Background Living donor liver transplantation (LT) is the main treatment for paediatric biliary atresia (BA) in Asia. During LT, a series of haemodynamic changes often occur during LT reperfusion, which is called postreperfusion syndrome (PRS), and PRS is related to a prolonged postoperative hospital stay, delayed recovery of graft function and increased mortality. To reduce adverse reactions after paediatric living donor LT (LDLT), our study’s objectives were to ascertain the incidence of PRS and analyse possible risk factors for PRS.
Methods With the approval of the Ethics Committee of our hospital, the clinical data of 304 paediatric patients who underwent LDLT from January 2020 to December 2021 were analysed retrospectively. According to the presence or absence of PRS, the paediatric patients were divided into the non-PRS group and the PRS group. Independent risk factors of PRS were analysed using logistic regression analysis.
Results PRS occurred in 132 recipients (43.4%). The peak values of AST (816 (507–1625) vs 678 (449–1107), p=0.016) and ALT (675 (415–1402) vs 545 (389–885), p=0.015) during the first 5 days after LDLT in paediatric patients with PRS were significantly higher than those in the non-PRS group. Meanwhile, the paediatric patients in the PRS group had longer intensive care unit stays and hospital stays, as well as lower 1-year survival rates. Graft cold ischaemic time (CIT) ≥90 min (OR (95% CI)=5.205 (3.094 to 8.754)) and a temperature <36°C immediately before reperfusion (OR (95% CI)=2.973 (1.669 to 5.295)) are independent risk factors for PRS.
Conclusions The occurrence of hypothermia (<36.0℃) in children immediately before reperfusion and graft CIT≥90 min are independent risk factors for PRS. PRS was closely related to the postoperative adverse outcomes of paediatric patients.
- Adolescent Health
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Postreperfusion syndrome (PRS) is one of the most common complications during the perioperative period of liver transplantation, which has a great impact on the prognosis of paediatric patients after liver transplantation. To date, the data available to assess the risk factors for PRS in children undergoing living donor liver transplantation are limited.
WHAT THIS STUDY ADDS
The occurrence of hypothermia (<36.0°C) in children immediately before reperfusion and graft cold ischaemic time ≥90 min are independent risk factors for PRS.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Help to reduce the incidence of PRS and improve the survival rate of children after living donor liver transplantation.
Postreperfusion syndrome (PRS) is one of the most common perioperative complications of liver transplantation, with a reported incidence between 8% and 60%.1–4 Recent studies have found that the difference in the incidence of PRS is related not only to the difference in the definition,5 but also to the use of inhaled anaesthetics6 and the location of arterial pressure measurement during surgery.7 PRS seriously affects the success or failure of liver transplantation and the prognosis of patients.8–11 To date, the reliable pathophysiological mechanism of PRS has not been fully revealed. However, it is certain that a number of variables, such as hyperkalaemia, metabolic acidosis, hypocalcaemia, hypothermia, air embolism and vasoactive chemicals produced after reperfusion, are responsible for the development of PRS.9 10 12–14 For a long time, research on PRS has mainly focused on adults, but there is relatively little information on PRS in children with living donor liver transplantation (LDLT). Therefore, in this study, our main purpose was to further determine the independent risk factors for PRS and the adverse effects of PRS on prognosis in paediatric LDLT to provide clinical direction for the prevention of PRS during LDLT in children.
Patients and methods
This study included 304 BA paediatric patients (<18 years old) who received LDLT in Tianjin First Central Hospital from January 2020 to December 2021.
The children arrived without having any anaesthetic premedications and were monitored using ECG, pulse oximetry and non-invasive monitoring. Anaesthesia was induced with midazolam (0.15 mg/kg), propofol (2–3 mg/kg), fentanyl (2–5 µg/kg) and rocuronium (0.6–1.0 mg/kg). After intubation, mechanical ventilation was performed with a fraction of inspired oxygen of 50%–60%, a tidal volume of 8–10 mL/kg, a respiratory rate of 20–28/min, an inspiration-to-expiration ratio of (1.0:1.5)–2.0 and an end-tidal CO2 partial pressure of 30–35 mm Hg. The anaesthesia maintenance included sevoflurane (1.5%–2.5%), intravenous infusion of propofol (9–15 mg/kg/hour), intermittent intravenous fentanyl (1–3 µg/kg) and intravenous infusion of atracurium besylate (1–2 µg/kg/min). Right internal jugular vein puncture was performed under ultrasound guidance to monitor central venous pressure (CVP). A radial artery puncture was performed to monitor invasive arterial pressure. Albumin and acetate Ringer’s solution were used for fluid therapy based on haemodynamic parameters and CVP. Red blood cells (RBCs) were given to maintain a haemoglobin level of 80–100 g/L. The coagulation function was detected by a Sonoclot analyzer (Sienco, Arvada, Colorado, USA). When there was an obvious coagulation disorder, fresh frozen plasma (FFP) was infused. The patients were monitored, and the fluctuations in systolic blood pressure and heart rate were kept within 20% of baseline during surgery. When haemodynamic changes occurred, we used anaesthetics, cardioactive drugs and fluids for the necessary intervention.
For the donor, a left lobectomy was performed, and piggyback liver transplantation was performed for the recipient. HTK (histidine-tryptophan-ketoglutarate) solution was used as a perfusion solution to perfuse the transplanted liver. The specific components of HTK solution include NaCl, KCl, MgCl2 · 6H2O, histidine · HCI · H2O, histidine, tryptophan, mannitol, CaCl2 · 2H2O and 2-ketoglutarate-hydrogen-potassium. After occlusion of the inferior vena cava (IVC), the left hepatic vein of the transplanted liver was anastomosed with the recipient hepatic vein, and the IVC was opened after the anastomosis was completed. The donor and recipient portal veins were anastomosed. Reperfusion of the liver graft started with opening of the portal vein. The venovenous bypass was not performed during the operation. The left hepatic artery of the donor was anastomosed with the hepatic artery of the recipient. After arterial reperfusion, the bile duct was connected to the recipient’s jejunum (Roux-en-Y cholangiojejunostomy). The vascular morphology and blood flow velocity were examined by ultrasound after hepatic artery opening and abdominal closure, respectively.
PRS was considered to be a decrease of more than 30% in mean arterial pressure (MAP) compared with the end of the anhepatic phase, and it had to last at least 1 min and to occur in the first 5 min after liver graft reperfusion.10 15 16 The anhepatic phase was defined as the time from the physical removal of the liver from the recipient to recirculation of the graft. We used a dopamine infusion to maintain the patient’s MAP during this complication. When severe hypotension along with bradycardia occurred, we used an epinephrine bolus and infusion. In summary, the paediatric patients with and without PRS syndrome were divided into two groups, the PRS group and the non-PRS group, and the data from the two groups were compared and evaluated.
The preoperative recipient variables included age, sex, height, weight, left ventricular ejection fraction (LVEF), QTc Interval, paediatric end-stage liver disease (PELD) score, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), international normalised ratio, creatinine and HB. The intraoperative data were graft weight, graft cold ischaemia time, haemodynamic parameters, blood gas parameters and core temperature before the reperfusion, duration of the anhepatic period, duration of operation, duration of anaesthesia, blood loss, urine output, blood transfusions and FFP infusion. The following postoperative variables were included: mechanical ventilation time, intensive care unit (ICU) time in days, hospital stay, peak ALT, AST and TB examination in the first 5 days after LDLT, incidence of AKI and 1-year survival rate. AKI was evaluated based on the Kidney Disease: Improved Global Outcome criteria.17
All continuous variable data were tested for normality by the Shapiro-Wilk test and Q-Q plots. Measures that conformed to the normal distribution are shown using the mean±SD, and independent samples t tests were applied. The non-normally distributed continuous variables were expressed using the median (IQR), and Mann-Whitney U tests were used. Categorical variables are shown by the number of cases and percentages, using the Pearson χ2 test. Loess regression and univariate logistic regression were used to evaluate the relationship between univariate and PRS. Potentially relevant variables with loess fitted smooth line and p values <0.10 in the univariate analysis were further examined to find the independent risk factors connected to PRS. In the multivariable regression analysis, restricted cubic spline (RCS) was used to explore the nonlinear relationship between each variable and PRS. The number of knots was set to 4. Logistic multivariable regression was used to analyse the relationship between factors and PRS while the variables did not meet the non-linear correlation. The data are reported in the form of ORs and corresponding 95% CIs. The Kaplan-Meier method was used to show the survival status of the patients. Log-rank test was used to compare the survival status between the two groups. SPSS software V.20.0 (SPSS) and R (R for Windows V.4.1.2, R Foundation for Statistical Computing, Vienna) were used for statistical analysis. P values <0.05 were considered to be statistically significant.
During the study period, 331 paediatric patients underwent LDLT. Metabolic disease occurred in 13 patients, Alagille syndrome in 2 patients, Langerhans cell hyperplasia in 2 patients, cavernous portal vein in 1 patient, and liver retransplantation in 1 patient, and 8 patients had incomplete data and were excluded. Finally, a total of 304 patients with biliary atresia were included in this retrospective study (figure 1).
The demographic data of the recipients and donors are shown in table 1. A total of 172 patients (56.6%) in the non-PRS group had an overall mean age of 8 months (6–12 months) and included 85 male patients (49.4%). In contrast, 132 patients (43.4%) developed PRS, the overall average age was 8 months (6–12 months) and the group included 66 male patients (50.0%). The comparison of the preoperative data between the two groups showed that there was no significant difference in age, sex, height, weight, LVEF, QTc, PELD score or preoperative liver function indexes (ALT, AST and TB) (table 1). Similarly, there was no significant difference in graft weight between the two groups. However, the cold ischaemia time in the non-PRS group was significantly lower than that in the PRS group (76 (60–91) vs 105 (80–139) min; p<0.01) (table 2).
The data in table 2 show that the duration of the anhepatic phase in the paediatric patients with PRS (50.0 (42.0–62.0) vs 47.0 (38.5–56.5) min; p=0.018), operative duration (570 (500–620) vs 530(480–574) min; p=0.002), anaesthetic duration (622 (570–675) vs 610 (555–644) min; p=0.045), bleeding volume (350 (255–500) vs 300 (200–400); p<0.001), and RBCs transfusion (2.0 (2.0–3.0) vs 2.0 (1.5–2.5); p<0.001) were significantly higher than those in the non-PRS group. Eventually, significantly more paediatric patients in the PRS group experienced hypothermia (<36.0°C) immediately prior to perfusion than in the non-PRS group (50 (37.9%) vs 30 (17.4%); p<0.001). For the other intraoperative indexes, there was no statistically significant difference (table 2).
The postoperative data revealed no statistically significant differences between the two groups in the duration of mechanical ventilation, the incidence of AKI, or the peak TB value in the first 5 days following LDLT. However, the postoperative ICU stay days (3 (2–4) vs 2 (2–3), p=0.001), hospitalisation days (22 (18–30) vs 20 (16–25) p=0.023), and peak values of ALT and AST in the first 5 days after LDLT in the PRS group were significantly higher than those in the non-PRS group (table 3). Even the non-PRS group receiving LDLT had a considerably higher 1-year survival rate for paediatric patients with biliary atresia than did the PRS group (97.7% vs 92.4%, p=0.030) (figure 2).
The results of the univariate analysis showed that the considerable risk factors for PRS in paediatric patients with biliary atresia were graft cold ischaemic time (CIT), the duration of the anhepatic period, and the temperature immediately before reperfusion (table 4). In multivariate logistic regression analysis, graft CIT ≥90 min (OR (95% CI)=5.205 (3.094 to 8.754)) and temperature＜36°C immediately before reperfusion (OR (95% CI)=2.973 (1.669 to 5.295)) were independent risk factors for PRS (table 5). The relevant factors before reperfusion and PRS were fitted to the loess and presented in the form of images (online supplemental figures 1–3). According to the results of RCS (online supplemental figure 4), there is no non-linear relationship between variables and PRS that has been identified.
Our observational study’s primary findings can be summarised with two conclusions: among paediatric patients receiving liver transplants from living donors: (1) hypothermia before reperfusion (<36.0°C) and an increase in cold ischaemia duration of the donor are independent predictors of PRS and (2) a decreased 1-year survival rate following surgery is linked to PRS occurring during LDLT.
With the deepening of the definition of PRS, it is generally accepted that when MAP falls by more than 30% from the value at the end of the anhepatic phase and persists for at least 1 min within the first 5 min following reperfusion of the transplanted liver, the condition is known as PRS.10 16 A total of 132 (43.4%) of the paediatric patients in our research who had biliary atresia experienced PRS during LDLT.
PRS, a significant LDLT complication, may have a negative impact on postoperative prognosis. We analysed the postoperative outcomes of the two groups of recipients. Among these variables, the peak ALT and peak AST in the first 5 days after operation in the PRS group were significantly higher than those in the non-PRS group. Meanwhile, postoperative peak AST or ALT levels can well reflect the functional status of early grafts after liver transplantation. In addition, the paediatric patients with PRS after LDLT experienced longer ICU stays and hospital stays in our study. Finally, the patients with PRS had a considerably poorer 1-year survival rate than the children without PRS. Therefore, it is particularly important to reveal more independent risk factors for PRS. Timely detection and correction during surgery may improve the prognosis of paediatric patients and give them a better experience.
Hypothermia during paediatric surgery will bring many adverse results to patients.18 Under normal circumstances, the normal core body temperature of children under 5 years old is 36.5°C–38.0°C.19 Hypothermia is generally defined as a core body temperature that is lower than 36.5°C in children under the age of 5 and lower than 36.0°C in children over the age of 5. During the operation, we recorded the bladder temperature as the core temperature. In our research, we discovered that paediatric patients with PRS had much lower prereperfusion temperatures than the non-PRS group. According to our research, the incidence of PRS was significantly impacted by hypothermia (<36.0°C) prior to reperfusion. Infection of the surgical site, inhibition of a series of coagulation cascade enzymes, impairment of platelet function and an extension of the postoperative ICU stay as well as the overall length of hospitalisation are all frequently caused by intraoperative hypothermia.20–22 Arrhythmias, myocardial ischaemia and cardiac arrest may also result from it.23 The effect of hypothermia on thrombin and platelets leads to an increase in blood loss and blood transfusion in children. Our results also support this view. In addition, hypothermia can prolong the QT interval, which in turn slows cardiac repolarisation time and heart rate and prolongs atrioventricular node conduction time.24 Meanwhile, hypothermia can also lead to cardiac troponin-I phosphorylation, which limits the inhibition of myocardial contractility.25 It is clear that the development of intraoperative hypothermia will result in intricate cardiovascular responses. In our study, paediatric patients with PRS had considerably lower core temperatures before reperfusion than those in the non-PRS group. Hypothermia before reperfusion may be a potentially separate risk factor for PRS, according to Manning et al.26 Our research further confirms this conjecture. Children’s thermoregulation mechanism is not very mature and the ratio of body area to body weight is relatively high, which causes their body temperature to drop faster. However, using an intraoperative air warming blanket, warming blood and infusion supplies, controlling the operating room’s temperature and preoperative prewarming may successfully lower the incidence of intraoperative hypothermia in paediatric patients.
Many clinical articles have shown that cold ischaemia duration is an independent predictor of PRS.10 27 However, these articles have mainly focused on adults rather than paediatric patients. As early as 2000, a retrospective study by Chui et al 28 reported that there were harmful effects of prolonged duration of cold ischaemia. Continuous cold preservation time can significantly damage liver regeneration, increase ATP consumption and aggravate ischaemia-reperfusion injury.10 Sinusoidal endothelial cells may initially become necrotic as a result of cold ischaemia, which is then followed by hepatocyte apoptosis and liver damage.29 In a study of rat liver transplantation, protracted CIT resulted in the activation of cellular nuclear factor kappa B, which is detrimental to inflammation and may exacerbate neutrophil-mediated graft damage.30 Moreover, TLR4/MYD88/NF-κB signalling pathway activation can encourage an inflammatory response and exacerbate myocardial damage.31 According to reports, patients will have numerous negative consequences from prolonged cold ischaemia, including a lower chance of transplant survival,32 graft dysfunction33 and a disproportionately protracted hospital stay.34 Interestingly, with further study of the relationship between CIT and the incidence of complications, 6 hours is considered to be a critical time; that is, a CIT more than 6 hours may lead to a higher incidence of complications.35 Our research provides additional evidence that prolonged cold ischaemia poses a distinct risk for PRS in paediatric patients. Therefore, the next problem we will face is how to successfully shorten the CIT. Some possible solutions include earlier liver transplant operation or exploring other preservation methods instead of cold storage.
In addition to CIT and hypothermia, there are many independent risk factors for adult PRS, including male sex, hypocalcaemia and high pulmonary artery pressure before reperfusion.3 Even, the use of different inhaled anaesthetics can have a very large difference in the incidence of PRS in adults.6 All of these factors require further prospective studies on paediatric patients to determine their specific impact on the occurrence of PRS in children. It is noteworthy that further studies are needed to determine whether drugs that inhibit inflammation will reduce the incidence of PRS.
The sample size of this study is very large, and thus far, no study of this scale has been conducted to assess the risk factors for PRS in children undergoing LDLT, which may be the advantage of this study. However, there are several limitations in our study. First, due to the lack of partial records of the anhepatic electrolyte test data, which was not included in the regression analysis, so we were unable to analyse the relationship between electrolytes and PRS. Second, since this was an observational study, we could not address causal relationships. Third, because this is a single-centre study conducted in China, we are not sure if the results can be extended to other ethnic groups. On the basis of our retrospective single-centre study, further prospective multicentre studies are recommended.
In conclusion, our study suggested that temperature <36°C in children immediately before reperfusion and graft CIT ≥90 min were independent risk factors for PRS in paediatric patients undergoing LDLT. For anaesthesiologists, this finding may help to predict the possibility of developing PRS in paediatric patients receiving LDLT and to provide effective anaesthetic management interventions during surgery. However, anaesthetic management programmes still need to be further improved to prevent PRS in LDLT.
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information.
Patient consent for publication
This study is a retrospective and observational study that was approved by the Institutional Review Committee of Tianjin First Central Hospital (2022DZX02).
TL and YW are joint first authors.
Contributors TYL and YQW conceived the manuscript. LC and MWS coordinated and supervised data collection. XYG carried out the statistical analysis. TYL and YLW wrote and prepared the tables and figures. LLJ and HXL revised the manuscript with additional detail. WLY and YQW critically reviewed the manuscript for important intellectual content. All authors have read and agreed to the published version of the manuscript. YQW is the study's guarantor.
Funding This research was funded by grants from Science and Technology Foundation of Tianjin Health Bureau (ZC20052), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-045A), Natural Science Foundation of Tianjin (21JCQNJC01730) and Tianjin Anesthesia Research Development Programme of Bethune Charitable Foundation (TJMZ2022-005).
Competing interests None.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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