dimethylarginine and Critical-Illness

Critically ill patients experience metabolic disorders including hypercatabolic state and hyperglycaemia, and these are associated with poor outcome. Hyperglycaemia and asymmetrical dimethylarginine (ADMA) are reported to have significant influences on endothelial dysfunction. The aim of this study was to examine the relationship between plasma ADMA and related arginine metabolism in patients with critical illness.. Two venous blood samples (EDTA) (104 patients), on admission and follow-up sample in the last day in intensive care unit (ICU) (died or discharge sample median 7, interquartile range (IQR) 6-8, range 5-15). Plasma ADMA, arginine, homoarginine and SDMA were measured by high-performance liquid chromatography (HPLC).. ADMA (P < 0·01) and SDMA (P < 0·05) were elevated, and homoarginine was decreased (P < 0·05) in nonsurvivors and was directly associated with predicted mortality rate (P < 0·05 and P < 0·001), Sequential Organ Failure Assessment (SOFA) (P < 0·05, P < 0·001), ICU stay (P < 0·05, P < 0·001) and mortality (P < 0·01, P < 0·05). ADMA was directly associated with SDMA (P < 0·001), albumin (P < 0·05), ICU stay and mortality (P < 0·01). SDMA was directly associated with creatinine (P < 0·001) and Acute physiology and Chronic Health Evaluation II score (P < 0·001). In the follow-up measurements, there was a significant decrease in SOFA score (P < 0·01), homoarginine (P < 0·01), aminotransferase (P < 0·01), Laboratory Glucose (P < 0·01) and albumin (P < 0·01). In contrast, there was an increase in arginine (P < 0·01), ADMA (P < 0·01), ADMA:SDMA ratio (P < 0·01) and the norepinephrine administration (P < 0·01).. In the present longitudinal study, ADMA metabolism was altered in patients with critical illness and was associated with disease severity and mortality.

Topics: Adult; Aged; Arginine; Chromatography, High Pressure Liquid; Critical Care; Critical Illness; Endothelium, Vascular; Female; Humans; Length of Stay; Longitudinal Studies; Male; Middle Aged; Young Adult

Topics: Arginine; Critical Care; Critical Illness; Humans; Nitric Oxide; Sepsis

In the context of the hypercatabolic response to stress, critically ill patients reveal hyperglycemia and elevated levels of asymmetrical-dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases. Both hyperglycemia and elevated ADMA levels predict increased morbidity and mortality. Tight glycemic control by intensive insulin therapy lowers circulating ADMA levels, and improves morbidity and mortality. Methylarginines are released from proteins during catabolism. ADMA is predominantly cleared by the enzyme dimethylarginine-dimethylaminohydrolase (DDAH) in different tissues, whereas its symmetrical isoform (SDMA) is cleared via the kidneys. Therefore, glycemic control or glycemia-independent actions of insulin on protein breakdown and/or on DDAH activity resulting in augmented ADMA levels may explain part of the clinical benefit of intensive insulin therapy. Therefore, we investigated in our animal model of prolonged critical illness the relative impact of maintaining normoglycemia and of glycemia-independent action of insulin over 7 d in a four-arm design on plasma and tissue levels of ADMA and SDMA, on proteolysis as revealed by surrogate parameters as changes of body weight, plasma urea to creatinine ratio, and plasma levels of SDMA, and on tissue DDAH activity. We found that ADMA levels remained normal in the two normoglycemic groups and increased in hyperglycemic groups. SDMA levels in the investigated tissues remained largely unaffected. The urea to creatinine ratio indicated reduced proteolysis in all but normoglycemic/normal insulin animals. DDAH activity deteriorated in hyperglycemic compared with normoglycemic groups. Insulin did not affect this finding independent of glycemic control action. Conclusively, maintenance of normoglycemia and not glycemia-independent actions of insulin maintained physiological ADMA plasma and tissue levels by preserving physiological DDAH activity.

Topics: Amidohydrolases; Animals; Arginine; Blood Glucose; Body Weight; Creatinine; Critical Illness; Disease Models, Animal; Humans; Insulin; Rabbits