Prognosis of liver transplantation: Does postoperative ileus matter?

Background Nowadays, liver transplantation has become a main therapy for end-stage liver disease. However, studies show that there are high mortality and severe complications after liver transplantation. Although gastrointestinal dysfunction is a common and major complication after liver transplantation, there was rarely relative research. This study aims to elucidate the factors about ileus after liver transplantation and patients’ survival. Methods We collected and analyzed the data (n = 318, 2016–2019) from the First Affiliated Hospital of Xi’an Jiaotong University. After excluding cases, a total of 293 patients were included for this study. The subjects were divided into a non-ileus group and an ileus group. We reviewed 38 variables (including preoperative, operative and postoperative relative factors). Additionally, other complications after liver transplantation and survival data were compared between two groups. Results Of the 293 patients, 23.2% (n = 68) experienced postoperative ileus. Ileus patients were not different with non-ileus patients in preoperative, operative and postoperative factors. HBV-positive patients with ileus had a lower MELD score (P = 0.025), and lower postoperative total bilirubin was correlated with ileus (P = 0.049). Besides, Child–Pugh score of HCC patients with ileus was low (P = 0.029). The complications after liver transplantation were not different between two groups. Compared with the patients without ileus, the patients with ileus had a higher mortality rate. Conclusion According to our research, ileus-patients had a lower 1-year survival rates. The preoperative MELD score and postoperative total bilirubin of HBV-positive patients with ileus were lower, and Child–Pugh score of HCC patients with ileus was also lower.


Background
Liver disease accounts for approximately 2 million deaths every year worldwide [1]. Apart from cirrhosis and hepatocellular carcinoma due to viral hepatitis as well as alchohol, non-alchoholic fatty liver disease and drug induced hepatitis continue to increase as a main cause of acute liver injury. Liver diseases were estimated to become the 12th leading cause of mortality by 2020 [2].
complication following especially open abdominal surgery. Preoperative malnutrition, operative procedure, anesthesia and postoperative managements may increase the risk of gastrointestinal dysfunction [9]. According to clinical experience, once the gastrointestinal function is abnormal, the recovery of LT patients is delayed, even may affect survival rate of patients. Our study is designed to identify risk factors, obtain possible predictive factors and the effects of ileus to survival rate after LT patients.

Data collection
We collected the data from the First Affiliated Hospital of Xi'an Jiaotong University from January 2016 to March 2019 all recipients that underwent orthotopic liver transplantation (OLT). All of the liver grafts were from cardiac-dead donors. We excluded the candidates who were in gastrointestinal dysfunction before surgery, needed enteral feeding or nasogastric tube after surgery, homeostasis disturbance, secondary liver transplantation, multiple organ dysfunction syndrome (MODS) before surgery, critically ill after surgery (included extended immobility or narcotic use) and incomplete data. The duct-to-duct biliary reconstruction was performed for every patient, and there were no any cases of biliodigestive anastomosis. Data elements included preoperative, operative and postoperative factors. Additionally, patients were classified as postoperative ileus when the time of the first passage of flatus and the first defecation was over 72 h, or normal. In our study, all ileus-patients were paralytic ileus without requiring reoperation for adhesiolysis, and there were no patients with mechanical ileus.

Follow up
In view of regular check-up of post-LT patients, we used the inhospital or outhospital numbers, which are unique to each patient, to obtain patients' outcome in this study. The single endpoint of the study was all-cause mortality. Observations were stopped at the date of one year after surgery. Finally, 293 patients finished follow up.

Statistic analysis
The patients were categorized into 2 groups according to postoperative ileus. Continuous variables were summarized as means ± standard deviation or median and interquartile ranges, whereas frequencies and percentages were used for categorical variables. Student's t-test or Mann-Whitney U-test for continuous independent variables, the Pearson chi 2 test or Fisher's exact test was used to compare qualitative variables. The log-rank test (Mantel-Cox) was used to compare group survival curves. Statistical significance for all analyses was determined at P < 0.05. All analyses were undertaken by using Statistical Package for Social Sciences (SPSS) software, version 25.0 (IBM SPSS, Armonk, NY, USA).

Preoperative risk factors of postoperative ileus
The study demonstrated that age, male, BMI (body mass index), history of abdominal surgery, hepatic encephalopathy, portal hypertension, Model for End-Stage Liver Disease (MELD score), platelet counts, albumin, total bilirubin, serum creatinine, lactic acid and atiology of liver disease were not significantly different between groups (Table 1). Table 2 shows the results of risk factors for HBVpositive patients with and without ileus. Except for MELD score (P = 0.025), no significant differences were observed between patients with and without ileus for other factors analyzed.
There were not different between with and without ileus of HCC (hepatocellular carcinoma) patients for intraoperative risk factors, except for Child-Pugh score (P = 0.029; Table 3).

Intraoperative and postoperative risk factors of postoperative ileus
Intraoperative factors included duration of surgery, anhepatic phase, blood loss, total infusion fluid, red cell transfusion, cryoprecipitate transfusion and anesthesia (drug doses of propofol, sufentanil, renifentanil, sevoflurane, dexmedetomidine and etomidate) were not different among groups (Table 1). Retention time of tracheal tube, length of Intensive Care Unit of Surgery (SICU), length of hospital-stay, total bilirubin, lactic acid, platelet counts were postoperative possible risk factors. All were not different (Table 4).
There were not different between with and without ileus of HBV-positive patients for intraoperative risk factors (Table 2), but postoperative total bilirubin was significantly different between groups (P = 0.049; Table 5).
Tables 3 and 6 showed that no significant differences were observed in HCC patients with and without ileus for intraoperative and postoperative risk factors.

Overall survival rates of ileus and normal patients
Univariate analysis of 52 patients showed that 1-, 2-and 3-year overall survival rates post-LT were 89%, 89% and 89% in ileus patients, respectively, and 91%, 88% and 88% in non-ileus patients, respectively. The mean survival time was 11.24 months in patients with ileus and 11.76 months in patients without ileus in 1-year overall survival analysis. Kaplan-Meier survival curves showed that the overall survival rate was significantly different (P = 0.008) between groups (Fig. 1A).
1-, 2-and 3-year overall survival rates post-LT of HCC patients were 88%, 88% and 88% in ileus patients, respectively, and 93%, 88% and 88% in normal patients, respectively. 1-year overall survival rates post-LT were not different among groups (P = 0.580; Fig. 1C). Table 7 shows the results of donor's characteristics for patients with and without ileus. There were no

Discussion
Liver transplantation is not only a definitive treatment for liver diseases, but also is the second most common solid organ transplantation. Although doctors and researchers take complications of liver transplantation seriously and carry out treatments, POI is ignored by researchers. Postoperative ileus is a common complication after most abdominal surgeries, which is associated with longer hospitalization and increased medical costs [10]. Fluid overload, exogenous opioids, surgical procedure are key mechanisms of POI [11,12]. Among the 293 patients enrolled in this study with liver diseases who underwent LT, univariate analysis indicated that there was no significant difference in preoperative, intraoperative and postoperative factors between patients with and without POI, apart from the lower MELD score and postoperative total bilirubin in HBV-patients with ileus, and Child-pugh score of HCC patients with ileus was low. Study has reported that goal-directed fluid therapy does not reduce postoperative ileus in gastrointestinal surgery. It is possible that fluid overload is not necessary risk factor [13], which also been proved in our results. Besides, patients with POI had worse overall survival rates than patients without POI. Model of end-stage liver disease (MELD) and Child-Pugh scores have been widely used to assess the prognosis and predict the outcomes of cirrhotic patients [14]. MELD score is incorporated only 3 objective variables, including total bilirubin, creatinine and INR. Studies has proved that the MELD score system could reduce the mortality in patients waiting for a liver transplantation, and downgrading MELD score can improve the outcomes after liver transplantation in patients with acute-on-chronic hepatitis B liver failure [15,16]. The Child-Pugh score, based on clinical symptoms of insufficient liver function (ascites/encephalopathy), and laboratory analysis of parameters of liver function (albumin, bilirubin, and PT) can be used to identify low or highrisk patients [17]. And the Child-Pugh score has been proved that it is not only as a predictor of postoperative  mortality after portocaval shunt surgery but also predicts mortality risk associated with other major operations [18].The preoperative MELD score and postoperative total bilirubin of HBV-positive patients with ileus were lower than without ileus. And Child-Pugh score of HCC patients with ileus was lower than without ileus. There were no differences in other observed factors and overall survival rates among groups. MELD and Child-Pugh scores are lower, the liver function is better. According to the results, we can get that POI after liver transplantation may predict the recovery of normal liver function. Then, complications after liver transplantation including biliary infection, vascular complication, pulmonary infection, kidney injury were not different in LT patients with ileus and without ileus according to our study. We demonstrated that compared with the patients without ileus, the patients with ileus had a higher mortality rate within one year after surgery, which is consistent with the clinical observation. Several limitations of this study must be considered. First, this study was retrospective. Second, postoperative ileus was determined based on medical history, and the diagnosis of postoperative ileus lacks objective standards, which needs further research and discussion of professionals, especially ileus after liver transplantation. However, this study indicate that ileus of liver transplantation is a worthy research direction and demands sufficient clinical attention.

Conclusion
In conclusion, compared with non-ileus patients, we didn't obtain the risk factors of patients with ileus. Ileus-patients didn't increase complications after liver  Cold ischemia time (hours) 6.0 (5.00-6.00) 6.0 (5.00-6.00) 6.0 (5.00-6.00) 0.527 transplantation, but decrease post-LT one-year survival rates. But the preoperative MELD score and postoperative total bilirubin of HBV-positive patients with ileus were lower, and Child-Pugh score of HCC patients with ileus was also lower. A future prospective cohort study with larger a sample size should be conducted to confirm these observations, or POI may not be vital in the liver transplantation patients.