Evaluating mortality and recovery of extreme hyperbilirubinemia in critically ill patients by phasing the peak bilirubin level: A retrospective cohort study.

BACKGROUND: Hyperbilirubinemia is a devastating complication in patients admitted to an intensive care unit (ICU). The sequential organ failure assessment (SOFA) score classifies hyperbilirubinemia without further detailed analyses for bilirubin increase above 12 mg/dL. We evaluated whether the level of bilirubin increase in patients with extreme hyperbilirubinemia (total bilirubin ≥ 12 mg/dL) affects and also helps estimate mortality or recovery. METHODS: A retrospective cohort analysis comprising 427 patients with extreme hyperbilirubinemia admitted to the ICU of Samsung Medical Center, Seoul, Korea between 2011 and 2015 was conducted. Extreme hyperbilirubinemia was classified into four grades: grade 1 (12-14.9 mg/dL), grade 2 (15-19.9 mg/dL), grade 3 (20-29.9 mg/dL), and grade 4 (≥ 30 mg/dL). These grades were then assessed for their association with hospital mortality and recovery from hyperbilirubinemia to SOFA grade (point) 2 or below (total bilirubin < 6 mg/dL). The influences of various factors, some of which caused extreme hyperbilirubinemia, while others induced bilirubin recovery, were assessed. RESULTS: A total of 427 patients (mean age: 59.8 years, male: 67.0%) were evaluated, and the hospital mortality for these patients was very high (76.1%). Extreme hyperbilirubinemia was observed in 111 (grade 1, 26.0%), 99 (grade 2, 23.2%), 131 (grade3, 30.7%), and 86 (grade 4, 20.1%) patients with mortality rates of 62.2%, 71.7%, 81.7%, and 90.7%, respectively (p < 0.001). The peak bilirubin value correlated with the mortality (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.04-1.15, p < 0.001). Compared to those with grade 1 extreme hyperbilirubinemia, the mortality rate gradually increased as the grade increased (OR [95% CI]: 1.92 [0.70-5.28], 3.55 [1.33-9.48], and 12.47 [3.07-50.59] for grades 2, 3 and 4, respectively). The main causes of extreme hyperbilirubinemia were infection including sepsis and hypoxic hepatitis. The recovery from hyperbilirubinemia was observed in 110 (25.8%) patients. Mortality was lower for those who recovered from hyperbilirubinemia than for those who did not (29.1% vs. 92.4%, p < 0.001). The favorable factors of bilirubin recovery were albumin and ursodeoxycholic acid (UDCA). CONCLUSIONS: This study determined that the level of extreme hyperbilirubinemia is an important prognostic factor in critically ill patients. We expect the results of this study to help predict the clinical course of and determine the optimal treatment for extreme hyperbilirubinemia.

Acute human parvovirus B19 infection triggers immune-mediated transient bone marrow failure syndrome, extreme direct hyperbilirubinaemia and acute hepatitis in patients with hereditary haemolytic anaemias: multicentre prospective pathophysiological study.

A total of 244 patients with hereditary haemolytic anaemias (HHA) were screened for acute symptomatic human parvovirus B19 infection (HPV-B19) in a prospective study. To assess the risks associated with HPV-B19 infection, patients were classified into Group I and Group II according to presence or absence (symptoms, signs and specific serology) of acute HPV-B19 infection respectively. In all, 131 (53·7%) patients had ß-thalassaemia, 75 (30·7%) hereditary spherocytosis (HS), 27 (11·1%) sickle cell anaemia (SCA) and 11 (4·5%) glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 33 (13·5%) patients who presented with symptomatic HPV-B19 infection, 19 (57·5%) had HS, nine (27·3%) had ß-thalassaemia and five (15·2%) had SCA. In Group I, there were significant differences in the mean white blood cell, red blood cell and platelet counts, haemoglobin concentration, total bilirubin (TB), alanine aminotransferase, aspartate aminotransferase and serum creatinine (all P < 0·001) compared to Group II. In all, 27 (81·8%) patients had arthropathy and bone marrow failure (BMF); 13 (39·4%) had acute kidney injury (AKI), more in SCA (80%); and 12 (36·4%) patients had hepatitis, more in HS (66·8%). Five (15·2%) patients with HS had BMF, AKI, nervous system involvement and extreme hyperbilirubinaemia (TB range 26·3-84·7 mg/dl). Five (15·2%) patients had haemophagocytic syndrome. Two patients with HS combined with Type-I autoimmune hepatitis presented with transient BMF. Complete recovery or stabilisation was noted at 12 months in every patient except for one patient with SCA who died during the infection. HPV-B19 must be suspected and screened in patients with HHA with typical and atypical presentations with careful follow-up.

Characteristics and outcomes of Stanford type A aortic dissection patients with severe post-operation hyperbilirubinemia: a retrospective cohort study.

BACKGROUND: Hyperbilirubinemia is one of the common complications after cardiac surgery and is associated with increased mortality. However, to the best of our knowledge, the reports on clinical significance of postoperative severe hyperbilirubinemia in Stanford type A aortic dissection (AAD) patients were limited. METHODS: Patients who underwent surgical treatment for AAD in our center between January 2015 and December 2018 were retrospectively screened. In-hospital mortality, long-term mortality, acute kidney injury (AKI), and the requirement of continuous renal replacement therapy (CRRT) were assessed as endpoints. Univariate and multivariate regression models were employed to identify the risk factors of these endpoints. RESULTS: After screening, 271 patients were included in our present study. Of the included patients, 222 (81.9%) experienced postoperative AKI, and 50 (18.5%) received CRRT. The in-hospital mortality was 30.3%. The 1-year, 2-year, and 3-year cumulative mortality were 32.9, 33.9, and 35.3%, respectively. Multivariate Logistic regression analysis indicated that age (P < 0.033), AKI stage 3 (P < 0.001), the amount of blood transfusion after surgery (P = 0.019), mean arterial pressure (MAP) in the first postoperative day (P = 0.012), the use of extracorporeal membrane oxygenation (ECMO) (P = 0.02), and the peak total bilirubin (TB) concentration (P = 0.023) were independent risk factors of in-hospital mortality. The optimal cut-off value of peak TB on predicting in-hospital mortality was 121.2 µmol/L. Patients with post-operation TB ≥ 121 µmol/L was associated with worse long-term survival as well. CONCLUSIONS: Severe post-operation hyperbilirubinemia is a common clinical situation in patients had AAD repair. In AAD patients with severe post-operation hyperbilirubinemia, older age, lower MAP, increased blood transfusion, stage 3 AKI, the use of ECMO, and the increased peak TB lead to increase in-hospital mortality.

Predischarge transcutaneous bilirubin screening reduces readmission rate for hyperbilirubinaemia in diverse South African newborns: A randomised controlled trial.

BACKGROUND: In South Africa (SA), healthy term newborns are usually discharged ˂72 hours after delivery. Discharged babies remain at risk for severe hyperbilirubinaemia if it is not identified early. Hyperbilirubinaemia is an important cause of readmission, and also leads to neonatal mortality and morbidity. Use of transcutaneous bilirubin (TcB) screening before hospital discharge has been controversial. OBJECTIVES: To test the clinical benefits of TcB screening of healthy newborns before discharge for the outcomes of readmission for jaundice and severe hyperbilirubinaemia in a randomised controlled trial (RCT). METHODS: This was a RCT. We compared predischarge TcB screening with visual assessment (alone) for jaundice in apparently healthy newborns at a public tertiary hospital in Cape Town, SA. Patients or study participants were not involved in the study design and implementation. RESULTS: Of the 1 858 infants, 63% were black, 35% of mixed race and 1% white. There was a significant reduction in the rate of readmission for jaundice (risk ratio (RR) 0.25; 95% confidence interval (CI) 0.14 - 0.46; p<0.0001) and in the incidence of severe hyperbilirubinaemia (RR 0.27; 95% CI 0.08 - 0.97; p=0.05) with the use of TcB screening compared with visual inspection. CONCLUSIONS: Predischarge TcB screening is superior in identifying newborns at risk of severe hyperbilirubinaemia compared with visual inspection. We recommend that every newborn, regardless of skin pigmentation, should receive objective bilirubin screening before hospital discharge. Universal bilirubin screening in newborns could potentially reduce hyperbilirubinaemia-related morbidity and mortality.

The prevalence and prognostic implications of pre-procedural hyperbilirubinemia in patients undergoing transcatheter aortic valve replacement.

Preoperative hyperbilirubinemia is associated with increased mortality and morbidity after cardiac surgery. However, this clinical significance is unclear with transcatheter aortic valve replacement (TAVR) procedures. The aims of this study were to determine the prevalence and prognostic implications of preoperative elevations of serum total bilirubin on TAVR outcomes. In 611 consecutive patients who underwent an elective TAVR procedure, 576 patients had recorded serum total bilirubin levels. Hyperbilirubinemia was defined as any value of serum total bilirubin ≥ 1.2 mg/dL obtained within 30-days prior to the TAVR procedure. The primary composite endpoint was post-TAVR all-cause in-hospital mortality or stroke. The overall prevalence of hyperbilirubinemia was 10% (n = 58). There were no patients with a prespecified diagnosis of liver cirrhosis. Pre-TAVR hyperbilirubinemia compared to normal bilirubin level was more common in younger (78 ± 10 vs. 82 ± 8 years old, p < 0.001) males (15 vs. 6%, p < 0.001), with history of pacemaker or ICD (33 vs. 18%, p = 0.005), congestive heart failure New York Heart Association class IV within 2 weeks from TAVR (35 vs. 14%, p < 0.001), severe tricuspid regurgitation (14 vs. 4%, p < 0.001), and atrial fibrillation or flutter (60 vs. 40%, p = 0.004, respectively). Pre-TAVR hyperbilirubinemia was independently associated with an increased post-TAVR in-hospital mortality (7 vs. 2% in normal bilirubin, p = 0.03), stroke (5 vs. 1%, p = 0.019, respectively), and a composite endpoint of death or stroke (12 vs. 3%, p < 0.001). Preoperative hyperbilirubinemia in patients undergoing TAVR is more prevalent than previously considered with multifactorial causes. Hyperbilirubinemia is independently associated with an increased post-TAVR in-hospital mortality and stroke.

Increased risk of neonatal complications or death among neonates born small for gestational age to mothers with gestational diabetes.

AIMS: To evaluate if neonatal complications or death were poorer for neonates born small for gestational age (SGA) than for those born with adequate weight or large for gestation age (LGA) to women with gestational diabetes mellitus (GDM). METHODS: Retrospective analysis of the clinical outcomes of neonates born to 3413 women with GDM. The prevalence of neonatal hypoglycaemia, hypocalcaemia, hyperbilirubinemia, polycythaemia, and death was compared among three birthweight groups: SGA, adequate, and LGA. A two-sided chi-squared or Fisher's exact test was used for between-group comparisons. A forward multiple logistic regression was performed to determine the odds ratio (OR) associated with SGA. RESULTS: Neonatal complications were more frequent in the SGA group (20.1%) than in the adequate (9.9%) or LGA (15.2%) groups. There were four deaths (1.6%) in the SGA group compared to one in the LGA (0.4%) and six in the adequate (0.2%) groups (P = 0.002). SGA was a risk factor for neonatal complications or death (OR. 2.122; 95% confidence interval, 1.552-2.899), independent of maternal age, weight gain, fasting glucose, glycaemic control, gestational hypertension, pre-eclampsia, smoking, or neonatal prematurity. CONCLUSION: SGA birthweight is an important risk factor for neonatal complications or death among neonates born to mothers with GDM.

Contributing factors and outcomes of burn-associated cholestasis.

BACKGROUND & AIMS: Cholestasis often occurs after burn injuries. However, the prevalence of cholestasis and its effect on outcomes in patients with severe burn injuries are unknown. The aim of this study was to describe the course and the burden of cholestasis in a cohort of severely burned adult patients. METHODS: We investigated the relationship between burn-associated cholestasis (BAC) and clinical outcomes in a retrospective cohort of patients admitted to our unit for severe burn injuries between 2012 and 2015. BAC was defined as an increased level of serum alkaline phosphatase (ALP) ≥1.5x the upper limit of normal (ULN) with an increased level of gamma-glutamyltransferase (GGT) ≥3x ULN, or as an increased level of total bilirubin ≥2x ULN. RESULTS: A total of 214 patients were included: 111 (52%) patients developed BAC after a median (IQR) stay of 9 (5-16) days. At 90 days, the mortality rate was 20%, including 34 and 9 patients with and without BAC (p <0.001), respectively, which corresponded to a 2.5-fold higher (95% CI 1.2-5.2, p = 0.012) risk of 90-day mortality for patients with BAC. After being adjusted for severity of illness, patients with BAC, hyperbilirubinemia and without elevated ALP and GGT levels had a hazard ratio of 4.51 (95% CI 1.87-10.87) for 90-day mortality. BAC was associated with the severity of the burn injury, shock and bacteraemia. BAC was present in 38 (51%) patients at discharge, and 7 (18%) patients had secondary sclerosing cholangitis. These patients maintained elevated levels of ALP and GGT that were 5.8x (1.7-15) the ULN and 11x the ULN (4.5-22), respectively, 20 months (3.5-35) after discharge. CONCLUSION: BAC is prevalent among patients with severe burn injuries and is associated with worse short-term outcomes, especially when total bilirubin levels were increased without elevated ALP and GGT levels. BAC survivors are at risk of developing sclerosing cholangitis. LAY SUMMARY: Cholestasis is common after burn injuries and is associated with burn severity, sepsis, organ failure and mortality. Patients with hyperbilirubinemia without elevated alkaline phosphatase and gamma-glutamyltransferase levels after the burn injury have a poor prognosis. Patients with burn-associated cholestasis may develop sclerosing cholangitis and secondary biliary cirrhosis.

Safety and efficacy of Nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer suffering from cholestatic hyperbilirubinaemia-A retrospective analysis.

INTRODUCTION: Treatment of patients with advanced pancreatic carcinoma (APC) and hyperbilirubinaemia is problematic because these patients were regularly excluded from clinical studies. Nanoparticle albumin-bound paclitaxel and gemcitabine (nab-P/G) is an evidence-based treatment for patients with APC. This retrospective study investigated the safety and efficacy of nab-P/G in patients with APC and cholestatic hyperbilirubinaemia. METHODS: We screened our prospective database for patients with APC treated with nab-P/G at total bilirubin levels of ≥1.2 mg/dl. Patients were assigned into three groups according to their bilirubin level (A: 1.2-3 mg/dl, B: >3-5 mg/dl, C: >5 mg/dl). Analyses with regard to safety and survival were performed. RESULTS: Twenty-nine of 168 patients screened between Dec 2013 and Dec 2015 fulfilled the inclusion criteria. Most patients (83%) were male; median age was 63 [41-79] years. Nab-P/G administrations in patients with an elevated bilirubin level (median, range) did not result in unexpected toxicities assessed by predefined (non-)haematological parameters. Median overall survival (mOS) for the whole group was 11.7 (95% confidence interval [CI]: 6.8-14.0) months; for A: 11.8 (95% CI: 6.5-16.5), B: 9.2 (95% CI: 1.1 - NA) months and C 11.8 (95% CI: 5.9-20.0] months (p = 0.843). Again, mOS from the first application of nab-P/G did not differ between the groups (p = 0.13). CONCLUSION: Nab-P/G administrations in our pts with cholestatic hyperbilirubinaemia suffering from APC were feasible and safe with respect to individualised dose administrations. A multicenter phase 1 trial in pts with hyperbilirubinaemia is started (AIO-PAK-0117) to confirm these findings in a prospective setting.

Increased mortality in critically ill patients with mild or moderate hyperbilirubinemia.

PURPOSE: Increased bilirubin concentrations may be related to outcome, but this has not been well studied. We evaluated the relationship between total serum bilirubin levels and outcome in critically ill patients. MATERIALS AND METHODS: Data were analyzed from adult critically ill patients included in a 1-day international prevalence study after excluding those with an obvious underlying cause of hyperbilirubinemia. RESULTS: Serum bilirubin concentrations were >1 mg/dL in 2803 (31%) of 8973 patients, and these patients had higher mortality rates than patients with lower bilirubin concentrations (30% vs 21%, P<.01). For serum bilirubin values of 1.1-6 mg/dL, there was a linear increase in crude mortality (R2=0.96), with the highest hospital mortality (42%) in patients with bilirubin concentrations between 3.7 and 6.0 mg/dL. There was no further increase in the mortality rates for patients with bilirubin concentrations >6 mg/dL. A serum bilirubin concentration >1 mg/dL was an independent risk factor for mortality in multilevel analysis. CONCLUSIONS: Hyperbilirubinemia without a recognized cause was common and independently associated with increased mortality. There was a linear correlation of mortality with bilirubin concentration for values between 1 and 6 mg/dL but not for higher values.

Post-hepatectomy hyperbilirubinemia: The point of no return.

BACKGROUND: Post-hepatectomy hyperbilirubinemia is associated with liver insufficiency and failure. The highest survivable peak total bilirubin (ptbili) is not defined. This study aimed to identify the postop ptbili beyond which survival is improbable or impossible. METHODS: An institutional database of major hepatectomies (≥3 segments, no biliary resections), 2000-2012 was reviewed. Data were analyzed to find ptbili in the first 45 postop days. Factors associated with 90-day mortality (90 DM) and those predictive of ptbili were determined. RESULTS: 603 pts were analyzed with 90DM of 4.5%. 90 DM for a ptbili ≥ 18 (n = 15) was 86.6%, but only 2.5% for a ptbili < 18. All 6 pts with a ptbili ≥ 30 died. On multivariate analysis, postop ptbili ≥ 18 (HR34.95, CI 3.8-324; p = 0.002) and cirrhosis (HR6.4, CI 1.2-33.2; p = 0.027) were associated with 90DM. Factors associated with a ptbili ≥ 18 were age >65 (HR14.24, CI 2.9-70.5; p = 0.001), preop chemotherapy (HR4.77, CI 1.3-18.2; p = 0.02) and postop FFP (HR12.5, CI 2.6-56.2; p = 0.001). CONCLUSION: Postop ptbili ≥ 18 after major hepatectomy has an 86.6% risk of 90DM; there are no survivors for tbili ≥ 30. These values may guide postop counseling for prognosis. Future studies may evaluate tbili ≥ 18 as an indication for hepatic replacement therapy.

Hyperbilirubinemia after cardiac surgery: An observational study.

BACKGROUND: We aimed to assess the incidence and perioperative risk factors for hyperbilirubinemia after cardiac surgery, and determine its influence on early operative outcome. METHODS: This prospective observational study was conducted on 476 patients who underwent cardiac surgical procedures from January 2014 to March 2014. Postoperative hyperbilirubinemia was defined as serum total bilirubin >2.0 mg dL(-1). RESULTS: The overall incidence of postoperative hyperbilirubinemia was 25% (119 patients). Patients undergoing valve repair or replacement had the highest incidence of hyperbilirubinemia (36.2%), followed by coronary artery bypass grafting with concomitant valve surgery (34.1%), congenital heart surgery (23.1%), and coronary artery bypass alone (12.7%). Postoperative hyperbilirubinemia was associated with increased duration of inotropic support (p = 0.0001), mechanical ventilation (p = 0.0001), intensive care unit stay (p = 0.001), hospital stay (p = 0.006), and mortality (p = 0.014). The perioperative factors associated with postoperative hyperbilirubinemia were increased preoperative bilirubin level (p < 0.0001), preoperative prothrombin time (p < 0.0001), cardiopulmonary bypass time (p = 0.028), aortic crossclamp time (p = 0.004), and blood transfusion units (p = 0.0001). CONCLUSIONS: Postoperative hyperbilirubinemia is common in patients undergoing cardiopulmonary bypass and is associated with high hospital mortality. The factors associated with its occurrence are increased preoperative bilirubin level, preoperative prothrombin time, cardiopulmonary bypass time, aortic crossclamp time, and blood transfusion units. Persistent hyperbilirubinemia is associated with a worse outcome than early transient hyperbilirubinemia.

The association of serum bilirubin levels on the outcomes of severe sepsis.

PURPOSE: Admission serum bilirubin levels have been incorporated into severity of illness scoring systems in critical illness as a marker of liver dysfunction. The purpose of our study is to determine the independent association of serum bilirubin with mortality in severe sepsis and septic shock. METHODS: We conducted a retrospective study of adult patients admitted with severe sepsis and septic shock. We excluded patients with a prior history of liver disease. We identified the highest serum bilirubin within 72 hours of admission and stratified bilirubin levels into ≤1 mg/dL (normal), 1.1 to 2 mg/dL (abnormal up to 2 mg/dL), and >2 mg/dL. We sought to determine the independent association of hyperbilirubinemia with mortality and length of intensive care unit stay in persons with severe sepsis and septic shock. RESULTS: A total of 251 patients met criteria for severe sepsis. In all, 200 patients had a bilirubin of <1 mg/dL, and 51 had a bilirubin of >1 mg/dL. Of these 51, 12 had a bilirubin >2 mg/dL. Mortality was 12%, 24%, and 42% in persons with a bilirubin ≤1, 1.1 to 2, and >2 mg/dL, respectively. Compared to those with a bilirubin ≤ 1 mg/dL, adjusted odds of mortality in patients were 3.85 (95% confidence interval [CI] 1.21-12.2) and 9.85 (95% CI 1.92-50.5) times higher in persons with bilirubin levels between 1.1 and 2 and >2 mg/dL, respectively. CONCLUSION: After multivariable adjustment for potential confounding factors, elevated serum bilirubin levels within 72 hours of admission are associated with an increased risk of mortality in patients with severe sepsis and septic shock. Prospective studies are warranted to further validate our findings.

Prognostic factors of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children: report of the Japan Histiocytosis Study Group.

BACKGROUND: Despite several advances in the treatment of Epstein-Barr virus (EBV) in recent years, patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) do not always show satisfactory outcomes. We here conducted a nationwide survey in Japan to identify prognostic factors of EBV-HLH in children with this disease in an effort to improve the management and the outcomes of these patients. PROCEDURE: Between January 2003 and June 2008, we enrolled 98 children younger than 18 years of age who were diagnosed with EBV-HLH. We then studied the clinical characteristics and laboratory findings at the time of diagnosis with the aim to identify prognostic factors for EBV-HLH. RESULTS: The mean age of onset of EBV-HLH was 3.9 ± 2.8 years. Most of our patients presented with fever, hepatosplenomegaly, lymphadenopathy, and hemophagocytosis of bone marrow. Sixty-two percent of patients showed T cell clonality, and 97% had EBV infection in either T or natural killer cells. Most patients (60%) were treated with a multi-agent chemotherapeutic regimen, including corticosteroid, etoposide, and cyclosporine. After initial treatment, 90.3% of patients were in remission, and 7 patients (8.2%) experienced recurrence of EBV infection. Among several prognostic factors, patients with both hyperbilirubinemia (>1.8 mg/dl) and hyperferritinemia (>20,300 ng/ml) at the time of diagnosis had significantly poorer outcomes than those with low serum bilirubin and ferritin levels. CONCLUSIONS: These findings suggest that the therapeutic strategy for children with EBV-HLH could be tailored according to the laboratory findings at diagnosis.

Withholding parenteral nutrition during critical illness increases plasma bilirubin but lowers the incidence of biliary sludge.

UNLABELLED: Cholestatic liver dysfunction (CLD) and biliary sludge often occur during critical illness and are allegedly aggravated by parenteral nutrition (PN). Delaying initiation of PN beyond day 7 in the intensive care unit (ICU) (late PN) accelerated recovery as compared with early initiation of PN (early PN). However, the impact of nutritional strategy on biliary sludge and CLD has not been fully characterized. This was a preplanned subanalysis of a large randomized controlled trial of early PN versus late PN (n = 4,640). In all patients plasma bilirubin (daily) and liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyl transpeptidase [GGT], alkaline phosphatase [ALP], twice weekly; n = 3,216) were quantified. In a random predefined subset of patients, plasma bile acids (BAs) were also quantified at baseline and on days 3, 5, and last ICU-day (n = 280). Biliary sludge was ultrasonographically evaluated on ICU-day 5 (n = 776). From day 1 after randomization until the end of the 7-day intervention window, bilirubin was higher in the late PN than in the early PN group (P < 0.001). In the late PN group, as soon as PN was started on day 8 bilirubin fell and the two groups became comparable. Maximum levels of GGT, ALP, and ALT were lower in the late PN group (P < 0.01). Glycine/taurine-conjugated primary BAs increased over time in ICU (P < 0.01), similarly for the two groups. Fewer patients in the late PN than in the early PN group developed biliary sludge on day 5 (37% versus 45%; P = 0.04). CONCLUSION: Tolerating substantial caloric deficit by withholding PN until day 8 of critical illness increased plasma bilirubin but reduced the occurrence of biliary sludge and lowered GGT, ALP, and ALT. These results suggest that hyperbilirubinemia during critical illness does not necessarily reflect cholestasis and instead may be an adaptive response that is suppressed by early PN.

Frequency, risk factors and prognosis of postoperative hyperbilirubinemia after heart valve surgery.

OBJECTIVES: Despite recent advances in cardiovascular surgery, hyperbilirubinemia after heart valve surgery occurs often and the mechanism is not well clarified. We evaluated the incidence and nature of postoperative hyperbilirubinemia in heart valve surgery patients to analyze its risk factors and to identify its clinical significance for associated morbidity and mortality. METHODS: We investigated 334 consecutive patients who underwent heart valve surgery. Postoperative hyperbilirubinemia was defined as total serum bilirubin concentration greater than 3 mg/dl at any postoperative measurement point. RESULTS: Postoperative hyperbilirubinemia developed in 63 patients (19.0%) and was associated with greater in-hospital mortality (15.9 vs. 1.5%, p < 0.01). Univariate analysis revealed congestive heart failure history, cardiogenic shock, infective endocarditis, preoperative liver dysfunction, longer cardiopulmonary bypass time and transfusion as significantly related to postoperative hyperbilirubinemia. In multivariate analysis, preoperative liver dysfunction [odds ratio (OR) 6.5, p < 0.05] and longer cardiopulmonary bypass time (OR 1.007, p < 0.01) were independent predictors. In postoperative hyperbilirubinemia patients, preoperative New York Heart Association status and history of heart failure were associated with outcome. CONCLUSIONS: Postoperative hyperbilirubinemia remains common in patients undergoing heart valve surgery and is associated with a high rate of in-hospital mortality. For patients with heart failure or liver dysfunction, meticulous operative management is required to reduce cardiopulmonary bypass time and transfusion.

Incidence and risk factors for early hepatotoxicity and its impact on survival in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is commonly associated with hepatic complications. Patients with myelofibrosis (MF) often develop liver dysfunction in the early posttransplantation period; however, this has not yet been studied in a systematic fashion. We retrospectively evaluated 53 patients with MF who underwent HCT to assess the prevalence of acute liver toxicity and risk factors and the impact on survival. We compared the prevalence of acute hepatic complications in that group and a matched control group of 53 patients with myelodysplastic syndrome (MDS). In the MF group, during the first 6 weeks after HCT, the incidence of mild (34.2-102.6 µM), moderate (102.6-342 µM), and severe (>342 µM) hyperbilirubinemia was 34%, 40%, and 4%, respectively (normal, <22 µM). The incidence of mild/moderate transaminitis (2-10 times the upper limit of normal) was 23%, and that of severe transaminitis (>10 times the upper limit of normal) was 6%. Veno-occlusive disease as defined by the Baltimore criteria was observed in 19 patients (36%) in the MF group. Compared with MDS, MF was associated with a significantly higher incidence of moderate/severe hyperbilirubinemia (44% versus 21%; P = .02) and veno-occlusive disease (36% versus 19%; P = .05). A history of portal hypertension, biopsy-proven hepatic iron overload, or splanchnic vein thrombosis was a strong predictor of moderate/severe hyperbilirubinemia (P = .02). Acute hepatocellular injury with moderate/severe hyperbilirubinemia or transaminitis was associated with inferior survival at 12 months (P = .02) in the MF group. We conclude that patients with MF are at significant risk of early hepatotoxicity after HCT, which is associated with an adverse impact on survival.

Incidence, characteristics and risk factors of marked hyperbilirubinemia after allogeneic hematopoietic cell transplantation with reduced-intensity conditioning.

To analyze the incidence, characteristics and risk factors of hyperbilirubinemia after allogeneic hematopoietic cell transplantation with reduced-intensity conditioning (allo-RIC), we conducted a retrospective study in three Spanish centers. We analyzed 452 consecutive patients receiving allo-RIC. Of these, 92 patients (20%) developed marked hyperbilirubinemia (>4 mg/day or >68.4 µM) after allo-RIC. The main causes of marked hyperbilirubinemia after transplant were cholestasis due to GVHD or sepsis (n=57, 62%) and drug-induced cholestasis (n=13, 14%). A total of 22 patients with marked hyperbilirubinemia (24%) underwent liver biopsy. The most frequent histological finding was iron overload alone (n=6) or in combination with other features (n=6). In multivariate analysis, the risk factors for marked hyperbilirubinemia after allo-RIC were non-HLA-identical sibling donors (hazard ratio (HR) 2.2 (95% confidence interval (CI) 1.4-3.6) P=0.001), female donors to male recipients (HR 2.1 (95% CI 1.3-3.3) P=0.003) and high levels of bilirubin and γ-glutamyl transpeptidase before transplant (HR 4.5 (95% CI 2.5-8.4) P<0.001 and HR 4.6 (95% CI 2.6-8.1) P<0.001, respectively). Patients with marked hyperbilirubinemia showed higher 4-year nonrelapse mortality (HR 1.3 (95% CI 1-1.7), P=0.02) and lower 4-year OS (HR 1.4 (95%CI 1.3-1.7), P<0.001) than patients without. In conclusion, we confirm that marked hyperbilirubinemia is frequent and diverse after allo-RIC. Development of marked hyperbilirubinemia after allo-RIC is associated with worse outcome of the procedure.

Liver graft failure and hyperbilirubinemia in liver transplantation recipients after Clostridium difficile infection.

INTRODUCTION: Liver transplant recipients are at high risk for Clostridium difficile infection. We have recently encountered multiple cases of CDI in our liver transplant recipients and for some of them it led to severe hyperbilirubinemia, liver failure, and even death. Our goals are to report our experience and analyze the factors that contributed to unfavorable outcomes. MATERIAL AND METHODS: All liver transplant recipients diagnosed with CDI between December 1, 2007, and January 30, 2009, were included and retrospectively reviewed. RESULTS: Twenty-four patients were identified, 14 men and 10 women. Fourteen patients experienced hyperbilirubinemia after the infection and 7 progressed to liver failure. Pre-CDI biopsy-proven liver abnormality, use of extended-criteria donors (ECDs) and a donor risk index (DRI) greater than 1.9 were associated with a higher risk of graft failure (P<.05). Hepatitis C, inpatient versus outpatient diagnosis, and a donor age greater than 50 years were not associated with a higher risk of graft failure. Use of ECDs and timing of the infection at more than 1 month but less than 1.5 years posttransplant were also associated with higher chances of sustained hyperbilirubinemia (P<.05). CONCLUSION: CDI in liver transplant patients can be very serious and may lead to sustained hyperbilirubinemia or graft failure. Marginal grafts are more susceptible to decompensate after such an infection than standard criteria grafts; moreover, already abnormal grafts do not tolerate this infection well and decompensate to complete failure in 85% of the cases.

The optimal timing of referral to an intestinal failure program: the relationship between hyperbilirubinemia and mortality.

PURPOSE: Multidisciplinary treatment of pediatric intestinal failure has shown promising results. However, there are limited data as to the optimal time frame for referral of patients to intestinal failure programs. The aim of this study was to explore the relationship of hyperbilirubinemia at referral with patient outcomes in a multidisciplinary program. METHODS: A retrospective analysis was performed of a prospectively collected database from a multidisciplinary intestinal failure program. Multivariable logistic regression adjusted for age at referral was used to model the association between the conjugated bilirubin at referral and risk of mortality. Median values with range are reported. RESULTS: Sixty-two patients were referred from 2005 to 2009. Patients presented at age 6.4 months (0.4-261.4 months) and were followed up for 16.8 (0.3-53.0) months. Nine subjects (14.5%) died, and 12 subjects (19.4%) were listed for combined liver-intestine transplant. A 50% mortality was seen in patients referred with a conjugated bilirubin ≥ 7.2 mg/dL (n = 12), whereas mortality at referral bilirubin levels <7.2 mg/dL was 6%. After adjusting for age at referral, patients with a conjugated bilirubin ≥ 7.2 mg/dL at referral were 15.4 times more likely to die than patients who presented with lower bilirubin levels (P = .001; 95% confidence interval, 2.8-83.4). CONCLUSION: Within a pediatric intestinal failure program, mortality is associated with the degree of hyperbilirubinemia at time of referral. These data strongly suggest that these patients should be referred to a multidisciplinary program early in the evolution of their liver disease.

Prognostic value of direct bilirubin in neonatal hyperbilirubinemia.

OBJECTIVE: To determine the prognostic value of indirect and direct hyperbilirubinemia in neonates with jaundice. METHODS: A cohort of 92 consecutive neonates reporting with hyperbilirubinemia to a tertiary care center were followed up till well and discharged, or, till death to assess risk and rate of mortality. RESULTS: The baseline median values of total, direct and indirect bilirubin in the cohort of 21.8, 1.6 and 18.6 mg/dl, respectively, were used as cut-offs for high and low levels. Using survival analyses i.e. Kaplan-Meier plots, logrank tests and multivariate Cox proportional hazards regression models to adjust for other strong predictors such as receipt of breastfeeding, being small for gestational age (SGA) and exchange transfusion, high direct bilirubin (> or = median value of 1.6 mg/dl) was independently associated with a higher and faster mortality. CONCLUSION: This study showed that direct bilirubin has independent and additive prognostic value and due attention should be given to newborns with raised levels.