• Michiel P C Siroen, Paul A M van Leeuwen, Robert J Nijveldt, Tom Teerlink, Pieter J Wouters, and Greet Van den Berghe.
• Department of Surgery, VU University Medical Center, Amsterdam, The Netherlands.
• Crit. Care Med. 2005 Mar 1;33(3):504-10.

ObjectiveAsymmetric dimethylarginine, which inhibits production of nitric oxide, has been shown to be a strong and independent predictor of mortality in critically ill patients with clinical evidence of organ dysfunction. Interestingly, intensive insulin therapy in critically ill patients improved morbidity and mortality, but the exact mechanisms by which these beneficial effects are brought about remain unknown. Therefore, we aimed to investigate whether modulation of asymmetric dimethylarginine concentrations by intensive insulin therapy is involved in these effects.DesignA prospective, randomized, controlled trial.SettingA 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital.PatientsFrom a study of 1,548 critically ill patients who were randomized to receive either conventional or intensive insulin therapy, we included 79 patients who were admitted to the intensive care unit after complicated pulmonary and esophageal surgery and required prolonged (>/=7 days) intensive care.InterventionsDetermination of asymmetric dimethylarginine concentrations.Measurements And Main ResultsAsymmetric dimethylarginine concentrations were determined with high-performance liquid chromatography on the day of admission, on day 2, on day 7, and on the last day at the intensive care unit. Although the asymmetric dimethylarginine levels did not change between day 0 and day 2 in patients receiving intensive insulin treatment, there was a significant increase during this period in the conventionally treated patients (p = .043). Interestingly, the mean daily insulin dose was inversely associated with the asymmetric dimethylarginine concentration on the last day (r = -.23, p = .042), and the asymmetric dimethylarginine concentration on the last day at the intensive care unit was significantly lower in the intensive insulin treatment group (p = .048). Furthermore, asymmetric dimethylarginine was positively associated with duration of intensive care unit stay, duration of ventilatory support, duration of inotropic and vasopressor treatment, number of red cell transfusions, duration of antibiotic treatment, presence of critical illness polyneuropathy, mean Acute Physiology and Chronic Health Evaluation II score, and cumulative Therapeutic Intervention Scoring System-28 score. In addition, asymmetric dimethylarginine levels in patients who died were significantly higher compared with survivors, and changes in the course of asymmetric dimethylarginine plasma concentrations were predictive for adverse intensive care unit outcome.ConclusionsModulation of asymmetric dimethylarginine concentration by insulin at least partly explains the beneficial effects found in critically ill patients receiving intensive insulin therapy.

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