of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model. J Appl Physiol 97: 1349 -1357, 2004. First published May 28, 2004 10.1152 10. /japplphysiol.01161.2003 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 ϭ 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 ϭ 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 Ϯ SE), dependent on whether control mortality rates were greater or less than the median (66%) (ϩ0.19 Ϯ 0.12 vs. Ϫ0.25 Ϯ 0.10, P ϭ 0.01). In a subset of animals examined (n ϭ 152) at 9 h after E. coli challenge, M40401 increased (mean effect Ϯ SE compared with control) mean arterial blood pressure (8 Ϯ 5 mmHg) and decreased platelets (Ϫ37 Ϯ 22 cells ϫ 10 3 /ml) with high-control mortality rates but had opposing effects on each parameter (Ϫ3 Ϯ 3 mmHg and 28 Ϯ 19 cells ϫ 10 3 /ml, respectively) with low rates (P Յ 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 Ͼ66%. However, across experiments from published studies, these agents were less beneficial as control mortality rate decreased (P ϭ 0.03) in a relationship not altered (P ϭ not significant) by other variables associated with septic challenge or regimen of treatment and which was similar, compared with experiments with M40401 (P ϭ 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. septic shock; treatments; superoxide dismutase mimetic; M40401

In an experimental model of LV acute ischemia of limited duration, the main independent predictors of PV systolic anterograde flow velocities are LA relaxation and compliance (LA peak v pressure) and LV systole--all vis a fronte factors. In the setting of mildly increased LA pressures, PV systolic flow (LA reservoir filling) is an independent predictor of PV early diastolic flow (LA early conduit).

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