Pediatr Surg Int (2014) 30:39–46 DOI 10.1007/s00383-013-3436-z
ORIGINAL ARTICLE
Reconstructing single hepatic artery with two arterial stumps: biliary complications in pediatric living donor liver transplantation Karan D. Julka • Tsan-Shiun Lin • Chao-Long Chen Chih-Chi Wang • Andrzej L. Komorowski
•
Accepted: 14 November 2013 / Published online: 30 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Introduction Liver grafts can at times have two hepatic arterial stumps. This can result in a dilemma whether to reconstruct single or both the arteries. Hepatic artery (HA) thrombosis is the most dreaded complication in pediatric living donor liver transplantation (LDLT) as it can result in biliary complications and subsequent graft loss. We herein report the feasibility of reconstructing single hepatic artery in pediatric living donor liver transplantation having two arterial stumps in the liver graft. Materials and methods From 2008 to 2010, 87 pediatric patients undergoing LDLT were divided into three groups. Group 1 (n = 20): two HA stumps with two HA reconstruction, Group 2 (n = 22): two HA stumps with one HA reconstruction and Group 3 (n = 45): one HA stump with one HA reconstruction. The decision regarding the reconstruction of single or multiple HAs was made depending on the preoperative radiological and intraoperative assessments. Results The incidence of HA thrombosis (p = 0.126) and biliary complications (p = 0.617), was similar in the three groups. Conclusion Single HA reconstruction does not increase the risk of biliary strictures in pediatric LDLT recipients having dual hepatic arterial stumps in the liver graft.
K. D. Julka and T.-S. Lin have contributed equally to this work. K. D. Julka (&) T.-S. Lin C.-L. Chen C.-C. Wang A. L. Komorowski Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Song, Kaohsiung 833, Taiwan e-mail: [email protected]
Keywords Hepatic artery Hepatic artery thrombosis Biliary complication Pediatric Living donor liver transplantation Abbreviations LDLT Living donor liver transplantation HA Hepatic artery PELD Pediatric end-stage lived disease HAT Hepatic artery thrombosis CTA Computed tomography angiography MRA Magnetic resonance angiography DUS Doppler ultrasound
Introduction Living donor liver transplantation (LDLT) has been introduced as one of the procedures that can compensate for the shortage of available grafts in pediatric liver transplantation [1–5]. Hepatic artery (HA) thrombosis is the most feared complication in LDLT, especially in pediatric transplantation. The incidence of hepatic artery thrombosis (HAT) in pediatric LDLT cases, as reported in various studies, is around 18 % [6–9]. The liver grafts can at times have a varied hepatic arterial anatomy. The incidence of multiple HAs in left lobe liver grafts is about 25.8 % [10]. In pediatric patients, the left lobe (segments II, III and IV), the left lateral segment (segments II and III) and extended left lateral segment (segments II, III and part of IV) are mainly used. The complexity is increased as the caliber of the arteries in the pediatric recipients is small, resulting in size discrepancy. Earlier studies have considered hepatic artery (HA) size \2 mm a relative contraindication to LDLT [2, 11]. The microsurgical techniques in LDLT,
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introduced by the Kyoto group [12], has been routinely adopted by many liver transplant centers resulting in a better outcome after reconstructing even small caliber hepatic arteries. Even with the recent technical advancement of liver transplant procedures, whether to reconstruct both HA stumps on such a graft is not well addressed. Suehiro et al. [13] reported a higher incidence of biliary stricture caused by single HA artery reconstruction in presence of the two HAs in the graft. In contrast, studies have demonstrated that reconstructing only 1 HA is sufficient in most LDLTs [12, 14]. However, all these studies are limited to mostly adult recipients. Hence the aim of our study was to assess the safety and feasibility of reconstructing single HA in the presence of dual HA stumps of liver graft in pediatric LDLT recipients and its impact on the incidence of biliary strictures.
Methods
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Briefly, in the donor, all the arterial structures were carefully dissected and preserved. The proper HA was exposed up to the bifurcation of the left (or middle HA) and the right HA. The plane of division of HA was determined by the length and size of the artery, its relation with the cutting plane of the liver and the position of the arteries. Before division of the arteries, an intra-operative Doppler ultrasound (DUS) was done to confirm the vascular anatomy. HA reconstruction The variations encountered in the graft HAs are shown in Fig. 1. A detailed technique of HA reconstruction has been described in detail elsewhere [18]. The recipient’s HA considered to be the primary candidate for HA reconstruction was the left HA. In case of dual HAs, the second arterial anastomosis was done with the artery to segment IV (n = 7) and left Gastroepiploic artery (n = 13) in the recipient. No interposition vascular grafts were required in any of the cases.
Patients Criteria for reconstructing second HA From March 2008 to September 2010, a total of 87 pediatric recipients (\18 years of age) underwent LDLT procedures at Kaohsiung Chang Gung Memorial Hospital, Taiwan. The Institutional Review Board (IRB) of the Kaohsiung Chang Gung Memorial Hospital (KCGMH) in Taiwan approved the study under number 101-0930B. Data included the recipient and donor demographic data, operative techniques and details, postoperative outcome, types of grafts used, indications for transplantation, complications and long-term follow up. The median follow up period was 48 months (range 12–96). The grafts were divided into three groups. In Group 1, the graft had two HA stumps and both were reconstructed (n = 20); in Group 2, the graft had two HA stumps and only one of them was reconstructed (n = 22); and in Group 3 graft had single HA stump which was reconstructed (n = 45). Donor evaluation Donor graft selection was done according to the volumetric results of CT calculations [15]. Routinely, pre-operative assessment of the vascular anatomy of the potential donor was done by Doppler ultrasound of the potential liver graft, CT angiography (CTA) and magnetic resonance angiography (MRA). Operative techniques The techniques of donor hepatectomy and recipient hepatectomy have been described in detail elsewhere [16, 17].
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Initially the larger diameter arterial branch was reconstructed first and if back-bleeding from the second HA was poor or absent, it was reconstructed. In case, the arterial flow signals were not detected in all the liver segments of the graft on intra operative DUS, post reconstruction of the larger diameter branch, the second arterial branch was reconstructed. The intra operative DUS was also used to confirm the patency of reconstructed HV and portal vein by determining the waveforms and velocities of the respective vasculature. The techniques of biliary reconstruction are described in detail elsewhere [19]. A biliary-enteric reconstruction, using a Roux-en-Y technique (n = 77), was done in recipients undergoing LDLT for biliary atresia, Alagille syndrome or presence of multiple small bile ducts in the liver graft. Duct-to-duct anastomosis (n = 10) was done in the rest of cases. No internal or external biliary stents were used. Post-operative immunosuppression and anti-coagulation The immunosuppression regimen included cyclosporine (Novartis, Basel, Switzerland). The dose was adjusted to a minimum level required so as to avoid an episode of rejection. The dose of Mycophenolate Mofetil (Roche Basel, Switzerland) was 10 mg/kg. Methyl prednisolone initial dose was 20 mg/kg, intravenous during surgery and then reduced to 3 mg/kg/day on post-operative day (POD) 1 and gradually tapered to 0.5 mg/kg/day on POD 6. In
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Fig. 1 Branching patterns and transection line of donor graft hepatic arteries. a Single left hepatic artery arising from proper hepatic artery; b two arteries, artery to segment IV and left hepatic artery arising from proper hepatic artery; c two hepatic arteries, branch from left gastric artery and left hepatic artery arising from proper hepatic artery; d two arteries, artery to segment III and segment II arising
from right hepatic artery. The dotted line indicates the plane of artery transection. LHA left hepatic artery, RHA right hepatic artery, GDA gastroduodenal artery, LGA left gastric artery, PHA proper hepatic artery, LS left lateral segment, exLS left lateral segment with part of segment IV, LL left lobe. Artery drawn in the bold line was divided and attached to the graft
majority of the cases, steroids were discontinued at 6 months post-transplantation. Heparin or fresh frozen plasma was administered after operation to maintain prothrombin time and activated coagulation time at around 15 and 150 s, respectively. Dipyridamole was (4 mg/kg/day) was taken orally in lieu of heparin from post-operative day 8 and continued for 3 months.
presence of a notable anastomotic narrowing, on the basis of symptoms or on the basis of abnormal liver function tests. Biliary complications, including leaks and strictures, were commonly managed with non-operative measures including radiological interventions like endoscopic biliary drainage and percutaneous trans-hepatic biliary drainage using balloon dilation or biliary stents.
Assessment of outcomes and complications
Statistical analysis
In the recipients, routine DUS was done post liver transplantation to determine adequate blood flow and velocities in the reconstructed arteries and veins. A diagnosis of vascular stenosis or thrombosis was suspected when repeated Doppler studies failed to detect arterial spectrum at anastomotic site. This was then confirmed by 3D CTA which showed either non visualization or narrowing of the arteries with no contrast signal in the distal arterial segment. Magnetic resonance cholangiography was done in cases where there was suspicion of biliary complications. Bile leakage was defined as the presence of bile material in a closed suction drain that persisted for more than 7 days post-surgery or as presence of biloma around the area of anastomosis. Biliary leakage through the cut surface, diagnosed by radiological and endoscopic means, was excluded from this study. Anastomotic biliary stricture was defined as an intrahepatic biliary dilation [3 mm in
Survival statistics were calculated by the Kaplan–Meier analysis and survival curves were compared using Log rank test. The Kruskal–Wallis one-way analysis of variance was used to compare three independent variables. To compare frequencies, we used the v2 test. The multivariate Cox regression model was performed on variables found to be significant on univariate analysis. Statistical significance was defined as p \ 0.05. All statistics were performed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA).
Results The demographic and operative characteristics of the three study groups are shown in Tables 1, 2. The median size of the donor HAs was smaller in Group 1 (p = 0.03) as compared with Group 3.
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Table 1 Demographic characteristics among the groups Category
Group 1
Group 2
Group 3
p value (\0.05)
Donor age (years)
35 (28–39)
35.5 (28.75–42.5)
37 (31–41)
0.444
8:12
10:12
20:25
0.928
12 (9–36)
11.5 (8–12)
12 (9–36)
0.127
13:7
13:9
21:24
0.337
17:1:2:0
21:0:1:0
40:2:1:2
0.563
17:3:0
20:1:1
34:10:1
0.317
11.5 (7–12.75)
12 (9.75–13)
13 (6.5–19)
0.196
Donor sex M:F Recipient age (months) Recipient sex M:F Diagnosis BA:metabolic:alagellie:neonatal hepatitis Type of graft LS:exLS:LL PELD
BA biliary atresia, LS left lateral segment, exLS extended left lateral segment, PELD pediatric end stage liver disease score, GRWR graft recipient weight ratio
Table 2 Comparison of surgical factors among the three groups Category
Group 1
Group 2
Group 3
p value
Graft artery size (mm)
2.0 (1.0–3.0)
2.5 (1–3.5)
2.5 (1.5–4.0)
0.03
Recipient artery size (mm)
2.5 (1.5–4.0)
2.5 (2.0–4.0)
2.5 (1.5–3.5)
0.578
Bile duct size (mm)
3.0 (2.0–4.5)
3.0 (1.5–5.5)
3.0 (1.5–6.0)
0.486
Cold ischemic time (min)
34 (23–45)
40 (27–57)
36 (17–59)
0.161
Warm ischemic time (min)
43 (26–56)
38 (24–63)
40 (20–70)
0.186
Duration of surgery (min)
610 (520–765)
508 (473–720)
521 (413–720)
0.001
Duration of HA anastomosis (min)
90 (55–130)
56 (30–115)
55 (30–140)
0.001
Duration of biliary reconstruction (min)
70 (15–100)
47 (15–110)
50 (10–140)
0.112
18:2 235 (60–1000)
18:4 113 (30–550)
40:5 200 (15–900)
0.662 0.05
18:2
20:2
39:6
0.869
Number of bile ducts One:two Blood loss (ml) Type of biliary reconstruction Roux-limb:duct-to-duct
Group 1: graft had two HA stumps and both were reconstructed (n = 20), Group 2: graft had two HA stumps and only one of them were reconstructed (n = 22) and Group 3: graft had single HA stump, which was reconstructed (n = 45) HA hepatic artery All data are expressed as median and range Table 3 Biliary complications among the three groups Biliary complication
Group 1 (%)
Group 2 (%)
Group 3 (%)
Biliary strictures
2/20 (10)
2/22 (9.09)
4/45 (9.3)
Bile leaks
1/20 (5)
1/20 (4.45)
5/45 (11.62)
Group 1: graft had two HA stumps and both were reconstructed (n = 20), Group 2: graft had two HA stumps and only one of them were reconstructed (n = 22) and Group 3: graft had single HA stump which was reconstructed (n = 45)
The total duration of surgery (p = 0.001), the duration of HA reconstruction (p = 0.001) and the average intraoperative blood loss (p = 0.05), were significantly higher
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in Group 1. The rest of the variables were comparable among all the three groups (Table 3). HA-related complications Hepatic artery thrombosis was observed in six (6.9 %) cases. The incidence of HAT was similar among all the three groups (p = 0.126) (Fig. 2). One recipient was successfully treated with systemic thrombolytic agent. Inj. urokinase was administered with initial loading dose of 4,400 IU/kg ideal body weight over 10 min, followed by maintenance dose of continuous infusion of 4,400 IU/h/kg ideal body weight over 12 h. The other recipient received
Pediatr Surg Int (2014) 30:39–46 Fig. 2 Overall survival of hepatic artery thrombosis-free cases a and biliary stricture-free cases b among group 1 (two hepatic artery stump with two reconstructions), group 2 (two hepatic artery stumps with one reconstruction) and group 3 (one hepatic artery stump with one reconstruction). The survival curves are comparable in all the three groups
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A
At risk 20
no event occurred
22
16
10
8
6
45
24
18
12
8
B
At risk 20
6
1
1
1
22
16
10
7
6
45
24
19
13
8
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re-transplantation. Both the recipients later had uneventful recovery. Four cases with HAT were recognized early and managed by re-exploration of the recipient and revascularization of the arteries. Revascularizations were done either with same artery, after trimming (n = 2) or using an alternative artery (n = 2). Out of these four patients with HAT, two patients died due to subsequent graft failure and multi-organ dysfunction. HAT occurred in 6/77 patients undergoing Roux-en-Y biliary reconstruction and 0/10 patients undergoing duct-to-duct reconstruction. Biliary complications The overall incidence of biliary strictures was 9.19 % (8/87). (Table 3) All the strictures were anastomotic biliary strictures. The incidence of biliary strictures was comparable among the three groups (p = 0.617) (Fig. 2). Majority of the strictures occurred within first 3 months post-transplantation (6/87). The remaining two strictures occurred in 4th and 5th months post- transplantation. The incidence of biliary leakage in our study was 8 % (7/87) and they were managed non-surgically. Three of those seven patients subsequently developed biliary strictures. Most of the bile leaks (5/7) occurred within the first postoperative month. The incidence of biliary stricture was similar in Roux-en-Y (7/77) and duct-to-duct (1/10) reconstruction (p = 0.989). Survival curves The overall patient survival was comparable among the three groups (p = 0.103, Fig. 2). There were 11/87 cases of mortality (12.7 %), including portal vein thrombosis (n = 3), HAT (n = 1), sepsis and multi-organ dysfunction (n = 3), post-transplant lymphoproliferative disorder (n = 1), severe acute on chronic rejection with hepatic venous thrombosis (n = 1), lung hemorrhage (n = 1) and intra-cerebral hemorrhage (n = 1).
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Discussion The results aptly demonstrate that the incidence of biliary strictures and HAT in liver with single HA reconstruction were comparable to the liver grafts with dual HA reconstruction. It is well known that hepatic grafts have fine, intra-hepatic arterial networks [19] so that even reconstruction of only one of the two HAs may maintain minimum arterial flow for the graft to survive. This fact has been the founding basis of our study. It has been reported in the earlier study by Uchiyama et al. [20] that the incidence of biliary strictures was higher in recipients in whom only one HA out of the two was reconstructed. The reported overall incidence of HA thrombosis was 2.3 %. Majority of the recipients in the study were adults. Sugawara et al. [21] have reported no difference in overall patient survival and the incidence of biliary stricture in cases in which only one HA was reconstructed out of the two present. The reported incidence of HAT was 1.4 %. Their experience was again only limited to adult patients. In the same study, cold saline test was used to confirm intra hepatic arterial communications on the backtable. In a systematic review done by Bekker et al. [7] involving 21 studies, the reported incidence of HAT was 8.3 % among pediatric recipients. However, most of these studies were done in pediatric recipients having single HA in the liver graft. The incidence of biliary strictures, in the group with only single HA reconstruction out of the two HAs, was 58 % as reported in the study by Sugawara et al. and 44 % as reported by Uchiyama group, which is much more than that reported in our study. The overall incidence of biliary strictures reported in our study is lower than those reported in other studies, varying from 11 to 40 % [22]. Problems with pediatric recipients
Risk factors for biliary strictures The various risk factors analyzed for incidence of anastomotic biliary strictures are shown in Table 4. On univariate analysis, by Kaplan–Meier using log rank test, we compared cumulative anastomotic biliary stricture with free survival curves in each factor. The factors found to be significant were size of the graft HA, size of the recipient HA stump, size of the graft bile duct, history of prior bile leak and history of hepatic artery thrombosis (Table 4). On further multivariate analysis using Cox regression test, only the history of prior bile leak was found to be significant independent risk factor for anastomotic biliary strictures (p = 0.002 and 95 % CI of 6.603–164.679; Hazard ratio of 32.975).
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Most of the pediatric recipients receiving LDLT usually have a previous history of Kasai procedure for biliary atresia which is associated with severe adhesions in hilar area. This can result in more operative complications and intra-operative blood loss [23]. However, in our study, there was no significant increase in biliary strictures (p = 0.178), duration of surgery (p = 0.367) or intra operative blood loss (p = 0.454) in recipients having previous history of Kasai procedure. Another concern is need for multiple arterial inflow options for dual HA reconstruction. To address this problem, we advocate dissecting distally in the hilum so as to make available the branches of HA as inflow arteries [21].
Pediatr Surg Int (2014) 30:39–46 Table 4 Analysis of risk factors associated with anastomotic biliary stricture
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Category
Univariate analysis p value
Multivariate analysis p value
Hazard ratio
95 % CI
Graft artery size
0.036
0.897
–
–
Recipient artery size
0.047
0.360
–
–
Donor age
0.455
–
–
–
Recipient age
0.409
–
–
Donor sex
0.666
–
–
–
Recipient sex
0.390
–
–
–
Type of graft Indication for transplantation
0.631 0.076
– –
– –
– –
PELD
0.945
–
–
–
Cold ischemic time
0.526
–
–
–
Warm ischemic time
0.728
–
–
–
Duration of surgery
0.903
–
–
–
Blood loss
0.586
–
–
–
Non-reconstructed artery
0.651
–
–
–
Hepatic artery thrombosis
0.001
0.986
–
–
Type of biliary reconstruction
0.699
–
–
–
Duration for HA anastomosis
0.358
–
–
–
Duration for biliary anastomosis
0.801
–
–
–
p \ 0.05 is significant
Number of bile ducts
0.940
–
–
–
PELD pediatric end stage liver disease score, HA hepatic artery, CI confidence interval
Size of bile duct
0.038
0.073
–
–
History of previous bile leakage
0.002
0.002
32.975
6.603–164.679
Why do only single arterial reconstructions when we can do both? With the recent improvements in technique and use of microsurgery for HA reconstruction, it is now possible to reconstruct multiple HA with acceptable complication rate [18]. However, we have to be discrete in our decision to reconstruct multiple HA, especially in pediatric recipients. From Table 2, it is evident that the median size of graft HA was significantly lower in Group 1. This increases the risk for HAT [4, 10, 24]. The duration of surgery, the duration of HA reconstruction and total blood loss were higher in Group 1 since two HAs had to be reconstructed. Each of these is an independent risk factor for occurrence of anastomotic biliary strictures [25, 26]. Risk factors for biliary strictures In the multivariable analysis in this study, history of previous bile leak was revealed as the significant risk factor for biliary strictures in pediatric LDLT. The various reported risk factors for biliary strictures in LDLT include warm ischemic time, biliary leakage history, recipient age and incidence of HAT [19, 25, 27].
Hepatic artery complications, both thrombosis and stenosis, have been recognized as major risk factors for anastomotic and non-anastomotic biliary strictures [28]. Contrary to this, our results prove that HAT was not a significant risk factor for development of biliary strictures, on multivariate analysis. Although the incidence of HAT was more in patients with Roux-en-Y hepaticojejunostomy, it could not reach level of statistical significance. Also, the occurrence of biliary strictures in these patients was comparable to those undergoing Duct-to-Duct biliary reconstruction. Suehiro et al. [13] have reported a higher incidence of biliary strictures caused by partial HA reconstruction, but the relation between insufficient HA flow and biliary strictures remains uncertain. In our study, HA thrombosis was not found to be a significant risk factor for occurrence of biliary strictures. The best way of tackling the problem of HAT is strict post-operative vigilance and identification of at risk patients. When HAT is diagnosed, initially a conservative approach is attempted with systemic thrombolytic agent. If conservative attempts fail, showing no improvement on repeated Doppler evaluations, laparotomy with re-do of the HA anastomosis has been found to be successful in majority of the cases as shown in our study. However, if these measures fail or if there is graft failure, re-transplantation is the only rescue option
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available. In our results, history of prior bile leak has been found to be a predictor of anastomotic biliary strictures as also confirmed by other studies [29–31]. In conclusion, in our study, the incidence of biliary strictures in pediatric recipients undergoing single HA reconstruction is comparable to those undergoing dual HA reconstruction. However, there are certain drawbacks of our study. This is a retrospective study with a comparatively small sample size. This could contribute to some degree of Type 2 errors. Also, the results hold true only if the aforementioned criteria for second HA reconstruction were followed. Hence we have to be discrete in interpreting these conclusions. A randomized control trial with a larger sample size should be carried out before we can conclusively adopt this policy.
13.
14.
15.
16.
17. 18.
19. Conflict of interest
No conflicts of interest to disclose.
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ORIGINAL ARTICLE
Reconstructing single hepatic artery with two arterial stumps: biliary complications in pediatric living donor liver transplantation Karan D. Julka • Tsan-Shiun Lin • Chao-Long Chen Chih-Chi Wang • Andrzej L. Komorowski
•
Accepted: 14 November 2013 / Published online: 30 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract Introduction Liver grafts can at times have two hepatic arterial stumps. This can result in a dilemma whether to reconstruct single or both the arteries. Hepatic artery (HA) thrombosis is the most dreaded complication in pediatric living donor liver transplantation (LDLT) as it can result in biliary complications and subsequent graft loss. We herein report the feasibility of reconstructing single hepatic artery in pediatric living donor liver transplantation having two arterial stumps in the liver graft. Materials and methods From 2008 to 2010, 87 pediatric patients undergoing LDLT were divided into three groups. Group 1 (n = 20): two HA stumps with two HA reconstruction, Group 2 (n = 22): two HA stumps with one HA reconstruction and Group 3 (n = 45): one HA stump with one HA reconstruction. The decision regarding the reconstruction of single or multiple HAs was made depending on the preoperative radiological and intraoperative assessments. Results The incidence of HA thrombosis (p = 0.126) and biliary complications (p = 0.617), was similar in the three groups. Conclusion Single HA reconstruction does not increase the risk of biliary strictures in pediatric LDLT recipients having dual hepatic arterial stumps in the liver graft.
K. D. Julka and T.-S. Lin have contributed equally to this work. K. D. Julka (&) T.-S. Lin C.-L. Chen C.-C. Wang A. L. Komorowski Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 123 Ta-Pei Road, Niao-Song, Kaohsiung 833, Taiwan e-mail: [email protected]
Keywords Hepatic artery Hepatic artery thrombosis Biliary complication Pediatric Living donor liver transplantation Abbreviations LDLT Living donor liver transplantation HA Hepatic artery PELD Pediatric end-stage lived disease HAT Hepatic artery thrombosis CTA Computed tomography angiography MRA Magnetic resonance angiography DUS Doppler ultrasound
Introduction Living donor liver transplantation (LDLT) has been introduced as one of the procedures that can compensate for the shortage of available grafts in pediatric liver transplantation [1–5]. Hepatic artery (HA) thrombosis is the most feared complication in LDLT, especially in pediatric transplantation. The incidence of hepatic artery thrombosis (HAT) in pediatric LDLT cases, as reported in various studies, is around 18 % [6–9]. The liver grafts can at times have a varied hepatic arterial anatomy. The incidence of multiple HAs in left lobe liver grafts is about 25.8 % [10]. In pediatric patients, the left lobe (segments II, III and IV), the left lateral segment (segments II and III) and extended left lateral segment (segments II, III and part of IV) are mainly used. The complexity is increased as the caliber of the arteries in the pediatric recipients is small, resulting in size discrepancy. Earlier studies have considered hepatic artery (HA) size \2 mm a relative contraindication to LDLT [2, 11]. The microsurgical techniques in LDLT,
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introduced by the Kyoto group [12], has been routinely adopted by many liver transplant centers resulting in a better outcome after reconstructing even small caliber hepatic arteries. Even with the recent technical advancement of liver transplant procedures, whether to reconstruct both HA stumps on such a graft is not well addressed. Suehiro et al. [13] reported a higher incidence of biliary stricture caused by single HA artery reconstruction in presence of the two HAs in the graft. In contrast, studies have demonstrated that reconstructing only 1 HA is sufficient in most LDLTs [12, 14]. However, all these studies are limited to mostly adult recipients. Hence the aim of our study was to assess the safety and feasibility of reconstructing single HA in the presence of dual HA stumps of liver graft in pediatric LDLT recipients and its impact on the incidence of biliary strictures.
Methods
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Briefly, in the donor, all the arterial structures were carefully dissected and preserved. The proper HA was exposed up to the bifurcation of the left (or middle HA) and the right HA. The plane of division of HA was determined by the length and size of the artery, its relation with the cutting plane of the liver and the position of the arteries. Before division of the arteries, an intra-operative Doppler ultrasound (DUS) was done to confirm the vascular anatomy. HA reconstruction The variations encountered in the graft HAs are shown in Fig. 1. A detailed technique of HA reconstruction has been described in detail elsewhere [18]. The recipient’s HA considered to be the primary candidate for HA reconstruction was the left HA. In case of dual HAs, the second arterial anastomosis was done with the artery to segment IV (n = 7) and left Gastroepiploic artery (n = 13) in the recipient. No interposition vascular grafts were required in any of the cases.
Patients Criteria for reconstructing second HA From March 2008 to September 2010, a total of 87 pediatric recipients (\18 years of age) underwent LDLT procedures at Kaohsiung Chang Gung Memorial Hospital, Taiwan. The Institutional Review Board (IRB) of the Kaohsiung Chang Gung Memorial Hospital (KCGMH) in Taiwan approved the study under number 101-0930B. Data included the recipient and donor demographic data, operative techniques and details, postoperative outcome, types of grafts used, indications for transplantation, complications and long-term follow up. The median follow up period was 48 months (range 12–96). The grafts were divided into three groups. In Group 1, the graft had two HA stumps and both were reconstructed (n = 20); in Group 2, the graft had two HA stumps and only one of them was reconstructed (n = 22); and in Group 3 graft had single HA stump which was reconstructed (n = 45). Donor evaluation Donor graft selection was done according to the volumetric results of CT calculations [15]. Routinely, pre-operative assessment of the vascular anatomy of the potential donor was done by Doppler ultrasound of the potential liver graft, CT angiography (CTA) and magnetic resonance angiography (MRA). Operative techniques The techniques of donor hepatectomy and recipient hepatectomy have been described in detail elsewhere [16, 17].
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Initially the larger diameter arterial branch was reconstructed first and if back-bleeding from the second HA was poor or absent, it was reconstructed. In case, the arterial flow signals were not detected in all the liver segments of the graft on intra operative DUS, post reconstruction of the larger diameter branch, the second arterial branch was reconstructed. The intra operative DUS was also used to confirm the patency of reconstructed HV and portal vein by determining the waveforms and velocities of the respective vasculature. The techniques of biliary reconstruction are described in detail elsewhere [19]. A biliary-enteric reconstruction, using a Roux-en-Y technique (n = 77), was done in recipients undergoing LDLT for biliary atresia, Alagille syndrome or presence of multiple small bile ducts in the liver graft. Duct-to-duct anastomosis (n = 10) was done in the rest of cases. No internal or external biliary stents were used. Post-operative immunosuppression and anti-coagulation The immunosuppression regimen included cyclosporine (Novartis, Basel, Switzerland). The dose was adjusted to a minimum level required so as to avoid an episode of rejection. The dose of Mycophenolate Mofetil (Roche Basel, Switzerland) was 10 mg/kg. Methyl prednisolone initial dose was 20 mg/kg, intravenous during surgery and then reduced to 3 mg/kg/day on post-operative day (POD) 1 and gradually tapered to 0.5 mg/kg/day on POD 6. In
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Fig. 1 Branching patterns and transection line of donor graft hepatic arteries. a Single left hepatic artery arising from proper hepatic artery; b two arteries, artery to segment IV and left hepatic artery arising from proper hepatic artery; c two hepatic arteries, branch from left gastric artery and left hepatic artery arising from proper hepatic artery; d two arteries, artery to segment III and segment II arising
from right hepatic artery. The dotted line indicates the plane of artery transection. LHA left hepatic artery, RHA right hepatic artery, GDA gastroduodenal artery, LGA left gastric artery, PHA proper hepatic artery, LS left lateral segment, exLS left lateral segment with part of segment IV, LL left lobe. Artery drawn in the bold line was divided and attached to the graft
majority of the cases, steroids were discontinued at 6 months post-transplantation. Heparin or fresh frozen plasma was administered after operation to maintain prothrombin time and activated coagulation time at around 15 and 150 s, respectively. Dipyridamole was (4 mg/kg/day) was taken orally in lieu of heparin from post-operative day 8 and continued for 3 months.
presence of a notable anastomotic narrowing, on the basis of symptoms or on the basis of abnormal liver function tests. Biliary complications, including leaks and strictures, were commonly managed with non-operative measures including radiological interventions like endoscopic biliary drainage and percutaneous trans-hepatic biliary drainage using balloon dilation or biliary stents.
Assessment of outcomes and complications
Statistical analysis
In the recipients, routine DUS was done post liver transplantation to determine adequate blood flow and velocities in the reconstructed arteries and veins. A diagnosis of vascular stenosis or thrombosis was suspected when repeated Doppler studies failed to detect arterial spectrum at anastomotic site. This was then confirmed by 3D CTA which showed either non visualization or narrowing of the arteries with no contrast signal in the distal arterial segment. Magnetic resonance cholangiography was done in cases where there was suspicion of biliary complications. Bile leakage was defined as the presence of bile material in a closed suction drain that persisted for more than 7 days post-surgery or as presence of biloma around the area of anastomosis. Biliary leakage through the cut surface, diagnosed by radiological and endoscopic means, was excluded from this study. Anastomotic biliary stricture was defined as an intrahepatic biliary dilation [3 mm in
Survival statistics were calculated by the Kaplan–Meier analysis and survival curves were compared using Log rank test. The Kruskal–Wallis one-way analysis of variance was used to compare three independent variables. To compare frequencies, we used the v2 test. The multivariate Cox regression model was performed on variables found to be significant on univariate analysis. Statistical significance was defined as p \ 0.05. All statistics were performed using SPSS version 16.0 (SPSS Inc., Chicago, IL, USA).
Results The demographic and operative characteristics of the three study groups are shown in Tables 1, 2. The median size of the donor HAs was smaller in Group 1 (p = 0.03) as compared with Group 3.
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Table 1 Demographic characteristics among the groups Category
Group 1
Group 2
Group 3
p value (\0.05)
Donor age (years)
35 (28–39)
35.5 (28.75–42.5)
37 (31–41)
0.444
8:12
10:12
20:25
0.928
12 (9–36)
11.5 (8–12)
12 (9–36)
0.127
13:7
13:9
21:24
0.337
17:1:2:0
21:0:1:0
40:2:1:2
0.563
17:3:0
20:1:1
34:10:1
0.317
11.5 (7–12.75)
12 (9.75–13)
13 (6.5–19)
0.196
Donor sex M:F Recipient age (months) Recipient sex M:F Diagnosis BA:metabolic:alagellie:neonatal hepatitis Type of graft LS:exLS:LL PELD
BA biliary atresia, LS left lateral segment, exLS extended left lateral segment, PELD pediatric end stage liver disease score, GRWR graft recipient weight ratio
Table 2 Comparison of surgical factors among the three groups Category
Group 1
Group 2
Group 3
p value
Graft artery size (mm)
2.0 (1.0–3.0)
2.5 (1–3.5)
2.5 (1.5–4.0)
0.03
Recipient artery size (mm)
2.5 (1.5–4.0)
2.5 (2.0–4.0)
2.5 (1.5–3.5)
0.578
Bile duct size (mm)
3.0 (2.0–4.5)
3.0 (1.5–5.5)
3.0 (1.5–6.0)
0.486
Cold ischemic time (min)
34 (23–45)
40 (27–57)
36 (17–59)
0.161
Warm ischemic time (min)
43 (26–56)
38 (24–63)
40 (20–70)
0.186
Duration of surgery (min)
610 (520–765)
508 (473–720)
521 (413–720)
0.001
Duration of HA anastomosis (min)
90 (55–130)
56 (30–115)
55 (30–140)
0.001
Duration of biliary reconstruction (min)
70 (15–100)
47 (15–110)
50 (10–140)
0.112
18:2 235 (60–1000)
18:4 113 (30–550)
40:5 200 (15–900)
0.662 0.05
18:2
20:2
39:6
0.869
Number of bile ducts One:two Blood loss (ml) Type of biliary reconstruction Roux-limb:duct-to-duct
Group 1: graft had two HA stumps and both were reconstructed (n = 20), Group 2: graft had two HA stumps and only one of them were reconstructed (n = 22) and Group 3: graft had single HA stump, which was reconstructed (n = 45) HA hepatic artery All data are expressed as median and range Table 3 Biliary complications among the three groups Biliary complication
Group 1 (%)
Group 2 (%)
Group 3 (%)
Biliary strictures
2/20 (10)
2/22 (9.09)
4/45 (9.3)
Bile leaks
1/20 (5)
1/20 (4.45)
5/45 (11.62)
Group 1: graft had two HA stumps and both were reconstructed (n = 20), Group 2: graft had two HA stumps and only one of them were reconstructed (n = 22) and Group 3: graft had single HA stump which was reconstructed (n = 45)
The total duration of surgery (p = 0.001), the duration of HA reconstruction (p = 0.001) and the average intraoperative blood loss (p = 0.05), were significantly higher
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in Group 1. The rest of the variables were comparable among all the three groups (Table 3). HA-related complications Hepatic artery thrombosis was observed in six (6.9 %) cases. The incidence of HAT was similar among all the three groups (p = 0.126) (Fig. 2). One recipient was successfully treated with systemic thrombolytic agent. Inj. urokinase was administered with initial loading dose of 4,400 IU/kg ideal body weight over 10 min, followed by maintenance dose of continuous infusion of 4,400 IU/h/kg ideal body weight over 12 h. The other recipient received
Pediatr Surg Int (2014) 30:39–46 Fig. 2 Overall survival of hepatic artery thrombosis-free cases a and biliary stricture-free cases b among group 1 (two hepatic artery stump with two reconstructions), group 2 (two hepatic artery stumps with one reconstruction) and group 3 (one hepatic artery stump with one reconstruction). The survival curves are comparable in all the three groups
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A
At risk 20
no event occurred
22
16
10
8
6
45
24
18
12
8
B
At risk 20
6
1
1
1
22
16
10
7
6
45
24
19
13
8
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re-transplantation. Both the recipients later had uneventful recovery. Four cases with HAT were recognized early and managed by re-exploration of the recipient and revascularization of the arteries. Revascularizations were done either with same artery, after trimming (n = 2) or using an alternative artery (n = 2). Out of these four patients with HAT, two patients died due to subsequent graft failure and multi-organ dysfunction. HAT occurred in 6/77 patients undergoing Roux-en-Y biliary reconstruction and 0/10 patients undergoing duct-to-duct reconstruction. Biliary complications The overall incidence of biliary strictures was 9.19 % (8/87). (Table 3) All the strictures were anastomotic biliary strictures. The incidence of biliary strictures was comparable among the three groups (p = 0.617) (Fig. 2). Majority of the strictures occurred within first 3 months post-transplantation (6/87). The remaining two strictures occurred in 4th and 5th months post- transplantation. The incidence of biliary leakage in our study was 8 % (7/87) and they were managed non-surgically. Three of those seven patients subsequently developed biliary strictures. Most of the bile leaks (5/7) occurred within the first postoperative month. The incidence of biliary stricture was similar in Roux-en-Y (7/77) and duct-to-duct (1/10) reconstruction (p = 0.989). Survival curves The overall patient survival was comparable among the three groups (p = 0.103, Fig. 2). There were 11/87 cases of mortality (12.7 %), including portal vein thrombosis (n = 3), HAT (n = 1), sepsis and multi-organ dysfunction (n = 3), post-transplant lymphoproliferative disorder (n = 1), severe acute on chronic rejection with hepatic venous thrombosis (n = 1), lung hemorrhage (n = 1) and intra-cerebral hemorrhage (n = 1).
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Discussion The results aptly demonstrate that the incidence of biliary strictures and HAT in liver with single HA reconstruction were comparable to the liver grafts with dual HA reconstruction. It is well known that hepatic grafts have fine, intra-hepatic arterial networks [19] so that even reconstruction of only one of the two HAs may maintain minimum arterial flow for the graft to survive. This fact has been the founding basis of our study. It has been reported in the earlier study by Uchiyama et al. [20] that the incidence of biliary strictures was higher in recipients in whom only one HA out of the two was reconstructed. The reported overall incidence of HA thrombosis was 2.3 %. Majority of the recipients in the study were adults. Sugawara et al. [21] have reported no difference in overall patient survival and the incidence of biliary stricture in cases in which only one HA was reconstructed out of the two present. The reported incidence of HAT was 1.4 %. Their experience was again only limited to adult patients. In the same study, cold saline test was used to confirm intra hepatic arterial communications on the backtable. In a systematic review done by Bekker et al. [7] involving 21 studies, the reported incidence of HAT was 8.3 % among pediatric recipients. However, most of these studies were done in pediatric recipients having single HA in the liver graft. The incidence of biliary strictures, in the group with only single HA reconstruction out of the two HAs, was 58 % as reported in the study by Sugawara et al. and 44 % as reported by Uchiyama group, which is much more than that reported in our study. The overall incidence of biliary strictures reported in our study is lower than those reported in other studies, varying from 11 to 40 % [22]. Problems with pediatric recipients
Risk factors for biliary strictures The various risk factors analyzed for incidence of anastomotic biliary strictures are shown in Table 4. On univariate analysis, by Kaplan–Meier using log rank test, we compared cumulative anastomotic biliary stricture with free survival curves in each factor. The factors found to be significant were size of the graft HA, size of the recipient HA stump, size of the graft bile duct, history of prior bile leak and history of hepatic artery thrombosis (Table 4). On further multivariate analysis using Cox regression test, only the history of prior bile leak was found to be significant independent risk factor for anastomotic biliary strictures (p = 0.002 and 95 % CI of 6.603–164.679; Hazard ratio of 32.975).
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Most of the pediatric recipients receiving LDLT usually have a previous history of Kasai procedure for biliary atresia which is associated with severe adhesions in hilar area. This can result in more operative complications and intra-operative blood loss [23]. However, in our study, there was no significant increase in biliary strictures (p = 0.178), duration of surgery (p = 0.367) or intra operative blood loss (p = 0.454) in recipients having previous history of Kasai procedure. Another concern is need for multiple arterial inflow options for dual HA reconstruction. To address this problem, we advocate dissecting distally in the hilum so as to make available the branches of HA as inflow arteries [21].
Pediatr Surg Int (2014) 30:39–46 Table 4 Analysis of risk factors associated with anastomotic biliary stricture
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Category
Univariate analysis p value
Multivariate analysis p value
Hazard ratio
95 % CI
Graft artery size
0.036
0.897
–
–
Recipient artery size
0.047
0.360
–
–
Donor age
0.455
–
–
–
Recipient age
0.409
–
–
Donor sex
0.666
–
–
–
Recipient sex
0.390
–
–
–
Type of graft Indication for transplantation
0.631 0.076
– –
– –
– –
PELD
0.945
–
–
–
Cold ischemic time
0.526
–
–
–
Warm ischemic time
0.728
–
–
–
Duration of surgery
0.903
–
–
–
Blood loss
0.586
–
–
–
Non-reconstructed artery
0.651
–
–
–
Hepatic artery thrombosis
0.001
0.986
–
–
Type of biliary reconstruction
0.699
–
–
–
Duration for HA anastomosis
0.358
–
–
–
Duration for biliary anastomosis
0.801
–
–
–
p \ 0.05 is significant
Number of bile ducts
0.940
–
–
–
PELD pediatric end stage liver disease score, HA hepatic artery, CI confidence interval
Size of bile duct
0.038
0.073
–
–
History of previous bile leakage
0.002
0.002
32.975
6.603–164.679
Why do only single arterial reconstructions when we can do both? With the recent improvements in technique and use of microsurgery for HA reconstruction, it is now possible to reconstruct multiple HA with acceptable complication rate [18]. However, we have to be discrete in our decision to reconstruct multiple HA, especially in pediatric recipients. From Table 2, it is evident that the median size of graft HA was significantly lower in Group 1. This increases the risk for HAT [4, 10, 24]. The duration of surgery, the duration of HA reconstruction and total blood loss were higher in Group 1 since two HAs had to be reconstructed. Each of these is an independent risk factor for occurrence of anastomotic biliary strictures [25, 26]. Risk factors for biliary strictures In the multivariable analysis in this study, history of previous bile leak was revealed as the significant risk factor for biliary strictures in pediatric LDLT. The various reported risk factors for biliary strictures in LDLT include warm ischemic time, biliary leakage history, recipient age and incidence of HAT [19, 25, 27].
Hepatic artery complications, both thrombosis and stenosis, have been recognized as major risk factors for anastomotic and non-anastomotic biliary strictures [28]. Contrary to this, our results prove that HAT was not a significant risk factor for development of biliary strictures, on multivariate analysis. Although the incidence of HAT was more in patients with Roux-en-Y hepaticojejunostomy, it could not reach level of statistical significance. Also, the occurrence of biliary strictures in these patients was comparable to those undergoing Duct-to-Duct biliary reconstruction. Suehiro et al. [13] have reported a higher incidence of biliary strictures caused by partial HA reconstruction, but the relation between insufficient HA flow and biliary strictures remains uncertain. In our study, HA thrombosis was not found to be a significant risk factor for occurrence of biliary strictures. The best way of tackling the problem of HAT is strict post-operative vigilance and identification of at risk patients. When HAT is diagnosed, initially a conservative approach is attempted with systemic thrombolytic agent. If conservative attempts fail, showing no improvement on repeated Doppler evaluations, laparotomy with re-do of the HA anastomosis has been found to be successful in majority of the cases as shown in our study. However, if these measures fail or if there is graft failure, re-transplantation is the only rescue option
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available. In our results, history of prior bile leak has been found to be a predictor of anastomotic biliary strictures as also confirmed by other studies [29–31]. In conclusion, in our study, the incidence of biliary strictures in pediatric recipients undergoing single HA reconstruction is comparable to those undergoing dual HA reconstruction. However, there are certain drawbacks of our study. This is a retrospective study with a comparatively small sample size. This could contribute to some degree of Type 2 errors. Also, the results hold true only if the aforementioned criteria for second HA reconstruction were followed. Hence we have to be discrete in interpreting these conclusions. A randomized control trial with a larger sample size should be carried out before we can conclusively adopt this policy.
13.
14.
15.
16.
17. 18.
19. Conflict of interest
No conflicts of interest to disclose.
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