Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model

1 Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; 2 Department of Pharmacological and Physiological Science, St. Louis University School of Medicine, St. Louis 63104; and 3 Metaphore Pharmaceuticals, St. Louis, Missouri 63114 Submitted 28 October 2003 ; accepted in final form 21 May 2004 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 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 s