Effects of intravenous and inhaled levosimendan in severe rodent sepsis.
OBJECTIVE
We aimed at comparing the effects of intravenous (i.v.) and inhaled (inh.) levosimendan (LEVO) on survival, inflammatory cytokines and the apoptotic mediator caspase-3 in a rat model of severe sepsis induced by cecal ligation and incision (CLI).


METHODS
Twenty-eight anesthetized/ventilated male Sprague-Dawley rats (body weight 528 +/- 20 g) underwent laparotomy. Cecal mobilisation served as control (SHAM, n = 7). In all other groups, severe sepsis was induced by CLI. No further intervention occurred in the CLI-group (n = 7). 180 min after CLI, 24 microg/kg i.v. LEVO was administered in the CLI + LEVO-IV-group (n = 7), and 24 microg/kg inh. LEVO was administered via jet nebulizer in the CLI + LEVO-INH-group (n = 7).


RESULTS
CLI induced arterial hypotension, with i.v. and inh. LEVO attenuating blood pressure decrease over 390 min [CLI 34(31/50), CLI + LEVO-IV 82(69/131)*, CLI + LEVO-INH 78(62/85)* mmHg; median(25/75% quartile), *P < 0.05]. CLI induced metabolic acidosis. I.v. and inh. LEVO avoided arterial pH [CLI 7.18(7.16/7.2), CLI + LEVO-IV 7.27(7.24/7.31)*, CLI + LEVO-INH 7.26(7.24/7.28)*] and base excess deterioration [CLI -19(-21.8/-17.9), CLI + LEVO-IV -13(-14.8/-12)*, CLI + LEVO-INH -12.7(-14/-12.2)* mmol/l]. Overall mortality in the CLI-group was 57% compared to 0%* in both LEVO-treated groups after 390 min. LEVO administration significantly attenuated the increase in proinflammatory interleukin (IL)-1beta [CLI 896(739/911), CLI + LEVO-IV 302(230/385)*, CLI + LEVO-INH 346(271/548) pg/ml] and IL-6 [CLI 35651(31413/35816), CLI + LEVO-IV 21156(18397/28026), CLI + LEVO-INH 13674(10105/24843) pg/ml] in the plasma and reduced cleaved caspase-3 expression in the spleen.


CONCLUSIONS
In a rat model of severe sepsis induced by CLI, i.v. and inh. LEVO equally attenuated arterial hypotension, metabolic acidosis and prolonged survival. Moreover, i.v. and inh. LEVO inhibited proinflammatory mediator release and reduced splenic caspase-3 expression.
Hospital of the Johann Wolfgang Goethe-University, Frankfurt/Main, Germany. pscheiermann@gmail.com
Patrick
P
Scheiermann
Devan
D
Ahluwalia
Sandra
S
Hoegl
Andrea
A
Dolfen
Marc
M
Revermann
Bernhard
B
Zwissler
Heiko
H
Muhl
Kim A
KA
Boost
Christian
C
Hofstetter
D000280:Administration, Inhalation; D000818:Animals; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D023421:Models, Animal; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012377:Rodentia; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D012720:Severity of Illness Index; D000077464:Simendan; D016019:Survival Analysis; D016896:Treatment Outcome
D006835:Hydrazones; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D000077464:Simendan