Effects of levosimendan in normodynamic endotoxaemia: a controlled experimental study.
OBJECTIVE
Levosimendan is an inotropic and vasodilator drug that has proved to be useful in cardiogenic shock. Pretreatment with levosimendan in experimental hypodynamic septic shock in pigs has shown valuable effects in oxygen transport. Our goal was to assess the effects of levosimendan in a normodynamic model of endotoxaemia.


METHODS
Twelve sheep were anaesthetized and mechanically ventilated. After taking basal haemodynamic and oxygen transport measurements, sheep were assigned to two groups during 120 min: (1) endotoxin (5 microg/kg endotoxin); (2) levosimendan (5 microg/kg endotoxin plus levosimendan 200 microg/kg followed by 200 microg/kg/h). Both groups received hydration of 20 ml/kg/h of saline solution.


RESULTS
In the endotoxin group, cardiac output, intestinal blood flow and systemic and intestinal oxygen transports and consumptions (DO(2) and VO(2)) remained unchanged. In the levosimendan group, systemic and intestinal DO(2) were significantly higher than in the endotoxin group. Because stroke volume did not change (basal versus 120': 0.9+/-0.1 ml/kg versus 0.9+/-0.2 ml/kg, p=0.3749), the elevation in cardiac output by levosimendan (145+/-17 ml/min/kg versus 198+/-16 ml/min/kg, p=0.0096) was related to an increased heart rate (159+/-32 beats l/min versus 216+/-19 beats l/min, p=0.0037). Levosimendan precluded the development of gut intramucosal acidosis at 120' (endotoxin versus levosimendan, ileal intramucosal-arterial PCO(2) difference: 19+/-4 Torr versus 10+/-4 Torr, p=0.0025). However, levosimendan decreased mean arterial blood pressure (99+/-20 Torr versus 63+/-13 Torr, p=0.0235) and increased blood lactate levels (2.4+/-0.9 mmol/l versus 4.8+/-1.5 mmol/l, p=0.0479). All p-values are differences in specific points (paired or unpaired t-test with Bonferroni correction) after two-way repeated measures ANOVA. A p-value<0.05 was considered significant.


CONCLUSIONS
Levosimendan improved oxygen transport and prevented the development of intramucosal acidosis in this experimental model of endotoxaemia. However, systemic hypotension and lactic acidosis occurred. Additional studies are needed to show if different doses and timing of levosimendan administration in septic shock might improve gut perfusion without adverse effects.
Dubin
Arnaldo
A
Cátedra de Farmacología, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 42 No. 577, 1900 La Plata, Argentina. arnaldodubin@speedy.com.ar
Maskin
Bernardo
B
Murias
Gastón
G
Pozo
Mario Omar
MO
Sottile
Juan Pablo
JP
Barán
Marcelo
M
Edul
Vanina Siham Kanoore
VS
Canales
Héctor Saúl
HS
Estenssoro
Elisa
E
D000138:Acidosis / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D006835:Hydrazones / Q000494:pharmacology* / Q000627:therapeutic use; D007413:Intestinal Mucosa / Q000098:blood supply / Q000378:metabolism; D019344:Lactic Acid / Q000097:blood; D010100:Oxygen / Q000097:blood* / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D012756:Sheep; D000077464:Simendan; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
D006835:Hydrazones; D011724:Pyridazines; D014665:Vasodilator Agents; D019344:Lactic Acid; D000077464:Simendan; D010100:Oxygen