Risk of death does not alter the efficacy of hydrocortisone therapy in a mouse E. coli pneumonia model: risk and corticosteroids in sepsis.
BACKGROUND
Risk of death may influence the efficacy of anti-inflammatory agents in sepsis. "Physiologic" dose corticosteroids, while improving survival in earlier trials with higher control mortality rates (>50%), were not beneficial in the recent CORTICUS trial with lower control mortality (31%). We investigated whether risk of death altered the effects of hydrocortisone in a mouse pneumonia model.


METHODS
Mice (n=637) challenged with high, medium or low intratracheal E. coli doses were randomized to receive one of three hydrocortisone doses (5, 25 or 125 mg/kg) or normal saline (NS) only (control) for 4 days. All animals were treated with similar volumes of ceftriaxone and NS support following E. coli and were observed for 168 h.


RESULTS
Decreasing E. coli doses reduced control mortality rates (from 94 to 12%). In similar patterns (not significant) each hydrocortisone dose increased the odds ratio (OR) of survival (95% confidence interval) with each E. coli dose (ORs ranging from 1.2 [0.4, 3.7] to 6.1 [0.6, 61.0]). The effect of hydrocortisone on the OR was not related to control mortality rate (r=-0.13, p=0.29) and overall was highly significant (2.04 [1.37, 3.03], p=0.0004). In randomly selected animals 48 h after the highest E. coli dose, compared with the control, hydrocortisone (125 mg/kg) significantly decreased IL-6, INFgamma, and nitric oxide levels.


CONCLUSIONS
In this mouse model the beneficial effects of hydrocortisone were independent of risk of death. These findings suggest that factors other than risk of death may underlie the differing effects of corticosteroids in recent sepsis trials.
Li
Yan
Y
Critical Care Medicine Department, Clinical Center, Building 10, Room 7D43, National Institutes of Health, Bethesda, MD 20892, USA.
Cui
Xizhong
X
Li
Xuemei
X
Solomon
Steven B
SB
Danner
Robert L
RL
Banks
Steven M
SM
Fitz
Yvonne
Y
Annane
Djillali
D
Natanson
Charles
C
Eichacker
Peter Q
PQ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016470:Bacteremia / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D002443:Ceftriaxone / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000254:growth & development; D006854:Hydrocortisone / Q000627:therapeutic use*; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000097:blood / Q000188:drug therapy*; D012720:Severity of Illness Index; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D002443:Ceftriaxone; D006854:Hydrocortisone