Acute lung injury (ALI) is a common diagnose in critically ill children and account for high proportion of pediatric intensive care unit (ICU) admissions. Significant long-term effects were also reported in pediatric survivors of ALI including reduced quality of life and diminished neurocognitive function.1 Several studies report that comorbid conditions, such as an immunocompromised state, increase the risk of mortality of children with ALI, per “2-hit” theory proposed by Michael et al.2 Liver transplantation is also an important preexisting condition in pediatric patients who developed ALI. Postoperative pulmonary complications contribute to the morbidity and mortality of liver transplant recipients, with incidences ranging from 13% to 50% of transplanted patients.3 Many factors, such as perioperative hemodynamic alterations due to surgical procedure on its own, bleeding, and the release of cytokines and toxins have been implicated.4 Compared with adults, the risk of the problems among pediatric recipients would be higher partly because of their fragile respiration center and poor oxygen reserve capacity. Therefore, it is vital to understand the clinical phenomenon, including its risk factors, not only to direct care of children but also for designing new potential therapies and rehabilitative strategies to improve their quality of life.
As a specific marker of myocardial injury, cardiac troponin I (cTnI) is not due to a clinically detectable acute cardiac pathology in most cases. They can be increased in up to 31% of patients without cardiovascular diseases such as sepsis, pulmonary embolism, chronic obstructive pulmonary disease, end-stage renal disease, and so on.5,6 However, the elevated troponin level itself cannot provide any information about the underlying mechanism of troponin release. The prevalence and prognostic significance of increased troponin levels in the absence of myocardial events need to be further addressed. Previous studies have found that high preoperative serum cTnI concentration was associated with greater postoperative risk of cardiovascular events and graft loss for patients receiving liver transplantation.7 Lee et al8 have confirmed the predictive value of cTnI in severe pneumonia. But the implications of intraoperative cTnI anomalies in the ALI after pediatric living donor liver transplantation are unknown. The primary objectives of this retrospective study were to evaluate the link between intraoperative cTnI alterations in the absence of a clear cardiac cause and ALI in the first week after pediatric living donor liver transplantation.
MATERIALS AND METHODS
Data Source and Study Population
After obtaining approval from Tianjin First Center Hospital Institutional Review Board, medical records of pediatric liver transplant recipients (January 2012 to December 2015) were retrospectively reviewed. The study population included pediatric patients who had biliary atresia and received grafts from the family members of the pediatric recipients. Children with congenital cardiopulmonary deformity or acute respiratory infection before surgery or retransplantation were excluded. The clinical and laboratory data were collected by a dedicated research nurse as the part of the standard of care in our hospital. We collected data in the preoperative, intraoperative, and postoperative periods.
In this study, serum cTnI levels were analyzed by the third-generation enhanced AccuTnI assay (Beckman Coulter, Brea, CA). In our study, cTnI elevation was defined as troponin I ≥ 0.07 ng/mL, which was the lowest value measurable with a 10% coefficient of variation above the 99th percentile upper reference limit per the manufacturer's instruction.9,10 Patients were divided into 2 categories per the level of serum cTnI at 30 minutes after reperfusion. Sixty-four children comprised the high-cTnI group (≥0.07 ng/mL) and 59 children were divided into the control group (<0.07 ng/mL).
Clinical Data Collection
The following preoperative variables were included: patient characteristics, pediatric end-stage liver disease (PELD) model score which is calculated as follows: PELD score = 0.436 (age < 1 year)–0.687 · loge albumin (g/dL) + 0.480 · loge total bilirubin (mg/dL) + 1.875 · loge international normalized ratio (INR) + 0.667 (growth failure height or weight ≥2 SDs below age- and sex-adjusted mean), serum creatinine, serum bilirubin, serum albumin, INR. Intraoperative data were graft cold ischemia time, serum cTnI, urine output, bleeding volume, blood products, and fluid transfusions as well as the duration of the surgery. Postoperative data included the highest serum creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels during the first week after operation, the ICU stay time, ICU mortality, hospitalization time, in-hospital mortality, and the occurrence of ALI in the first week after operation. The criteria of ALI were defined as follows11: (1) acute onset, (2) PaO2/FiO2 less than 300, (3) pulmonary artery wedge pressure less than 18 mm Hg or without clinical evidence of left atrial hypertension, (4) bilateral infiltrates on chest radiograph.
Data are shown as absolute number (n), frequencies, and percentages or mean ± SD as appropriate. Baseline characteristics were compared using analysis of variance for continuous variables. The χ2 test and the Fisher exact test were used for the categorical variables. Univariable and multivariable logistic regression models were used to identify the risk factors associated with the high cTnI level at 30 minutes of neohepatic phase and determine the impact of early posttransplant complications using clinical variables. Data are reported as odds ratios (ORs) with corresponding 95% confidence interval (CI). A P value less than 0.05 was considered statistically significant for all variables. The collinearity of parameters was diagnosed by the value of variance inflation factor, and no interaction effects were found in our study. Statistical comparisons were based on prespecified analyses. Analyses were performed using SPSS19.0 software (SPSS, Inc., Chicago, IL).
From January 2012 to December 2015, 370 pediatric patients underwent living donor liver transplantation. Of the 158 patients with cTnI measurement in our initial cohort, 35 were excluded because of acute respiratory infection, congenital heart disease, and retransplantation. Among 123 children meeting the inclusion criteria, the cTnI level of 64 patients were above 0.07 ng/mL (Figure 1). Table 1 compares the baseline demographic characteristics of children with elevated intraoperative cTnI levels and children with normal levels. Of the 64 recipients, whose cTnI level was above 0.07 ng/mL in the study cohort, 42.8% were men. Children with elevated intratransplant cTnI levels showed lower level of serum albumin but higher PELD scores before transplantation. During the surgery, the consumption of fresh frozen plasma and colloid solution would be larger. Postoperative data demonstrated a significant higher bilirubin peak in high-cTnI group, namely, from 52.1 IU/L versus 90.1 IU/L (P = 0.01).
During the follow-up period, a total of 22 children with cTnI elevation developed postoperative ALI, which was higher than those children with normal cTnI level (34.3% vs 11.9%, P = 0.005). Elevated cTnI children surviving to discharge also had longer ICU stay time compared with normal cTnI children (P = 0.005). But there was no association between cTnI level and other postoperative complications including intestinal fistula/biliary fistula and rejection reaction. Likewise, there was no significant difference in ICU mortality (3.4% vs 4.7%, P = 0.539), hospitalization time (41.27 ± 8.11 vs 44.19 ± 10.42, P = 0.102), and in-hospital mortality (6.8% vs 10.9%, P = 0.314) (Table 2).
Prediction Model of Early Posttransplant ALI Using Clinical Variables
Univariate and multivariate logistic regressions were conducted to determine if an elevated cTnI level was an independent predictor of posttransplant ALI after pediatric living donor liver transplantation (Table 3). Age, pretransplant albumin, pretransplant bilirubin, intraoperative cTnI ≥ 0.07 ng/mL, and postoperative bilirubin peak were predictors of an elevated cTnI during the operation on univariate analysis. On multivariate logistic regression analysis, pretransplant albumin (OR, 0.897; 95% CI, 0.814-0.988; P = 0.028), pretransplant bilirubin (OR, 1.005; 95% CI, 1.002-1.009; P = 0.004), and intraoperative cTnI ≥ 0.07 ng/mL (OR, 3.475; 95% CI, 1.114-10.842; P = 0.032) were the independent predictors of these adverse events.
Predisposing Factors for Intraoperative Serum cTnI Elevation of Children
Of note, neither sex, weight nor most preoperative variables were associated with the elevation of serum cTnI at 30 minutes of neohepatic phase. The univariable analysis demonstrated that the considerable risk factors for cTnI elevation were age, graft cold ischemia time, pretransplant albumin, pretransplant bilirubin, and pretransplant INR. After fitting a multivariate logistic regression model, only pretransplant albumin (OR, 0.915; 95% CI, 0.849-0.986; P = 0.02) and pretransplant bilirubin (OR, 1.005; 95% CI, 1.002-1.008; P = 0.001) remained significantly associated with the increase of cTnI during surgery (Table 4).
Serum cardiac troponin (I or T), a highly specific cardiac protein is released in several cardiac illnesses, such as infarction, myocarditis, pericarditis, functional failure, and pericardial effusion. Its levels may be augmented in other noncardiac conditions, such as chronic kidney disease.12 Customarily, I isoform is sensitive to assist with the diagnosis of acute coronary syndrome compared with T isoform. Previous studies have reported that cTnI alteration is an independent predictor of adverse short-term outcomes in sepsis and unselected critically ill patients.13 In contrast to these reports, our study focused on children with biliary atresia undergoing pediatric living donor liver transplantation. In this study, we demonstrated that almost 50.9% of pediatric recipients with no prior history of cardiovascular diseases showed the abnormal cardiac enzyme level at 30 minutes after reperfusion during the surgical procedure. Interestingly, no phenomena of early postoperative adverse cardiovascular events were predicted. One plausible explanation was that infants had enhanced vascular elasticity and stronger compensative capacity in circulatory system. In the study by Siniscalchi et al,14 increased cTnT levels in patients with cirrhosis were linked to the lower glomerular filtration rate and the greater incidences of acute kidney injury than control patients. However, the predictivity of intraoperative troponin elevation for posttransplant ALI and the risk factors on cTnI elevation have not been studied.
Pulmonary complications after liver transplantation have not been uncommon, which develops up to 34% to 44% among adult transplant recipients.15 It has been a major contributor to a fatal outcome after liver transplantation. Several studies reported that the pulmonary complication rates were higher, and complications were more severe in pediatric than in adult recipients. Due to the weakness of respiratory muscles and the decreased number of alveoli, infants always show the poor oxygen reserve capacity and high risk in respiratory disorders. Per our results of 123 children with biliary atresia during early postoperative period (≤7 day), the incidence of ALI in our series was 23.6%, much lower than that reported in the literature.15 Its root might be attributed to the exclusion of cases with congenital respiratory deformity or uncontrolled acute respiratory infection before surgery. The data on risk factors for ALI after living donor liver transplantation that exist in literatures to date are limited. Recent evidence suggested that patient age, history of respiratory diseases, intraoperative transfusion requirement, and the duration of mechanical ventilation were all considered the risk factors of early postoperative respiratory complications in liver transplant recipients.2,16 Fouquet et al17 indicated that the age under 1 year was strongly associated with the occurrence of posttransplant pulmonary events in children with end-stage liver disease. Rivara et al18 reported that the troponin levels were frequently elevated in patients with acute respiratory distress syndrome and associated with adverse outcomes including organ failure and death. Our laboratory has demonstrated that intraoperative cTnI ≥ 0.07 ng/mL (OR, 3.475; 95% CI, 1.114-10.842; P = 0.032) provided important prognostic information in the occurrence of early posttransplant ALI among pediatric recipients. It is intuitive that lung and heart are very intimately associated organs: some factors such as the hyperdynamic circulation may sensitize lung to the postreperfusion syndrome, bleeding, and fluid overload during liver transplantation, which lead to the lung ischemia. cTnI elevation can mirror subtle myocardial damage in a context of the reperfusion-induced multiorgan impairment and manifested itself later with ALI.
Besides cTnI alternation, pretransplant albumin (OR, 0.897; 95% CI, 0.814-0.988; P = 0.028) and bilirubin (OR, 1.005; 95% CI, 1.002-1.009; P = 0.004) were also the reliable predictors of subsequent ALI after operation. Albumin has long been considered effective to maintain the microvascular integrity and colloid osmotic pressure. Hypoalbuminemia might decrease the cross-wall osmotic pressure thereby result in pulmonary edema. In 1 sense, bilirubin is believed to reflect the hepatic function. For children with end-stage liver disease, hepatic dysfunction lowers the serum albumin level which is synthesized in the liver. Both factors give rise to ALI. Dani et al19 found that bilirubin could enter the lung tissue and exert a detrimental effect on lung surfactant surface tension properties in the rabbit model of hyperbilirubinemic juvenile. However, previous studies showed controversial results regard to the antioxidative effects of bilirubin. One possible explanation for the phenomenon is that the concentrations of bilirubin are different. And moderate-to-severe unconjugated hyperbilirubinemia is always associated with higher oxidative stress and the predictors of poor outcome.20
The level of serum albumin and bilirubin are also 2 useful parameters to evaluate the severity of hepatic function for children awaiting liver transplantation. Nicolau et al21 assessed that serum total bilirubin was probably a surrogate marker for worsening cardiovascular function and all-cause mortality. According to the results of univariable and multivariable logistic regression analyses, only pretransplant albumin (OR, 0.915; 95% CI, 0.849-0.986; P = 0.02) and bilirubin (OR, 1.005; 95% CI, 1.002-1.008; P = 0.001) were found to be more likely associated with intraoperative cTnI elevation, which offered the intimately correlation between liver and heart. A similar study has described that PELD score greater than 25 was a significant risk factor of graft loss among children undergoing living donor liver transplantation.22 It is commonly thought that inflammation is the crucial aspect of myocardial injury secondary to liver transplantation. As the specialized macrophages located in the liver, Kupffer cells are characterized by the activation of proinflammatory cytokines. Koh et al23 reported that the concentrations of IL-1β and IL-4 at 60 minutes after reperfusion during liver transplantation were higher among the high MELD versus the low MELD group. Another study revealed that the recipients with increased levels of preoperative direct/and bilirubin, AST/ALT, MELD scores, and INR suffered more proinflammatory cytokines and oxidative stress induced by ischemic reperfusion.24 For children diagnosed with chronic liver disease, IL-6 levels were associated with liver disease severity assessed by Child-Pugh score.25 Prospective studies using disease-matched controls to assess the association between liver function and the inflammation triggered by reperfusion injury during pediatric liver transplantation are needed to better answer the questions.
This is the first time to demonstrate the relationship between serum cTnI elevation after reperfusion and postoperative ALI among pediatric recipients who suffered from biliary atresia. During pediatric liver transplantation, the elevation of highly sensitive cTnI may mirror the subtle myocardial injury in a context of a transient low-perfusion damage of remote organs. The predictive value of cTnI is incremental to clinical, electrocardiographic, and radiographic data. Although the therapeutic strategy to prevent the elevation of cTnI after reperfusion is not very clear, knowledge of this risk parameter assists in clinically stratification for pediatric recipients who have potential high risk of postoperative ALI. Strict monitoring of pulmonary function and even early intervention should be conducted to prevent severe or unrecoverable respiratory damage.
There are some limitations in this study. First, the overall number of the cases in our study is small, which may lead to no statistical significance of some variables. A larger, more ethnically diverse cohort is required for further confirmation. Second, considering that the data were collected retrospectively by dedicated personnel, the analysis could have limited identification of numerous confounding factors and lead to the occurrence of selection bias. Lastly, the follow-up time after surgery is short, which might miss some important adverse events in the long run. Additional prospective studies are expected to investigate the influence of cTnI elevation on their long-term outcomes.
In conclusion, this study showed the elevation of intraoperative cTnI level (≥0.07 ng/mL) and documented its predictive value of ALI after surgery among children suffered from biliary atresia. Pretransplant albumin and creatinine were also the risk factors of ALI in our model. Pretransplant albumin and bilirubin remained significantly associated with the cTnI elevation during operation. Close monitoring of pulmonary function and careful fluid management early in the posttransplant course must be considered among those adequate-risk candidates with cTnI elevation. Further validation about the causality between cTnI elevation and adverse outcomes after transplantation is warranted and underway.
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