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British Journal of Anaesthesia 102 (2): 198–204 (2009)
doi:10.1093/bja/aen367
Levosimendan pre-treatment improves outcomes in patients
undergoing coronary artery bypass graft surgery†
L. Tritapepe1‡, V. De Santis1*, D. Vitale1, F. Guarracino2‡, F. Pellegrini3,
P. Pietropaoli1 and M. Singer4‡
1
Department of Anesthesiology and Intensive Care, ‘Sapienza’ University of Rome, Rome, Italy.
Cardiothoracic Department, Cardiothoracic Anesthesia and Intensive Care Unit, University Hospital of
Pisa, Pisa, Italy. 3Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud,
Santa Maria Imbaro, Chieti, Italy. 4Bloomsbury Institute of Intensive Care Medicine, University College
London, London, UK
2
*Corresponding author. E-mail: [email protected]
Background. The calcium sensitizer levosimendan has anti-ischaemic effects mediated via the
opening of sarcolemmal and mitochondrial ATP-sensitive potassium channels. These properties
suggest potential application in clinical situations where cardioprotection would be beneficial,
such as cardiac surgery. We thus decided to investigate whether pharmacological pre-treatment
with levosimendan reduces intensive care unit (ICU) length of stay in patients undergoing elective myocardial revascularization under cardiopulmonary bypass.
Methods. One hundred and six patients undergoing elective coronary artery bypass grafting
were randomly assigned in a double-blind manner to receive levosimendan or placebo.
Levosimendan (24 mg kg21) or placebo was administered as a slow i.v. bolus over a 10 min
period before the initiation of bypass.
Results. Tracheal intubation time and the length of ICU stay were significantly reduced in the
levosimendan group (P,0.01). The number of patients needing inotropic support for .12 h
was significantly higher in the control group (18.0% vs 3.8%; P¼0.021). Compared with control
patients, levosimendan-treated patients had lower postoperative troponin I concentrations
(P,0.0001) and a higher cardiac power index (P,0.0001).
Conclusions. Pre-treatment with levosimendan in patients undergoing surgical myocardial
revascularization resulted in less myocardial injury, a reduction in tracheal intubation time, less
requirement for inotropic support, and a shorter length of ICU stay.
Br J Anaesth 2009; 102: 198–204
Keywords: heart, coronary artery bypass; heart, inotropism; heart, ischaemia; surgery,
cardiovascular
Accepted for publication: November 18, 2008
The myocardium has to endure periods of ischaemia and
reperfusion during coronary artery bypass grafting
(CABG) surgery. Despite some degree of ischaemic protection afforded by cardioplegia, which establishes electromechanical arrest and reduces myocardial oxygen
consumption, myocardial contractile dysfunction is a frequent complication. This often necessitates inotropic and
mechanical circulatory support and is associated with an
increase in morbidity and mortality.1 2
Levosimendan is a cardiovascular drug licensed for the
treatment of acute decompensated heart failure.3 It has
positive inotropic4 and anti-stunning effects mediated by
calcium sensitization of contractile proteins;5 in addition,
it has vasodilatory6 and anti-ischaemic effects mediated by
the opening of ATP-sensitive potassium (KATP) channels.7
The KATP channel is an important mediator or end-effector
of cardioprotection, thus, levosimendan may offer a
beneficial approach in situations of myocardial stress.
†
Trial registration: clinicaltrials.gov identifier: nCT00610350.
Declaration of interest. L.T., F.G., and M.S. have sat on advisory
boards for levosimendan on behalf of Orion, the manufacturer, and
Abbott, the distributor. They have also received honoraria for
chairing/speaking at satellite symposia.
‡
# The Board of Management and Trustees of the British Journal of Anaesthesia 2009. All rights reserved. For Permissions, please e-mail: [email protected]
Levosimendan pre-treatment in patients undergoing CABG
In clinical studies to date, levosimendan has improved
cardiac performance in left ventricular failure8 – 10 and in
myocardial stunning after percutaneous coronary intervention.11 In a randomized, placebo-controlled study of 24
patients undergoing CABG, we demonstrated lower postoperative troponin I concentrations (P,0.05) and a higher
cardiac index in those randomized to receive a short duration infusion of levosimendan before the initiation of cardiopulmonary bypass (CPB).12 This pilot study
encouraged us to see whether this improvement in postoperative cardiac function would translate into clinical
outcome benefit and a consequently shorter postoperative
length of stay on the intensive care unit (ICU).
Methods
Between January 2005 and February 2007, we recruited
adult patients with coronary artery disease undergoing elective CABG surgery into our double-blind, single-centre, prospective, randomized, placebo-controlled trial. The study
was approved by the local research ethics committee, and all
patients provided written informed consent. Inclusion criteria were age 18 yr and an intention to perform first-time
multi-vessel CABG. Exclusion criteria were unstable
angina, valvular disease, diabetes mellitus treated with
sulphfonylurea drugs, renal failure (plasma creatinine.130
mmol litre21), severe hepatic disease (alanine aminotransferase or aspartate aminotransferase.100 IU litre21), severe
chronic obstructive pulmonary disease (forced expired
volume in 1 s ,50% of predicted or ,2.0 litre), a history of
prior CABG surgery or recent myocardial infarction (MI)
within the previous month. Randomization was achieved
with the use of computer-generated random numbers.
The study drug [levosimendan (Abbott Pharmaceuticals,
Abbott Park, IL, USA), 24 mg kg21] or an identicalappearing placebo prepared and labelled by the pharmacy
was administered as a slow i.v. 50 ml bolus through the
central venous port of a pulmonary artery catheter over the
10 min before the initiation of CPB. All patients and
medical and nursing staff members remained unaware of
study group assignments throughout the study period.
In the operating room, patients were connected to
routine monitoring, which included five-lead ECG, radial
and pulmonary artery catheters, pulse oximetry, and capnography. Anaesthesia was induced with a targetcontrolled infusion of propofol (site effect 1.6– 1.8 mg
mL21), sufentanil (0.35 – 0.5 mg kg21), and rocuronium
(0.6 mg kg21). After tracheal intubation, the lungs were
mechanically ventilated with an oxygen – air mixture (FIO2
40%). Anaesthesia was maintained with propofol (site
effect 1.6 – 2.2 mg mL21), sufentanil (0.35 mg kg21 h21),
and supplemental boluses of rocuronium. CPB was established with the cannulation of the right atrium and ascending aorta and mild hypothermia (328C). A retrograde
coronary sinus cannula was inserted transatrially for
cardioplegia infusions (cold-blood cardioplegia 6 – 88C).
The first cardioplegia infusion was given antegradely via
an aortic root cannula for 2 min, and then retrograde
cardioplegia was given for a further 2 min. The potassium
concentration of the induction cardioplegia was 20 mmol
litre21. After each distal anastomosis, additional cardioplegic solution was delivered for 1 min. Warm-blood retrograde cardioplegia was administered at the end of
cross-clamping. A standard coronary artery bypass operation was undertaken using one internal thoracic artery,
and one to three peripheral vein grafts obtained from the
lower limbs. After rewarming with a 378C maximal
heat-exchanger temperature, CPB was discontinued at 36–
378C nasopharyngeal temperature. Intraoperative ventricular tachyarrhythmias were treated with internal cardioversion or lidocaine (1– 1.5 mg kg21). Reversal of heparin
was achieved with protamine 1 mg per milligram of
heparin. Inotropic support, initially with dopamine (5– 10
mg kg21 min21) and secondly with epinephrine (0.02–
0.15 mg kg21 min21), was commenced if the mean arterial
pressure (MAP) was ,65 mm Hg with a cardiac index
(CI) 2 litre min21 m22 in the presence of a pulmonary
artery wedge pressure (PAWP) of 15 mm Hg and a heart
rate of 70– 110 beats min21. I.V. vasoconstrictors were
used for a MAP,65 mm Hg, a systemic vascular resistance (SVR) ,800 dyne s21 cm25, and a CI .3 litre
min21 m22. Bolus phenylephrine was used until the
administration of protamine, after which norepinephrine
infusion was used as the vasoconstrictor agent.
While in the ICU, patients were routinely sedated with a
continuous infusion of sufentanil 0.3 mg kg21 h21 and propofol 1.5 mg kg21 h21 until CI exceeded 2.2 litre min21
m22, no significant dysrhythmias were present, temperature
exceeded 368C, haemoglobin .8 g dl21 and no signs of
excessive bleeding (.150 ml h21) were present. The
patients were weaned from mechanical ventilation with
reduction in propofol when the following criteria were met:
temperature .368C, maintained haemodynamic stability,
chest tube drainage ,100 ml h21, and urine output 0.5 ml
kg21 h21. After 15 min, sufentanil was titrated down at 30
min intervals. The tracheal tube was removed when the following criteria were achieved: adequate response to
command, arterial oxygen saturation measured by pulse oximetry (SpO2) 95% at a fraction of inspired oxygen
(FIO2) 0.5, pH 7.3, arterial carbon dioxide tension
(PaO2) 6.7 kPa, and adequate respiratory effort.
Patients were eligible for transfer out of the ICU when
the following criteria were met: SpO2 90% at an FIO2 0.5
by facemask, adequate cardiac stability with no haemodynamically significant arrhythmia, chest tube drainage ,50
ml h21, urine output 0.5 ml kg21 h21, no i.v. inotropic
or vasopressor therapy, and no seizure activity. The criteria for eligibility for hospital discharge were haemodynamic and cardiac rhythm stability, the presence of
clean and dry incisions, no pyrexia, the ability to void and
move bowels and independent ambulation and feeding.
199
Tritapepe et al.
Haemodynamic data [MAP, PAWP, CI, cardiac power
index (CPI) and systemic vascular resistance normalized
for body surface area (SVRI)] were recorded just before
the start of surgery, on admission to the ICU, and at 6 and
24 h later. CPI is a novel haemodynamic measure, which
is the product of simultaneously measured CI and MAP.13
Cardiac output was measured using the bolus thermodilution method by injecting 10 ml cold saline at
end-expiration. Three measurements within 10% of each
other were averaged. Blood samples for cardiac troponin I
(cTnI) were drawn at baseline, on arrival in the ICU and
at 6, 24 and 48 h after operation. The limit of quantification of cTnI determination was 0.04 ng ml21. When
values below the detection limit were reported, zero was
used as the value. The coefficient of variation for this
assay is 15% for TnI values up to 0.08 ng ml21, 6% for
values between 0.47 and 1.44 ng ml21 and 5% for values
above 1.44 ng ml21. Standard 12-lead ECG recordings
were obtained before operation and on postoperative days
1 and 4.
The primary endpoint of the study was the length of
ICU stay. Secondary endpoints included the length of hospital stay, tracheal intubation time and reduction in inotropic support over the first 7 days. Additional postoperative
data specifically collected included number of deaths,
number of acute MIs, incidence of atrial fibrillation, any
type of adverse event, and serum creatinine concentrations.
The definition of acute MI was as follows: new Q-wave
or new persistent ST-segment or T-wave changes
accompanied by a creatine kinase MB isoenzyme
level .50 units litre21 and a creatine kinase-MB/creatine
kinase ratio .5% or a troponin I level .10 mg litre21.
A sample size of 100 subjects was estimated to provide
a 90% power (with a two-sided a¼0.05) to detect a
decrease of at least 11 h (i.e. 24 vs 35 h) in the median
ICU length of stay in the levosimendan arm. To account
for the skewed distribution of the primary endpoint,
sample size estimation was performed using nonparametric methods based on bootstrap simulation. A pilot
study data set,12 from which the ICU length of stay
empirical distribution had been estimated, was used for the
bootstrap resampling.14 One hundred and forty patients
were screened for eligibility, anticipating a 40% rate of
potential dropouts, either for non-willingness to participate
or lack of eligibility.
Patients’ baseline characteristics in treated and control
groups are reported as mean (SD), median (range), or frequencies and percentages. Differences were assessed using
x 2 or the Fisher exact test for categorical variables and the
Mann – Whitney U-test for continuous ones. Owing to the
non-normal distribution of ICU and hospital stay, the
Mann – Whitney U-test was also used to assess differences
in the main endpoints between the treatment group and
controls. As secondary outcomes, cTnI and haemodynamic
data (i.e. MAP, PAWP, CI, SVRI and CPI) were analysed
with a hierarchical linear model for repeated
measurements to assess differences over time between
treatment and control groups.15 16 An unstructured correlation type was used to account for unequally spaced time
occasions during follow-up. P-values ,0.05 were considered statistically significant. All analyses were performed using SAS Statistical Package Release 9.1 (SAS
Institute, Cary, NC, USA).
Results
One hundred and forty patients were assessed for eligibility, of whom 106 were randomly assigned to levosimendan (n¼53) or placebo (n¼53). One patient in the
levosimendan group and three in the placebo group were
withdrawn after randomization because their surgery was
cancelled (Fig. 1).
Preoperative patient characteristics are summarized in
Table 1. The ICU length of stay (time meeting
fit-for-discharge criteria) and duration of tracheal intubation were significantly lower in the levosimendan group
(P¼0.002 and P¼0.02, respectively), although the hospital
length of stay showed no difference between the groups
(Table 2). Troponin I increased transiently in both groups
(Fig. 2), but this increase was significantly lower in the
levosimendan group (treatment-by-time interaction
P,0.0001).
Haemodynamic data are presented in Figure 3. After
operation, there were significantly higher values of MAP,
CI and CPI (all treatment-by-time P,0.007) and a lower
SVRI (P¼0.005) in those treated with levosimendan. Four
patients in the levosimendan group developed hypotension,
which was successfully treated with phenylephrine.
In the first 7 days after surgery, 34% (17/50) of the
patients in the placebo group vs 17.3% (9/52) of the levosimendan patients (P¼0.053) received inotropic support
with dopamine 5 mg kg21 min21 (Table 2). The number
of patients requiring inotropic support for .12 h was significantly higher in the control group (18.0% vs 3.8%;
P¼0.02). The groups were similar with respect to frequency of atrial fibrillation, MI and postoperative serum
creatinine .130 mmol litre21, and mortality (Table 2).
Discussion
Variable degrees of postoperative myocardial stunning
occur after cardiac surgery, and these may result in transient myocardial dysfunction. Different cardioprotective
strategies have been tested to reduce myocardial injury
during cardiac surgery, including short-term preconditioning using ischaemia,17 volatile anaesthetic agents18 – 20 and
opiates.21 To our knowledge, the current study using a
short-term infusion of levosimendan before CPB in
patients undergoing first-time surgical myocardial revascularization is the first to demonstrate a reduction in the ICU
stay in addition to reduced tracheal intubation time and
inotropic support requirements.
200
Levosimendan pre-treatment in patients undergoing CABG
140 subjects
screened for eligibility
34 excluded
(20 refused to participate,
14 did not meet inclusion criteria)
106 randomized
53 assigned to
receive
placebo
53 assigned to
receive
levosimendan
1 withdrawn as
surgery was
cancelled
3 withdrawn as
surgery was
cancelled
52 received
levosimendan
50 received
placebo
Fig 1 Study flow diagram.
Table 1 Baseline characteristics. Data are reported as mean (range) for age,
mean (SD), median (range) or frequencies and percentages. P-values refer to
x 2 or the Fisher exact test for categorical variables and Mann –Whitney U-test
for continuous ones
Variable
Control
Treatment
n
Age, yr
Sex: male, n (%)
Body mass index, kg m22
EuroSCORE
Ejection fraction, %
Aortic cross-clamp time, min
CPB time, min
Number of bypasses
ACE-inhibitor, n (%)
b-Blockers, n (%)
Calcium channel blockers, n (%)
Antiarrhythmic drugs, n (%)
Diuretics, n (%)
Nitrates, n (%)
Platelet inhibitor therapy, n (%)
Statins, n (%)
50
66.5 (54.0 –87.0)
39 (78.0)
28.8 (2.3)
3.5 (1.0 – 7.0)
44.1 (9.8)
53.6 (7.1)
83.2 (12.4)
3.0 (2.0 – 4.0)
20 (40.0)
40 (80.0)
17 (34.0)
5 (10.0)
10 (20.0)
18 (36.0)
24 (48.0)
39 (78)
52
64.0 (54.0 –86.0)
43 (82.7)
28.1 (2.5)
2.5 (1.0 – 7.0)
41.6 (10.7)
54.6 (6.7)
85.8 (10.2)
3.0 (2.0 – 4.0)
17 (32.7)
43 (82.7)
16 (30.8)
4 (7.7)
9 (17.3)
16 (31.4)
26 (51.0)
41 (79)
Table 2 Postoperative results. Data are reported as mean (SD), or frequencies
and percentages. P-values refer to x 2 or the Fisher exact test for categorical
variables and Mann –Whitney U-test for continuous ones
Variable
Control
Treatment
P-value
n
Thirty-day mortality
MI, n
Atrial fibrillation, n (%)
Time on ventilator, h
Received inotropes, n (%)
Received inotropes .12 h, n (%)
Postoperative serum
creatinine .130 mmol litre21, n
(%)
ICU stay, h
Hospital stay, days
Re-admission to ICU, n (%)
Re-exploration for bleeding, n (%)
50
0
1
10 (20.0)
13.6 (4.5)
17 (34.0)
9 (18.0)
4 (8)
52
0
0
12 (23.1)
11.3 (2.5)
9 (17.3)
2 (3.8)
2 (3.8)
NS
0.5
0.7
0.02
0.053
0.02
0.4
32.7 (12.9)
12.0 (2.5)
1 (2.0)
1 (2.0)
24.8 (7.1)
11.1 (2.3)
0
1 (1.9)
0.002
0.09
0.5
0.9
P-value
0.2
0.6
0.07
0.1
0.2
0.4
0.3
0.2
0.4
0.7
0.7
0.7
0.7
0.6
0.8
0.9
A considerable body of experimental and clinical evidence indicates that levosimendan pre-treatment induces
protection against subsequent ischaemic stress through its
KATP channel-opening properties.22 The opening of mitochondrial KATP channel protects the heart against
ischaemia – reperfusion damage.23 The increased potassium
influx associated with mitochondrial KATP channel
opening is sufficient to protect/preserve mitochondrial
function, perhaps via the normalization of matrix and
intermembrane space volumes, in situations of distress
such as ischaemia or reperfusion.
Previous studies have demonstrated improved survival
with post hoc treatment with levosimendan after MI9 24
201
Tritapepe et al.
Troponin I (ng/ml)
6
Control
Control
Levosimendan
Levosimendan
Mean arterial pressure (mm Hg)
4
80
2
0
Baseline 0
76
72
6
24
48
68
h
Cardiac index (litre min–1 m–2)
Fig 2 Cardiac troponin I concentrations (mean and 95% confidence
intervals) in the levosimendan and placebo groups before surgery
(baseline), on arrival in the intensive care unit (0), and after 6, 24, and
48 h.
3.5
3.0
2.5
and in one of the two multi-centre studies of patients with
acute decompensation of chronic heart failure.25 26 To our
knowledge, this study is the first to confirm improved
cardiac function (haemodynamics, and inotropic requirements), reduced myocardial damage ( postoperative cTnI
concentrations) and outcome benefit (reduced ICU length
of stay) with the use of levosimendan pre-treatment.
Postoperative serum cTnI concentrations, indicative of
myocardial damage, have been shown to increase to some
extent in all patients undergoing cardiac surgery, even in
the absence of postoperative MI.27 This may be influenced
by the type of surgery,28 the choice of cardioplegic solution
and its mode of delivery.29 However, after accounting for
the complexity of the surgery and other potential confounding factors, cTnI levels at 24 h remain independent predictors of short, medium, and long-term outcome.30 An
increased cTnI (.13 ng/ml) in adults undergoing cardiac
surgery is associated with major postoperative complications31 with delayed extubation and a prolonged length of
ICU stay.32 On the basis of published literature, including
our previous pilot study findings,12 we predicted that
greater preservation of cardiac function immediately after
CPB would result in a better recovery after cardiac surgery.
Our results are indeed consistent with these findings. We
did not find any significant difference in 30 day mortality,
likely because of the low perioperative risk profile of the
patients enrolled. Further studies are required to determine
whether benefit can be achieved in high-risk patients.
Larger outcome effects may be achieved, though potentially, at the risk of more adverse events such as hypotension. We also did not perform any cost– benefit analysis
arising from a shorter ICU stay.
The duration of tracheal intubation in the current study
is comparable with what has been reported in other studies
that did not use fast-rack anaesthesia protocols. The length
of stay in our ICU and that in hospital are longer than
those reported by North American centres33 34 but reflect
typical practice in Italy and other countries,35 36 where
there is less economic pressure for earlier discharge.
2.0
1.5
Pulmonary artery wedge pressure (mm Hg)
16
14
12
10
Systemic vascular resistance index (dyne s–1 cm–5 m–2)
2100
2000
1900
1800
Cardiac power index (W m–2)
0.6
0.5
0.4
0.3
Baseline
0
6
24
h
Fig 3 Longitudinal assessment of arterial pressure, cardiac index, cardiac
power index, pulmonary artery wedge pressure and systemic vascular
resistance. Data shown as mean and 95% confidence intervals.
CPI is a relatively novel haemodynamic parameter,
which was the strongest haemodynamic correlate of
in-hospital mortality in patients admitted with cardiogenic
202
Levosimendan pre-treatment in patients undergoing CABG
shock.13 In our study, levosimendan treatment led to a
significant postoperative increase in both CI and CPI. The
increase in CPI indicates that increased myocardial contractility contributes to the increase in CI, rather than a
reduction in SVRI alone. Reported kinetics for levosimendan37 would exclude the haemodynamic benefit being
derived from its calcium-sensitizing effect. We thus feel
the observed effect is more likely to be related to a cardioprotective effect that persists after drug elimination. The
dosage used and the mode of administration in our study
would achieve neither a minimum effective concentration
of the drug nor appreciable amounts of its active metabolite, OR-1896.38 Kinetic models have not yet considered
the potential influences of hypothermia or CPB; however,
we feel this low dose of levosimendan (and its metabolite)
is very unlikely to exert any haemodynamic effect after
operation.
Owing to its KATP channel-opening properties, levosimendan will produce vasodilatation and, potentially, significant hypotension. In our study, we observed mild
hypotension (MAP,65 mm Hg) in four patients treated
with levosimendan during CPB. This was transient (,10
min) and easily managed by titrated doses of
phenylephrine.
In conclusion, short pre-treatment with levosimendan in
patients undergoing myocardial revascularization resulted
in a reduction of tracheal intubation time, decreased
requirement for inotropic support and thus a shorter duration of ICU stay. Further studies should investigate
patients undergoing high-risk cardiac surgery and procedures where myocardial stress is likely, for example
invasive aortic – iliac vascular surgery requiring vessel
cross-clamping.
Funding
This study was funded by an independent research grant
from the Department of Anesthesiology and Intensive
Care of the ‘Sapienza’ University of Rome.
References
1 Christakis GT, Fremes SE, Naylor CD, Chen E, Rao V, Goldman
BS. Impact of preoperative risk and perioperative morbidity on
ICU stay following coronary bypass surgery. Cardiovasc Surg 1996;
4: 29 –35
2 Loop FD, Higgins TL, Panda R, Pearce G, Estafanous FG.
Myocardial protection during cardiac operations. Decreased morbidity and lower cost with blood cardioplegia and coronary sinus
perfusion. J Thorac Cardiovasc Surg 1992; 104: 608 – 18
3 Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic
and clinical effects of levosimendan in patients with severe heart
failure. Study Investigators. Circulation 2000; 102: 2222 – 7
4 De Hert SG, Lorsomradee S, Cromheecke S, Van der Linden PJ.
The effects of levosimendan in cardiac surgery patients with poor
left ventricular function. Anesth Analg 2007; 104: 766 – 73
5 Toller WG, Stranz C. Levosimendan, a new inotropic and vasodilator agent. Anesthesiology 2006; 104: 556 – 69
6 Michaels AD, McKeown B, Kostal M, et al. Effects of intravenous
levosimendan on human coronary vasomotor regulation, left ventricular wall stress, and myocardial oxygen uptake. Circulation
2005; 111: 1504– 9
7 Du Toit EF, Muller CA, McCarthy J, Opie LH. Levosimendan:
effects of a calcium sensitizer on function and arrhythmias and
cyclic nucleotide levels during ischemia/reperfusion in the
Langendorff-perfused guinea pig heart. J Pharmacol Exp Ther 1999;
290: 505 – 14
8 De Santis V, Vitale D, Tritapepe L, Greco C, Pietropaoli P. Use of
levosimendan for cardiogenic shock in a patient with the apical
ballooning syndrome. Ann Intern Med 2008; 149: 365– 7
9 Moiseyev VS, Põder P, Andrejevs N, et al. RUSSLAN Study
Investigators Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute
myocardial infarction. A randomized, placebo-controlled, doubleblind study (RUSSLAN). Eur Heart J 2002; 23: 1422 – 32
10 Russ MA, Prondzinsky R, Christoph A, et al. Hemodynamic
improvement following levosimendan treatment in patients with
acute myocardial infarction and cardiogenic shock. Crit Care Med
2007; 35: 2732– 9
11 Sonntag S, Sundberg S, Lehtonen LA, Kleber FX. The
calcium sensitizer levosimendan improves the function of
stunned myocardium after percutaneous transluminal coronary
angioplasty in acute myocardial ischemia. J Am Coll Cardiol 2004;
43: 2177 – 82
12 Tritapepe L, De Santis V, Vitale D, et al. Preconditioning effects of
levosimendan in coronary artery bypass grafting – a pilot study.
Br J Anaesth 2006; 96: 694– 700
13 Fincke R, Hochman JS, Lowe AM, et al. SHOCK Investigators
Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004; 44: 340 – 8
14 Walters SJ. Sample size and power estimation for studies with
health related quality of life outcomes: a comparison of four
methods using the SF-36. Health Qual Life Outcomes 2004; 2: 26
15 Singer JD, Willett JB. Applied Longitudinal Data Analysis: Modeling
Change and Event Occurrence. New York: Oxford University Press,
2003
16 Diggle PJ, Liang KY, Zeger SL. Analysis of Longitudinal Data.
Oxford: Oxford University Press, 1994
17 Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote
ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 2007; 370: 575 – 9
18 Piriou V, Mantz J, Goldfarb G, et al. Sevoflurane preconditioning
at 1 MAC only provides limited protection in patients undergoing
coronary artery bypass surgery: a randomized bi-centre trial. Br J
Anaesth 2007; 99: 624 – 31
19 Meco M, Cirri S, Gallazzi C, Magnani G, Cosseta D. Desflurane
preconditioning in coronary artery bypass graft surgery: a
double-blinded, randomised and placebo-controlled study. Eur J
Cardiothorac Surg 2007; 32: 319 – 25
20 Tritapepe L, Landoni G, Guarracino F, et al. Cardiac protection by
volatile anaesthetics: a multicentre randomized controlled study
in patients undergoing coronary artery bypass grafting with
cardiopulmonary bypass. Eur J Anaesthesiol 2007; 24: 323 – 31
21 Murphy GS, Szokol JW, Marymont JH, Avram MJ, Vender JS.
Opioids and cardioprotection: the impact of morphine and fentanyl on recovery of ventricular function after cardiopulmonary
bypass. J Cardiothorac Vasc Anesth 2006; 20: 493 – 502
203
Tritapepe et al.
22 Pollesello P, Papp Z. The cardioprotective effects of levosimendan: preclinical and clinical evidence. J Cardiovasc Pharmacol 2007;
50: 257 – 63
23 Garlid KD, Dos Santos P, Xie ZJ, Costa AD, Paucek P.
Mitochondrial potassium transport: the role of the mitochondrial
ATP-sensitive K(þ) channel in cardiac function and cardioprotection. Biochim Biophys Acta 2003; 1606: 1 – 21
24 Fuhrmann JT, Schmeisser A, Schulze MR, et al. Levosimendan is
superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction. Crit Care Med 2008; 36:
2257– 66
25 Follath F, Cleland JG, Just H, et al. Steering Committee and
Investigators of the Levosimendan Infusion versus Dobutamine
(LIDO) Study Efficacy and safety of intravenous levosimendan
compared with dobutamine in severe low-output heart failure
(the LIDO study): a randomized double-blind trial. Lancet 2002;
360: 196– 202
26 Mebazaa A, Nieminen MS, Packer M, et al. SURVIVE Investigators
Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA 2007;
297: 1883– 91
27 Jaffe AS, Ravkilde J, Roberts R, et al. It’s time for a change to a
troponin standard. Circulation 2000; 102: 1216– 20
28 Etievent JP, Chocron S, Toubin G, et al. Use of cardiac troponin I
as a marker of perioperative myocardial ischemia. Ann Thorac Surg
1995; 59: 1192 – 9
29 Chocron S, Alwan K, Toubin G, et al. Crystalloid cardioplegia
route of delivery and cardiac troponin I release. Ann Thorac Surg
1996; 62: 481 – 5
30 Croal BL, Hillis GS, Gibson PH, et al. Relationship between postoperative cardiac troponin I levels and outcome of cardiac
surgery. Circulation 2006; 114: 1468 – 75
31 Lasocki S, Provenchère S, Bénessiano J, et al. Cardiac troponin I
is an independent predictor of in-hospital death after adult
cardiac surgery. Anesthesiology 2002; 97: 405– 11
32 Fellahi JL, Gué X, Richomme X, Monier E, Guillou L, Riou B.
Short- and long-term prognostic value of postoperative cardiac
troponin I concentration in patients undergoing coronary artery
bypass grafting. Anesthesiology 2003; 99: 270 – 4
33 Howie MB, Cheng D, Newman MF, et al. A randomized doubleblinded multicenter comparison of remifentanil versus fentanyl
when combined with isoflurane/propofol for early extubation in
coronary artery bypass graft surgery. Anesth Analg 2001; 92:
1084– 93
34 Cheng DCH, Newman MF, Duke P, et al. The efficacy and
resource utilization of remifentanil and fentanyl in fast track coronary artery bypass graft surgery: a prospective randomized,
double-blinded controlled, multi-center trial. Anesth Analg 2001;
92: 1094 –102
35 Al-Ruzzeh S, George S, Bustami M, et al. Effect of off-pump coronary artery bypass surgery on clinical, angiographic, neurocognitive, and quality of life outcomes: randomised controlled trial. Br
Med J 2006; 332: 1365 – 72
36 Van der Linden PJ, De Hert SG, et al. Hydroxyethyl starch 130/
0.4 versus modified fluid gelatin for volume expansion in cardiac
surgery patients: the effects on perioperative bleeding and transfusion needs. Anesth Analg 2005; 101: 629 – 34
37 Lilleberg J, Sundberg S, Nieminen MS. Dose-range study of a new
calcium sensitizer, levosimendan, in patients with left ventricular
dysfunction. J Cardiovasc Pharmacol 1995; 26: S63– 9
38 Sundberg S, Antila S, Scheinin H, Hayha M, Virtanen M, Lehtonen
L. Integrated pharmacokinetics and pharmacodynamics of the
novel calcium sensitizer levosimendan as assessed by systolic
time intervals. Int J Clin Pharmacol Ther 1998; 36: 629 – 35
204