Serum bilirubin levels on ICU admission are associated with ARDS development and mortality in sepsis

Background: Hyperbilirubinaemia is a common complication of sepsis. Elevated bilirubin may induce inflammation and apoptosis. It was hypothesised that increased serum bilirubin on Intensive Care Unit (ICU) admission contributes to sepsis-related acute respiratory distress syndrome (ARDS). Methods: Serum bilirubin on ICU admission was measured in 1006 patients with sepsis. Serial serum bilirubin was analysed prospectively in patients with sepsis who had ARDS for a period of 28 days. The effects of clinical factors and variants of the UGT1A1 gene on serum bilirubin levels were determined. Outcomes were ARDS risk and mortality. Results: During 60-day follow-up, 326 patients with sepsis developed ARDS, of whom 144 died from ARDS. The hyperbilirubinaemia (⩾2.0 mg/dl) rate in patients with ARDS (22.4%) was higher than in those without ARDS (14.1%, p = 0.002). For each 1.0 mg/dl increase in admission bilirubin, ARDS risk and 28- and 60-day ARDS mortalities were increased by 7% (OR = 1.07; p = 0.003), 20% (OR = 1.20; p = 0.002) and 18% (OR = 1.18; p = 0.004), respectively. Compared with subjects with bilirubin levels <2.0 mg/dl, patients with hyperbilirubinaemia had higher risks of ARDS (OR = 2.12; p = 0.0007) and 28-day (OR = 2.24; p = 0.020) and 60-day ARDS mortalities (OR = 2.09; p = 0.020). In sepsis-related ARDS, serial bilirubin levels in non-survivors were consistently higher than in survivors (p<0.0001). Clinical variables explained 29.5% of the interindividual variation in bilirubin levels, whereas genetic variants of UGT1A1 contributed 7.5%. Conclusion: In sepsis, a higher serum bilirubin level on ICU admission is associated with subsequent ARDS development and mortality.

[1]  I. L. Cohen.  Guidelines for the use of innovative therapies in sepsis. , 1993, Critical care medicine.

[2]  P. Kraft,et al.  Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDS , 2007, Thorax.

[3]  R. Bone,et al.  Hepatic dysfunction in the adult respiratory distress syndrome. , 1989, Chest.

[4]  A. M. del Batlle,et al.  Bilirubin is highly effective in preventing in vivo delta-aminolevulinic acid-induced oxidative cell damage. , 2003, Biochimica et biophysica acta.

[5]  A. Fein,et al.  Acute lung injury and acute respiratory distress syndrome in sepsis and septic shock. , 2000, Critical care clinics.

[6]  Y. Benjamini,et al.  Quantitative Trait Loci Analysis Using the False Discovery Rate , 2005, Genetics.

[7]  A. Peitzman,et al.  Hepatic dysfunction increases length of stay and risk of death after injury. , 2002, The Journal of trauma.

[8]  Rui F. M. Silva,et al.  Inflammatory signalling pathways involved in astroglial activation by unconjugated bilirubin , 2006, Journal of neurochemistry.

[9]  Alexander Rokitansky,et al.  Thorax , 2009, Pediatric Surgery Digest.

[10]  Giuseppe Toffoli,et al.  The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  Kazuo Komamura,et al.  UGT1A1 Haplotypes Associated with Reduced Glucuronidation and Increased Serum Bilirubin in Irinotecan‐administered Japanese Patients with Cancer , 2004, Clinical pharmacology and therapeutics.

[12]  D. Mannino,et al.  The epidemiology of sepsis in the United States from 1979 through 2000. , 2003, The New England journal of medicine.

[13]  J. Singer,et al.  A simple multiple system organ failure scoring system predicts mortality of patients who have sepsis syndrome. , 1993, Chest.

[14]  J. Miners,et al.  Genetic polymorphisms of UDP-glucuronosyltransferases and their functional significance. , 2002, Toxicology.

[15]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. 1992. , 2009, Chest.

[16]  A. Sanyal,et al.  Sepsis‐induced cholestasis , 2007, Hepatology.

[17]  G. Rubenfeld,et al.  Epidemiology and outcomes of acute lung injury. , 2007, Chest.

[18]  T. Fiore,et al.  Jaundice in critical illness: promoting factors of a concealed reality , 2006, Intensive Care Medicine.

[19]  R. Tukey,et al.  Human UDP-glucuronosyltransferases: metabolism, expression, and disease. , 2000, Annual review of pharmacology and toxicology.

[20]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. , 1992, Chest.

[21]  Michael Z. Man,et al.  Limited influence of UGT1A1*28 and no effect of UGT2B7*2 polymorphisms on UGT1A1 or UGT2B7 activities and protein expression in human liver microsomes. , 2007, British journal of clinical pharmacology.

[22]  R. Maunder,et al.  Clinical risks for development of the acute respiratory distress syndrome. , 1995, American journal of respiratory and critical care medicine.

[23]  J. Ostrow,et al.  Molecular basis of bilirubin-induced neurotoxicity. , 2004, Trends in molecular medicine.

[24]  Rui F. M. Silva,et al.  Bilirubin toxicity to human erythrocytes: a review. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[25]  N. Robles,et al.  The Surgical Intensive Care Unit , 1968 .

[26]  C. Rodrigues,et al.  Bilirubin directly disrupts membrane lipid polarity and fluidity, protein order, and redox status in rat mitochondria. , 2002, Journal of hepatology.

[27]  M. Lamy,et al.  The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. , 1994, American journal of respiratory and critical care medicine.

[28]  D. Schoenfeld,et al.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. , 2000, The New England journal of medicine.

[29]  A. Sanyal,et al.  Sepsis and cholestasis. , 2008, Clinics in liver disease.

[30]  R. Hoffmann,et al.  Serial bilirubin determinations as a prognostic marker in clinical infections. , 1989, The American journal of the medical sciences.

[31]  M W Whitehead,et al.  The causes of obvious jaundice in South West Wales: perceptions versus reality , 2001, Gut.

[32]  J. Potter,et al.  UDP-glucuronosyltransferase (UGT1A1*28 and UGT1A6*2) polymorphisms in Caucasians and Asians: relationships to serum bilirubin concentrations. , 1999, Pharmacogenetics.

[33]  C. Vascotto,et al.  Bilirubin-induced cell toxicity involves PTEN activation through an APE1/Ref-1-dependent pathway , 2007, Journal of Molecular Medicine.

[34]  Rui F. M. Silva,et al.  Assessment of bilirubin toxicity to erythrocytes. Implication in neonatal jaundice management , 2000, European journal of clinical investigation.

[35]  I. Rubinfeld,et al.  Hyperbilirubinemia: a risk factor for infection in the surgical intensive care unit. , 2008, American journal of surgery.

[36]  D. Pietraforte,et al.  Bilirubin is an effective antioxidant of peroxynitrite-mediated protein oxidation in human blood plasma. , 1998, Archives of biochemistry and biophysics.

[37]  A. Artigas,et al.  Report of the American-European consensus conference on ARDS: Definitions, mechanisms, relevant outcomes and clinical trial coordination , 1994, Intensive Care Medicine.

[38]  J. Reuben,et al.  Acute Lung Injury:Apoptosis and Signaling Mechanisms , 2009, Experimental biology and medicine.