The Midwest Surgical Association Hyperbilirubinemia: a risk factor for infection in the surgical intensive care unit Erin Field, M.D.*, H. Mathilda Horst, M.D., Ilan S. Rubinfeld, M.D., Craig F. Copeland, M.D., Usman Waheed, M.D., Jack Jordan, M.S., Aaron Barry, B.S., Mary-Margaret Brandt, M.D. Department of Surgery, Henry Ford Hospital, Detroit, MI, USA Manuscript received November 16, 2007; revised manuscript December 7, 2007 Abstract Background: Hyperbilirubinemia in intensive care unit (ICU) patients is common. We hypothesized that hyperbilirubinemia in the surgical ICU predisposes patients to infection. Methods: Patients with bilirubin 3 mg/dL were compared to patients with bilirubin 3 mg/dL. We then compared the low bilirubin patients to high bilirubin patients who developed infection after their hyper- bilirubinemia. Results: There were 1,620 infections in 5,712 patients with low bilirubin (28%), compared with 284 in 409 patients in the high bilirubin group (69%, P  .001). After removing the patients in whom hyperbilirubinemia developed after infection, we found infection in 156 of 281 remaining patients (56%, P  .001). This group had a 3-fold increased risk of infection compared with low bilirubin (odds ratio [OR] 3.17, 95% confidence interval [CI] 2.48 – 4.03, P  .001). Conclusions: There is an increased susceptibility to infection among jaundiced surgical ICU (SICU) patients that persists even when sepsis-related hyperbilirubinemia patients are excluded. © 2008 Elsevier Inc. All rights reserved. Keywords: Jaundice; Hyperbilirubinemia; Bilirubin; Infection; Critical illness Hyperbilirubinemia in intensive care unit (ICU) patients is not uncommon, occurring in as many as 40% of patients. This liver dysfunction is often a result of an insult such as shock, trauma, or infection. However, multiple etiol- ogies exist and may include biliary obstruction, liver disease, hemolysis, resorption of hematoma, and drug toxicity [1]. Since most physicians view ICU liver dys- function as the result of a previous event, which may include sepsis, the relationship of elevated serum biliru- bin to development of subsequent infection is unclear. There is little evidence to implicate elevated bilirubin levels in critically ill patients with an increased risk of infection. To our knowledge, the question of whether hyperbilirubinemia predisposes patients to infection has not previously been answered. With the exception of obstructive jaundice and sepsis- induced liver dysfunction, there are few data supporting a relationship between jaundice and infection in patients. A recent multicenter prospective study including more than 38,000 patients found that early hepatic dysfunction, de- fined as bilirubin 2 mg/dL within 48 hours of admission, occurred in 11% of critically ill patients and was a risk factor for mortality; however, infection was not reported as an outcome [2]. Laboratory research suggests a relationship between jaun- dice and immune function, especially in models of biliary obstruction. Rats that underwent bile duct ligation as a model of obstructive jaundice had increased expression of toll-like receptor (TLR) 4 and increased levels of the hepatotoxic cy- tokine tumor necrosis factor-alpha (TNF-), as well as the hepatoprotective cytokine interleukin (IL)-6 in response to lipopolysaccharide (LPS) compared to sham animals [3]. Lab- oratory research supports that bilirubin and the other products of heme metabolism, as well as the enzyme HO-1 (inducible heme oxygenase), have anti-inflammatory activity, especially a cytoprotective role in the liver, lung, and small intestine [4 –7]. The question of how this anti-inflammatory action may relate to risk of infection is unclear. In theory, this altered immune response should increase infection risk. We hypothesized that hyperbilirubinemia in surgical ICU patients increases the risk of infection. * Corresponding author. Tel.: +1-313-916-3057; fax: +1-313-916-8007. E-mail address: efield1@hfhs.org The American Journal of Surgery 195 (2008) 304 –307 0002-9610/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.12.010