Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model.
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.
Cui
Xizhong
X
Critical Care Medicine Dept., National Institutes of Health, Bldg. 10, Rm. 7D43, Bethesda, MD 20892, USA. cxizhong@mail.cc.nih.gov
Parent
Chantal
C
Macarthur
Heather
H
Ochs
Scott D
SD
Gerstenberg
Eric
E
Solomon
Steve
S
Fitz
Yvonne
Y
Danner
Robert L
RL
Banks
Steven M
SM
Natanson
Charles
C
Salvemini
Daniela
D
Eichacker
Peter Q
PQ
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
C426066:M40401; D009942:Organometallic Compounds; D013481:Superoxides; D013482:Superoxide Dismutase