ObjectiveExpression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-&kgr;B. Inhibition of nuclear factor-&kgr;B activation may be beneficial in critically ill patients.N-acetylcysteine is an antioxidant that inhibits nuclear factor-&kgr;B activationin vitro. In this pilot study we investigated the effect ofN-acetylcysteine on nuclear factor-&kgr;B activation and circulating cytokine and adhesion molecules in patients with sepsis.DesignProspective, randomized, double blind, placebo-controlled pilot trial.SettingEight-bed intensive care unit in a university teaching hospital.PatientsTwenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis.InterventionsA bolus of 150 mg/kgN-acetylcysteine in 100 mL of 0.9% saline over 15 mins, then 50 mg/kg in 100 mL of 0.9% saline over 4 hrs as a loading dose, and then a maintenance infusion of 50 mg/kg in 200 mL of 0.9% saline over each 24-hr period for a total of 72 hrs, or an equivalent volume of saline.Measurements and Main ResultsNuclear factor-&kgr;B activation was measured in mononuclear leukocytes using electrophoretic mobility shift assay, at baseline and 24, 48, 72, and 96 hrs later. Activation decreased significantly in patients treated withN-acetylcysteine (p= .016) but not placebo and was significantly reduced at 72 hrs compared with both preinfusion values (p= .028) and patients receiving placebo (p= .01). Plasma interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 concentrations were measured using enzyme immunoassay. Interleukin-6 concentrations were high initially and then decreased in all patients, regardless of whether they receivedN-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who receivedN-acetylcysteine (p= .0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients.ConclusionsAdministration ofN-acetylcysteine results in decreased nuclear factor-&kgr;B activation in patients with sepsis, associated with decreases in interleukin-8 but not interleukin-6 or soluble intercellular adhesion molecule-1. These pilot data suggest that antioxidant therapy withN-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.