Hyperbilirubinemia is a common complication after OPCAB. However, there is no consensus on the diagnostic criteria of perioperative hyperbilirubinemia. Previous studies set it at the upper limit of normal value to 51.3 µmol/L. In these studies, incidences of hyperbilirubinemia after CABG were significantly different (13% ~ 51%)(4, 6). In most studies, elevated serum total bilirubin levels ≥ 34.2µmol/L within 5 days after operation were defined as hyperbilirubinemia(2, 4, 5). This diagnostic standard is also used in this study. In this study, the incidence of hyperbilirubinemia after OPCAB was found to be 7.7%, while the incidence of severe hyperbilirubinemia was 1.4%, which were less than those reported in previous studies. This difference may be attributed to the strict exclusion criteria of our study.
Regarding the nature of postoperative hyperbilirubinemia, most patients (71.88%) exhibited elevated direct bilirubin levels, which is in agreement with previous reports(1, 10). Nishi et al. reported that patients with elevated direct bilirubin levels were more likely to have higher mortality rates and worse prognostic outcomes than patients with elevated indirect bilirubin levels(10). This difference was also found in this study (17.39% for direct bilirubin vs. 0% for indirect bilirubin, p = 0.303), although the difference was not significant. In contrast, Mastoraki et al. reported that patients with elevated indirect bilirubin levels have worse prognostic outcomes, which may be due to the longer operation time and extracorporeal circulation time, larger intraoperative blood loss and perioperative blood transfusion, resulting in increased hemolytic hyperbilirubinemia(1).
In this study, in the hyperbilirubinemia group, 19 patients (59.38%) had direct bilirubin / total bilirubin ratio > 50%, 10 patients (31.25%) had direct bilirubin / total bilirubin ratio between 20% and 50%, 3 patients (9.38%) had direct bilirubin / total bilirubin ratio < 20%, while 5 patients (15.63%) had elevated liver enzyme levels, implying that the main cause of hyperbilirubinemia after OPCAB was intrahepatic cholestasis, followed by hepatocyte damage, and hemolysis in a few patients. Which is in agreement to the conclusion of Mastoraki et al(1).
Univariate logistic regression analysis revealed that there were significant differences in gender, preoperative total bilirubin level, perioperative IABP implantation and perioperative blood transfusion between the two groups. Preoperative serum total bilirubin levels (OR = 1.241, p < 0.001), perioperative IABP implantation (OR = 0.238, p = 0.003) and perioperative blood transfusion (OR = 0.237, p = 0.002) were found to be independent risk factors for hyperbilirubinemia after OPCAB.
Perioperative IABP implantation ensures blood supply to the heart and brain, therefore, it is bound to reduce blood supply to the liver, resulting in insufficient liver perfusion, ischemia and hypoxia of liver cells, triggering atrophy and apoptosis, as well as inhibition of liver functions to varying degrees(1, 11). Therefore, all stages of the bilirubin circulatory pathway, including albumin transport, hepatocyte uptake, carrier protein transport and related enzyme catalysis, are blocked by inhibition of hepatocyte function, resulting in continuous accumulation of bilirubin in serum(7, 12). At the same time, functions of Kupffer cells of macrophages in hepatic sinuses are inhibited, while their roles in clearing aging, damaged red blood cells, as well as clearing microorganisms and poisons from the intestinal tract are weakened, resulting in pathophysiological changes such as bilirubin stasis and intestinal endotoxemia(13, 14). The former aggravates inhibition of the roles of Kupffer cells, while the latter can damage the intestinal mucosal barrier through a series of actions and promote endotoxin absorption, thereby leading to a vicious cycle. Endotoxin accumulation may cause hepatocyte injury and induce apoptosis through immune cell activation, induction of the production of free oxygen radicals, secretion of cytokines and inflammatory mediators, inhibiting bilirubin circulation, and finally, by leading to the formation of hepatocyte hyperbilirubinemia(7, 12–14).
Lockey et al. and Wang et al. reported that elevated indirect bilirubin levels were the main causes of postoperative hyperbilirubinemia(6, 11), implying that hemolysis is an important factor in hyperbilirubinemia occurrence and development. Massive intraoperative and early postoperative blood transfusion, exceeding treatment threshold of the liver with functional inhibition, and hemolysis of red blood cells in stored blood can lead to massive accumulation of bilirubin, resulting in postoperative hyperbilirubinemia(15). Mathie et al. reported that massive blood transfusion may cause microthrombosis, elevated free radical levels and disorders of liver blood flow, further aggravating liver injury and forming hyperbilirubinemia(7). Moreover, An et al. proposed that prolonged operation time is an independent risk factor for postoperative hyperbilirubinemia(8), implying that elevated tissue oozing and bleeding associated with prolonged operation time, intraoperative destruction and loss of red blood cells and coagulation factors may be some of the involved mechanisms(4). There were no significant differences in operation time between the two groups, however, intraoperative and early postoperative blood transfusion was an independent risk factor for postoperative hyperbilirubinemia.
Most studies were positive about the correlation between hyperbilirubinemia and postoperative complications as well as with adverse events(3, 5, 10–12, 16–18). Hyperbilirubinemia after cardiac surgery (especially after cardiopulmonary bypass) is a risk factor for postoperative respiratory(8), circulatory(12, 18), urinary(19, 20), gastrointestinal complications(21) and hospital mortality. In this study, incidences of pulmonary infection, new acute renal failure, continuous renal replacement therapy, perioperative myocardial infarction and other related complications in the hyperbilirubinemia group were elevated, while incidences of MODS and hospital mortality were higher than those of the normal serum total bilirubin group, with statistically significant differences.
The mechanisms through which hyperbilirubinemia leads to complications and poor prognosis are complex, and have not been fully elucidated. Elevated bilirubin concentrations can trigger cell oxidative stress, induce apoptosis, and participate in a variety of pathological processes, including respiratory dysfunction, thrombocytopenia(19), renal tubular epithelial cell damage(19), neural cell differentiation and myelination inhibition(23). In addition, persistent hyperbilirubinemia is only a manifestation of a potential disease, such as persistent low cardiac output syndrome, rather than a direct cause of death(2).
Prolonged bilirubin peak time in patients with hyperbilirubinemia is an independent predictor of death. Chen et al., Sharma et al. and others reported that early jaundice after cardiac surgery is mostly transient, and is mainly caused by surgical strikes, while late and persistent hyperbilirubinemia (lasting for more than 5 days after operation) may be related to cardiac failure(12, 17, 18) or septicemia, leading to acute liver failure, with rapidly elevated in-hospital mortality rates(2, 11, 20). Farag et al. reported that patients with bilirubin peak time more than 3.5 days and peak value exceeding 91.5 µmol/L had significantly higher mortality rates while patients with bilirubin peak value exceeding 436.1 µmol/L had mortality rates above 99%(16). However, these conclusions lack support from molecular biology experiments. Studies should aim at elucidating the pathophysiological significance of bilirubin at the molecular level.
This study has certain significance for clinical practice. First, for patients with elevated serum total bilirubin levels before OPCAB, potential causes should be investigated and corresponding therapy for the primary disease administered. Second, the experience level of the surgical team should be improved to reduce iatrogenic complications of IABP implantation, decrease intraoperative bleeding, shorten operation time, so as to suppress the chances of perioperative hyperbilirubinemia caused by iatrogenic factors. Third, there is a need to improve the management ability of blood products. For patients with more intraoperative bleeding and a higher possibility of perioperative blood transfusion, restrictive and autologous blood transfusion strategy(15, 24) should be adopted. Moreover, active and regular measurements of postoperative serum total bilirubin levels is necessary. For patients with mild elevations of serum total bilirubin, choleretic drugs such as Smectite and Yinzhihuang could be effective; for patients with severe elevations of serum total bilirubin and acute liver failure, artificial liver support system (ALSS), including plasma bilirubin adsorption (PBA), plasma exchange (PE), hemofiltration (HF), hemodialysis (HD) and their combination strategies should be applied, according to the indications. If the progress of hyperbilirubinemia cannot be controlled by the above methods, liver transplantation may be the last chance(25, 26).
This study is associated with some limitations. First, as a single center retrospective study, the collection of bilirubin index data is limited to a certain extent. Only the bilirubin peak near the measurement time was recorded. Therefore, false negatives might be in existence. Studies should aim at establishing standardized time points, where serum bilirubin levels among all patients can be continuously and repeatedly measured, so as to reduce the above bias. Second, we did not record factors such as storage time of blood products, IABP mode and duration of use, which may affect the results of this study. Therefore, multicenter prospective randomized controlled trials are need to overcome these biases.