Asian Cardiovasc Thorac Ann 1999;7:3-8
© 1999 Asia Publishing EXchange Pte Ltd
Hyperbilirubinemia After Cardiopulmonary Bypass: A Prospective Study
Abha Chandra, MCh,
Debasish Gupta, MD1,,
K Sri Satya Saibaba, MD2,,
Dronamraju Dilip, FRCS,
Srinivas Kola, MS,
Madhu Sudan Naidu, BSc, DPT
Department of Cardiovascular & Thoracic Surgery India
1 Department of Transfusion Medicine India
2 Department of Biochemistry Sri Venkateswara Institute of Medical Sciences Tirupati, Andhra Pradesh, India
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For reprint information contact: Abha Chandra, MCh Tel: 91 8574 51222 Ext. 2378 Fax: 91 8574 28803 email: svims{at}ap.ap.nic.in Department of Cardiovascular & Thoracic Surgery, Sri Venkateswara Institute of Medical Sciences, Tirupati, AP 517507, India.
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Abstract
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Postoperative hyperbilirubinemia is one of the complications of cardiopulmonary bypass. This prospective study was conducted on 77 patients who underwent open-heart surgery, to evaluate the incidence, risk factors, and prognostic significance of postoperative hyperbilirubinemia. Liver function tests were conducted preoperatively, immediately after surgery and on the 1st, 3rd, and 7th postoperative days. The overall incidence of postoperative hyperbilirubinemia was 26%. The incidence was significantly higher in patients who underwent prosthetic valve replacements (31%) than in those without prostheses (22%) and very high in patients undergoing double valve replacement (50%) compared to single valve replacement (27%). Most (90%) of the increase in serum bilirubin was due to a rise in unconjugated bilirubin on the 1st postoperative day. There was no mortality related to postoperative hyperbilirubinemia but it prolonged intensive care stay when it occurred early after surgery and prolonged hospital stay when it occurred later. Preoperative total bilirubin concentration, number of valves to be replaced, and preoperative high right atrial pressure were the factors associated with increased risk of postoperative hyperbilirubinemia by logistic regression analysis.
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Introduction
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Postoperative hyperbilirubinemia has been cited as a cause of mortality in several studies.1,2 With improvements in anesthesia, cardiopulmonary bypass, surgical techniques, and postoperative care, the incidence and mortality of postoperative hyperbilirubinemia has been significantly reduced but the associated morbidity remains high. The aims of this study were to determine the incidence and nature of postoperative hyperbilirubinemia in patients undergoing various cardiac operations, to identify risk factors for postoperative hyperbilirubinemia, and to evaluate the clinical and prognostic significance of hyperbilirubinemia in terms of morbidity and mortality.
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Patients and Methods
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This prospective study was conducted on 77 consecutive patients undergoing cardiac operations under cardiopulmonary bypass between April 1996 and November 1996. Informed written consent was obtained from every patient and the study protocol was approved by the ethical committee of this institute. The patients (54 male and 23 female) were divided into 5 groups according to their surgical procedures: coronary artery bypass grafting (CABG); first-time valve replacement; reoperation for valve replacement; correction of congenital heart diseases; and reconstructive procedures comprising 2 mitral valve reconstructions, 1 unruptured sinus of Valsalva aneurysm, and 1 open aortic valvotomy. The demographic profiles of the patients in the various groups is shown in Table 1
and those of patients who underwent single and double valve replacements in Table 2.
Anesthesia was induced with sodium pentothal (3 to 5 mg•kg–1), diazepam (0.2 to 0.3 mg•kg–1), morphine (0.1 mg•kg–1), and pancuronium bromide (0.08 to 0.1 mg•kg–1). Halothane was not used because of its hepatotoxic effects. Routine monitoring included electrocardiograms with leads II and V5, a radial arterial line, a pulse oximeter, end-tidal carbon dioxide measurements, nasopharyngeal and rectal temperatures, urine output via a Foley catheter, and a central venous pressure line.
Patients were operated under moderate hypothermia with a nasopharyngeal temperature of approximately 28°C in 24 patients (10 of whom had postoperative hyper-bilirubinemia). Normothermia with a nasopharyngeal temperature 32°C was used in 53 patients (10 of whom had postoperative hyperbilirubinemia). Pulsatile flow was instituted with a roller pump (Sarns 9000; Sarns 3M, Ann Arbor, MI, USA). Electromechanical quiescence was achieved with intermittent cold crystalloid cardioplegia given every 30 minutes with surface cooling. A bubble oxygenator (Bentley 10 Plus; Baxter Healthcare Corp., Irvine, CA, USA) was used in 34 patients in whom the ischemic time was anticipated to be short; 7 had postoperative hyperbilirubinemia. Various membrane oxygenators were used in the other patients. Perfusion flow was kept above 2.2 L•min–1•m–2 during normothermia and above 1.8 L•min–1•m–2 during hypothermia. The mean perfusion pressure was maintained between 50 and 70 mm Hg during cardiopulmonary bypass. Arterial blood gases were monitored routinely every hour and when considered necessary. The prime consisted of 600 mL Ringer's lactate solution with 500 mL of gelatin (Haemaccel; Hoechst Marion Roussel Ltd., Mumbai, India) or pentastarch solution (Haes-steril; Fresenius AG, Homburg, Germany) containing 10,000 units of heparin (5000 units in 31 cases where a Bentley Spiral Gold hollow fiber oxygenator [Baxter Healthcare Corp., Irvine, CA, USA] was used). The other ingredients used in 1 L of the prime solution were 40 mL of 7.5% w/v sodium bicarbonate, 80 mg of gentamycin, 5 mL of 20% w/v mannitol, and 8 mg of dexamethasone.
Starr-Edwards prosthetic ball valves model 6120 (Baxter Edwards AG, Horw, Switzerland) were inserted in the mitral position in 29 patients and 9 patients received CarboMedics bileaflet heart valves model 500 (Sulzer Carbomedics Inc., Austin, TX, USA) in the aortic position. The operating time, cardiopulmonary bypass time, aortic cross-clamp time, type of oxygenator, quantity of blood prime used, and the types and numbers of valves replaced were recorded.
Right atrial pressures were obtained either by cathe-terization or before going on bypass. Preoperative samples for liver function tests were collected 2 days before the operation. After surgery, samples were obtained immediately after the patient was moved to the intensive care unit and on the 1st, 3rd, and 7th postoperative days. The blood samples were analyzed for total serum bilirubin, unconjugated bilirubin, conjugated bilirubin, total serum protein, serum albumin, serum globulin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase by an automated biochemical analyzer (Beckman Synchron CX 4; Beckman, Inc., Brea, CA, USA). Postoperative hyper-bilirubinemia was defined as total serum bilirubin concentration above 20 mg•L–1 in any one of the four postoperative measurements. The duration of intensive care and hospital stay, the use of intraaortic balloon counterpulsation, and hospital deaths were recorded.
Statistical Analysis
Data were expressed as mean ± standard deviation. The Student t test was used to assess the statistical significance of differences in the mean values of variables in patients with or without postoperative hyperbilirubinemia. The chi-squared test was used to analyze the differences between patients with and without postoperative hyper-bilirubinemia and Bonferroni's correction was used in comparisons of more than two groups against a single control group. The operative variables including type of oxygenator, amount of blood prime, number of valves replaced, type of operation, cardiopulmonary bypass time, aortic cross-clamp time, and the preoperative liver function tests were evaluated with a logistic regression model to identify predictors for developing postoperative hyper-bilirubinemia by the forward likelihood ratio method.
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Results
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Preoperative hyperbilirubinemia of greater than 20 mg•L–1 was present in 9 patients (11.7%). The incidence of postoperative hyperbilirubinemia in the various groups of patients is shown in Tables 1 and 2
. Twenty patients developed postoperative hyperbilirubinemia, giving an overall incidence of 26% (if the 9 patients with preoperative hyperbilirubinemia are excluded, the post-operative incidence was 16%). For the 9 patients with preoperative hyperbilirubinemia, the incidence of postoperative hyperbilirubinemia was 78% (7/9). Two of these patients developed severe hyperbilirubinemia with serum bilirubin levels above 60 mg•L–1, whereas only 2 of the 68 patients without preoperative hyperbilirubinemia had serum bilirubin levels above 60 mg•L–1 post-operatively. The mean postoperative peak bilirubin level was significantly higher in patients with preoperative hyperbilirubinemia compared to patients with normal preoperative bilirubin levels (45.9 ± 22.7 versus 14.6 ± 5.5 mg•L–1, p < 0.01).
None of the patients who underwent reconstructive surgery developed postoperative hyperbilirubinemia (Table 1). The incidence of postoperative hyperbilirubinemia was higher in the group of patients undergoing valve replacement compared to those having other procedures (31% versus 22%, p < 0.01). None of the patients undergoing aortic valve replacement with a CarboMedics valve developed postoperative hyperbilirubinemia, whereas 7 of the 23 patients undergoing mitral valve replacement with Starr-Edwards valves developed postoperative hyperbilirubinemia (Table 2). Double valve replacement patients (Starr-Edwards valves in the mitral position and CarboMedics valves in the aortic position) had a higher incidence of postoperative hyperbilirubinemia than single valve replacement patients (50% versus 27%, p < 0.01); one of the 3 double valve replacement patients with postoperative hyperbilirubinemia had a level above 60 mg•L–1.
Of the 20 cases of postoperative hyperbilirubinemia, 30% were detectable in the immediate postoperative period, 90% on the 1st postoperative day, 25% on the 3rd postoperative day, and 10% on the 7th postoperative day. Perioperative changes in the total, unconjugated, and conjugated bilirubin concentrations are shown in Figure 1. Mean serum bilirubin (total and unconjugated) increased significantly on the first postoperative day in both groups of patients (p < 0.05).
There were no deaths related to postoperative hyper-bilirubinemia (Table 3). Two patients with normal postoperative serum bilirubin died of intractable ventricular tachycardia and one died of acute right heart failure after intracardiac repair for tetralogy of Fallot. This study showed a significant relationship between the development of postoperative hyperbilirubinemia and use of an intraaortic balloon pump. Patients with early development of postoperative hyperbilirubinemia had a longer intensive care stay, while the late appearance of hyperbilirubinemia was associated with prolonged hospital stay (Table 3).
There was no association of age, sex, body surface area, or type of oxygenator with the occurrence of postoperative hyperbilirubinemia (Table 4). None of the patients suffered an episode of hypoxia before or during the surgical procedure. The results of logistic regression analyses are shown in Table 5. Right atrial pressure, the number of valves replaced, and preoperative total serum bilirubin concentration were identified as predictors for the development of postoperative hyperbilirubinemia. The combination of at least 2 of these preoperative risk factors correctly predicted the development of postoperative hyperbilirubinemia in 75% (15/20) of the patients.
There were postoperative increases in the levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and serum alkaline phosphatase in both groups of patients but no difference was observed between the two groups except in the levels of lactate dehydrogenase. These levels returned to preoperative values by the 7th postoperative day.
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Discussion
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The incidence of postoperative hyperbilirubinemia varies with the type of surgery.3 The incidence in early retrospective studies ranged from 8.6% to 13%.4,5 Thereafter, as the number of complex open-heart operations increased, the incidence rose to 23.4%.3 A prospective study in 1985 reported an incidence as high as 40%.6 In a more recent prospective study by Michalopoulos and colleagues7, the incidence of hepatic dysfunction was only 3.2%. We found a 26% incidence of postoperative hyperbilirubinemia but when patients with preoperative hyperbilirubinemia were excluded, the actual incidence was 16%. We noted that 78% of patients with preoperative hyperbilirubinemia had postoperative hyperbilirubinemia. Similar results were reported by Wang and colleagues2 who also found a higher incidence of postoperative hyperbilirubinemia in patients undergoing valve replacement, particularly double valve replacement. Postoperative hyperbilirubinemia may be attributed to decreased hepatic capacity for bilirubin disposal as well as to an increase in unconjugated bilirubin due to hemolysis caused by cardiopulmonary bypass, cardiotomy suction, or mechanical prostheses.
Mortality from postoperative hyperbilirubinemia has been reported to range from 5.6% to 25%.1,8 There was no mortality in our series attributable to postoperative hyperbilirubinemia. However, we observed that patients with an early rise of serum bilirubin in the postoperative period required prolonged ventilation and a longer intensive care stay, whereas late onset of hyper-bilirubinemia resulted in prolonged hospital stay.
The pathogenesis of hepatic dysfunction seems to be multifactorial. There have been conflicting reports regarding the nature of hyperbilirubinemia after open-heart surgery. Collins and colleagues1 and Chu and colleagues3 attributed it mainly to failure of the canalicular excretion of bilirubin because of an increase in conjugated bilirubin. In this study, we found that 90% of the increase in total bilirubin in the immediate postoperative period was due to unconjugated bilirubin. The simultaneous rise in serum lactate dehydrogenase indicates that postoperative hyperbilirubinemia resulted from hemolysis due to blood cell trauma. The early rise in unconjugated bilirubin in both groups of patients suggests there was a similar mechanism of bilirubin production. These findings agree with those of Klepetko and Miholic6 who concluded that postoperative hyperbilirubinemia after cardiac surgery was mainly from unconjugated bilirubin of hemolytic origin. However, the late appearance of high bilirubin levels with a lower proportion of unconjugated bilirubin suggests a different mechanism at this stage, which may be related to the use of pharmacological and mechanical support, hepatic dysfunction due to decreased perioperative hepatic flow, or increased bilirubin load as a result of cardiac failure.
The risk factors we identified were the number of valves to be replaced, preoperative high right atrial pressure, and preoperative hyperbilirubinemia. These risk factors have been identified in previous studies.1,2,6,7 Preoperative hyperbilirubinemia has been reported mainly in patients with severe preoperative congestive cardiac failure, high right atrial pressure, and liver congestion.3,7 We found that preoperative hyperbilirubinemia was the most significant risk factor for the incidence and severity of postoperative hyperbilirubinemia. Our findings indicate that a raised preoperative serum bilirubin level should alert the surgeon to the possibility of higher morbidity but it should not be considered as a risk factor for mortality.
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Acknowledgments
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We extend our sincere appreciation to the efforts taken by the staff of the Departments of Cardiovascular and Thoracic Surgery and Anaesthesiology in patient care. Our thanks are due to the staff of the Departments of Biochemistry and Transfusion Medicine without whose efforts we would not have been able to complete this project.
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References
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Collins JD, Bassendine MF, Ferner R, Blesovsky A, Murray A, Pearson DT. Incidence and prognostic importance of jaundice after cardiopulmonary bypass surgery. Lancet 1983;1:1119–23.[Medline]
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Wang MJ, Chao A, Huang CH, Tsai CH, Lin FY, Wang SS, et al. Hyperbilirubinemia after cardiac operation. J Thorac Cardiovasc Surg 1994;108:429–36.[Abstract/Free Full Text]
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Chu CM, Chang CH, Liaw YF, Shieh MJ. Jaundice after open heart surgery: a prospective study. Thorax 1984; 39:52–6.[Abstract/Free Full Text]
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Sanderson RG, Ellison JH, Benson JA, Starr A. Jaundice following open heart surgery. Ann Surg 1967;165:217–24.[Medline]
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Lockey E, Melntyre N, Ross DN, Brookes E, Sturridge MF. Early jaundice after open heart surgery. Thorax 1967;22:165–9.[Abstract/Free Full Text]
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Klepetko W, Miholic J. Jaundice after open heart surgery: a prospective study [letter]. Thorax 1985;40:80.[Free Full Text]
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Michalopoulos A, Alivizatos P, Geroulanos S. Hepatic dysfunction following cardiac surgery: determinant and consequences. Hepatogastroenterol 1997;44:779–83.
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Abstract
Introduction
