Influence of early biliary complications on survival rates after pediatric liver transplantation—A positive outlook

Early biliary complications (EBC) constitute a burden after pediatric liver transplantation frequently requiring immediate therapy. We aimed to assess the impact of EBC on short‐ and long‐term patient and graft survival as well as post‐transplant morbidity.


| BACKG ROUND/INTRODUC TI ON
Pediatric liver transplantation (PLT) in the Eurotransplant (ET) region has evolved with the introduction of split-liver and living-donor liver transplantation in 1988 and 1991. 1,2 Annually, approximately 200 pediatric liver transplantations are performed in the ET region. The 10-year graft survival rate ranges between 63% and 75% and therefore compares favorably to that of the adult population. 3 Despite the good overall survival, PLT is associated with several graft-related complications. [4][5][6][7][8] In 75% of liver transplantations in the ET cohort, technical variant procedures including smaller vessels and surplus bile ducts are recorded. 1 These variations are not only associated with an increased risk of early (<3 months, EBCs), but also of late biliary complications (>3 months, LBCs).
The classification of early and late BCs is relevant since different mechanisms are involved and complication management may differ. Early biliary complications are often directly related to the surgical technique; LBCs, in contrast, are most often caused by chronic inflammation. [9][10][11][12] Reports on the overall incidence of BC range from 10% to 45%. 9,[13][14][15] Untreated BCs lead to a higher risk of graft loss. 5,16 These diverging data most likely suggest that different definitions are used to characterize BCs. Previous studies have found that prolonged cold ischemic time (CIT), hepatic artery thrombosis (HAT), donor age, graft quality, ischemic injury of the biliary system, and duct-to-duct reconstructions as risk factors for BCs. 10,[17][18][19] This study aims to assess the impact of early biliary complications on short-and long-term patient and graft survival as well as post-transplant morbidity following PLT in our cohort. Donor and recipient characteristics (age, sex, weight, body mass index (BMI), blood work, blood type, cytomegalovirus (CMV) status, surgical data (donor type, CIT, anhepatic time (AN), type of bile duct reconstruction and details of the post-operative course (complications, reoperation, hospital stay, intensive care unit stay, acute rejections))) were collected from medical records. All patients were followed until March 2020, death or until lost to follow-up. Median follow-up time of our cohort was 65.5 months (SD: 23.3-131 months).

| Surgical procedure of pediatric liver transplantation
The living-donor liver transplant program at the Medical University of Innsbruck has been established in 1997. The choice of technical approach was chosen based on the indication, availability of a living donor, surgical conditions, and urgency. In case of a full-size liver transplant, a bicaval technique with cava replacement was performed, while split-liver transplantations (SLTs) were performed using the piggy back technique. Graft type, underlying disease, and previous surgical interventions decided about the biliary reconstructions. Whenever possible, a duct-to-duct anastomosis was performed. In patients with biliary atresia, pre-existing bile duct conditions, or grafts with short bile ducts, a hepaticojejunostomy with a Roux-en-Y reconstruction was used. In case of multiple bile ducts, the distance between both orifices determined whether they were anastomoses conjointly or separately.
The hepaticojejunostomy or duct-to-duct reconstruction were performed with monofilament absorbable sutures in an interrupted fashion. T-tubes and stents have been used when indicated. The hepatic artery anastomosis was performed with interrupted sutures employing microsurgical principles. Vascular intrahepatic flow monitoring during transplantation was routinely assessed by Doppler ultrasound after portal vein, arterial, and bile duct anastomosis as well as before and after abdominal closure. In case of large liver volume in relation to upper abdominal cavity capacity, the initial abdominal closure was performed using a Gore-Tex patch for abdominoplasty. Subsequently, the patch was gradually reduced and eventually removed in all cases. All patients underwent close postoperative monitoring with repeat laboratory testing and ultrasound every 6-8 h for the first post-transplantation week followed by two daily examinations during the second week and daily examinations until discharge from hospital. PLTs were categorized into living and deceased liver transplants as well as split-liver transplantations comprising all living-and deceased-donor split-liver transplantations.

| Primary and secondary end-points
Primary outcome parameters were patient as well as all-cause (ACGS) and death-censored graft survival (DCGS). Patients that died with functioning grafts were censored. Secondary end-points include the median initial length of stay at the intensive care unit (ICU) and at the hospital, the occurrence of early hepatic artery and early and late portal vein complications, bowel obstruction/perforation, late biliary complications, and rejections.    Table 5.
Feier et al. reported an overall BC rate of 14.5% (n = 71). In their study, the authors provided a detailed overview of the different biliary complication types, but also elaborated on diagnostic steps and treatment approaches. In our cohort, the frequent use of Gore-Tex ® patches for abdominoplasty (43% of cases), especially in infants of less than 5 years, may factor into the detection rate since subsequent surgeries for patch-size reduction and removal offer the opportunity to inspect the bile duct anastomosis and detect clinically mild or silent fistulas. signs of infection, the management was conservatively. Our data further suggest that long-term graft loss was rare not directly associated with EBC (7.4% vs. 16.4% in non-EBC).
The incidence of biliary complications following living-related liver transplantation (LLT) is reported to be around 33%. 21,[24][25][26] Some studies describe an even higher incidence of BC in reduced size deceased-donor liver grafts, deceased-donor split grafts, and livingdonor liver grafts. 20,24,27 While a trend toward a higher incidence of EBC in living-related liver transplantation was observed in our co- A rare complication is the orphan duct syndrome or excluded segmental bile duct leakage that has been described after major liver resections and is classified as type D leakage after the classification of Nagano et al. 29 The leakage results from a bile duct which is separate from the main biliary tree but drains bile fluids of functioning This study has several limitations. First, we analyzed results over a period of thirty-five years. Over time, surgical techniques, immunosuppressive protocols, organ acceptance and utilization criteria, and recipient selection have changed profoundly and outcomes were not similar across the study period. Different surgical procedures and our rather small annual case load complicate statistical evaluation and accuracy.
In summary, this study demonstrates that EBCs lead to a prolonged ICU and initial hospital stay without compromising patient or graft survival. While no association between EBCs and vascular complications was seen, significantly more bowel obstructions/perforations were recorded in recipients with EBCs. The presence of multiple bile ducts was the only factor significantly associated with the occurrence of EBCs.

| CON CLUS ION
The relatively high biliary complication rate illustrates the complexity and vulnerability of bile duct anastomoses in pediatric liver transplantation. Whereas a prolonged intensive care unit and hospital stay in patients with early biliary complications was recorded, this had no negative influence on patient and graft survival. EBCs correlated with a higher incidence of LBCs, and thus, these patients should be monitored closely in order to anticipate their occurrence.

ACK N OWLED G M ENTS
The authors would like to thank Heinz Zoller from the Department of Gastroenterology and the Transplant Coordination at the Medical University of Innsbruck for their contribution in pretransplant evaluation.

CO N FLI C T O F I NTE R E S T
The authors have no conflict of interest to declare.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data supporting the findings of this study are available from the corresponding author SS on reasonable request.