Time course of endogenous nitric oxide inhibitors in severe sepsis in humans

Asymmetric and symmetric dimethylarginines (ADMA and SDMA, respectively) are protein breakdown markers; both compete with arginine for cellular transport and both are excreted in urine. Moreover, ADMA is a non-selective inhibitor of nitric oxide (NO) synthase that is metabolized by a specific hydrolase in which the activity during stress remains controversial. While an increase in ADMA is known to be associated with adverse events, little is known about SDMA. We investigated plasma ADMA and SDMA levels during ICU stay to reveal the time course of endogenous NO inhibition in patients with sepsis.

A post hoc analysis from a prospective random controlled trial conducted in three ICUs was performed to study the pathophysiological pathways of sepsis. ADMA, SDMA, the ratio of ADMA/SDMA (a marker of ADMA catabolism), arginine, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C reactive protein (CRP) were measured on days 1, 3, 6, 9, 12 and at discharge in 72 consecutive severely septic patients.

Fasting basal glycemia, creatinine, IL-6, TNF-alpha, CRP, ADMA, and SDMA were higher than normal. The ADMA/SDMA ratio was decreased by 50%, and arginine levels were low. ADMA levels were related to the total Sequential Organ Failure Assessment (SOFA) scores and arginine levels, and inversely related to IL-6 and CRP levels. SDMA levels were related to Simplified Acute Physiologic Scores II (SAPS II), SOFA scores, blood urea, creatinine, and arginine levels. The ADMA/SDMA ratio was inversely related to IL-6 levels. In 58 ICU survivors, creatinine, IL-6, and CRP levels decreased over time; ADMA levels increased, SDMA levels remained stable, and the ADMA/SDMA ratio increased. In 14 non-survivors, creatinine, IL-6, TNF-alpha, CRP, and ADMA levels were stable, whereas the SDMA levels increased and the ADMA/SDMA ratio remained low. In both ICU survivors and non-survivors, the levels on the last ICU day confirmed the data trends. SDMA, but not ADMA, was associated with ICU mortality.

ADMA catabolism appears to be activated by inflammation; its increase during the advanced septic phase in surviving patients may suggest an endogenous inhibition of NO synthesis during the full-blown septic phase. In severe sepsis, SDMA, but not ADMA, appears to be a marker of alterations in vital functions and mortality.