Laboratory Investigations
Levosimendan is superior to milrinone and dobutamine in
selectively increasing microvascular gastric mucosal oxygenation
in dogs*
Lothar A. Schwarte, MD; Olaf Picker, MD; Stefan R. Bornstein, MD; Artur Fournell, MD;
Thomas W. L. Scheeren, MD
A
dequate splanchnic oxygen-
ation, particularly of the gas-
trointestinal mucosa, is re-
garded crucial for the
prevention and therapy of critical illness
(1–3). However, splanchnic perfusion and
oxygenation are impaired early in the
course of reduced systemic oxygen trans-
port (4), so that therapeutic strategies to
improve regional oxygenation are
needed.
Levosimendan is a novel inotropic and
vasodilating agent (inodilator) (5–7) with
a unique hybrid mode of action: Levosi-
mendan acts as a myocardial calcium
sensitizer; that is, it amplifies systolic cal-
cium binding to the contractile myofila-
ment apparatus and thereby increases in-
otropy and cardiac output (8). In
addition, levosimendan stimulates vascu-
lar adenosine triphosphate (ATP)-sensi-
tive potassium channels (K
+
ATP
chan-
nels), causing vasodilation (9). Since
levosimendan may be used in conditions
that render the splanchnic region at risk
of hypoperfusion and hypoxia, it seems
important to study the impact of levosi-
mendan per se on splanchnic mucosal
oxygenation.
However, the effects of levosimen-
dan on gastrointestinal mucosal oxy-
genation are unknown and difficult to
predict: Levosimendan may increase
gastrointestinal perfusion and oxygen-
ation by both its inotropic and vasodi-
latory activity. On the other hand, un-
desired systemic hemodynamic side
effects of levosimendan, for example,
tachycardia and hypotension (5), may
evoke splanchnic (reflex)-vasoconstric-
tion and thus compromise gastrointes-
tinal mucosal oxygenation. Thus, the
net effect of levosimendan on microvas-
cular gastrointestinal mucosal oxygen-
ation is unpredictable. Moreover, it is
unclear whether the effects of levosi-
mendan are selective for the splanchnic
region or just mirror effects of levosi-
mendan on systemic hemodynamics.
*See also p. 246.
From the Departments of Anesthesiology (LAS, OP,
AF, TWLS) and Internal Medicine (SRB), University
Hospital of Düsseldorf, Germany.
Supported, in part, by a grant from the research
commission, Medical Faculty, University of Düsseldorf;
by departmental funds; and by Orion-Pharma, Espoo,
Finland, which provided Levosimendan (Simdax) with-
out restriction.
Dr. Bornstein is currently with the Department of
Medicine 3, University of Dresden, Germany. Dr.
Scheeren is currently with the Department of Anesthe-
siology and Intensive Care, University of Rostock, Ger-
many.
Copyright © 2005 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000150653.89451.6F
Objective: The effect of levosimendan, a novel inotropic vasodi-
lator (inodilator), on the microvascular gastric mucosal hemoglobin
oxygenation (HbO
2
) is unknown. A possible effect could thereby be
selective for the splanchnic region or could primarily reflect changes
in systemic oxygen transport (D
˙
O
2
) and/or oxygen consumption (V
˙
O
2
).
We compared systemic and regional effects of levosimendan with
those of established inotropes, milrinone and dobutamine.
Design: Laboratory experiment.
Setting: University animal research laboratory of experimental
anesthesiology.
Subjects: Chronically instrumented dogs with flow probes for
cardiac output measurement.
Interventions: Anesthetized, mechanically ventilated dogs
(each group n 6) on different days randomly received levosi-
mendan (10 g·kg
1
, followed by four infusion steps: 0.125–1.0
g·kg
1
·min
1
), milrinone (5.0 g·kg
1
, followed by 1.25–10
g·kg
1
·min
1
), or dobutamine (2.5–10.0 g·kg
1
·min
1
). Since
these drugs may modify regional or systemic responses to fluid
load, an additional predefined volume challenge was subse-
quently performed with hydroxyethyl starch 6% (10 mL·kg
1
).
Measurements and Main Results: We measured HbO
2
(reflec-
tance spectrophotometry), D
˙
O
2
,V
˙
O
2
, and systemic hemodynamics.
Levosimendan significantly increased HbO
2
from baseline
(55% for all groups) to 64 4% and further to 69 2% with
volume challenge (mean SEM). At the systemic level, levosimen-
dan alone only slightly increased D
˙
O
2
at a stable V
˙
O
2
. Milrinone
elicited similar systemic effects (D
˙
O
2
,V
˙
O
2
, hemodynamics) but
failed to increase HbO
2
. Dobutamine, conversely, increased
HbO
2
to a similar extent as levosimendan; however, this was
accompanied by marked increases in D
˙
O
2
and V
˙
O
2
. The gastric
mucosa selectivity of these interventions, expressed as slope of
the HbO
2
/D
˙
O
2
relation, was highest for levosimendan (1.89 and
1.14, without and with volume challenge), compared with mil-
rinone (0.45 and 0.47) and dobutamine (0.48 and 0.33).
Conclusions: Levosimendan is superior to milrinone (no sig-
nificant regional effects) and dobutamine (marked systemic ef-
fects) in increasing gastric mucosal oxygenation selectively (i.e.,
at only moderately increased D
˙
O
2
and stable V
˙
O
2
). If our experi-
mental data apply to the clinical setting, levosimendan may serve
as an option to selectively increase gastrointestinal mucosa ox-
ygenation in patients at risk to develop splanchnic ischemia. (Crit
Care Med 2005; 33:135–142)
135 Crit Care Med 2005 Vol. 33, No. 1