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.
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.
From the Divisions of Critical Care (SLW, MSW) and Neurology (HRR, MSW), Department of Pediatrics and the Department of Pathology and Laboratory Medicine (SH), Children’s Memorial Hospital, Northwestern Feinberg School of Medicine, Chicago, IL; the Biostatistics Research Core (DW), Children’s Memorial Research Center, Chicago, IL; the Newborn Screening Quality Assurance Program (VRD), Centers for Disease Control and Prevention, Atlanta, GA; and Pediatrix Analytical (DHC), Pediatrix Medical Group, Center for Research Education and Quality, Sunrise, FL.
Financial support was provided by the Medical Research Junior Board Foundation (MSW), the Department of Pathology and Laboratory Medicine (SH), the Colman Family Grant (SW), and by grant UL1RR025741 from the National Center for Research Resources, National Institutes of Health.
The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
This study was performed at Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL.
Dr. Chace has employment and stock ownership with Pediatrix Medical Group. The remaining authors have not disclosed any potential conflicts of interest.
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