We conducted this study in accordance with the tenets of the Declaration of Helsinki, and the Clinical Research Ethics Committee of Renji Hospital, School of Medicine, Shanghai Jiaotong University. The Clinical Research Ethics Committee of Huashan Hospital, Fudan University approved the protocol [Rj (2018) 218].

In Shanghai, two hospitals (Renji and Huashan) had performed pediatric LDLT by the end of 2016. We reviewed 559 records of all the pediatric LDLTs performed between October 21, 2006 and August 10, 2016 in Renji Hospital (School of Medicine, Shanghai Jiaotong University, n = 543) and in Huashan Hospital (Fudan University, n = 16), and set up a follow-up cut-off date of August 10, 2018. Data from 15 patients who were older than 12 years at the time of LT were excluded, and the final analysis comprised data from 544 children (Renji Hospital 530 LDLTs, Huashan Hospital 14 LDLTs).

Demographic data, including age, body weight, gender, diagnoses, preoperative PELD score, and history of Kasai procedure (KP) were extracted. Additionally, general donor information (age, donor liver weight, donor liver cold ischemia time, the relationship between donor and recipient) was collected. The etiology of transplantation was classified into three categories (cholestatic, metabolic, and others).

We documented the following intraoperative details: Anesthesia duration, surgery duration, intraoperative blood loss, donor liver weight, donor liver cold ischemia time, intraoperative packed red blood cell (PRBC) transfusions, total volume of liquid, transfusion threshold, and postoperative hemoglobin (Hb) level.

Additionally, we collected postoperative data including duration of mechanical ventilation (MV) in the intensive care unit (ICU), ICU length of stay, postoperative length of stay, PRBC administered in the ICU; 30-d, 90-d, 1-year, and 2-year survival rates were calculated. We defined patient survival as the time between transplantation and the end of follow-up or death. We calculated the annual caseload to describe the transplant trends from 2006 to 2016. Furthermore, we also performed uni- and multivariable survival analysis to determine the predominant factors affecting patient survival.

The suitable age for donors ranged from 18 to 55 years. Donors were evaluated using routine blood examinations, liver and kidney function examination, chest radiography, and electrocardiography. The quality, volume, and anatomy of the donor liver were carefully evaluated using computed tomography angiography.

Recipients underwent a series of laboratory and imaging examinations prior to surgery. The severity of illness was measured using the pediatric end-stage liver disease and Child–Pugh scores. Complete medical history, physical, radiological and laboratory examinations, and cardiac ultrasound were carefully evaluated by the anesthesiologist. Moreover, growth and nutritional assessments were also performed prior to surgery.

All recipients underwent routine anesthesia management: Patients fasted 6 h for solid food and 2–4 h for clear fluid before anesthesia. The operating table was equipped with a warming blanket. All patients were anesthetized using sevoflurane by mask or total intravenous anesthesia, maintained with sevoflurane, muscle relaxant and sufentanil intravenously via a pump. Patients were monitored by electrocardiography, continuous arterial blood pressure, continuous central venous pressure, and pulse oximetry. End-tidal CO₂, body temperature, and urine output were also monitored. If necessary, dopamine or norepinephrine was infused through the portal vein to maintain hemodynamic stability.

All surgical procedures were performed by experts in the pediatric LT technique in the Department of Liver Surgery. Intraoperative real-time cholangiography was essential and an ultrasonic surgical aspirator was used in the donor operation, and the graft was implanted into the recipient’s abdominal cavity using the piggyback technique. All patients underwent Roux-en-Y hepaticojejunostomy for bile duct reconstruction[11].

Blood gas analysis was regularly performed to detect levels of Hb and other biochemical indices after induction of anesthesia, before the anhepatic phase, in the middle of the anhepatic phase, 5–10 min after the neohepatic phase, and at the end of surgery. The intraoperative PRBC transfusion was determined according to the amount of intraoperative blood loss, hemodynamic stability, and Hb level. No cell salvage or venovenous bypass was performed in these patients. Platelets were not regularly used as they were an independent risk factor for survival after LT[13].

Patients were sent to ICU after the operation, where blood gas analysis was performed immediately upon arrival, and at least twice/day thereafter. Similarly, liver function tests and the coagulation profile were monitored. Doppler ultrasound was performed at the end of surgery and every 24 h for the first 7 postoperative days to assess the patency of liver vessels.

We carried out statistical analyses using the IBM SPSS Statistics 23.0 (SPSS Inc., Armonk, NY, United States). The Kolmogorov–Smirnov test was carried out to obtain all distributions for normality. We expressed continuous variables as means ± standard deviation or medians with interquartile range (IQR: 25%–75%), and reported categorical variables as numbers (n) or proportions (%). We plotted the survival rates of recipients using Kaplan–Meier curves, and evaluated the differences in selected factors using the log-rank test.

To identify independent predictive factors of patients’ overall survival, univariable Cox regression analysis was used. Significant independent predictive factors (P < 0.05) were then included in the multivariable Cox proportional hazard regression analysis. Multivariable regression curves were also generated after multivariable Cox regression analyses. During the statistical analyses, 30-d survival analysis, 1-year survival analysis, 3-year survival analysis and overall survival analysis were all conducted to identify independent predictive factors of patients’ overall survival. To identify independent predictive factors of in-hospital patient survival, the χ² test with the Yates correction or the Fisher’s exact test were used, as appropriate. All statistical tests were two-sided, and P values < 0.05 were considered statistically significant.

The first pediatric LDLT in Shanghai was performed at the Renji Hospital on October 21, 2006; and the first pediatric LDLT performed in Huashan Hospital was on September 3, 2014. As shown in Figure 1A, there was a rapid increase in pediatric LDLT cases from 2006 to 2016 with one case in 2006, which rose to 179 in 2015 (Renji Hospital 172, Huashan Hospital 5), and at the time of database lock on August 10, 2016, remained at 120 (Renji Hospital 112, Huashan Hospital 8).

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Figure 1 Patient number and the survival rates from 2006 to 2016 (n = 544). A: Annual caseload of pediatric living donor liver transplantation from 2006 to 2016; B: Overall survival rates; C: Patient survival rates before and after January 1, 2011 (2-year: 74.47% vs 90.74%, P = 0.0004); D: Patient survival rates before and after January 1, 2012 (77.78% vs 91.10%, P = 0.0005); E: Patient survival rates before and after January 1, 2013 (2-year: 82.24% vs 91.08%, P = 0.007); F: Patient survival rates before and after January 1, 2014 (2-year: 84.52% vs 91.48%, P = 0.016).

After surgery, 518 (95.22%) of the 544 patients had survived at least 30 d, 508 (93.38%) at least 90 d, 497 (91.36%) at least one year, and 486 (89.34%) at least two year (Figure 1B). We found that the 2-year patient survival rate improved from 74.47% before 2011 to 90.74% after January 1, 2011 [hazard ratio (HR) = 2.92; 95% confidence interval (CI): 2.16–14.14; P = 0.0004] (Figure 1C). Similarly, the 2-year patient survival rate after January 1, 2012 had improved (91.10%) compared with the previous period (77.78%) (HR = 2.63; 95%CI: 1.85–8.67; P = 0.0005) (Figure 1D), the 2-year survival rate in 2013 (91.08%) had improved compared to the previous period (82.24%) (HR = 2.06; 95%CI: 1.29–4.77; P = 0.007) (Figure 1E), and the 2-year survival rate in 2014 (91.48%) had improved compared to the previous period (84.52%) (HR = 1.86; 95%CI: 1.15–3.67; P = 0.016) (Figure 1F).

As shown in Figure 2A and B, the median recipient age was 8.20 mo (IQR: 7.00–13.95), and the median weight was 7.70 kg (IQR: 6.80–9.20). Cholestatic cirrhosis was the most common indication for LT in this study; 488 recipients (89.71%) were diagnosed as having cholestatic cirrhosis preoperatively (Figure 2C) and 216 (39.85%) of the 544 recipients had undergone KP prior to LT (Table 1).

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Figure 2 Characteristics of donors and recipients. A: Age of the recipients; B: Weight of the recipients; C: Demographics of the recipients; D: The relationship between donors and recipients; E: Duration of anesthesia and operation; F: Time period between anesthesia induction and surgery initiation. G: Duration of MV in ICU; H: ICU length of stay; I: Postoperative length of stay; J: Perioperative RBC transfusion. LDLT: Living donor liver transplantation; MV: Mechanical ventilation; ICU: Intensive care unit; RBC: Red blood cell.

The 544 living donors examined in this study comprised 306 (56.3%) mothers, 203 (37.3%) fathers, 24 (4.4%) grandmothers, 6 (1.1%) grandfathers, 3 (0.6%) aunts, and 2 (0.4%) uncles (Figure 2D). The average donor age was 32.27 ± 7.24 years, the average donor liver weight was 261.95 ± 64.67 g, and the average donor liver cold ischemia time was 69.15 ± 26.14 min (Table 1).

The median anesthesia duration was 525 min (IQR: 476.50–587.50), and the median operation duration was 425 min (IQR: 384.00–480.00) (Figure 2E). The time period between anesthesia induction and surgery initiation showed a decreasing trend, which started at 194 min in 2006, and fell to 88.00 min (IQR: 77.50–98.50) in 2016 (Figure 2F).

The overall median ICU MV duration was 18 h (IQR: 15.2 5–20.25) (Figure 2G), the median ICU length of stay was 6 d (IQR: 4.80–9.00) (Figure 2H), and the median postoperative length of stay was 24 d (IQR: 18.00–34.00) (Figure 2I).

The median intraoperative blood loss was 200 mL (IQR: 100.00–250.00) and the median perioperative PRBC transfusion (intraoperative transfusion + ICU transfusion) was 1 unit (IQR: 1.00–2.00) (Figure 2J). The median blood transfusion threshold was 6 g/dL (IQR: 5.40–6.70). Of the 544 patients, 47 (8.60%) did not require PRBC transfusions during the operation, and 35 (6.40%) did not receive perioperative PRBC transfusions (Supplemental Table 1).

Univariable analysis was performed on 18 variables that may have an impact on the patient survival rate, including age (≤ 36 mo or > 36 mo), gender (male or female), recipient body weight (≤ 10 kg or > 10 kg), diagnosis (cholestatic cirrhosis, metabolic disease, or others), PELD score (≤ 2 or > 2), previous KP (yes or no), preoperative Hb level (≤ 8 g/dL or > 8 g/dL), anesthesia duration (≤ 600 min or > 600 min), operation duration (≤ 480 min or > 480 min), anhepatic phase (≤ 40 min or > 40 min), intraoperative blood loss (≤ 200 mL or > 200 mL), graft to recipient weight ratio (< 2.0%, 2.0%–4.0%, or ≥ 4.0%), cold ischemia (≤ 60 min or > 60 min), perioperative PRBC transfusion (≤ 1 U or > 1 U), perioperative blood transfusion (yes or no), ICU MV duration (≤ 24 h or > 24 h), ICU length of stay (≤ 9 d or > 9 d), and postoperative length of stay (≤ 30 d or > 30 d).

Of the 18 variables examined, PELD score, anesthesia duration, operation duration, intraoperative blood loss and ICU length of stay were independent predictive factors of in-hospital patient survival (P < 0.05) (Table 2). In addition, four of these factors were associated with 1-year patient survival, including PELD score (P = 0.029), preoperative Hb level (P = 0.034), operation duration (P = 0.016), and ICU length of stay (P = 0.003) (Supplemental Table 2). When these variables were fitted into the multivariable Cox regression model, three (PELD score, operation duration, and ICU length of stay) predicted 1-year patient survival (Table 3). For the 3-year patient survival, 3 of the 18 variables, including PELD score (P = 0.016), operation duration (P = 0.013), and ICU length of stay (P = 0.002) were independent predictive factors (Supplemental Table 3) in univariable analysis, and in the multivariable Cox regression model (Table 4).

Since the first successful pediatric living donor liver transplantation (LDLT) in 1989 by Strong, the procedure has become the gold standard for patients with end-stage liver disease. With improvements in organ preservation, immunosuppression, and surgical and anesthesia techniques, the survival rates and long-term outcomes of patients after LDLT have significantly improved worldwide. However, data on anesthetic management and postoperative survival rate of pediatric LDLT in mainland China are rare.

The purpose of this study was to provide information on the status of pediatric LDLT in Shanghai in recent years and to determine which of the perioperative management-related factors might impact survival rate in pediatric LDLT. These findings will help to optimize perioperative management in pediatric patients receiving LDLT in the future.

To summarize the status of pediatric LDLT in Shanghai in recent years and to investigate the impact of perioperative management-related factors on the survival rate in pediatric LDLT.

A retrospective observational study was conducted by reviewing 544 records of patients who underwent pediatric LDLT since the first operation on October 21, 2006 until August 10, 2016 at Renji Hospital and Huashan Hospital. Cox regression analysis was used to identify independent predictive factors of patients’ overall survival.

The 30-d, 90-d, 1-year, and 2-year survival rates were 95.22%, 93.38%, 91.36%, and 89.34%, respectively. The 2-year patient survival rate after January 1, 2011 significantly improved compared with the previous period (74.47% vs 90.74%; hazard ratio: 2.92; 95%CI: 2.16–14.14; P = 0.0004). Moreover, the pediatric end-stage liver disease (PELD) score, operation duration, and intensive care unit (ICU) length of stay were independent predictive factors of 1-year and 3-year patient survival.

In summary, our findings demonstrated that the annual caseload of pediatric LDLT has been growing rapidly and recipients have achieved excellent outcomes in Shanghai with a 2-year patient survival rate of 89.34%. The PELD score, operation duration, and ICU length of stay were independent predictive factors of 1-year and 3-year patient survival.

The present retrospective study demonstrates that the PELD score, operation duration, and ICU length of stay are independent predictive factors of in-hospital patient survival as well as of 1- and 3-year patient survival, and suggests that prospective trials exploring the effects of these factors on pediatric LDLT patient survival are warranted.