugs requirements in liver transplantation: a comparative study. Transplant Proc 2003; 35: Palomo Sanchez JC, Jimenez C, Moreno Gonzalez E, Garcia I, Palma F, Loinaz C, et al. Effects of intraoperative blood transfusion on postoperative complications and survival after orthotopic liver transplantation. Hepatogastroenterology 1998; 45: Mueller AR, Platz KP, Krause P, Kahl A, Rayes N, Glanemann M, Lang M, Wex C, Bechstein WO, Neuhaus P. Perioperative factors influencing patient outcome after liver transplantation. Transpl Int. 2000;13 Suppl 1:S Reddy KS, Johnston TD, Putnam LA, Isley M, Ranjan D. Piggyback technique and selective use of veno-venous bypass in adult orthotopic liver transplantation. Clin Transplant 2000; 14(4 Pt 2): Belghiti J, Ettorre GM, Durand F, Sommacale D, Sauvanet A, Jerius JT, et al. Feasibility and limits of caval-flow preservation during liver transplantation. Liver Transpl. 2001; 7: Yan LN, Wang W, Li B, Lu SC, Wen TF, Zeng Y, et al. Venovenous bypass ahead of mobilization of the liver in orthotopic liver transplantation. Hepatobiliary Pancreat Dis Int 2003; 2: Schwarz B, Pomaroli A, Hoermann C, Margreiter R, Mair P. Liver transplantation without venovenous bypass: morbidity and mortality in patients with greater than 50% reduction in cardiac output after vena cava clamping. J Cardiothorac Vasc Anesth 2001;15: Nemes B, Kóbori L, Fehérvári I, Fazakas J, Gerlei Zs, Ther G, et al. Comparison of the results of conventional, crossclamp and piggyback technique in liver transplantation. Magy Seb 2005; 58: Cabezuelo JB, Ramirez P, Acosta F, Torres D, Sansano T, Pons JA, et al. Does the standard vs piggyback surgical technique affect the development of early acute renal failure after orthotopic liver transplantation? Transplant Proc 2003; 35: Li GS, Ye QF, Xia SS, Chen ZS, Zeng FJ, Lin ZB, et al. Acute respiratory distress syndrome after liver transplantation: etiology, prevention and management. Hepatobiliary Pancreat Dis Int 2002; 1: 330

74 Analysis of differences in outcome of two European liver transplant centers van der Plaats A, t Hart NA, Morariu AM et al. Effect of University Wisconsin organpreservation solution on haemorheology. Transplant Int 2004; 17: Juttner B, Kuse ER, Elsner HA et al. Differential platelet receptor expression following hydroxyethyl starch infusion in thrombocytopaenic orthotopic liver transplantation recipients. Eur J Anaesthesiol. 2004; 21: Ferraz-Neto BH, Mirza DF, Gunson BK, Ismail T, Mayer AD, Buckels JA, et al. Bile duct splintage in liver transplantation: is it necessary? Transpl Int 1996; 9 Suppl: S Nemec P, Ondrasek J, Studenik P, Hokl J, Cerny J. Biliary complications in liver transplantation. Ann Transplant 2001; 6: Urbani L, Catalano G, Biancofiore G, Bindi L, Consani G, Bisa M, et al. Surgical complications after liver transplantation. Minerva Chir 2003; 58:

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76 CHAPTER 4 LIVER TRANSPLANTATION WITH PRESERVATION OF THE INFERIOR VENA CAVA. A COMPARISON OF CONVENTIONAL AND PIGGYBACK TECHNIQUES IN ADULTS Miyamoto S, Polak WG, Geuken E, Peeters PMJG, de Jong KP, Porte RJ, van den Berg AP, Hendriks HG, Slooff MJH Clinical Transplantation 2004; 18:

77 76 Chapter 4 ABSTRACT The aim of this study is to analyse a single centre s experience with two techniques of liver transplantation (OLT), conventional (CON-OLT) and piggyback (PB-ES), and to compare outcome in terms of survival, morbidity, mortality and post-operative liver function as well as operative characteristics. A consecutive series ( ) of 167 adult primary OLT were analysed. Ninety-six patients had CON-OLT and 71 patients had PB-ES. In the PB-ES group two revascularization protocols were used. In the first protocol reperfusion of the graft was performed first via the portal vein followed by the arterial anastomosis (PB-seq). In the second protocol the graft was reperfused simultaneously via portal vein and hepatic artery (PB-sim). One-, 3- and 5-yr patient survival in the CON-OLT and PB-ES groups were 90, 83 and 80%, and 83, 78 and 78%, respectively (p=ns). Graft survival at the same time points was 81, 73 and 69%, and 78, 69 and 65%, respectively (p=ns). Apart from the higher number of patients with cholangitis and sepsis in CON-OLT group, morbidity, retransplantation rate and post-operative liver and kidney function were not different between the two groups. The total operation time was not different between both groups (9.4 h in PB-ES vs h in CON-OLT), but in PB-ES group cold and warm ischaemia time (CIT and WIT), revascularization time (REVT), functional and anatomic anhepatic phases (FAHP and AAHP) were significantly shorter (8.9 h vs h, 54 min vs. 63 min, 82 min vs. 114 min, 118 min vs. 160 min and 87 min vs. 114 min, respectively, p < 0.05). RBC use in the PB-ES group was lower compared to the CON-OLT group (4.0 min vs units, p < 0.05). Except for WIT and REVT there were no differences in operative characteristics between PB-Sim and PB-Seq groups. The WIT was significantly longer in PB-Sim group compared with PB-Seq group (64 min vs. 50 min, p < 0.05); however REVT was significantly shorter in PB-Sim group (64 min vs. 97 min, p < 0.05). Results of this study show that both techniques are comparable in survival and morbidity; however PB-ES results in shorter AAHP, FAHP, REVT and WIT as well as less RBC use. In the PB-ES group there seems to be no advantage for any of the revascularization protocols.

78 Liver transplantation with preservation of the inferior vena cava 77 INTRODUCTION Conventional orthotopic liver transplantation (CON-OLT) with resection of the native liver of the recipient together with the retrohepatic inferior vena cava (IVC) and interposition of the donor IVC attached to the new graft, has been the most common surgical approach in liver transplantation 1,2. Although incidentally used and mentioned by pioneers in liver transplantation in the early 1960s, Tzakis et al. in 1989 were the first to fully describe a new technique of implantation of the donor liver, the piggyback orthotopic liver transplantation (PB-OLT) 3-5. PB-OLT is a procedure preserving the full length of the recipient IVC with subsequent anastomosis of the suprahepatic donor IVC to the joined common orifices of the recipient left and middle hepatic veins. In the original series by Tzakis et al. all adult cases were performed with veno-venous bypass (VVB) 5. Currently several modifications of the PB-OLT are used. Instead of only using the joint orifices of the hepatic veins this orifice is enlarged by an incision of the IVC in caudal direction in order to widen the anastomosis 6. Belghitti et al. was the first to use a side to side cavo-cavostomy to join both caval veins without complete occlusion of IVC and without the need for a VVB 7. Additionally, many centres currently using this PB- OLT technique consider VVB redundant, because of the preservation of the caval flow. Others replaced the VVB by a temporary portocaval shunt (TPCS) Among the advantages claimed for piggyback techniques are a shorter operation time (OT), shorter anhepatic phase and warm ischemia time (WIT), and a reduction of blood loss By the preservation of caval flow to the heart, patient hemodynamics are kept more stable and kidney function is less harmed. Also the total costs of the operative procedure and hospital charges are reported to be reduced 12,14. Consequently the PB- OLT has become increasingly popular among liver transplantation centres all over the world. The aim of this paper is to describe and analyse a single centre s experience with such PB-OLT technique and compare the outcome in terms of survival morbidity, mortality and liver function. Furthermore operative characteristics are compared between patients having a conventional OLT and those having a piggyback OLT in the same time period.

79 78 Chapter 4 PATIENTS AND METHODS Between January 1994 and December 2000, 190 adult patients (> 16 years old) underwent a primary full-size OLT at our hospital. Patients with a retransplantation or combined transplantations with other organs were excluded. Ninety-six (50.5%) patients had their donor liver implanted in the conventional way without preservation of the recipient IVC (CON-OLT group) and 94 (49.5%) patients had their graft implanted with a piggyback technique (PB-OLT group). The distrubution of both techniques over the 7 yr of the study period is shown in Fig % 80% 60% 40% 20% 0% PB-OLT group CON-OLT group Figure 1. The distribution of conventional and piggyback technique in OLT between 1994 and In the first years of the study the CON-OLT was the preferred method for implantation and the minority was PB-OLT. During the study this preferrence was reversed in favor of the piggyback technique. Three types of the hepatic outflow reconstruction were performed in PB-OLT group (Table 1). In 16 patients hepatic outflow was reconstructed by an end-to-end anastomosis between the common orificies of the recipient hepatic veins and the suprahepatic IVC cuff of the donor (PB-EE group). In seven patients the donor IVC was closed at both ends and the donor IVC was anastomosed side-to-side to the preserved recipient IVC

80 Liver transplantation with preservation of the inferior vena cava 79 (PB-SS group). In remaining 71 patients the caval anastomosis was made in end-to-side fashion (PB-ES group). In order to have homogeneous groups of procedures in this analysis the CON-OLT group (n=96) was compared with the piggyback end to side group (PB-ES group) (n=71). Donor selection criteria are described earlier by our group 15. All grafts were procured from heart-beating brain-dead ABO identical or compatible donors with standard donor procurement techniques and all grafts were flushed and preserved in University of Winsconsin (UW) preservation solution. Table 1. Outflow reconstruction and revascularisation techniques. Recontruction type of IVC Reperfusion Total Sequential Simultaneous CON-OLT PB-EE PB-SS PB-ES 48 (5) 23 (2) 71 NOTE: ( ) number of patients with temporary portocaval shunt Abbreviations: CON-OLT conventional technique, PB-EE piggyback end to end technique, PB-SS piggyback side to side technique, PB-ES piggyback end to side technique Surgical technique All CON-OLT patients were transplanted with a VVB as described by Shaw et al. or as modified by us 1,16. All grafts were sequentially reperfused. This means that the portal vein anastomosis was completed first and reperfused followed by the hepatic artery anastomosis. All PB-ES were performed without a VVB. In seven patients a TPCS was constructed because of splanchic congestion. The suprahepatic IVC of the donor was connected in a end to side fashion to a logitudinal opening in ventral wall of the recipient IVC. In the patients transplanted with the PB-ES technique two reperfusion protocols were used. In the first protocol (PB-seq) graft reperfusion was performed directly after completion of the portal vein anastomosis and subsequent arterial reperfusion was done. In the second protocol (PB-sim) both portal vein and arterial anastomosis were completed, followed by simultaneous reperfusion via portal vein and artery. The choice of protocol was decided by the surgeon. The distribution of the vascular reconstruction techniques is summarised in Table 1. In the CON-OLT group 82 patients (85%) had a duct to duct biliary reconstruction, in 12 patients (13%) a hepaticojejunostomy was made, one (1%) patient recieved a hepaticoduodenostomy and another (1%) died on the table before biliary anastomosis

81 80 Chapter 4 could be made. In the PB-ES group 63 patients (89%) received a duct to duct biliary recontruction and in eight patients (11%) a hepaticojejunostomy was performed. Transfusion policy The transfusion regimen was standarised as published earlier by our group 17. For this report it is relevant that packed allogeneic and autologous red blood cells (RBC) were transfused to maintain hematocrit between 0.25 and Infection prevention Until September 2000, selective bowel decontamination (SBD) was used for infection prevention as described earlier by our group 18. Additionally, parenteral antibiotics were given (tobramycin and cefroxim) for 48 hours. After September 2000, only parenteral antibiotics were given for 48 hours perioperatively (amoxicillin/clavunate and ciprofloxacin). For Herpes virus prophylaxis oral acyclovir was given for four weeks. In case of a CMV-positive graft in a CMV-negative recipient oral ganciclovir was given from day 10 onwards up to week 12. Immunosupression Two types of immunosupresive schemes were used during these 7 years of the study. For patients with autoimmune diseases like autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis a triple immunosuppressive scheme (prednisolon, azathioprine and cyclosporine A). All other patients recieved a double immunosuppressive scheme, consisting of prednisolon together with either tacrolimus (Tac) or CyA. In patients with a compromised kidney function calcineurin inhibitors were withheld until creatinine clearance was over 50 ml/min. If renal insufficiency was anticipated, induction therapy with basiliximab was started. Only clinical relevant and biopsy proven rejections were treated with methylprednisolon boluses on three consecutive days. Steroid resistant rejections were treated either by conversion to a Tac scheme or by ATG treatment. Outcome Parameters Patient survival was defined as the time period between transplantation and the end of follow-up or patient death. Graft survival was defined as the time period between transplantation and the end of follow-up or graft loss, either by patient death or by graft failure necessitating retransplantation.

82 Liver transplantation with preservation of the inferior vena cava 81 Morbidity was assessed by analysing the incidence of biliary, vascular, bleeding, infectious and septic complications within 1 year after transplantation. The inclusion criteria for such complications are shown in an ealier report of our group 19. Complication and intervention rates were defined as the proportions of patients with one or more complication or reintervention. Additionally, complications were expressed as the mean number of complications per patient and reinterventions as the mean number of the sum of endoscopic, radiological or surgical interventions per patient. Kidney function was determined by calculating the delta creatinine clearance (ΔCcr). The ΔCcr is defined as Ccr at day seven after OLT subtracted by the last known preolt Ccr. The ΔCcr was compared between both study groups and were stratified according to the presence or abcense of pre-olt hepatorenal syndrome (HRS). HRS was defined according to the criteria given by Arroyo et al. 20. Alkaline phosphatase (AP), aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), γ-glutamyltranspeptidase (GGT), lactate dehydrogenase (LDH) and total bilirubin were assesed on day 1, 3, 5, 7, 10, 14 and 28 after OLT. Operative characteristics (definitions see Table 5) were assessed by analysing the total operation time (OT), the cold ischemia time (CIT), the warm ischemia time (WIT), functional anhepatic phase (FAHP), anatomical anhepatic phase (AAHP) and the revascularization time (REVT). The number of units of allogeneic and/or autologous (RBC) required during the operation was used as an indicator for blood loss. The duration of intensive care unit (ICU) stay after OLT was recorded. The WIT, FAHP, AAHP and REVT in PB-ES were compared separately between two subgroups according to the different reperfusion techniques; PB-seq and PB-sim. All surviving patients had a minimal follow up of 2 years. The overall median follow-up period was 4.6 years (range years). The median follow-up period for CON-OLT and PB-ES was 5.8 ( ) and 2.8 ( ) years, respectively. Statistical Analysis Cumulative patient and graft survival rates were calculated according to the Kaplan- Meier s method. Differences between both groups were investigated using the logrank test. Categorial variables were analyzed using the Pearson s Chi-square test or the Fisher s exact test. Comparison of medians and means between two groups were done using the Mann-Whitney U-test and the independent sample T-test, respectively. The level of significance was set at Statistical analysis was performed using the SPSS/ PC+ Advanced Statistics Package, Version 11.0.

83 82 Chapter 4 RESULTS Demographic data about the patients in both groups are shown in Table 2. Table 2. Demographic data of the recipient based on type of OLT. CON-OLT n=96 PB-ES n=71 PB-seq n=48 PB-sim n=23 Gender Male 55 (57) 36 (51) Female 41 (43) 35 (49) Age 44 (20-68) 47 (17-63) Diagnosis Parenchymal disease 41 (43) 45 (63) Cholestatic 29 (32) 13 (18) 10 3 Acute liver failure 5 (5) 4 (6) 3 1 Metabolic 11 (12) 6 (9) 4 2 Others 10 (10) 3 (4) 3 0 Child-Pugh class A <7 6 (17) 14 (20) 10 4 B (7-9) 37 (39) 30 (42) C (>9) 26 (45) 27 (38) 19 8 Variceal bleeding 26 (27) 19 (27) 1 18 Encephalopathy 22 (23) 15 (21) 10 5 Hepatorenal syndrome 11 (12) 10 (14) 6 4 Malignancy 6 (6) 11 (15)* 5 6 Previous operation 36 (38) 23 (32) 15 8 High urgency No 78 (81) 65 (92) Yes 18 (19) 6 (8) 5 1 NOTE. Continuous variables are presented as median (range) and categorical variables as number (percentage). PB-ES vs CON-OLT *p=0.05 Apart from a borderline significant higher number of patients with a malignancy (hepatocellular carcinoma and cholangiocarcinoma) in the PB-ES group, no other differences were observed between both groups. The median age of the donors in the CON-OLT group was 40 years (range 13-63) and it was significantly lower (p<0.01) in comparison to the PB-ES group (median age of the donor 47 years (range 7-69)). There were no differences between two groups in the ICU stay of the donors. Patient and graft survival was not different between the CON-OLT group and the PB-ES group. The 1-, 3- and 5-yr patient survival in the CON-OLT and PB-ES groups were 90, 83 and 80% and 83, 78 and 78% respectively (p = ns). Graft survival rate at 1, 3 and

84 Liver transplantation with preservation of the inferior vena cava 83 5 yr were 81, 73 and 69% in CON-OLT group and 78, 69 and 65% with PB-ES group (p = ns). As shown in table 3, morbidity was not different between the CON-OLT and PB-ES groups. Patients with episodes of sepsis and cholangitis occured more frequently in the CON-OLT group compared to the PB-ES group, but difference did not reach significance (p = 0.067). Table 3. Complications according to the type of OLT. CON-OLT n=96 PB-ES n=71 PB-seq n=48 PB-sim n=23 Biliary complications Leakage 10 (10) 8 (11) 3 (6) 5 (21) Stenosis 11 (12) 7 (13) 3 (6) 4 (17) Necrosis 2 (2) 2 (3) 2 (4) 0 (0) ITBL 7 (7) 4 (6) 2 (4) 2 (9) Abdominal bleeding 10 (10) 8 (11) 3 (6) 5 (21) Vascular complications HAT 4 (4) 4 (6) 3 (6) 1 (4) PVT 1 (1) 1 (1) 1 (2) 0 (0) VOTO 0 (0) 0 (0) 0 (0) 0 (0) Infectious complications Abdominal 23 (24) 12 (17) 8 (17) 4 (17) Cholangitis 14 (15) 4 (6)* 4 (8) 0 (0) Sepsis 14 (15) 4 (6)* 2 (4) 2 (9) Complications (per patients) 1,0 (1-6) 0.8 (1-7) 0,7 1,0 Reintervention (per patient) 1,1 (0-8) 0,9 (0-11) 0,7 1,4 ICU stays (days) 4 (1-52) 4 (1-64) 3 (1-35) 5 (1-64) NOTE. Continuous variables are presented as median (range) and categorical variables as number (percentage). *p=0.067 CON-OLT vs. PB-ES Abbreviations: ITBL- ischemic type biliary lesions, HAT hepatic artery thrombosis, PVT portal vein thrombosis, VOTO venous outflow obstruction Neither individual complications nor proportion of patients with complications and complication rates showed a statistically significant difference. This counted for the subgroups in the PB-ES group as well. Reintervention rate was 49,5% in CON-OLT group and 44,3% in PB-ES group (p = ns). Retransplantation rate in CON-OLT group was 17% (16 patients) in comparison with 11% (8 patients) in PB-ES group (p = ns). No differences were observed in the postoperative period regarding GGT serum levels between CON-OLT and PB-ES group. However bilirubin level was significantly lower at certain time points in PB-OLT group (Fig. 2).

85 84 Chapter 4 T o ta l b iliru b in umol/l PB Con * 7* 10 14* Days after OLT Figure 2. Postoperative total bilirubin in CON-OLT and PB-ES group =p<0.05 After OLT also ASAT, ALAT and LDH levels in PB-ES group declined faster compared to the CON-OLT group. However, significance was only reached at a few time points (data not shown). After 3 and 4 weeks AP levels in the CON-OLT group were significantly lower compared with these in the PB-ES group. No significant differences in LFTs existed between PB-sim and PB-seq groups. ΔCcr did not differ between the CON-OLT and PB-ES group (Table 4). Also the need for renal replacement therapy was not different between both groups. In the CON-OLT group nine (9%) patients required postoperative renal support compared to nine (13%) patients in the PB-ES group (p = ns). Table 4. Renal function after CON-OLT and PB-ES OLT. ΔCcr in patients CON-OLT PB-ES p-value With HRS 30 ( ) (n = 11) 18 (-8-78) (n = 10) NS Without HRS -8 (-93-81) (n = 85) -18 ( ) (n = 61) NS In Table 5 the operative characteristics in the PB-OLT and PB-ES groups are shown. The total OT was not different between both groups. However, in the PB-ES group the CIT, WIT, REVT and FAHP and AAHP were all significantly shorter compared to the figures in the CON-OLT group. The median number of RBC units transfused in the PB-ES group was 4.0 (range 0 33) and significantly lower compared to the CON-OLT group (mean number of 10.0 units, range 0 51).

86 Liver transplantation with preservation of the inferior vena cava 85 Table 5. Operative characteristics in CON-OLT and PB-ES. CON-OLT n=96 PB-ES n=71 P value OT (hrs) 10 (5,5-18) 9,4 (4,8-14,6) P= ns CIT (hrs) 10,7 (3,4-16,5) 8,9 (4,6-14,2) P<0,01 WIT (min) 63 (38-104) 54 (20-91) P<0,01 AAHP (min) 114 (59-278) 87 (45-196) P<0,01 FAHP (min) 160 (92-349) 118 (59-303) P<0,01 REVT (min) 114 (72-220) 82 (46-242) P<0,01 RBC (units) 10 (0-51) 4 (0-33) P<0,01 NOTE. Continuous variables are presented as median (range) OT; total operation time - from incision until closure of the abdomen; CIT; cold ischemia time - from in situ flushing of the donor organ until the liver is removed from ice for implantation; WIT; warm ischemia time - time between the liver is removed from ice until reperfusion via portal vein, hepatic artery or both; FAHP; functional anhepatic phase - from the closure of hepatic artery and portal vein until reperfusion; AAHP; anatomical anhepatic phase - from explantation of the native liver until reperfusion of the new graft; REVT; revascularization time - time between removal of the liver from ice and reconstruction of both of the portal vein and the hepatic artery. Comparison of operative characteristics between the PB-seq and PB-sim groups revealed that WIT in the PB-sim group was significantly longer, but REVT was significantly shorter than in PB-seq group (Table 6). No differences were observed in OT, CIT, FAHP, AAHP and RBC transfusion rate between both reperfusion protocols. Table 6. Operative characteristics in PB-seq and PB-sim group. PB-seq n=48 PB-sim n=23 p value OT (hrs) 9,3 (4,8-13,8) 9,4 (6,9-14,6) p=ns CIT (hrs) 9,4 (4,6-14,2) 7,5 (4,9-13,0) p=ns WIT (min) 50 (20-75) 64 (46-91) p<0,01 AAHP (min) 82 (45-195) 96 (53-196) p=ns FAHP (min) 115 (59-303) 124 (63-219) p=ns REVT (min) 97 (48-242) 64 (46-91) p<0,01 RBC (units) 4 (0-33) 6 (0-20) p=ns NOTE. Continuous variables are presented as median (range) DISCUSSION This study compares the conventional technique of liver transplantation with the piggyback technique. In each group one unique operation technique was used by the same group of surgeons. In our hands both techniques have equal outcome in terms

87 86 Chapter 4 of patient and graft survival and morbidity. Because in the PB-ES group more patients had a malignancy, we repeated the analysis excluding patients with malignancy. There was still no statistical significant difference in patient survival between both groups (data not shown). Also other groups reported no difference in patient and graft survival between patients operated with one of these techniques 21,22. Morbidity was not different between both groups as well. The only exception is that in the CON-OLT group a borderline significant higher number of patients with septic episodes and cholangitis were observed compared to the PB-ES group. Two explanations are available for this discrepancy. One reason for the increased sepsis rate in the CON-OLT group is the fact that the majority of patients in this group were operated before 1998 when still the high prednison dosages were used in the immunosupresive schemes, which bears the inherent risk for more infections. It is conceivable that with the currently lower dosing schemes of prednisolon the difference in sepsis rate will disappear between both techniques. The second explanation is that patients with higher blood loss have an increased risk for infections including sepsis 23. In the CON-OLT group a significantly higher number of RBC transfusions were given compared to the PB-ES group. The lower RBC transfusion rate in patients undergoing PB-OLT has also been reported by others 11,22,24,25. So far it seems reasonable to conclude that outcome in terms of survival and morbidity for both techniques is equal. The OT was not different between the groups. This is probably caused by the fact that the extra time gained by ommiting the VVB and the isolation of the IVC in the CON- OLT group is again lost due to the separation of the native liver from the IVC in the PB-ES group. This absence of a difference in operation time between both techniques is in contrast to several reports demonstrating significantly shorter total operation time, when using the piggyback technique 11,12,22,24. Regarding the other operative characteristics striking differences were observed between CON-OLT and PB-ES groups. Cold ischemia time was nearly two hours shorter in the PB-ES group compared to that in the CON-OLT group. This however is not due to the technique itself but related to the fact in the PB-ES group donors were significantly older compared to the CON-OLT group. When using older donor livers it has become our policy to keep CIT as short as possible. The anhepatic phases, functional as well as anatomical, were significantly shorter in the PB-ES group compared with the CON-OLT group. The shorter FAHP can be explained by the fact that in the piggyback technique the patency of the portal vein is kept intact till just before the actual removal of the native liver. In the CON-OLT group this is not possible due to the cannulation of the portal vein for the VVB in an early

88 Liver transplantation with preservation of the inferior vena cava 87 phase of the recipient hepatectomy. On basis of the data presented we are not able to conclude if this shorter anhepatic phase is of any consequence. No significant differences existed in the early (uptill day 5) graft function assesed by liver function tests in PB-ES and CON-OLT group. However, in the later postoperative course we observed quicker normalisation of bilirubin, ALAT and LDH serum levels in PB-ES group. Clinically this may reflect a quicker recovery of the patients after PB-ES. Although the difference in bilirubin level between both groups can also reflect a higher use of RBC transfusions in the CON-OLT group. Others however, demonstrated that reduction in the lenght of the anhepatic phase significantly correlated with reduction of platelet and volume replacement during the surgery resulting in shorter ICU and hospital stay 12. No difference was observed in postoperative renal function between two groups, which is in accordance to other studies comparing conventional and piggyback technique 11,22,26. Whether sequential or simultaneous graft reperfusion deserves preference is difficult to state. Sequential reperfusion in context of the PB-ES operation offers the advantage of a significantly shorter WIT. However, this does not translate in better or quicker recuperation of liver functions. This was also reported by Post et al. 27. Simultaneous reperfusion offers a quicker arterial reperfusion of the graft. REVT in the PB-sim group was significantly shorter compared to the REVT in the PB-sim group. However, we did not observe any differences in biliary complications between patients reperfused simultanously or sequentially. However in two studies the incidence of biliary complications was higher in the sequential reperfusion group 28,29. The main advantage of piggyback technique is preservation of IVC and avoidance of VVB. However according to the results of two large series this technique carries the risk of 1,5-2,5% of intra- or postoperative outflow problems of the graft 30,31. This incidence seems not to be significantly higher to that (1,7%) in large conventional OLT series as reported by Glanemann et al. 32. In the current study no IVC-related complications were observed in PB-ES, which proves that this technique is safe and effective in regard to outflow reconstruction. PB-OLT is feasible in almost all transplant candidates 22,33,34. Preservation of IVC enables avoidance of splanchic congestion during OLT by using a TPCS 8,10. Our policy is to use a TPCS only in selected cases. However, results from a recent prospective study comparing PB-OLT with and without TPCS showed significantly better hemodynamic status and preservation of renal function during anhepatic phase and reduction of transfusion requirements in patients with a TPCS 35.

89 88 Chapter 4 In conclusion the results of this study show that both techniques are comparable in terms of survival and morbidity. No increased incidence of outflow problems was seen in our series. The piggyback technique results in shorter anhepatic phase, REVT and WIT, which may be responsible for a quicker recovery of liver function. Blood loss was significantly reduced, when PB-ES technique was used. So far we did not observe any advantage in the PB-ES group of any of the two reperfusion protocols. REFERENCES 1. Shaw BW Jr, Martin DJ, Marquez JM, Kang YG, Bugbee AC Jr, Iwatsuki S Griffith BP, Hardesty RL, Bahnson HT, Starzl TE. Venous bypass in clinical liver transplantation. Ann Surg 1984: 200: Starzl TE, Groth CG, Brettschneider L, Penn I, Fulginiti VA, Moon JB, Blanchard H, Martin AJ Jr, Porter KA. Orthotopic homotransplantation of the human liver. Ann Surg 1968: 168: Calne RY, William R. Liver transplantation in man. I. Observation on technique and organization in five cases. Br Med J 1968: 4: Starzl TE. Experience in hepatic transplantation. Philadelphia: WB Saunders, Tzakis A, Todo S, Starzl TE. Orthotopic liver transplantation with preservation of the inferior vena cava. Ann Surg 1989: 210: Cherqui D, Lauzet JY, Rotman N, Duvoux C, Dhumeaux D, Julien M, Fagniez PL. Orthotopic liver transplantation with preservation of the caval and portal flows. Technique and results in 62 cases. Transplantation 1994: 58: Belghiti J, Panis Y, Sauvanet A, Gayet B, Fekete F. A new technique of side to side caval anastomosis during orthotopic hepatic transplantation without inferior vena caval occlusion. Surg Gynecol Obstet 1992: 175: Belghiti J, Noun R, Sauvanet A. Temporary portocaval anastomosis with preservation of caval flow during orthotopic liver transplantation. Am J Surg 1995: 169: Steib A, Saada A, Clever B, Lehmann C, Freys G, Levy S, Boudjema K. Orthotopic liver transplantation with preservation of portocaval flow compared with venovenous bypass. Liver Transpl Surg 1997: 3: Tzakis AG, Reyes J, Nour B, Marino IR, Todo S, Starzl TE. Temporary end to side portacaval shunt in orthotopic hepatic transplantation in humans. Surg Gynecol Obstet 1993: 176: 180.

90 Liver transplantation with preservation of the inferior vena cava Gonzalez FX, Garcia-Valdecasas JC, Grande L, Pacheco JL, Cugat E, Fuster J, Lacy AM, Taura P, Lopez-Boado MA, Rimola A, Visa J. Vena cava vascular reconstruction during orthotopic liver transplantation: a comparative study. Liver Transpl Surg 1998: 4: Hosein Shokouh-Amiri M, Osama Gaber A, Bagous WA, Grewal HP, Hathaway DK, Vera SR, Stratta RJ, Bagous TN, Kizilisik T. Choice of surgical technique influences perioperative outcomes in liver transplantation Ann Surg 2002: 231: Jovine E, Mazziotti A, Grazi GL, Ercolani G, Masetti M, Morganti M, Pierangeli F, Begliomini B, Mazzetti PG, Rossi R, Paladini R, Cavallari A. Piggy-back versus conventional technique in liver transplantation: report of a randomized trial. Transpl Int 1997: 10: Lerut JP, Molle G, Donataccio M, De Kock M, Ciccarelli O, Laterre PF, Van Leeuw V, Bourlier P, de Ville de Goyet J, Reding R, Gibbs P, Otte JB. Cavocaval liver transplantation without venovenous bypass and without temporary portocaval shunting: the ideal technique for adult liver grafting? Transpl Int 1997: 10: Maring JK, Klompmaker IJ, Zwaveling JH, Kranenburg K, Ten Vergert EM, Slooff MJ. Poor initial graft function after orthotopic liver transplantation: can it be predicted and does it affect outcome? An analysis of 125 adult primary transplantations. Clin Transplant 1997: 11: Slooff MJ, Bams JL, Sluiter WJ, Klompmaker IJ, Hesselink EJ, Verwer R. A modified cannulation technique for veno-venous bypass during orthotopic liver transplantation. Transplant Proc 1989: 21: Hendriks HG, Meijer K, de Wolf JT, Klompmaker IJ, Porte RJ, de Kam PJ, Hagenaars AJ, Melsen T, Slooff MJ, van der Meer J. Reduced transfusion requirements by recombinant factor VIIa in orthotopic liver transplantation: a pilot study. Transplantation 2001: 71: Rosman C, Klompmaker IJ, Bonsel GJ, Bleichrodt RP, Arends JP, Slooff MJ. The efficacy of selective bowel decontamination as infection prevention after liver transplantation. Transplant Proc 1990: 22: Sieders E, Peeters PMJG, Ten Vergert EM, Bijleveld CMA, de Jong KP, Zwaveling JH, Boersma GA, Slooff MJH. Analysis of survival and morbidity after pediatric liver transplantation with full size and technical-variant grafts. Transplantation 1999: 68: Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, Reynolds TB, Ring-Larsen H, Scholmerich J. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996: 23: Busque S, Esquivel CO, Concepcion W, So SK. Experience with the piggyback technique without caval occlusion in adult orthotopic liver transplantation. Transplantation 1998: 65: 77.

91 90 Chapter Reddy KS, Johnston TD, Putnam LA, Isley M, Ranjan D. Piggyback technique and selective use of veno-venous bypass in adult orthotopic liver transplantation. Clin Transplant 2000: 14: Mor E, Jennings L, Gonwa TA, Holman MJ, Gibbs J, Solomon H, Goldstein RM, Husberg BS, Watemberg IA, Klintmalm GB. The impact of operative bleeding on outcome in transplantation of the liver. Surg Gynecol Obstet 1993: 176: Salizzoni M, Andorno E, Bossuto E, Cerutti E, Livigni S, Lupo F Maritano M, Massano G, Marchesa PE, Pinna Pintor M, Porelli P, Romagnoli R, Schieroni R, Zamboni F. Piggyback techniques versus classical technique in orthotopic liver transplantation: a review of 75 cases. Transplant Proc 1994: 26: Stieber AC. One surgeon s experience with the piggyback versus the standard technique in orthotopic liver transplantation: is one better than the other? Hepatogastroenterology 1995: 42: Jones R, Hardy KJ, Fletcher DR, Michell I, McNicol PL, Angus PW. Preservation of the inferior vena cava in orthotopic liver transplantation with selective use of veno-venous bypass: the piggy back operation. Transplant Proc 1992: 24: Post S, Bleyl J, Golling M, Herfarth C, Otto G. Modes of reperfusion in clinical liver transplantation. Langenbecks Arch Chir 1995: 380: Massarollo PC, Mies S, Raia S. Simultaneous arterial and portal revascularization in liver transplantation. Transplant Proc 1998: 30: Sankary HN, McChesney L, Frye E, Cohn S, Foster P, Williams J. A simple modification in operative technique can reduce the incidence of nonanastomotic biliary strictures after orthotopic liver transplantation. Hepatology 1995: 21: Navarro F, Le Moine MC, Fabre JM, Belghiti J, Cherqui D, Adam R, Pruvot FR, Letoublon C, Domergue J. Specific vascular complications of orthotopic liver transplantation with preservation of the retrohepatic vena cava: review of 1361 cases. Transplantation 1999: 68: Parrilla P, Sanchez-Bueno F, Figueras J, Jaurrieta E, Mir J, Margarit C, Lazaro J, Herrera L, Gomez-Fleitas M, Varo E, Vicente E, Robles R, Ramirez P. Analysis of the complications of the piggy-back technique in 1,112 liver transplants. Transplantation 1999: 67: Glanemann M, Settmacher U, Langrehr JM, Stange B, Haase R, Nuessler NC, Lopez-Hanninen E, Podrabsky P, Bechstein WO, Neuhaus P. Results of end-to-end cavocavostomy during adult liver transplantation. World J Surg 2002: 26: Belghiti J, Ettorre GM, Durand F, Sommacale D, Sauvanet A, Jerius JT, Farges O. Feasibility and limits of caval-flow preservation during liver transplantation. Liver Transpl 2001: 7: 983.

92 Liver transplantation with preservation of the inferior vena cava Fleitas MG, Casanova D, Martino E, Maestre JM, Herrera L, Hernanz F, Rabanal JM, Pulgar S, Solares G. Could the piggyback operation in liver transplantation be routinely used? Arch Surg 1994: 129: Figueras J, Llado L, Ramos E, Jaurrieta E, Rafecas A, Fabregat J, Torras J, Sabate A, Dalmau A. Temporary portocaval shunt during liver transplantation with vena cava preservation. Results of a prospective randomized study. Liver Transpl 2001: 7: 904.

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94 CHAPTER 5 END-TO-SIDE CAVAL ANASTOMOSIS IN ADULT PIGGYBACK LIVER TRANSPLANTATION Polak WG, Nemes BA, Miyamoto S, Peeters PMJG, de Jong KP, Porte RJ, Slooff MJH Clinical Transplantation 2006; 20:

95 94 Chapter 5 ABSTRACT No consensus exists regarding the optimal reconstruction of the cavo-caval anastomosis in piggyback orthotopic liver transplantation (PBLT). The aim of this study was to analyze our experience with end-to-side (ES) cavo-cavostomy. Outcome parameters were patient and graft survival and surgical complications. During the period full-size PBLT in 137 adult patients were performed with ES cavo-cavostomy without the routine use of temporary portocaval shunt (TPCS). In 12 patients (8%) this technique was used for implantation of second or third grafts. Venovenous bypass was not used in any case and TPCS was performed only in eight patients (6%). One-, three- and five-yr patient and graft survival were 84%, 79% and 75%, and 81%, 74% and 69%, respectively. The median number of intraoperative transfusion of packed red blood cells (RBC) was 2.0 (range 0 33) and 30% of the patients (n = 43) did not require any RBC transfusion. Surgical complications of various types were observed after 49 LT (34%) and none of the complications was specifically related to the technique of ES cavo-cavostomy. Our experience indicates that PB-LT with ES cavo-cavostomy is a safe procedure, can safely be performed without the routine use of a TPCS, has a very low risk of venous outflow obstruction and can also be used effectively during retransplantations.

96 INTRODUCTION End-to-side caval anastomosis in adult piggyback liver transplantation 95 In conventional orthotopic liver transplantation (LT) the retrohepatic inferior vena cava (IVC) is included in the hepatectomy of the native liver. This technique requires complete cross-clamping of the IVC and the portal vein with all hemodynamic consequences and possible complications reported before 1. To obviate these sequellas the routine use of the venous-venous bypass (VVB) was proposed 2. In the late 1980s LT with preservation of the IVC, the so called piggyback technique has been introduced. The piggyback technique was first described in the early years of LT 3-4. It was popularized in 1989 by Tzakis et al. 5. The PB technique offers several advantages to the conventional technique such as the avoidance of the VVB and its related complications like hypothermia, hemolytic and thrombembolic complications, avoidance of retrocaval dissection, less phrenic nerve injuries, shortening of warm ischemia time (WIT), and operation time Also perioperative blood loss is reported to be lower when using the PB technique 11,12,15. Therefore, many centers adopted this PB technique 11,12, However, no consensus exists regarding the optimal reconstruction of the venous anastomosis with the recipient IVC. In the original series by Tzakis et al. the caval anastomosis was performed between the suprahepatic part of donor IVC and the common orifice of all three hepatic veins or the common orifice of two hepatic veins (left and middle or right and middle). This is the so called classical piggyback technique 5. Some authors have modified this caval anastomosis by enlarging the orificies of hepatic veins by an incision in the anterior wall of the recipient IVC Belghiti et al. developed a technique of caval anastomosis in a side-to-side fashion 8. In this technique both ends of the donor IVC are closed and an anastomosis is made between two newly created openings: one on the anterior wall of the recipient IVC and one on the posterior wall of the donor IVC. The third type of caval anastomosis is the end-to-side (ES) technique, first described by Cherqui et al. 22. In their original series the caudal end of the donor infrahepatic IVC was closed and the anastomosis was made between the end of the donor suprahepatic IVC and a longitudinal incision on the anterior wall of the recipient IVC. Additionally, a temporary portocaval shunt (TPCS) was used routinely by these authors. At the University Medical Center Groningen (UMCG) the ES cavo-cavostomy, as described by Cherqui et al., is the preferred technique for the IVC anastomosis. However, a temporary portocaval shunt is not routinely used 14,23. The ES cavo-cavostomy is not widely used and only two reports have described the results of this PB technique, both

97 96 Chapter 5 in a small number of patients 11,22. The aim of this report is to describe our experience with ES caval anastomosis without the routine use of temporary portocaval shunt in adult full-size LT, particularly in terms of outcome and complications specific to this PB technique. PATIENTS AND METHODS From January 1995 till December 2002, a total of 292 full-size LT were performed in 256 adult (>16 years) patients. Patients transplanted with the conventional technique (n=121) or with the piggyback technique, using an end-to-end (n=16) or side-to-side caval anastomosis (n=7) were excluded from this analysis. In the remaining 148 LT performed in 137 patients, the piggyback implantation with an ES caval anastomosis was used. After exclusion of two patients who died intraoperatively before the caval anastomosis could be made, the study group consisted of 146 LT performed in 137 patients. Demographic data of the patients at time of the transplantation (primary and retransplantations) are shown in table 1. Table 1. Patient demographics at time of the liver transplantations. Recipient s age (yr) 47 (17-68) Indication for LT (%) Non-cholestatic liver cirrhosis 71 (48) Cholestatic liver cirrhosis 32 (22) Acute liver failure 13 (9) Metabolic liver disease 11 (7) Retransplantation 14 (9) Other* 8 (5) Child-Pugh class A 23 (16) B 67 (46) C 56 (38) Previous abdominal operation 55 (38) High urgency transplantation 17 (12) NOTE. Continuous variables are presented as median (range) and categorical variables as number (percentage). *Cystic fibrosis (2), polycystic liver disease (2), Budd-Chiari syndrome (1), non-alcoholic steatohepatitis (1), nodular regenerative hyperplasia (1), congenital liver fibrosis (1)

98 End-to-side caval anastomosis in adult piggyback liver transplantation 97 Twelve (8%) of the 146 LT were second transplantations (five after previous piggyback LT with ES caval anastomosis and seven after previous conventional LT) and two third transplantations (both after previous piggyback ES LT). Seven of 146 cases were combined organ transplantations; five liver-kidney and two liver-lung transplantations. Donors were selected as described earlier by our group 24. All grafts were obtained from heart-beating hemodynamically stable, brain death, ABO identical or compatible donors with standard donor procurement techniques using UW solution for preservation. As of the year 2000 aprotinin was routinely given intraoperatively in patients without renal dysfunction, to reduce hyperfibrinolytic bleeding 25. Two types of immunosuppressive schemes were used during these eight years of the study. For patients with autoimmune diseases, like autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis a triple immunosuppressive scheme (cyclosporine A, azathioprine and low dose steroids) was used. All other patients received a double immunosuppressive scheme, consisting of low dose steroids together with either tacrolimus or cyclosporine A. Only biopsy proven rejections were treated with boluses of methylprednisolon on three subsequent days. Steroid resistant rejections were treated either with conversion to tacrolimus for patients on cyclosporine A or with antithymocyte globulin for patients on tacrolimus. Infection prevention was routinely used as described earlier 14. In order to screen for vascular complications (arterial, portal and venous outflow) Doppler ultrasound was performed at postoperative day 1, 4 and 7, and on demand, as indicated by graft dysfunction 26. Protocol biopsy was taken at the end of the first postoperative week. In the second week a cholangiogram was performed via the biliary drain to verify for biliary complications. In case of fever, cultures were taken from blood, drains still present and/or from secretions (urine, sputum, bile). Surgical technique Recipient hepatectomy was performed with preservation of the IVC in a standard manner as described elsewhere 8,11. In summary, the hepatoduodenal ligament was dissected and the common bile duct was ligated and transected, whereas hepatic artery and portal vein were kept intact as long as possible to shorten the anhepatic phase (AHP). After mobilization of the liver, the right hepatic vein was oversewn or closed with a vascular stapler device. On the backtable, the caudal end of the donor IVC was shortened and closed over a silastic tube (for venting) with a purse string suture arround it. The suprahepatic IVC was left open and the opening extended by a longitudinal midline incision on the posterior wall (Fig. 1).

99 98 Chapter 5 Figure 1. Posterior aspect of the donor liver graft. The caudal end of the IVC is ligated and the cranial end is left open, and enlarged by midline incision on the posterior wall of the IVC. Next the native hepatic artery and portal vein were ligated and transected. The middle and left hepatic vein were oversewn and the liver was removed. TPCS was used only in selected cases to minimize the risk of splanchic congestion in patients without portal hypertension or in case of very large caudate lobe that encircled the IVC. After tangential clamping of recipient IVC, occluding aproximately a third of its lumen, the anterior wall of the IVC was incised longitudinally and the graft is placed orthotopically and rolled to the right. ES anastomosis between donor and recipient IVC was performed using two running sutures (Fig. 2). Figure 2. The recipient inferior vena cava (RIVC) is clamped tangentially and the anterior wall of the IVC is incised longitudinally. The graft (G) is placed orthotopically and rolled to the right. The beginning of ES anastomosis between donor IVC (DIVC) and recipient IVC is seen.