EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: Liver transplant in pediatric patients with body weight < 10 kg poses a challenge to the entire liver transplant team. Many reports have considered 10 kg to be a cutoff point for body weight for favorable posttransplant outcomes. With evolving surgical techniques and postoperative management, there is potential to improve outcomes in this subset of recipients. We compared the outcomes in pediatric patients with body weight < 10 kg with those >10 kg; also, we studied the factors of influence.

Materials and Methods: We performed a retrospective analysis to evaluate the outcomes of liver transplants in pediatric patients with < 10 kg body weight. The cohort consisted of 90 children subdivided into the following 2 subgroups: group A (n = 35) with > 10 kg body weight at liver transplant and group B (n = 55) with < 10 kg body weight at liver transplant. We compared the following pretransplant characteristics between the groups: graft weight, graft-to-recipient weight ratio, cold ischemia time, warm ischemia times, and liver transplant outcomes.

Results: Pediatric End-stage Liver Disease score was significantly higher in group B (score of 24) versus group A (score of 18). Group B had significantly higher graft-to-recipient weight ratio (2.8 in group B vs 1.7 in group A). Graft function showed no significant difference between the 2 groups. Portal vein thrombosis was seen only in group B, whereas biliary leaks were observed among 5 patients in group B and 1 patient in group A. Patient survival rate was higher in group B (86%) than in group A (77%).

Conclusions: Pediatric patients weighing < 10 kg have similar if not better survival rates after liver transplant compared with patients > 10 kg. Advancements in surgical techniques and a careful monitoring for complications and timely intervention are important to facilitate these outcomes.

Key words : High graft-to-recipient weight ratio, Improved surgical technique, Liver transplant in small infants, Outcome, Vascular complications

Rates of liver transplant (LT) for pediatric patients are rising around the world. In the United States, 599 pediatric LTs were performed in 2017; among these, only 22.4% of recipients were < 1 year old and only 14% were living donor LTs in patients < 6 years old.¹ Outcomes of pediatric LTs depend on various perioperative and recipient factors, including z score, patient weight, intraoperative factors, blood loss, and graft-to-recipient weight ratio (GRWR).² Among these factors, the weight of the patient at LT has been considered the most important factor. Long-term retrospective analysis has shown better outcomes in recipients with body weight > 10 kg.³ The factors attributable to this observation are inherent surgical complexities that result from associated anatomic malformations, portal vein atresia, the smaller caliber of vessels, presence of intra-abdominal adhesions due to previous Kasai portoenterostomy in the majority of cases, and larger graft size resulting in higher graft-to-recipient weight ratio.^4,5 In addition, the typical malnourished status of these children results in insufficient physiological reserves to overcome the stress of the surgery.⁶ Critical care management issues in children with low body weight are further compounded by the major functional stress induced by the transplant procedure. Hence, most centers consider 10 kg recipient body weight as a minimum requirement for a good outcome. The achievement of a target desirable weight before LT in infants with end-stage decompensated liver disease is an unrealistic clinical goal in the majority of the cases and results in longer wait list times, more severe decompensation complications, and higher risk of pre-LT mortality.⁷

With ongoing experience, the pre-LT optimization, surgical techniques, and post-LT care have been customized for small children in high-volume centers, and this has resulted in better outcomes in the recent past.⁸ At our center, we have performed more than 3000 LTs. Approximately 50 pediatric LTs are performed in our unit annually. After successful management of the complicated anatomic abnormalities that may occur in children, such as portal vein atresia and Abernathy syndrome, our unit has gained substantial experience with the perioperative management of these small children.⁹ This long-term experience supports our conclusion that weight cutoff points should not be one of the criteria for delaying a LT.¹⁰ To emphasize our point, we designed the following study to specifically evaluate the results of LT and its complications in small children.

Materials and Methods

This was a single-center, retrospective study to evaluate the outcomes of LT in pediatric patients weighing < 10 kg at the time of liver transplant. All patients included in our study were between 0 and 16 years old and underwent LT between May 2017 and April 2020 in our center.

After the first result of comparative survival between the overall cohort, recipients with body weight < 10 kg or > 10 kg (Table 1), we excluded the recipients with early mortality (< 30 days post-LT). Contrary to previous reports, we observed that survival outcomes of patients with < 10 kg body weight at LT were better than the other group. Hence, to better compare the course in the hospital, complications, and specific issues across different weight categories, we evaluated only the surviving patients, to better ensure a homogenous cohort.

Of the complete cohort of 109 patients, we selected 90 surviving patients for further analysis as explained above. They were subdivided into the following 2 subgroups: group A (n = 35) with body weight > 10 kg at LT and group B (n = 55) with body weight < 10 kg at LT. We assessed the 2 groups for the pre-LT characteristics of graft weight, GRWR, cold ischemia time, and warm ischemia time and compared these with the post-LT outcomes. The post-LT outcome parameters were selected to cover the progression of graft function, complication rate, and survival rate. The progression of graft function was assessed by time to normalize the bilirubin level, the international normalized ratio (INR), and the volume of abdominal drain output at days 7 and 10. For the purpose of comparison, the abdominal drain output was normalized by calculating it as milliliters per kilogram body weight per day. The complications were assessed as vascular, biliary, need for reexploration, and duration of hospital stay.

The standard protocol in our unit is to administer steroids at reperfusion and subsequently begin triple therapy, including calcineurin inhibitor, mycophenolate mofetil, and steroids, from post-LT day 1. We monitored graft vascularity with abdominal Doppler ultrasonography 3 times daily for 7 days and then twice daily for 3 weeks. Prophylactic low-molecular-weight heparin is given to all pediatric patients postoperatively once their INR is below 2.

Relationship of liver donors to respective recipients
Among the 90 survivors selected for analysis, all had living related liver donors, and of these donors there were 52 mothers, 25 fathers, 2 brothers, 2 sisters, and 9 second-degree relatives (aunts and uncles).

Statistical analyses
We performed statistical analyses with the SPSS Statistics package (2020). We used the t test and the chi-square test to compare the differences between the 2 study groups when the variables were continuous and nominal, respectively. We used the multiple logistic regression model to determine the predisposing factors after assessment of the correlation coefficients between related factors. The level of significance was selected as 5% (P < .05).

Overall cohort description
There were 109 pediatric patients who received LT between May 2017 and April 2020; 66 of these were boys, the mean recipient age was 47 months (range, 1-192 months), and the mean body weight at LT was 15.2 kg (range, 2.5-68 kg). The indication for LT was biliary atresia in 53 patients (49%), and 17 patients (16%) had primary genetic liver disease with molecular confirmation. All but 2 patients had living related liver donors, of whom 1 patient had a swap donor and the other a domino LT donor. Seven of 109 patients (6%) had ABO-incompatible LTs.

Patient characteristics before liver transplant
Pediatric End-stage Liver Disease (PELD) score was significantly higher in group B (PELD score of 24) versus group A (PELD score of 18). Other pre-LT parameters were assessed; aspartate transaminase-to-platelet ratio index, serum fibrinogen, albumin, and ammonia were found to be not significantly different between the 2 groups (Table 2).

Liver transplant details
The children in group B had significantly higher GRWR of 2.8 versus 1.7 in group A. The cold and warm ischemia times were similar between the 2 groups (Table 3).

Liver transplant outcome: graft function
We evaluated the following parameters to assess graft function: the time to achieve normal serum bilirubin, post-LT INR, and duration of hospital stay. All of these parameters showed no significant difference between the 2 groups. In addition, we evaluated the normalized abdominal drain output (expressed as milliliters per kilogram body weight per day) at post-LT days 7 and 10. Both of these parameters were significantly higher in group B (79 and 48 mL/kg/day) compared with group A (37 and 24 mL/kg/day) on days 7 and 10, respectively (Table 3).

Portal vein thrombosis (PVT) was seen only in group B, whereas biliary leaks were observed among 5 patients in group B and 1 patient in group A. There was no significant difference in the frequency of post-LT abdominal reexploration, gut perforation, or diarrhea between the 2 groups (Table 3).

Survival outcomes
Patient survival rate was higher in group B (86%) than in group A (77%) (Table 1).

The results of our transplant program show that small infants, ie, with < 10 kg body weight, have equal if not better outcomes than pediatric patients with > 10 kg body weight. These results reinforce our conclusion that the use of weight cutoff points to predict outcomes in pediatric LT recipients is an outdated concept, in the context of a competent and specialized team; in addition, these results suggest that smaller recipients (eg, < 10 kg body weight) should be treated only in specialized pediatric LT centers to ensure optimal outcomes.

Previous studies have shown higher survival rates among pediatric patients > 10 kg body weight,^11,12 but improvement in surgical techniques has resulted in better outcomes. Standard left lateral segment grafts are often excessively large for pediatric patients, and their portal flow is not sufficient to perfuse the peripheral area of graft, which may lead to stasis and promote thrombosis. Also, a higher value for GRWR is expected in pediatric patients and has been historically associated with a higher incidence of graft loss and vascular complications.¹³ Our most crucial advancement in surgical techniques has been the technique for medial reduction of the liver graft, which was pioneered at our center.¹⁴ The reduced space in the abdominal cavity (anteroposterior diameter) and increased abdominal pressure after closure may compromise graft vascular supply. This problem was circumvented in our series by the medial reduction technique described in a previously published study.¹⁴ Thus, even with significantly higher GRWR, outcomes were improved in the smaller children.

Vascular complications in LT have a devastating effect on the patient. The high volume of pediatric patients at our center has provided us the opportunity to increase proficiency and improve technical modifications, which has facilitated our ongoing success with pediatric patients.¹⁵ The pediatric patients with lower body weight have a higher risk of vascular complications, as was reported previously and also in this present study.¹⁶ Our study showed that vascular complications in the form of portal vein thrombosis were seen exclusively in group B; these included the PVT in 4 patients and no hepatic artery thrombosis was seen. Hepatic venous complications in the form of hepatic vein thrombosis and/or stenosis were seen equally in both groups, which were managed with either an interventional radiology-guided procedure or were managed conservatively. The cases of PVT were treated with early reexploration and revision of portal vein anastomosis, the outcomes of which were favorable. Vascular complications have been reported to be more common in patients with biliary atresia who underwent LT, due to the associated portal vein atresia.¹⁷ However, among our 53 patients with biliary atresia, only 2 developed PVT and no predisposition in this group was observed. Our surgical technique in cases with attenuated portal vein included the decision to not lengthen the portal vein by dissecting it from its supportive tissues (which would increase its redundancy); instead, we used an ABO-compatible portal vein graft to lengthen the portal vein. In cases with an atretic portal vein, portal vein reconstruction was done using a portal vein graft, which was anastomosed as close to the portovenous confluence as possible. Postoperatively, we practiced prophylactic anticoagulation with low-molecular-weight heparin in all patients. We monitored patency of vessels with Doppler ultrasonography 3 times daily until postoperative day 7.

The preoperative PELD score is another factor that can predict post-LT survival. Various studies have shown mixed results; some concluded that survival is independent of mortality, whereas others found it to be a major predictor of mortality.^18,19 In our experience, PELD is not an indicator for post-LT mortality risk, as it was higher in group B than in group A. However, patients with higher PELD scores had worse preoperative general conditions, which may add to morbidity.

Biliary leak as a complication was also common in group B (4 patients in group B vs 1 in group A). Two patients in group B required reexploration and lavage, whereas 2 were managed with interventional radiology-guided percutaneous drainage. All 4 patients recovered with these measures. The patient with bile leak in group A received a right-lobe graft with multiple (3) duct-to-duct anastomoses. She required a biliary diversion through a percutaneous transluminal biliary drainage tube, the insertion of which was guided by interventional radiology. Bile refeeding was performed, and then she underwent hepaticojejunostomy. Overall, no long-term biliary sequelae were seen on the follow-up magnetic resonance cholangiopancreatography, even though higher biliary complications are often observed in pediatric patients with lower body weight.

We evaluated postoperative graft function on the basis of time (in days) to normalize serum bilirubin and INR, and we did not find any significant difference with regard to the weight cutoff point in our study. This suggests that graft function and restoration of hepatic function are independent of these factors.

Patients in group B had high abdominal drain output compared with group A. Various factors have been studied for the persistence of post-LT ascites. Presence of hepatic outflow obstruction, pretransplant ascites, serum albumin, and splanchnic hypertension are some of the important contributory factors.²⁰ We did not do any invasive pressure studies in our recipients for high drain output, as most of them had ascites before transplant; also, the patients in group B were more malnourished, which contributed to protein deficiency. They responded to albumin infusions, and progressively reduced replacement of abdominal drain output.

Patients in group B had worse preoperative conditions than those in group A, as indicated by their significantly higher PELD score; however, their posttransplant outcomes did not show any major difference with respect to the normalization of graft function and duration of intensive care unit or hospital stay. The GRWR was significantly higher in group B, which was expected because of their low body weight. Incidences of vascular complications were also seen exclusively in group B patients. Despite these factors, the outcome in group B was better than in group A. Our experience for LT in pediatric patients with body weight < 10 kg suggests that, with advancements in surgical techniques and intensive postoperative management, this group of patients may be considered for early LT, with no requirement to achieve a higher body weight before transplant. A high level of awareness for vascular and biliary complications and timely intervention to address these complications are important for satisfactory outcomes.

Volume: 18 Issue: 6 November 2020

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