Eur J Cardiothorac Surg 2007;32:917-922. doi:10.1016/j.ejcts.2007.09.013
Copyright © 2007, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Incidence, risk factors, and prognosis of postoperative hyperbilirubinemia after heart transplantation
Ron-Bin Hsua,*,
Fang-Yue Lina,*,
Robert J. Chenb,
Nai-Kuan Choua,
Wen-Je Koa,
Nai-Hsin Chia,
Shoei-Shen Wanga,
Shu-Hsun Chua
a Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taiwan, ROC
b Division of Cardiovascular Surgery, Cheng-Hsin Rehabilitation Medical Center, Taipei, Taiwan, ROC
Received 30 May 2007;
received in revised form 13 September 2007;
accepted 15 September 2007.
* Corresponding authors. Address: National Taiwan University Hospital, No. 7, Chung-Shan S. Rd. Taipei, Taiwan 100, ROC. Tel.: +886 2 2312 3456x5580; fax: +886 2 23410933. (Email: ronbin{at}ha.mc.ntu.edu.tw).
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Abstract
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Objective: The clinical significance of postoperative hyperbilirubinemia after heart transplantation has not been reported. Here, we sought to evaluate the incidence, risk factors, and prognosis of postoperative hyperbilirubinemia after heart transplantation. Methods: Between 1987 and 2005, 256 consecutive patients undergoing heart transplantation were studied prospectively. Postoperative hyperbilirubinemia was defined as occurrence of a serum total bilirubin concentration of more than 3 mg/dl in any measurement during the postoperative period. Logistic regression was done to identify possible risk factors for postoperative hyperbilirubinemia and hospital mortality. Results: Overall incidence of postoperative hyperbilirubinemia was 57%. Among all patients, there were 35 hospital deaths (14%). In patients with postoperative hyperbilirubinemia, the mean onset time was 2.4 ± 4.4 days after transplantation and the mean peak serum total bilirubin was 10.1 ± 10.4 mg/dl. Development of postoperative hyperbilirubinemia was associated with a higher mortality (21% vs 5%, P
< 0.001 by Fisher's exact test). The onset time of postoperative hyperbilirubinemia, the peak serum total bilirubin level, and the time at which the peak bilirubin level was reached were associated with hospital mortality. Old donor age, valvular heart disease, high right atrial pressure, use of mechanical ventilation before transplant, and ascites at transplant were the significant risk factors for postoperative hyperbilirubinemia. Conclusions: Postoperative hyperbilirubinemia is common in patients undergoing heart transplantation and is associated with high hospital mortality. Patients with valvular heart disease, high preoperative right atrial pressure, and ascites at transplant, who then receive an old donor heart, are at greater risk for development of postoperative hyperbilirubinemia.
Key Words: Heart transplantation • Hyperbilirubinemia
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1. Introduction
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Postoperative hyperbilirubinemia after cardiac surgery using cardiopulmonary bypass is a relatively infrequent event but may result in significantly increased adverse outcomes [1–8]. The preoperative identification of patients at an increased risk for developing postoperative hyperbilirubinemia may allow heightened vigilance during the perioperative period and earlier diagnosis and intervention, possibly improving outcome. Hyperbilirubinemia was reported in early studies to occur in about 10% of patients after cardiac surgery. More recent studies estimate the incidence of postoperative hyperbilirubinemia to be more than 20% or even as high as 51% [1–8]. The occurrence of postoperative hyperbilirubinemia has been reported to be associated with mortality up to 25% [2]. However, the clinical significance of postoperative hyperbilirubinemia after heart transplantation has not been reported. Here, we sought to evaluate the incidence, risk factors, and prognosis of postoperative hyperbilirubinemia after heart transplantation.
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2. Patients and methods
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A total of 256 consecutive patients who underwent heart transplantation from June 1987 to October 2005 were studied retrospectively. Patients were not selected with any predetermined criteria. Patients with preoperative hyperbilirubinemia were also included.
2.1 Patient management
All of the procedures of heart transplantation were performed through a median sternotomy. Anesthesia was induced with fentanyl (30–100 µg/kg), dizapam (0.2–0.3 mg/kg) or etodimate (0.3–0.4 mg/kg), and pancuronium or vecuronium (0.1–0.15 mg/kg). Halothane was not used because of its possible hepatotoxic effects. The routine clinical monitors included lead II and V5 electrocardiogram, the radial arterial line, the pulse oximeter, end-tidal carbon dioxide, nasopharyngeal and rectal temperature, urine output via Foley catheter, the central venous pressure line, and pulmonary artery catheters.
In all patients, moderate hypothermic cardiopulmonary bypass with lowest nasopharyngeal temperature around 25 °C with pulsatile flow was instituted with the roller pump (Sarns 5000; Sarns 3M, Ann Arbor, MI). Membrane (Capiox E; Terumo, Tokyo, Japan) oxygenators were used. The perfusion flow was kept over 2.2 l/m2 during normothermia and over 1.8 l/m2 during hypothermia. The mean arterial pressure was kept between 50 and 100 mmHg during cardiopulmonary bypass. Arterial blood gas was monitored routinely every hour or any occasion when considered necessary. The priming solution contained 1.5–2 l of lactated Ringers solution, mannitol (300 mg/kg), heparin (2000 U/l), and 0.5–1 unit of packed red cells if blood cardioplegic solution was indicated or the predicted hematocrit level during cardiopulmonary bypass was below 22%. Systemic heparin was given through the right atrium at a dose of 300 U/kg just before cannulation. The cardiopulmonary bypass time and allograft ischemic time were recorded.
2.2 Immunosuppression
All patients received triple-drug immunosuppressive therapy according to our heart transplantation protocol previously described [9,10]. Since 1995, we have started using rabbit antithymocyte globulins for induction therapy. Azathioprine (4 mg/kg) was given 1 h before the operation. Solumedrol (1000 mg) was infused as the aortic cross-clamp was released. Rabbit antithymocyte globulin (1.5–2.5 mg/kg/day) was given after transplantation for 5 days. Cyclosporine was started orally within 5 days after transplantation or after the recovery of renal function. Cyclosporine dose was adjusted according to renal function and serum cyclosporine level, which was maintained at the trough level of 300–500 ng/ml during the first 3 months after transplantation and 200–300 ng/ml 1 year after transplantation. Azathioprine was given at 1–2 mg/kg/day after transplantation, with the dose adjusted to maintain a white blood cell count of 4000–6000/mm3. Prednisone (0.5 mg/kg/day) was started on the second postoperative day and tapered to 0.2 mg/kg/day by the first month after transplantation. Tacrolimus (FK-506) and mycophenolate mofetil (Cellcept) were used for recurrent rejection or severe adverse reactions to cyclosporine and azathioprine. Since 2004, we have started using mycophenolate mofetil for primary immunosuppression instead of azathioprine. To prevent nephrotoxicity, cyclosporine dose was decreased to maintain serum trough level of 250–350 ng/ml during the first 3 months after transplantation and 150–250 ng/ml 1 year after transplantation.
2.3 Data collection
Patient demographics, clinical, and laboratory data were collected using standardized case report forms. Data on age, sex, diagnosis of heart disease, renal and liver function tests, hemodynamics, and clinical outcome were recorded.
After the operation, blood samples were obtained from the central venous line or venipuncture daily within the first week after transplantation, and twice weekly thereafter. Blood samples were analyzed for concentrations of albumin, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alkaline phosphatase, total bilirubin, and direct bilirubin by an automated biochemical analyzer, which was calibrated and quality controlled periodically by the institution's clinical laboratory. Postoperative hyperbilirubinemia was defined as total bilirubin concentrations over 3 mg/dl in any one of the postoperative measurements [5].
2.4 Statistical analysis
The results are expressed as median with a range or mean with standard deviation and frequencies for the categorical variables. Univariate associations between potential preoperative and intraoperative predictors and postoperative hyperbilirubinemia were assessed with Chi-square test, Fisher's exact test, and Mann–Whitney test, as appropriate. Then, stepwise logistic regression was performed for risk factors for postoperative hyperbilirubinemia and included all potential predictors associated with P
< 0.1 from the univariate analysis. Results for the multivariate models are reported as odds ratios with associated 95% confidence intervals. The patient and graft survival curve was plotted by the Kaplan–Meier method. The survival was compared by log-rank test between patients with and without postoperative hyperbilirubinemia. P
0.05 was considered statistically significant.
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3. Results
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3.1 Patient characteristics
From 1987 through 2005, 256 patients with end-stage heart failure underwent heart transplantation. Patient demographics and laboratory data before transplantation were listed in Table 1
. There were 212 men and 44 women, and the median age was 49 years (range 0–71 years). The causes of heart failure were congenital heart disease in 10 patients (4%), dilated cardiomyopathy in 142 patients (55%), coronary artery disease in 71 patients (28%), valvular heart disease in 19 patients (7%), second transplantation in 8 patients (3%), and others in 6 patients. Four patients received combined heart and kidney transplantation and 72 patients (44%) had previous cardiac operation.
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Table 1 Patient characteristics in 256 heart transplant patients: comparison between patients with and without postoperative hyperbilirubinemia by Fisher's exact test and Mann–Whitney U-test
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The median level of serum total bilirubin was 1.3 mg/dl (range 0.1–34.8); serum albumin, 3.7 g/dl (range 1.4–5); serum blood urea nitrogen, 24 mg/dl (range 1–128); serum creatinine, 1.2 mg/dl (range 0.38–14.8). Forty-six patients (18%) had moderate-to-severe ascites by preoperative abdominal sonography and 41 patients (16%) had the prothrombin time prolongation more than 5 s. The hepatitis virus surface antigen was positive in 19 (8%) of 248 patients whose data were available. Among 254 donors whose data were available, there were 189 men and 65 women, and the median age was 30 years (range 1–66). The median duration of allograft ischemic time was 136 min (range 40–336). The median duration of cardiopulmonary bypass was 150 min (range 63–436).
3.2 Postoperative hyperbilirubinemia
One hundred and forty-five patients (57%) developed postoperative hyperbilirubinemia. The incidence of postoperative hyperbilirubinemia was 54% (44/82) in the years 1987–1997, 59% (48/81) in the years 1998–2001, and 57% (53/930 in the years 2002–2005. In patients with postoperative hyperbilirubinemia, the mean onset time was 2.4 ± 4.4 days after transplantation and the mean level of peak serum total bilirubin concentration was 10.1 ± 10.4 mg/dl. The mean time at which the peak bilirubin level was reached was 20.0 ± 111.1 days after transplantation. At the time of peak serum total bilirubin, the mean level of serum albumin concentration was 3.4 ± 0.6 g/dl, the mean level of serum direct (conjugated) bilirubin concentration was 6.6 ± 7.4 mg/dl, the mean level of serum aspartate aminotransferase concentration was 250 ± 838 U/dl, the mean level of serum alanine aminotransferase concentration was 86 ± 227 U/dl, the mean level of serum lactate dehydrogenase concentration was 1273 ± 1333 U/dl, the mean level of serum alkaline phosphatase concentration was 427 ± 1583 U/dl, the mean level of serum blood urea nitrogen concentration was 43.1 ± 28.3 mg/dl, and the mean level of serum creatinine concentration was 1.6 ± 1.8 mg/dl.
3.3 Risk factors
As shown in Table 1, more patients with postoperative hyperbilirubinemia had valvular heart disease, impaired preoperative liver and kidney function, high right atrial pressure, the presence of ascites at transplant, use of mechanical circulatory support or mechanical ventilation before transplant, and long duration of cardiopulmonary bypass. Hepatitis virus B surface antigen positivity did not predispose to the development of postoperative hyperbilirubinemia. The multivariate logistic regression in Table 2
identified five principal independent risk factors for postoperative hyperbilirubinemia: old donor age, diagnosis of valvular heart disease, high right atrial pressure, use of mechanical ventilation before transplant, and the presence of ascites at transplant.
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Table 2 Risk factors for postoperative hyperbilirubinemia in heart transplantation by multivariate logistic regression
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3.4 Clinical outcome
Among all patients, there were 35 hospital deaths (14%) occurring between 1 and 152 days after transplantation. As shown in Table 3
, patients with hospital death had more congenital heart disease, less dilated cardiomyopathy, and longer duration of cardiopulmonary bypass. Patients with postoperative hyperbilirubinemia had a higher hospital mortality rate than patients without postoperative hyperbilirubinemia (Table 1). Preoperative laboratory tests failed to identify patients at high risk for hospital death. In multivariate logistic regression analysis, the independent risk factors for hospital death were use of mechanical ventilation before transplant (odds ratio 2.01, 95% confidence interval 1.19–7.64; P
= 0.02), prolonged duration of cardiopulmonary bypass (odds ratio 1.01, 95% confidence interval 1.003–1.013; P
= 0.001), and postoperative hyperbilirubinemia (odds ratio 4.57, 95% confidence interval 1.50–13.95; P
= 0.008).
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Table 3 Patient characteristics in 256 heart transplant patients: comparison between patients with and without hospital death by Fisher's exact test and Mann–Whitney U-test
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Among 145 patients with postoperative hyperbilirubinemia, patients with peak serum total bilirubin concentration 
10 mg/dl had a higher hospital mortality rate than patients with peak concentrations between 3 and 10 mg/dl (48% vs 11%, P
< 0.001 by Fisher's exact test). The onset time of postoperative hyperbilirubinemia and the time at which the peak bilirubin level was reached were also associated with hospital mortality. Patients with hospital death had late onset of postoperative hyperbilirubinemia more often than patients without hospital death (4.2 ± 7.8 days vs 1.9 ± 2.9 days after transplantation, P
= 0.007 by Mann–Whitney test). Patients with the time at which the peak bilirubin level was reached 3 days after transplantation had higher hospital mortality rate than patients with the time at which the peak bilirubin level was reached <3 days after transplantation (29% vs 7%, P
= 0.001 by Fisher's exact test).
Follow-up was complete in all patients. Among all patients, the 1-year, 2-year, 3-year, 5-year, and 10-year patient and graft survival rates were 80.1 ± 2.5%, 75.0 ± 2.8%, 69.0 ± 3.1%, 61.2 ± 3.4%, and 43.3 ± 4.7%. For 145 patients with postoperative hyperbilirubinemia, the 1-year, 2-year, 3-year, 5-year, and 10-year patient and graft survival rates were 72.6 ± 3.7%, 70.2 ± 3.9%, 65.3 ± 4.2%, 60.1 ± 4.5%, and 47.8 ± 6.0% (Fig. 1
). For 111 patients without postoperative hyperbilirubinemia, the 1-year, 2-year, 3-year, 5-year, and 10-year patient and graft survival rates were 89.9 ± 2.9%, 81.4 ± 3.9%, 73.8 ± 4.6%, 62.5 ± 5.4%, and 38.9 ± 7.1% (Fig. 1). Patients with postoperative hyperbilirubinemia had lower 6-month and 1-year patient and graft survival rates than patients without postoperative hyperbilirubinemia.
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Fig. 1. Patient and graft survival curves plotted by Kaplan–Meier method in patients with and without postoperative hyperbilirubinemia.
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4. Discussion
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4.1 Heart transplantation
The clinical outcome of heart transplantation is improving. The 30-day survival rate improved from 84% during the early 1980s to 91% during the late 1990s [11]. The overall 1-year, 5-year, and 10-year survival rates for heart transplantation were 80%, 70%, and 50% [11]. However, the long-term survival remains unchanged in spite of the ongoing stepwise improvement in early transplant survival. The survival rate for the entire patient cohort of the worldwide registry showed that, after the steep fall in survival during the first 6 months, the survival decreases at a linear rate of 3.4% per year [12]. The reported risk factors for early mortality included old donor age, old recipient age, having congenital heart disease or coronary artery disease as the indication for heart transplantation, requiring mechanical circulatory support (temporary or pulsatile ventricular assist device), mechanical ventilation, or dialysis at the time of transplant, hospitalized at transplant, prolonged allograft ischemic time, and renal or hepatic dysfunction at the time of transplant [12]. We had a similar result with the hospital survival rate of 86% and the 1-year patient and graft survival rate of 80.1%. Having congenital heart disease was the most powerful preoperative risk factor for hospital death.
4.2 Postoperative hyperbilirubinemia
This prospective observational study examined the incidence, risk factors, and outcome of postoperative hyperbilirubinemia in 256 patients undergoing heart transplantation. The overall incidence of postoperative hyperbilirubinemia was 57% and the increased serum total bilirubin concentration mainly resulted from increased conjugated bilirubin. This incidence is more than the 3.2–51% incidence of postoperative hyperbilirubinemia after cardiac surgery in previous studies [1–8]. The high incidence of postoperative hyperbilirubinemia after heart transplantation may be related to poor preoperative heart and liver function in transplant recipients. Severe heart failure sets the stage for hyperbilirubinemia following heart transplantation [6,8].
Postoperative hyperbilirubinemia resulted in significantly increased hospital morbidity and mortality [1–8]. Collins et al. reported that the mortality of the patients with postoperative hyperbilirubinemia was as high as 25% [2]. In this study, we demonstrated that the presence of postoperative hyperbilirubinemia was a significant risk factor for hospital death. The hospital mortality rate increased from 5% in patients without postoperative hyperbilirubinemia to 21% in patients with postoperative hyperbilirubinemia. Furthermore, patients with late onset of postoperative hyperbilirubinemia and high peak serum bilirubin concentration were associated with high hospital mortality. Different time courses for postoperative hyperbilirubinemia suggest that mechanisms underlying the development of postoperative late peak bilirubin level differ from those of the early peak bilirubin level. The immediate occurrence of postoperative hyperbilirubinemia and rapid decline thereafter reflects the transient damaging effects by cardiopulmonary bypass, whereas late occurrence of postoperative hyperbilirubinemia is a consequence of hepatic dysfunction caused by persistent cardiac failure or sepsis [5].
4.3 Risk factors
The preoperative identification of patients at risk for postoperative hyperbilirubinemia is extremely important and clinically relevant because it may direct perioperative management with aggressive hemodynamic controls and intervention to enhance splanchnic perfusion. It will not only avoid the development of postoperative hyperbilirubinemia but also improve overall outcome.
Postoperative hyperbilirubinemia after cardiac surgery is multifactorial [1–8]. Splanchnic ischemia prior to, during, and especially postoperatively appears to be an important cause. Poor preoperative heart function, hemodynamic instability, emergency surgery, and preoperative liver dysfunction have also been identified as risk factors for postoperative hepatic dysfunction [6]. In addition, the incidence of postoperative hyperbilirubinemia differs among different disease categories. The incidence of postoperative hyperbilirubinemia is significantly higher in patients with valvular heart disease [5]. In this study, clinical parameters had a more important role in prediction of postoperative hyperbilirubinemia than laboratory parameters. High right atrial pressure, use of mechanical ventilation before transplant, and ascites at transplant were the significant preoperative risk factors for postoperative hyperbilirubinemia. The association of valvular heart disease and postoperative hyperbilirubinemia was also noted in our series. Patients with severe preoperative cardiac failure may have higher right atrial pressure and ascites, and with their liver in a congested state, its capacity to dispose of the bilirubin load may be impaired [13,14].
4.4 Study limitation
First, this study spans nearly 20 years and may not be fully representative of current clinical practice. However, over 95% of the cases were performed in the last 10 years. Although there have been a lot of changes in the technology of cardiopulmonary bypass and the practice of anesthesia for cases involving cardiopulmonary bypass, there was no change in the incidence of postoperative hyperbilirubinemia after heart transplantation. Second, this study was limited by retrospective study. The duration of right ventricular failure, pulmonary artery pressure, the amount of blood transfusion, and the state of postoperative heart function were unknown. Although our results were preliminary, this was the first study to assess the incidence, risk factors, and clinical significance of postoperative hyperbilirubinemia after heart transplantation. Patients should be carefully screened and managed, especially patients with valvular heart disease, high right atrial pressure, use of mechanical ventilation before transplant, and the presence of ascites at transplant. The development of postoperative hyperbilirubinemia is associated with high hospital mortality, especially in those patients with late onset (3 days), late peak time (3 days), and high peak bilirubin level (10 mg/dl).
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5. Conclusions
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Postoperative hyperbilirubinemia is common in patients undergoing heart transplantation and is associated with high hospital mortality. Patients with valvular heart disease, high preoperative right atrial pressure, use of mechanical ventilation before transplant, and ascites at transplant, who then receive an old donor heart, are at greater risk for development of postoperative hyperbilirubinemia.
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References
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- Taylor DO, Edwards LB, Boucek MM, Trulock EP, Deng MC, Keck BM, Hertz MI. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult heart transplant report—2005. J Heart Lung Transplant 2005;24:945-955.[CrossRef][Medline]
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Abstract
1. Introduction
