The effect of N-acetylcysteine on nuclear factor-kappa B activation, interleukin-6, interleukin-8, and intercellular adhesion molecule-1 expression in patients with sepsis.
OBJECTIVE
Expression of inflammatory mediators is controlled in part at the transcriptional level via nuclear factor-kappa B. Inhibition of nuclear factor-kappa B activation may be beneficial in critically ill patients. N-acetylcysteine is an antioxidant that inhibits nuclear factor-kappa B activation in vitro. In this pilot study we investigated the effect of N-acetylcysteine on nuclear factor-kappa B activation and circulating cytokine and adhesion molecules in patients with sepsis.


METHODS
Prospective, randomized, double blind, placebo-controlled pilot trial.


METHODS
Eight-bed intensive care unit in a university teaching hospital.


METHODS
Twenty consecutive patients within 12 hrs of fulfilling the consensus criteria for sepsis.


METHODS
A bolus of 150 mg/kg N-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.


RESULTS
Nuclear factor-kappa 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 with N-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 received N-acetylcysteine or placebo. Interleukin-8 decreased significantly only in those who received N-acetylcysteine (p =.0081). Soluble intercellular adhesion molecule-1 concentrations remained unchanged in all patients.


CONCLUSIONS
Administration of N-acetylcysteine results in decreased nuclear factor-kappa 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 with N-acetylcysteine may be useful in blunting the inflammatory response to sepsis. Further studies are warranted.
Paterson
Ross L
RL
Academic Unit of Anaesthesia & Intensive Care, University of Aberdeen, Scotland, UK.
Galley
Helen F
HF
Webster
Nigel R
NR
D000111:Acetylcysteine / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D005260:Female; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood* / Q000187:drug effects; D015850:Interleukin-6 / Q000097:blood*; D016209:Interleukin-8 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000097:blood* / Q000187:drug effects; D018805:Sepsis / Q000097:blood / Q000188:drug therapy*
D016166:Free Radical Scavengers; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D000111:Acetylcysteine