Evaluation of asymmetric dimethylarginine, arginine, and carnitine metabolism in pediatric sepsis

OBJECTIVE: Increased plasma concentrations of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, decreased arginine bioavailability, and mitochondrial dysfunction have been reported in adult sepsis. We studied whether asymmetric dimethylarginine, arginine, and carnitine metabolism (a measure of mitochondrial dysfunction) are altered in pediatric sepsis and whether these are clinically useful biomarkers. DESIGN: Prospective, observational study. SETTING: Pediatric intensive care unit at an academic medical center. PATIENTS: Ninety patients ≤18 yrs old, 30 with severe sepsis or septic shock, compared with 30 age-matched febrile and 30 age-matched healthy control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma asymmetric dimethylarginine and whole blood arginine, citrulline, ornithine, and acylcarnitine:free carnitine ratio were measured daily for septic patients and once for control subjects using tandem mass spectrometry. Plasma asymmetric dimethylarginine concentration (median; interquartile range μmol/L) on day 1 was lower in severe sepsis and septic shock (0.38; 0.30-0.56) compared with febrile (0.45; 0.40-0.59) and healthy (0.60; 0.54-0.67) control subjects (p < .001), although decreased asymmetric dimethylarginine was predominantly found in neutropenic patients. Day 1 arginine was lower in septic (10; interquartile range, 7-20 μmol/L) compared with healthy patients (32; interquartile range, 23-40; p < .001), and the arginine:ornithine ratio was decreased in sepsis, indicating increased arginase activity (an alternative pathway for arginine metabolism). The arginine:asymmetric dimethylarginine and acylcarnitine:free carnitine ratios did not differ between septic and control patients. Asymmetric dimethylarginine was inversely correlated with organ dysfunction by Pediatric Logistic Organ Dysfunction score (r = -0.50, p = .009), interleukin-6 (r = -0.55, p = .01), and interleukin-8 (r = -0.52, p = .03) on admission. Arginine, arginine:asymmetric dimethylarginine, and acylcarnitine:free carnitine were not associated with organ dysfunction or outcomes. CONCLUSIONS: Asymmetric dimethylarginine was decreased in pediatric sepsis and was inversely associated with inflammation and organ dysfunction. This suggests that inhibition of nitric oxide synthase by asymmetric dimethylarginine accumulation is unlikely to impact sepsis pathophysiology in septic children despite decreased arginine bioavailability. We did not find an association of asymmetric dimethylarginine with altered carnitine metabolism nor were asymmetric dimethylarginine, arginine, and acylcarnitine:free carnitine useful as clinical biomarkers.