Effect of metformin on survival rate in experimental sepsis.
OBJECTIVE
Because "metformin-associated lactic acidosis" refers to metformin and concurrent pathologies as co-precipitating factors, the respective impact in the outcome of metformin therapy, metformin accumulation, and general diseases should be determined. We therefore constructed a model of sepsis in mice treated with metformin at a dose corresponding to clinical practice, or to accumulation.


METHODS
460 mice were separated in 3 groups: no metformin therapy, a 7-day metformin therapy at 50 mg.kg(-1).day(-1) (MET50) or 500 mg.kg(-1).day(-1) (MET500). Blood was drawn on day 7 in 40 metformin-treated animals for determining metformin concentrations. The 420 other mice were divided in 14 subgroups according to the amount of an intra-peritoneal inoculum of E. coli ranging from 5.103 to 1010 CFU/ml in order to construct a lethal dose curve. The survival rate was assessed at 7, 13, 24, 36, 60 and 120 hours thereafter.


RESULTS
Plasma metformin concentrations were 0.26 +/- 0.13 mg/l in MET50, and 4.63 +/- 1.92 mg/l in MET500. The comparative analysis of the survival rates at 120 hours showed no difference of mortality, always occurring for an inoculum amount > 10(8) CFU/ml. Comparing the survival rates from time 0 to 120 hours using Kaplan-Meyer curves and the Logrank test, there was no difference between the different groups.


CONCLUSIONS
Metformin, even at a dose mimicking accumulation, does not aggravate the mortality rate in this model of sepsis. Consequently, metformin can not be considered as toxic in such a condition.
Gras
V
V
Service de Pharmacologie Clinique, Hôpital Sud, Amiens.
Bouffandeau
B
B
Montravers
P H
PH
Lalau
J D
JD
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003643:Death; D004195:Disease Models, Animal; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008687:Metformin / Q000633:toxicity*; D051379:Mice; D018805:Sepsis / Q000097:blood*
D001786:Blood Glucose; D008687:Metformin