title: Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Lorraine B
authors: LB
authors: Ware
authors: Jordan A
authors: JA
authors: Magarik
authors: Nancy
authors: N
authors: Wickersham
authors: Gary
authors: G
authors: Cunningham
authors: Todd W
authors: TW
authors: Rice
authors: Brian W
authors: BW
authors: Christman
authors: Arthur P
authors: AP
authors: Wheeler
authors: Gordon R
authors: GR
authors: Bernard
authors: Marshall L
authors: ML
authors: Summar
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002956:Citrulline / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012128:Respiratory Distress Syndrome / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology; D018805:Sepsis / Q000097:blood* / Q000175:diagnosis* / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D002956:Citrulline