title: Low-dose endotoxin elicits variability in the inflammatory response in healthy volunteers.
abstract: Endotoxin has been implicated as a cause of sepsis, inflammation and organ dysfunction after surgery. Patients differ in their response to endotoxin, and this may account for differences in outcome. The traditional human model of endotoxin challenge (2-4 ng/kg) is not associated with significant inter-individual variability in systemic inflammation and may not be suitable for studying variability in the inflammatory response. We examined whether low-dose regimens of endotoxin cause significant variability in inflammation. Volunteers (n = 30) were randomised in a double-blinded ('double-dummy') study to one of 6 dosing regimens: saline (placebo) or Escherichia coli O:113 endotoxin as a 4 ng/kg bolus (positive control), 0.25 ng/kg (bolus), 0.25 ng/kg (30 min infusion), 0.75 ng/kg (bolus) or 0.75 ng/kg (30 min infusion). Temperature, white cell count, platelet count, C-reactive protein and cytokine changes from baseline were measured. In contrast to subjects receiving placebo, those randomised to 4 ng/kg endotoxin exhibited significant systemic inflammation during the 10-h observation period. The four low-dose regimens elicited variability in most markers of inflammation. We conclude that low-dose endotoxin elicits inter-individual variability in inflammation and could be used to test factors that may affect the human response to endotoxin.
authors.affiliation: Institute of Child Health, London, UK. r.stephens@ich.ucl.ac.uk
authors.forename: Robert C M
authors.initials: RC
authors.lastname: Stephens
authors.forename: Catherine M N
authors.initials: CM
authors.lastname: O'Malley
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Frumento
authors.forename: Michael G
authors.initials: MG
authors.lastname: Mythen
authors.forename: Elliott
authors.initials: E
authors.lastname: Bennett-Guerrero
mesh_terms: D000293:Adolescent; D000328:Adult; D002097:C-Reactive Protein / Q000032:analysis; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004731:Endotoxins / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology*; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D016032:Randomized Controlled Trials as Topic; D013696:Temperature; D013997:Time Factors
chemical_list: D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D002097:C-Reactive Protein