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Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis

Lorraine B Ware12*, Jordan A Magarik1, Nancy Wickersham1, Gary Cunningham3, Todd W Rice1, Brian W Christman1, Arthur P Wheeler1, Gordon R Bernard1 and Marshall L Summar3

Author Affiliations

1 Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt University School of Medicine, T1218 MCN, 1161 21st Avenue S, Nashville, TN 37232-2650, USA

2 Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21st Avenue S, Nashville, TN 37232, USA

3 Department of Pediatrics, Division of Genetics and Metabolism, Children's National Medical Center, 111 Michigan Avenue, NW Washington, DC 20010, USA

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Critical Care 2013, 17:R10  doi:10.1186/cc11934

Please see related commentary by Cynober,

Published: 17 January 2013



The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis.


Plasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions.


Plasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness.


In severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function.