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

Lorraine B Ware,Gary Cunningham,Marshall L Summar,Arthur P Wheeler,Todd W Rice,Gordon R Bernard,Jordan A Magarik,Brian W Christman,Nancy Wickersham

doi:10.1186/cc11934

Lorraine B Ware, Gary Cunningham + Show 7 more

Open Access

https://doi.org/10.1186/cc11934

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Journal: Critical Care	Publication Date: Jan 1, 2013
Citations: 89	License type: cc-by

Affiliation: Vanderbilt University, Children's National

Abstract

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

Highlights

The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood
We have recently observed that in human vascular endothelial cells, extracellular citrulline and not arginine, is the effective precursor of NO production. These findings suggest that circulating levels of citrulline may be more predictive of nitric oxide synthases (NOS) function than arginine levels
Amino acid levels and ARDS The median plasma level of citrulline was very low at 9.2 uM (interquartile range (IQR) 5.2 to 14.4) compared to a normal range of 40 ± 10 uM in healthy adults [16]

Summary

Introduction

The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. 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. The role of nitric oxide synthases (NOS) and their product nitric oxide (NO) in the pathophysiology of clinical acute respiratory distress syndrome (ARDS) is still not well understood. We have recently observed that in human vascular endothelial cells, extracellular citrulline and not arginine, is the effective precursor of NO production. These findings suggest that circulating levels of citrulline may be more predictive of NOS function than arginine levels

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