title: Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model.
abstract: Previous analysis showed that selective inhibitors of five different host inflammatory mediators administered for sepsis, although beneficial with severe sepsis and high-control mortality rates, were ineffective or harmful with less severe sepsis. We hypothesized that severity of sepsis would also influence inhibition of superoxide anion, another inflammatory mediator. To test this, 6-h infusions of M40401, a selective SOD mimetic, or placebo were given to antibiotic-treated rats (n=547) starting 3 h after challenge with differing doses of intravenous Escherichia coli designed to produce low- or high-control mortality rates. There was a positive and significant (P=0.0008) relationship between the efficacy of M40401 on survival rate and control mortality rates. M40401 increased or decreased the log (odds ratio of survival) (means +/- SE), dependent on whether control mortality rates were greater or less than the median (66%) (+0.19 +/- 0.12 vs. -0.25 +/- 0.10, P=0.01). In a subset of animals examined (n=152) at 9 h after E. coli challenge, M40401 increased (mean effect +/- SE compared with control) mean arterial blood pressure (8 +/- 5 mmHg) and decreased platelets (-37 +/- 22 cells x 10(3)/ml) with high-control mortality rates but had opposing effects on each parameter (-3 +/- 3 mmHg and 28 +/- 19 cells x 10(3)/ml, respectively) with low rates (P < or = 0.05 for the differing effects of M40401 on each parameter with high- vs. low-control mortality rates). A metaregression analysis of published preclinical sepsis studies testing SOD preparations and SOD mimetics showed that most (16 of 18) had control mortality rates >66%. However, across experiments from published studies, these agents were less beneficial as control mortality rate decreased (P=0.03) in a relationship not altered (P=not significant) by other variables associated with septic challenge or regimen of treatment and which was similar, compared with experiments with M40401 (P=not significant). Thus, in these preclinical sepsis models, possibly related to divergent effects on vascular function, inhibition of superoxide anion improved survival with more severe sepsis and high-control mortality rates but was less effective or harmful with less severe sepsis. Extrapolated clinically, inhibition of superoxide anion may be most efficacious in septic patients with severe sepsis and a high risk of death.
authors.affiliation: Critical Care Medicine Dept., National Institutes of Health, Bldg. 10, Rm. 7D43, Bethesda, MD 20892, USA. cxizhong@mail.cc.nih.gov
authors.forename: Xizhong
authors.initials: X
authors.lastname: Cui
authors.forename: Chantal
authors.initials: C
authors.lastname: Parent
authors.forename: Heather
authors.initials: H
authors.lastname: Macarthur
authors.forename: Scott D
authors.initials: SD
authors.lastname: Ochs
authors.forename: Eric
authors.initials: E
authors.lastname: Gerstenberg
authors.forename: Steve
authors.initials: S
authors.lastname: Solomon
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Fitz
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
authors.forename: Steven M
authors.initials: SM
authors.lastname: Banks
authors.forename: Charles
authors.initials: C
authors.lastname: Natanson
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.forename: Peter Q
authors.initials: PQ
authors.lastname: Eichacker
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000145:classification / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy*; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D009942:Organometallic Compounds / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000145:classification / Q000175:diagnosis* / Q000188:drug therapy* / Q000209:etiology; D012720:Severity of Illness Index; D013482:Superoxide Dismutase / Q000008:administration & dosage; D013481:Superoxides / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: C426066:M40401; D009942:Organometallic Compounds; D013481:Superoxides; D013482:Superoxide Dismutase