EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: This study aimed to investigate the outcomes of adult liver transplant procedures using grafts from pediatric donors after circulatory death.

Materials and Methods: We retrospectively analyzed the data of 19 pediatric-to-adult liver transplant procedures from July 2013 to May 2016 in our hospital. Nineteen adult liver transplant procedures were performed using livers from pediatric donors after circulatory death.

Results: We performed 18 orthotopic and 1 piggyback liver transplant procedure. The median graft-to-recipient weight ratio was 1.26% (range, 0.86% to 2.46%). The median warm and cold ischemia times were 11 minutes (range, 8-20 min) and 638 minutes (range, 200-843 min), respectively. Complications after the operation included postoperative pulmonary infection (8 patients), fungal infection (1 patient), cytomegalovirus infection (1 patient), hepatic artery thrombosis and biliary stricture (1 patient), portal vein stenosis (1 patient), and graft failure (2 patients).

For patients with graft failure, 1 patient received retransplant and 1 died. The patients were followed for 22.44 months (range, 9.63-44.07 mo) after transplant and showed normal liver function and good health. The 3-year survival rates of grafts and patients were 89.47% and 94.74%, respectively.

Conclusions: Appropriate evaluation of donors and recipients and accurate intraoperative and postoperative treatment can ensure successful application of livers from pediatric donors after circulatory death in adult recipients.

Key words : Donation after circulatory death, Liver volume, Small-for-size syndrome

With development of an organ donation program in China, Chinese organ transplantation has been widely recognized by the international community. Some of the clinical applications of adult donor livers from donations after circulatory death (DCD) have achieved remarkable results in China. However, the outcomes of pediatric donor livers that are transplanted into adult recipients, especially with DCD, have not been well studied.^1,2Croome and associates3 showed that, when there is no matched recipient in the children’s population for pediatric donor livers, they can be applied to adults. They also showed that, when the graft-to-recipient weight ratio (GRWR) is ≥ 0.8 in adults, the survival rate is the same as that of pediatric recipients.

We conducted a retrospective study of 19 cases of adult liver transplant in our hospital in which the grafts were obtained from pediatric DCD. Here, we discuss selection of donors and recipients, selection of the surgical procedure, postoperative complications, and other related issues when livers from pediatric DCDs are applied in adult transplant recipients.

Materials and Methods

Organ procurement procedure
The donation procedure was initiated according to the Chinese national guidelines for DCD.4 Written informed consent was provided by the parents of the pediatric donors. After arrival in the operating room, the life support system was gradually withdrawn. Five minutes after cardiac arrest and ensuring that autoresuscitation did not occur, death was declared and organ procurement was initiated.

The abdominal aorta and mesenteric vein were catheterized. Liver and kidneys were jointly procured. University of Wisconsin solution was sequentially used for perfusion, and the inferior vena cava was also catheterized for drainage. The actual warm ischemia time was recorded as the duration from withdrawal of the life support system to perfusion of the abdominal aorta. The cold ischemia time was recorded as the duration from perfusion to blood reperfusion during transplant surgery.

The child transplant wait list from the registration center was checked twice in the Chinese Organ Transplant Response System. When there were no compatible pediatric candidates, the donor liver was applied to adult recipients. There were 19 cases of adult transplant procedures from July 2013 to May 2016 in our hospital, in which the grafts were obtained from pediatric DCDs. Among them, 5 were procured in our hospital, and the remaining 14 cases were allocated to our hospital through the Chinese Organ Transplant Response System because of a lack of a compatible recipient in the local hospital. All donors were tested for human immunodeficiency virus, hepatitis B virus, hepatitis C virus, Treponema pallidum antibody, liver function, renal function, coagulation, and other variables before the operation.

Intraoperative treatment
Operations were performed with the informed decision of patients and their families and the approval of the hospital’s ethics committee. During repair of the donor liver, the falciform ligament was retained in part to prepare for fixation with donor liver. Because of the small size of the donor liver, a change in its intraperitoneal position could easily cause vascular distortion.

A classical no-bypass operation was adopted. Notably, in the recipient’s operation, the hepatic artery, portal vein, and biliary tract were preserved as long as possible in the process of dissecting the diseased liver because of the relatively small size of the donor liver. After completion of portal and arterial anastomoses, an intraoperative ultrasonography was conducted to confirm satisfactory blood flow. For biliary reconstruction, we performed bile duct end-to-end anastomosis, with a T tube placed for recipients with a mismatched bile duct. For piggyback transplant, the right hepatic vein was isolated close to the inferior vena cava. We used the right side of the right hepatic vein as the base to create a large triangular opening with the tip toward the left for anastomosis. This was performed to prevent anastomotic stenosis or outflow obstruction because of graft hyperplasia and translocation in the future. Portal vein pressure was monitored, and a blood flowmeter and ultrasonographic unit were used to monitor portal vein flow after allowing blood flow to the graft. If portal vein flow was greater than 250 mL/min/100 g liver tissue,^5,6 we performed ligation of the splenic artery. Splenectomy was considered when no significant improvement occurred after ligation.

Postoperative treatment
Basiliximab immunosuppression induction therapy was performed intraoperatively and 4 days after transplant. Postoperative immunosuppressive treatment included tacrolimus, mycophenolate mofetil, and methylprednisolone. The immunosuppression protocol for ABO blood group incompatibility (ABOi) in liver transplant was as follows. Transfusion of rituximab 375 mg/m2 was completed before release of new liver blood flow. Gamma globulin was administered intraoperatively and during 1 to 7 days posttransplant to neutralize circulating antibodies. If rituximab was administered, basiliximab was not recommended during the operation and on day 4 posttransplant.

For anticoagulant therapy, heparin was administered posttransplant via a venous pump. The initial dose of heparin was 10 IU/kg/h. The activated partial thromboplastin time was adjusted to approximately 1.5 times the normal value. At 5 to 7 days posttransplant, we changed to oral administration of warfarin, and the international normalized ratio was adjusted to approximately 1.5 times the normal value until 2 weeks later.

We used color Doppler ultrasonography on days 1 to 7 posttransplant to monitor liver blood flow.

Donor characteristics
Nine of the 19 donors were boys. The median age was 94 months (range, 48-153 mo), and body mass index was 15.59 kg/m² (range, 12.8-20.41 kg/m2). Causes of death were trauma (n = 9), central nervous system tumor (n = 4), viral encephalitis (n = 3), anoxia (n = 1), intracranial hemorrhage (n = 1), and respiratory failure (n = 1). Donor characteristics are shown in Table 1.

Liver transplant procedure
Eighteen patients underwent orthotopic and 1 patient underwent piggyback liver transplant. The median GRWR was 1.26% (range, 0.86% to 2.46%). The median warm ischemia time and cold ischemia time were 11 minutes (range, 8-20 min) and 638 minutes (range, 200-843 min), respectively. Transplant procedure data are shown in Table 2.

Recipient characteristics
Eight of the 19 recipients were men. The median age was 57 years (range, 37-75 y), and body mass index was 21.5 kg/m² (range, 16.46-27.08 kg/m²). Primary disease included hepatitis B virus-related hepatocirrhosis (n = 6), hepatitis C virus-related hepatocirrhosis (n = 2), primary biliary cirrhosis (n = 5), alcoholic cirrhosis (n = 1), cryptogenic cirrhosis (n = 1), and hepatocellular carcinoma (n = 4). There were 2 cases of ABOi among the 19 cases. Eight patients had postoperative pulmonary infections, 1 patient had fungal infection, and 1 patient had cytomegalovirus infection. One patient had hepatic artery thrombosis 4 days after the operation, and embolectomy was performed. This patient had biliary strictures secondary to hepatic artery thrombosis, and liver function gradually improved after treatment by endoscopic nasobiliary drainage. One patient had portal vein stenosis, which improved after balloon dilatation. One patient died of acute liver necrosis on day 2 after liver transplant. Recipient characteristics are shown in Table 3.
Two patients developed small-for-size syndrome (SFSS) (Table 4). In one patient with a GRWR of 0.86%, clinical manifestations included elevated bilirubin levels, ascites, hypoproteinemia, and poor coagulation function. Enzymology and coagulation function mostly returned to normal at day 10 posttransplant, and bilirubin returned to normal levels 2 months later. The other patient had a GRWR of 1.58%, and hepatic steatosis of the donor liver was 70% to 80%. This patient developed graft failure, and retransplant was performed 6 days after the first transplant procedure.

The patients were followed for a median of 22.44 months (range, 9.63-44.07 mo) after transplant and showed normal liver function and good health. The 3-year survival rates of grafts and patients were 89.47% and 94.74%, respectively.

Some studies have suggested that outcomes of liver transplant using DCDs are inferior to those that use donations after brain death (DBDs) in terms of survival rates of the graft and patient, the incidence of biliary complications, and retransplant rates due to ischemic biliary lesions.^7,8 However, some single centers have reported that results of liver transplant with DCDs are similar to those with DBDs.^9,10 De Vera and associates¹¹suggested that transplant procedures with DCDs through controlled procedural withdrawal of life support can yield effects similar to liver transplants that use DBDs. We used livers from pediatric DCDs for adult liver transplant in our hospital and found good outcomes. The 3-year survival rates of grafts and patients were 89.47% and 94.74%, respectively. Pediatric-to-adult liver transplant can decrease wait times and can avoid organ wastage.

In pediatric-to-adult liver transplant, adult recipients receiving a pediatric liver have a relatively large abdominal space. The position of the liver can easily change and cause vascular distortion. Fixation of the falciform ligament to the abdominal wall can prevent rotation of the liver, and reduce complications of the vascular system and bile duct torsion.12 The spatial position of the donor liver in the recipient’s abdominal cavity is also an important factor that the surgeon should consider. After a relatively small pediatric liver is implanted into an adult abdominal cavity, the portal fissure of the donor liver tends to deviate to the upper right position. This causes a long distance between the donor’s porta hepatis and the recipient’s blood vessels, which leads to difficulties in anastomosis of blood vessels and the bile duct. In this situation, in the process of dissecting the diseased liver, the surgeon should consciously preserve the hepatic portal structure as long as possible. In conditions where there is long distance between the first and second porta hepatis of the donor and recipient, the original outflow tract opening at the second porta hepatis of the recipient should be closed. A separate opening on the inferior vena cava can be then created to lower the position of the outflow tract to achieve the required anastomosis.

For application of organs from pediatric DCDs to adult recipients, whether liver volume can meet the needs of the recipient is an important factor for determining the outcome of treatment. Emre and associates¹ reported that, when the ratio of the donor liver weight to the standard liver weight of the recipient was greater than 0.4, there was no significant difference in the incidence of donor liver complications and graft survival between the pediatric-to-adult and adult-to-adult liver transplant groups. Adam and associates¹³ found that, when the GRWR was less than 0.5%, the incidence of SFSS was significantly increased. The function and survival time of the graft were dependent not only on the graft size but also on the quality and severity of primary disease of the recipient. Even if a GRWR of 0.6% was feasible for patients without cirrhosis or grade A liver function, patients with high model for end-stage liver disease scores or severe cirrhosis required relatively larger graft volumes.¹⁴ Therefore, evaluation of graft and recipient match is based on 2 factors. First, regarding graft size, 2 indicators are used to determine whether the donor liver and the recipient match. (1) The ratio of graft volume to standard liver volume of the recipient should be greater than 40%.¹⁵ Computed tomography 3-dimensional imaging is applied to determine donor-recipient matching in living-donor liver transplant. However, this method is difficult to perform in livers from DCDs because of time constraints. The commonly used standard liver volume formula is as follows: -794.41 + 1267.28 × body surface area (m²).^16,17 (2) The GRWR should be no less than 0.8% to 1%.18 Second, in pediatric donor liver transplant to adult recipients, the relatively large portal venous flow and portal venous pressure of the adult enable SFSS to easily occur.¹⁹However, most patients with a tumor do not have portal hypertension as the main manifestation. Therefore, the incidence of SFSS is lower in these patients. Pediatric-to-adult liver mismatch will not only lead to a high perfusion risk but also cause portal hepatic blood flow to decrease, resulting in thrombosis.²⁰ Therefore, postoperative prophylactic anticoagulation is necessary. Postoperative somatostatin is administered to reduce portal vein blood perfusion. Splenectomy can lower portal pressure and reduce the incidence of postoperative upper gastrointestinal bleeding and SFSS.² However, strictly controlling the indications for this procedure is necessary because splenectomy may also increase the chance of infection.²¹Additionally, the degree of hepatic steatosis is also an important factor that induces SFSS. In our study, the median GRWR was 1.29% (range, 0.86% to 2.46%), and 2 patients developed SFSS. One of these patients had a GRWR of 0.86%. Although the above-mentioned measures were taken during and after transplant in this patient, SFSS still appeared. This syndrome was considered to be associated with the severe portal hypertension of this patient pretransplant. After conservative treatment, liver function returned to normal. In the other patient with SFSS, the GRWR was 1.58%, but hepatic steatosis of the donor liver was 70% to 80%. The recipient also developed SFSS and graft failure.

Complications of pediatric-to-adult liver transplant are mainly vascular complications of hepatic artery thrombosis and portal vein thrombosis/stenosis. Donor and recipient vessel diameter mismatches are important factors in the occurrence of complications. Additionally, high portal vein perfusion may easily cause reactive contraction of the hepatic artery, resulting in increased arterial resistance and reduced blood flow, leading to thrombosis.²² When there are differences in the diameter of the hepatic artery, generally, a donor artery with vascular loop anastomosis or a hepatic artery bypass method is adopted.²³ A previous study showed that hepatic artery thrombosis as the cause for graft loss was higher in the pediatric-to-adult group (3.6%) than in the adult-to-adult group (1.9%) (P < .001).3 We consider that diameters of vessels and bile ducts of pediatric donor livers are small and that outflow is relatively narrow in vessels but wide in the bile duct. Therefore, vascular complications are more common than biliary complications in pediatric-to-adult transplant. In the present study, there was one case of biliary stricture, and this was secondary to hepatic artery thrombosis.

Orthotopic liver transplant of ABOi is regarded as a high-risk operation because a blood group antigen-antibody reaction in the recipient may mediate a severe humoral immune response at any time. This can cause a hyperacute rejection, which leads to occurrence of biliary and vascular complications.^24,25 In recent years, some studies have reported that the 1-year survival rate of ABOi liver transplant is up to 90%26 and the 5-year survival rate can be higher than 70%.²⁷ Although the ABOi liver transplant survival rate is gradually approaching that of transplants with blood group compatibility, the overall incidence of postoperative complications is still controversial.²⁸ In our study, there were 2 cases of ABOi transplant, and 1 patient died because of postoperative early acute liver necrosis, which was considered to be caused by rejection. We believe that ABOi orthotopic liver transplant could be considered for recipients who have been waiting for a long time for a donor and are in a life-threatening situation.

The shortage of pediatric donor livers is more severe than that of adults. Therefore, pediatric donor livers should be given priority to pediatric recipients. When there are no compatible recipients in the children’s population, using a pediatric donor in adults can increase the utilization rate of donated organs to a greater extent and avoid a waste of organs.²⁹ When a pediatric donor liver from DCD is applied to adult recipients, preoperative systematic evaluation of the donor is made. This evaluation includes quality of the donor liver, differences in vascular diameters of the donor and recipient, position of the donor liver in the recipient’s abdominal cavity, and other factors. We believe that using a donor liver from pediatric DCDs in adult liver transplant is feasible if surgery is appropriately planned. However, because of the small number of cases in this study, some problems remain to be further analyzed and studied.

Our study showed that Chinese pediatric DCDs are feasible with appropriate evaluation of donors and recipients. Accurate intraoperative and postoperative treatment can ensure successful application of livers from pediatric DCDs in adult transplant recipients.

Volume: 16 Issue: 5 October 2018

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