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

Rihong Zhai ¹, Chau-Chyun Sheu ¹, Li Su ¹, Michelle N Gong ², Paula Tejera-Alvarez ¹, Feng Chen ¹, Zhaoxi Wang ¹, Maureen Convery ¹, Taylor B Thompson ³ and David C Christiani ^4*

¹ Harvard School of Public Health, United States
² Division of Pulmonary and Critical Care Medicine, Mount Sinai School of Medicine, United States
³ Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, United States
⁴ Harvard School of Public Health, Massachusetts General Hospital, United States

^* To whom correspondence should be addressed. E-mail: dchris{at}hsph.harvard.edu.

Accepted 2 April 2009

Abstract

Background: Hyperbilirubinemia is a common complication of sepsis. Elevated bilirubin may induce inflammation and apoptosis. We hypothesized that increased serum bilirubin on ICU admission contributes to sepsis-related ARDS.

Methods: Serum bilirubin on ICU admission was measured in 1006 septic patients. Serial serum bilirubin was analyzed prospectively in septic patients with ARDS for a period of 28 days. The effects of clinical factors and variants of UGT1A1 gene on serum bilirubin levels were determined. Outcomes were ARDS risk and mortality.

Results: During 60 day follow-up, 326 septic patients developed ARDS in whom 144 died from ARDS. The hyperbilirubinemia ( 2.0 mg/dl) rate in patients with ARDS (22.4%) was higher than those without ARDS (14.1%, p = 0.002). For each 1.0 mg/dL increase in admission bilirubin, ARDS risk, 28- and 60-day ARDS mortality 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 hyperbilirubinemia had higher risks of ARDS (OR = 2.12; p = 0.0007), 28-day (OR = 2.24; p = 0.02), and 60-day ARDS mortality (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 inter-individual variation in bilirubin levels, whereas genetic variants of UGT1A1 contributed 7.5%.

Conclusion: In sepsis, higher serum bilirubin level on ICU admission is associated with subsequent ARDS development and mortality.