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Risk Factors for Postoperative Prolonged Mechanical Ventilation After Pediatric Liver Transplantation

Objectives: Duration of postoperative mechanical ventilation after pediatric liver transplant may influence pulmonary functions, and postoperative prolonged mechanical ventilation is associated with higher morbidity and mortality. Here, we determined its incidence and risk factors after pediatric liver transplant at our center.

Materials and Methods: We retrospectively analyzed the records of 121 children who underwent liver transplant between April 2007 and April 2017 (305 total liver transplant procedures were performed during this period). Prolonged mechanical ventilation was defined as postoperative tracheal extubation after 24 hours.

Results: Mean age at transplant was 6.2 ± 5.4 years and 71/121 children (58.7%) were male. Immediate tracheal extubation was achieved in 68 children (56.2%). Postoperative prolonged mechanical ventilation was needed in 12 children (9.9%), with mean extubation time of 78.0 ± 83.4 hours. Reintubation was required in 13.4%. Logistic regression analysis revealed that presence of preoperative hepatic encephalopathy (odds ratio of 0.130; 95% confidence interval, 0.027-0.615; P = .01), high aspartate amino transferase levels (odds ratio of 1.001; 95% confidence interval, 1.000-1.002; P = .02), intraoperative usage of more packed red blood cells (odds ratio of 1.001; 95% confidence interval, 1.000-1.002; P = .04), and longer surgery duration (odds ratio of 0.723; 95% confidence interval, 0.555-0.940, P = .01) were independent risk factors for postoperative prolonged mechanical venti-lation. Although mean length of intensive care unit stay was significantly longer (12.6 ± 13.6 vs 6.0 ± 0.6 days; P = .001), mortality was similar in children with and without postoperative prolonged mechanical venti-lation.

Conclusions: Our results indicate that postoperative prolonged mechanical ventilation was needed in 9.9% of our children. Predictors of postoperative prolonged mechanical ventilation after pediatric liver transplant at our center were preoperative presence of hepatic encephalopathy, high aspartate amino transferase levels, intraoperative usage of more packed red blood cells, and longer surgery duration.


Key words : Children, Postoperative tracheal extubation, Pulmonary complications

Introduction

Postoperative tracheal extubation after pediatric liver transplant is predominantly performed within the first 24 hours. However, in some patients, the process may be prolonged. There are a number of studies regarding the high incidence of postoperative pulmonary complications (35% to 50%) after liver transplant.1,2 Prolonged mechanical ventilation is one of the postoperative pulmonary complications. Respiratory failure and the need for prolonged mechanical ventilation can lead to nosocomial infections, hemodynamic side effects, including low cardiac output, ventilator-associated lung injury, and prolonged intensive care unit (ICU) and hospital stay.3,4 With prolonged positive pressure ventilation, patients can develop congestion in the blood flow in the splanchnic area, which can act as a barrier to the inferior vena cava, and drainage of hepatic venules. This causes deterioration of graft oxygenation, which can lead to graft dysfunction. Therefore, spontaneous respiration can allow hemodynamic stability, hepatic venous drainage, and donor graft circulation in these patients.5-7

In this study, our aim was to determine the tracheal extubation time after pediatric liver transplant and to analyze the incidence and risk factors for post-operative prolonged mechanical ventilation (PPMV) after pediatric liver transplant.

Materials and Methods

This study was approved by the Baskent University Institutional Review Board (project no: KA 18/124) and supported by the Baskent University Research Fund.

We retrospectively analyzed the records of children who underwent liver transplant at Baskent University Ankara Hospital from April 2007 to April 2017. Among 305 liver transplant procedures performed during this period, 121 pediatric liver transplant recipients were evaluated. Patients over the age of 16 years and patients with missing data were excluded from the study.

Collected data included demographic charac-teristics of children (age, sex, body weight, body mass index), systemic diseases, drugs, Pediatric End-Stage Liver Disease (PELD) score, Model of End-Stage Liver Disease (MELD) score, perioperative laboratory values and hemodynamic parameters, perioperative urine output, incidence of intraoperative massive hemorrhage (massive hemorrhage was defined as blood loss exceeding 150 mL/min8), extubation time, lengths of ICU and hospital stays, and hospital mortality.

The same anesthetic technique was used for all pediatric recipients during liver transplant. Anesthesia was induced with a combination of propofol (1.5-2.5 mg/kg) and fentanyl (3-5 μg/kg). Rocuronium was given to facilitate endotracheal intubation (0.5-1.2 mg/kg) and to maintain paralysis during surgery (0.01-0.012 mg/kg/min). Anesthesia maintenance was achieved with a sevoflurane-air-oxygen mixture and an infusion of remifentanil (0.1-0.2 μg/kg/min).

Routine monitoring included electrocardiography, pulse oximetry, capnography, nasopharyngeal tem-perature, invasive arterial blood pressure (radial pressure), central venous pressure via the subclavian or internal jugular vein, and cardiac output (Pulse Index Continuous Cardiac Output [PiCCO], Pulsion Medical Systems, Germany) monitoring. The patients were extubated in the operating room at the end of surgery when they were awake, responsive, and met universally accepted criteria, including metabolic and hemodynamic stability. After surgery, all patients were admitted to the ICU. The same surgical, anesthesia, and intensivist teams were assigned during the perioperative period for all liver transplant surgeries.

Prolonged mechanical ventilation was defined as postoperative tracheal extubation after 24 hours. Children were divided into 2 groups: those who were extubated within 24 hours of surgery and those who were extubated 24 hours or more after surgery.

Statistical analyses
For statistical analysis, SPSS software was used (SPSS: An IBM Company, version 20.0, IBM Corporation, Armonk, NY, USA). Chi-square test was used to compare categorical variables. In terms of continuous variables, Mann-Whitney U test was applied to investigate differences in groups. In summary statistics, the median (minimum to maximum) was used for continuous variables, and frequency distributions and percentages were used for categorical variables. Graphs were also generated using percentages and frequencies to summarize the results. Statistically significant level of P < .05 was used in this study.

Results

During the 10-year study period, 121 children underwent liver transplant, with all included in our analyses. The mean age at transplant was 73.2 ± 63.6 months, and 71 children (59%) were male. The most frequent diagnosis was biliary atresia (25 children, 21%). The demographic characteristics, main diagnosis, and graft type of patients included in the study are shown in Table 1. Tracheal extubation time was 13.06 ± 37.06 hours among pediatric liver transplant recipients. We found that 109 patients (90%) were extubated in the first 24 hours after liver transplant. Immediate tracheal extubation at the operating room was achieved in 68 children (56.2%). Postoperative prolonged mechanical ventilation was needed in 12 children (9.9%), with mean time of extubation of 78.0 ± 83.4 hours. The incidence of reintubation was 13.2%.

Children with or without postoperative prolonged mechanical ventilation were similar in terms of demographic characteristics and mean calculated MELD and PELD scores (Table 2). When compared with children who did not have PPMV, preoperative presence of hepatic encephalopathy was significantly greater (4 children [36%] vs 6 children [7%]; P = .01) and aspartate aminotransferase (AST) levels were significantly higher (median [interquartile range] of 222.0 U/L [121.5-873.0 U/L] vs 112.0 U/L [56.5-207.5 U/L]; P = .01). Preoperative total protein levels were significantly lower (median [interquartile range] of 5.3 g/dL [4.0-5.9 g/dL] vs 6.2 g/dL [5.5-7.0 g/dL]; P = .03) versus those who had (Table 2). Patients with PPMV received significantly more packed red blood cells (median [interquartile range] of 31.1 mL/kg [21.4-37.6 mL/kg] vs 15.0 mL/kg [8.6-23.9 mL/kg]; P < .001) and less crystalloids (median [interquartile range] of 90.2 mL/kg [53.6-100.1 mL/kg] vs 113.6 mL/kg [80.6-151.5 mL/kg]; P = .01) intraoperatively (Table 3).

The mean length of ICU stay (median [interquartile range] of 5.0 days [3.0-25.0 d] vs 3.0 days [2.0-5.0 d]; P = .01) was significantly longer and postoperative use of antibiotics (12 [92%] vs 56 [52.0%]; P = .001) was higher in children with PPMV. Mortality was similar in children with and without PPMV (Table 4).

Logistic regression analyses, with odds ratio (OR) and 95% confidence interval (95% CI), revealed that presence of preoperative hepatic encephalopathy (OR of 0.130; 95% CI, 0.027-0.615; P = .01), high AST levels (OR of 1.001; 95% CI, 1.000-1.002; P = .02), intraoperative usage of more packed red blood cells (OR of 1.001; 95% CI, 1.000-1.002; P = .04), and longer duration of surgery (OR of 0.723; 95% CI, 0.555-0.940; P = .01) were independent risk factors for PPMV (Table 5).

Discussion

In this retrospective study of 121 pediatric patients who had undergone liver transplant over a period of 10 years, tracheal extubation was performed in about 90% of children within 24 hours. The incidence of PPMV was found to be 9.9%. The presence of preoperative hepatic encephalopathy, preoperatively high AST levels, high intraoperative packed red blood cell use, and long surgery duration were found to be risk factors for the development of PPMV. We also noted that PPMV was associated with prolonged ICU stay and increased duration of postoperative antibiotic use.

Previous studies have reported high incidences of postoperative pulmonary complications after liver transplant.1,2 In a retrospective study by Nafiu and associates, prolonged mechanical ventilation after pediatric liver transplant was defined as a requirement for mechanical ventilation for more than 4 days, with reported incidence of prolonged mechanical ventilation of 25%.9 In our study, we defined PPMV as requirement for mechanical ventilation for more than 24 hours, with almost half of our patients (56.2%) extubated in the operating room. The different incidences (25% vs 9.9%) between that study and our present study may be attributed to the fact that pediatric liver transplant procedures have been performed for many years in our university, and our transplant team is quite experienced and prefers immediate tracheal extubation when patients meet universally accepted criteria for extubation. In the literature, there are limited numbers of publications related to extubation in the operating room in adult and pediatric patients, with these studies reporting the use of similar protocols for extubation.10,11

Hepatic encephalopathy is a neuropsychiatric syndrome that occurs as a result of acute or chronic liver function impairment. It is associated with poor prognosis, with some reports indicating a 1-year mortality rate of almost 60%. Although its patho-genesis is still unclear, there are a number of mechanisms that are thought to play a role in the increased levels of circulatory neurotoxins, the neurotoxic effects of ammonium on the brain, increased GABA neurotransmissions in the brain, decreased glutamate levels, and increased endogenous benzodiazepine levels.12,13 Lee and colleagues reported hepatic encephalopathy as being a risk factor for need for pulmonary mechanical ventilation14 in their study investigating the perioperative risk factors for pulmonary mechanical ventilation in adult liver transplant recipients. In agreement with this earlier study, in the present study, we found that hepatic encephalopathy was also a risk factor for PPMV in pediatric transplant recipients. This relationship may be attributed to the state of sedation and agitation associated with hepatic encephalopathy. Because patients with hepatic encephalopathy are incapable of completely following commands and in meeting the weaning criteria, we believe that their need for mechanical ventilation may be longer.

In the present study, we found that preoperative AST elevation was associated with need for PPMV. Aspartate aminotransferase is both a cytosolic and mitochondrial isoenzyme and is found in the liver, striated muscle, brain, kidney, lung, pancreas cells, leukocytes, and erythrocytes. Accordingly, although not specific for liver, AST may be an indicator of liver cell damage.15 We can associate the relation between AST elevation and PPMV with longer mechanical ventilation requirements in patients with lower preoperative liver reserves.

We also found that high intraoperative packed red blood cell usage was a risk factor for the development of PPMV. In their study investigating the risk factors for mechanical ventilation in pediatric liver transplant recipients, Nafiu and associates reported that higher amounts of intraoperative packed red blood cells and fresh frozen plasma transfusion were associated with increased need for pulmonary mechanical ventilation.9 Glanemann and associates also stated that higher levels of intraoperative fresh frozen plasma transfusion were associated with an increased requirement for pulmonary mechanical ventilation.16 Consistent with the literature, our present study also reported that an increased amount of packed red blood cell transfusion was a risk factor for PPMV development; we believe that this may be the result of the negative effects of blood product transfusion on the lungs.

Several studies have shown that prolonged surgery, particularly cardiac surgeries, extended the time until extubation.17,18 In pediatric liver transplant, Nafiu and associates also associated long surgery durations with prolonged need for mechanical ventilation.9 In line with this observation, we also found that prolonged duration of surgery was a risk factor for PPMV.

It is also noteworthy that PPMV was associated with a higher amount of antibiotic use, which may be an effect of the prolonged duration of mechanical ventilation increasing the risk of developing ventilator-related pneumonia.

In our study cohort, patients who needed PPMV had a longer length of ICU stay, but the need for renal replacement therapy, overall hospital length of stay, and mortality were not different compared with those without PPMV. Although Nafiu and associates9 defined PPMV as ≥ 4 days, we defined PPMV as longer than 24 hours because the median duration of mechanical ventilation of our patients was below 48 hours. We believe that the different mortality results may be related to this finding.

The retrospective nature of our study and the insufficient number of reports in the literature detailing PPMV needs in pediatric liver transplant recipients can be considered limitations of the study. Future prospective studies should include larger patient groups.

Conclusions

In conclusion, in our study involving 121 pediatric liver transplant recipients, the incidence of PPMV was 9.9%. Our results showed that presence of preoperative hepatic encephalopathy, elevated preoperative AST levels, high intraoperative packed red blood cell use, and long surgery duration were risk factors for the development of PPMV and that PPMV is associated with longer durations of stay in the ICU.


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DOI : 10.6002/ect.2018.0317


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From the 1Anesthesiology and ICM Department and the 2Transplantation Department, Baskent University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors have no conflicts of interest to declare. This study was supported by the Baskent University Research Fund.
Corresponding author: Helin Sahinturk, Baskent University, Faculty of Medicine, Department of Anesthesiology and ICM, Fevzi Cakmak Caddesi 10, Sokak No:45 Bahcelievler, 06490 Ankara, Turkey
Phone: +90 312 2126868/4817
E-mail: helinsahinturk@yahoo.com