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

INTRODUCTION: 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

Nitric oxide precursors and congenital heart surgery: A randomized controlled trial of oral citrulline

ObjectiveThe study sought to determine whether citrulline supplementation, a precursor to nitric oxide synthesis, is safe and efficacious in increasing plasma citrulline concentrations and decreasing the risk of postoperative pulmonary hypertension.Study DesignForty children, undergoing cardiopulmonary bypass and at risk for pulmonary hypertension, were randomized to receive 5 perioperative doses (1.9 g/m2 per dose) of either oral citrulline or placebo. Plasma citrulline and arginine concentrations were measured at 5 time points. Measurements of systemic blood pressure and presence of pulmonary hypertension were collected.ResultsMedian citrulline concentrations were significantly higher in the citrulline group versus the placebo group immediately postoperatively (36 μmol/L vs 26 μmol/L, P = .012) and at 12 hours postoperatively (37 μmol/L vs 20 μmol/L, P = .015). Mean plasma arginine concentrations were significantly higher in the citrulline group versus the placebo group by 12 hours postoperatively (36 μmol/L vs 23 μmol/L, P = .037). Mean systemic blood pressure did not differ between groups (P = .53). Postoperative pulmonary hypertension developed in 9 patients, 6 of 20 (30%) in the placebo group and 3 of 20 (15%) in the citrulline group (P = .451), all of whom had plasma citrulline concentrations less than age-specific norms. Postoperative pulmonary hypertension did not develop in patients who demonstrated plasma citrulline concentrations in excess of 37 μmol/L (P = .036).ConclusionsOral citrulline supplementation safely increased plasma citrulline and arginine concentrations compared with placebo after cardiopulmonary bypass. Postoperative pulmonary hypertension did not occur in children with naturally elevated citrulline levels or elevations through supplementation. Oral citrulline supplementation may be effective in reducing postoperative pulmonary hypertension

The Effects of Ibuprofen on the Physiology and Survival of Patients with Sepsis

Sepsis is associated with a mortality rate of 30 to 50 percent and with substantial morbidity. 1 The relative contributions of the inflammatory response and infection to these adverse outcomes are unknown. 2 , 3 In animal models of sepsis, treatment with nonsteroidal antiinflammatory drugs improves survival and reduces physiologic abnormalities. 4 – 8 The synthesis of prostaglandin and thromboxane has been linked with abnormalities of airway mechanics, pulmonary hypertension, hypoxemia, cardiovascular collapse, and multiple organ failure in animals and in humans with the sepsis syndrome. 9 – 25 Ibuprofen has been shown to have effects on sepsis in humans, but because of their small samples (fewer . .