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J Thorac Cardiovasc Surg 1994;108:429-436
© 1994 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Taipei, Taiwan
Received for publication Aug. 24, 1993. Accepted for publication Jan. 9, 1994. Address for reprints: Shu-Hsun Chu, MD, Department of Surgery, National Taiwan University Hospital, 7 Chung-Shan South Rd., Taipei, Taiwan.
Abstract
Three hundred and two consecutive patients who had undergone cardiac operation for various cardiac lesions were studied prospectively to evaluate the incidence, risk factors, and the associated mortality of postoperative hyperbilirubinemia after cardiopulmonary bypass. Concentrations of the serum total (conjugated and unconjugated) bilirubin, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, albumin, globulin, and serum haptoglobin were measured before the operation and again on the first, second, and seventh postoperative days. 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. Overall incidence of postoperative hyperbilirubinemia was 35.1%; the incidence of postoperative hyperbilirubinemia was higher in patients whose valves were replaced with mechanical prostheses than in those without prostheses (p < 0.00001). In patients with postoperative hyperbilirubinemia, 70% of the increase of total bilirubin on the first postoperative day came about from an increase in unconjugated bilirubin. Serum haptoglobin decreased significantly at the same time (p < 0.01). Development of the postoperative hyperbilirubinemia was associated with a higher mortality (5.6% versus 0.5%, p < 0.01) and higher frequency of use of intraaortic balloon counterpulsation, especially for patients in whom the highest postoperative total bilirubin occurred after the first 2 days. The numbers of valves replaced, preoperative right atrial pressure, and preoperative total bilirubin concentration are the significant risk factors that, in combination, correctly predict the occurrence of postoperative hyperbilirubinemia in 80% of the patients. We concluded that postoperative hyperbilirubinemia results mainly from an increase in unconjugated bilirubin and is associated with higher mortality, especially for patients in whom highest postoperative total bilirubin occurred late after operation. Patients with the higher preoperative right atrial pressure and total bilirubin level who then underwent multiple valve replacement procedures are at greater risk for development of postoperative hyperbilirubinemia. (J THORAC CARDIOVASC SURG 1994;108:429-36)
Hyperbilirubinemia was reported in the early studies 
1,2 to occur in about 10% of patients after cardiac operations with cardiopulmonary bypass (CPB). However, more recent studies estimate the incidence of postoperative hyperbilirubinemia to be more than 20% or even as high as 40%. 3-5 In addition, it has not been clear whether postoperative hyperbilirubinemia resulted from increased conjugated or unconjugated bilirubin and whether the incidence of postoperative hyperbilirubinemia differs among various cardiac operations. 3-5 The occurrence of postoperative hyperbilirubinemia has been reported to be associated with mortality as high as 25% according to one study 4; another study reported no association between development of postoperative hyperbilirubinemia and mortality or morbidity. 3 The purpose of this present study was (1) to examine the incidence and nature of postoperative hyperbilirubinemia in patients undergoing different kinds of cardiac operations, (2) to identify possible preoperative risk factors for development of the postoperative hyperbilirubinemia, and (3) to determine the clinical significance of the postoperative hy perbilirubinemia with regard to the mortality and morbidity.
PATIENTS AND METHODS
Patients older than 18 years of age who had undergone cardiac operation with CPB from November 1991 to June 1993 were studied prospectively. Written informed consent was obtained from every patient, and the study protocol was approved by the Committee of Human Investigation of this institution. Patients were not selected with any predetermined criteria. Patients with preoperative hyperbilirubinemia, defined as total bilirubin concentrations of more than 2 mg/dl, were also included. Patients were separated into five groups according to their surgical procedures, which included coronary artery bypass grafting (CABG), first-time valvular replacements, reoperations for valvular replacements, correction of congenital heart disease, and operations for combinations of CABG and valvular replacements.
Anesthesia was induced with fentanyl (30 to 100 µg/kg), diazepam (0.2 to 0.3 mg/kg) or etodimate (0.3 to 0.4 mg/kg), and pancuronium or vecuronium (0.1 to 0.15 mg/kg). Halothane was not used because of its possible hepatotoxic effects. In every operation, the routine clinical monitors included lead II and V5 electrocardiogram, the radial arterial line, the pulse oximeter, end-tidal carbon dioxide, nasopharyngeal and rectal temperatures, urine output via Foley catheter, the central venous pressure line, and the pulmonary artery catheters.
In all patients, moderate hypothermic CPB with lowest nasopharyngeal temperature around 25° C with pulsatile flow was instituted with the roller pump (Sarns 5000; Sarns 3M, Ann Arbor, Mich.) and either bubble (William Harvey H1700; Bard, Billerica, Mass.) or membrane (Capiox E; Terumo, Tokyo, Japan) oxygenators were used. The perfusion flow was kept over 2.2 L/m 2 during normothermia and over 1.8L/m 2 during hypothermia in every patient. The mean arterial pressure was kept between 50 to 100 mm Hg with phenylephrine and phentolamine during CPB. Arterial blood gas was monitored routinely every hour or on any occasion when considered necessary. The priming solution contained 1.5 to 2 L of lactated Ringer's solution, mannitol (300 mg/kg), heparin (2000 U/L), and 
to 1 unit of packed red cells if blood cardioplegic solution was indicated or the predicted hematocrit level during CPB was below 22%. Systemic heparin was given through the right atrium at a dose of 300 U/kg just before cannulation. For valvular replacements operations, either a Carbomedics (Carbomedics, Inc., Austin, Tex.) or a St. Jude Medical (St. Jude Medical, Inc., St. Paul, Minn.) mechanical prosthesis was used. The operating time, CPB time, aortic crossclamp time, types of oxygenator, quantity of packed red cells primed during CPB, and the types and the numbers of mechanical valves replaced were recorded.
Right atrial pressure and pulmonary artery pressure were obtained from the preoperative cardiac catheterization record. Preoperative blood samples for biochemical analysis of the hepatobiliary function were collected within 2 days before operation by venipuncture. After the operation, blood samples were obtained from the central venous line or venipuncture on the first, second, and seventh postoperative days. Blood samples were analyzed for concentrations of albumin, globulin, aspartate aminotransferase, alanine aminotransferase, lactate de hydrogenase, alkaline phosphatase, total bilirubin, conjugated bilirubin, and unconjugated bilirubin by an automated biochemical analyzer (Hitachi 736; Hitachi, Tokyo, Japan), which was calibrated and quality controlled periodically by this institution's clinical laboratory. Postoperative hyperbilirubinemia was defined as total bilirubin concentrations over 3 mg/dl (50 µmol/dl) in any one of the three postoperative measurements. Serum concentrations of haptoglobin were measured with polyclonal antibody and an automated machine (Beckman array 3600; Beckman, Brea, Calif.) of the four time points stated previously. After the operation, the days of hospitalization in the intensive care unit (ICU), the use of intraaortic balloon counterpulsation (IABP), and the number of patients who died during hospitalization were registered.
Data are shown as mean ± standard error of the mean. Student's t test was used to compare the means between those patients with or without postoperative hyperbilirubinemia. One-way analysis of variance with post hoc Student-Newman-Keuls multiple comparisons test compared the means among three or more groups of patients. 
2 Test was used to analyze the proportions between patients with and patients without postoperative hyperbilirubinemia, and Bonferroni's correction was done for comparisons among more than two groups. Fisher's exact test was used if the expected frequency was less than 5. The Wilcoxon-matched pair rank-sum test was used to compare the haptoglobin measurement data, which included undetectable values in postoperative samples. The preoperative variables including types of oxygenator, amount of blood priming, numbers of valves replaced, types of operation, CPB time, operation time, aortic clamp time, and the results of preoperative liver function tests were evaluated with the logistic regression model to identify predictors for the development of postoperative hyperbilirubinemia by the forward-likelihood ratio method with the SPSS software (SPSS Inc., Chicago, Ill.).
RESULTS
Incidence and severity.
Among the 302 patients enrolled in this study, 29 had preoperative hyperbilirubinemia. Demographic data for the patients among different disease categories are shown in Table I. The incidence of the postoperative hyperbilirubinemia in these patients is shown in Fig. 1. The overall incidence of postoperative hyperbilirubinemia was 35.1% and, if the 29 patients with preoperative hyperbilirubinemia were excluded, the postoperative incidence was 28.9% (79 of 273). For patients with preoperative hyperbilirubinemia, the incidence of the postoperative hyperbilirubinemia was 93.1% (Fig. 1, B). Among the patients with preoperative hyperbilirubinemia, 70.4% had severe postoperative hyperbilirubinemia with highest total bilirubin concentration greater than 6 mg/dl, whereas in other patients only 19% had a highest total bilirubin concentration greater than 6 mg/dl (p < 0.0001). The highest total bilirubin concentration was significantly greater in patients with preoperative hyperbilirubinemia than patients without (12.98 ± 15.94 versus 2.99 ± 4.01, p < 0.001).
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Nature of the hyperbilirubinemia.
Perioperative changes of the total, unconjugated and conjugated, bilirubin concentrations are shown in Fig. 2 and Table II. On the first postoperative day, the total and unconjugated bilirubin concentrations increased in both the patients with postoperative hyperbilirubinemia and those with nonpostoperative hyperbilirubinemia compared with preoperative levels (p < 0.001). For patients with postoperative hyperbilirubinemia, 70% of the increased total bilirubin was from an increase of unconjugated bilirubin. Serum haptoglobin concentrations decreased significantly on the first postoperative day in both groups of patients (p < 0.0001). In patients with postoperative hyperbilirubinemia, 60.3% reached peak total bilirubin concentration on the first postoperative day, 30.1% on the second day, and 9.4% on the seventh day. Proportions of unconjugated bilirubin from total bilirubin at the peak level were 0.73 ± 0.01, 0.62 ± 0.03, and 0.53 ± 0.03 for the patients who reached their peak total bilirubin level at the first, second, and seventh postoperative days (p < 0.05), respectively. The time at which the peak bilirubin level was reached did not differ between the patients with and without preoperative hyperbilirubinemia.
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Table III. The only case that ultimately resulted in death in the nonpostoperative hyperbilirubinemia group involved reoperations for dysfunctional aortic porcine valves. The patient's serum total bilirubin concentration increased from a preoperative level of 0.6 mg/dl to 1.7 mg/dl on the first postoperative morning and decreased to 0.9 mg/dl on the seventh postoperative day. He died 24 days after the operation of respiratory failure. Among six operative mortality cases in the postoperative hyperbilirubinemia group, five involved an increase in total bilirubin immediately after operation (four on the first postoperative day), and in three cases the highest level (over 25 mg/dl) was reached on the seventh postoperative day. Four of these six patients underwent reoperations for valvular replacements, whereas the other two patients received CABG. IABP was used in the first or second postoperative day in five of these patients, and inotropic agents including dobutamine (6.78 ± 1.45 µg/kg per minute) and dopamine (5.64 ± 0.72 µg/kg per minute) were given to all patients during their stay in the ICU.
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Table IV). Of the ten patients whose peak bilirubin concentration developed on the seventh postoperative day, seven patients had a steady increase in bilirubin concentrations from the first postoperative day. Five of these seven patients died with clinical evidence of cardiac failure and high bilirubin concentration on the seventh postoperative day (mean 24.4 mg/dl, see previous data). Aortic crossclamp time, CPB time, preoperative total, unconjugated and conjugated bilirubin concentrations, and the values of other liver function tests did not differ in patients with postoperative hyperbilirubinemia whether their peak bilirubin level was reached before or after the second postoperative day (data not shown).
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Table V. The results of logistic regression are shown in Table VI. Right atrial pressure, the numbers of valves replaced, and preoperative total bilirubin concentrations were identified as the important predictors for development of postoperative hyperbilirubinemia. Combinations of these three preoperative risk factors could correctly predict development of postoperative hyperbilirubinemia in 80.61% of the patients.
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This prospective study showed that the incidence of postoperative hyperbilirubinemia is 35.1% (a figure similar to the data reported by Chu 3 and Collins 4 and their associates and Kleptko, Base, and Muller 5) despite progress in techniques of cardiac operations, CPB, and cardiac anesthesia in the past 10 years. Some arguments exist about whether incidence differs among different disease categories. 3,5 This study clearly showed that the incidence of postoperative hyperbilirubinemia is significantly higher in patients with valvular heart disease, regardless of whether the valve was replaced or reconstructed. Results showed that over 90% of patients with preoperative hyperbilirubinemia had postoperative hyperbilirubinemia, most of them in a severe form. Of these 29 patients, 27 had undergone valvular replacements with mechanical prostheses (
Table I). The decreased hepatic capacity for bilirubin disposal and the increased unconjugated bilirubin level as a result of hemolysis from CPB, cardiotomy suction, and mechanical prosthesis led to this much higher incidence and greater severity of postoperative hyperbilirubinemia.
Collins and associates 4 reported that the mortality of the patients with postoperative hyperbilirubinemia was as high as 25%, whereas only 5.6% of the patients with postoperative hyperbilirubinemia died in our present series. In the cited study, the serum total bilirubin concentration, mainly resulting from increased conjugated bilirubin, invariably reached a peak on the second postoperative day. They suggested that this single serum total bilirubin measurement on the second postoperative day could identify patients at high risk for mortality in the postoperative period. In the present studies, the serum total bilirubin reached its peak on the first postoperative day in 60% of the patients, and increase of serum total bilirubin came mainly from unconjugated bilirubin. The association of postoperative hyperbilirubinemia with higher postoperative morbidity or mortality was also noted in our series. However, the mortality of the patients with postoperative hyperbilirubinemia was significantly higher in patients whose total bilirubin concentration reached the peak level on the seventh postoperative day than in patients whose total bilirubin concentration increased to peak level on the first 2 days after operation. The occurrence of postoperative hyperbilirubinemia should alert the physician to the possibility of higher morbidity and mortality, but it should not necessarily be considered a "high risk" indicator.
As for the nature of the hyperbilirubinemia, both Collins 4 and Chu 3 and their associates reported that "post-pump jaundice" was mainly conjugated hyperbilirubinemia, and failure of the canalicular excretion of bilirubin was suggested as the cause of this conjugated hyperbilirubinemia. In contrast, Kleptko and Miholic 6 reported that postoperative hyperbilirubinemia comes mainly from an increase of unconjugated bilirubin with hemolytic origin in 155 patients who underwent cardiac operations. In this study, the results showed that 70% of the increase in total bilirubin after operation comes primarily from unconjugated bilirubin. Significant decrease of haptoglobin concentration with lactate dehydrogenase increasing immediately and maintaining at a higher level (Fig. 3, D) after operations suggests that postoperative hyperbilirubinemia is caused by an unconjugated bilirubin load originating from the hemolysis caused by blood trauma by the roller pump, the cardiotomy suction, or the mechanical prostheses replaced. Similar contribution of unconjugated bilirubin in the total bilirubin increased on the first postoperative day in both the patients with nonpostoperative hyperbilirubinemia and those with postoperative hyperbilirubinemia also suggests similar mechanisms of bilirubin increase in both groups of patients. Later appearance of the highest total bilirubin concentration is associated with higher mortality, morbidity, and peak bilirubin levels and lower proportions of unconjugated bilirubin. Different time courses for increase of the total bilirubin after operations, a lower proportion of unconjugated bilirubin, and the increased use of pharmacologic and mechanical circulatory support suggest that mechanisms underlying the development of postoperative late peak total bilirubin level differ from those of the early peak total bilirubin level. The immediate occurrence of postoperative hyperbilirubinemia and rapid decline thereafter may reflect the transient damaging effects on the blood and hepatic function after CPB, whereas steady increase of the total bilirubin level to reach its peak on the seventh day, mainly conjugated bilirubin, was a consequence of hepatic dysfunction caused by cardiac failure.
Results of the logistic regression showed that the combination of the numbers of valves replaced, preoperative right atrial pressure, and preoperative total bilirubin concentration may correctly predict development of postoperative hyperbilirubinemia in 80% of all patients. The results of various liver function tests, once thought to be important, 6 are not included in the regression equation. Preoperative right atrial pressure, total bilirubin concentrations, and disease categories have been reported by other authors 3,4,6 to show significantdifferences between the patients with and without the "post-pump jaundice." However, this is the first time that these preoperative characteristics have been clearly identified as predictors for the development of postoperative hyperbilirubinemia with high predictability. Patients with severe preoperative cardiac failure may have higher right atrial pressure and, with their liver in a "congested" state, 3 its capacity to dispose of the bilirubin load may be impaired, as reflected in a higher preoperative total bilirubin level. Multiple valve replacement with mechanical prostheses is associated with more hemolysis as a result of longer CPB time and the mechanical prosthesis itself. The significance of preoperative total bilirubin in the genesis of postoperative hyperbilirubinemia is shown with the higher partial correlation coefficient in the logistic regression equation, and with much higher incidence and greater severity of postoperative hyperbilirubinemia in patients with preoperative hyperbilirubinemia.
We concluded that (1) with great variation among different disease categories, the overall incidence of postoperative hyperbilirubinemia, which results mainly from unconjugated bilirubin, is approximately 30% in patients who have undergone cardiac operations; (2) preoperative total bilirubin concentration, the numbers of valves replaced, and the preoperative right atrial pressure are the most important risk factors for prediction of the postoperative hyperbilirubinemia; and (3) the later occurrence of the peak bilirubin was associated with higher mortality.
Footnotes
From the Departments of Anesthesiologyaand Surgery,bNational Taiwan University Hospital, Taipei, Taiwan. 
References
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