Levosimendan pre-treatment improves outcomes in patients
undergoing coronary artery bypass graft surgery
†L. Tritapepe
1‡, V. De Santis
1*, D. Vitale
1, F. Guarracino
2‡, F. Pellegrini
3,
P. Pietropaoli
1and M. Singer
4‡1
Department of Anesthesiology and Intensive Care, ‘Sapienza’ University of Rome, Rome, Italy.
2
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
*Corresponding author. E-mail: vincenzo.desantis@uniroma1.it
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 elec-tive 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 pro-tection afforded by cardioplegia, which establishes
electro-mechanical arrest and reduces myocardial oxygen
consumption, myocardial contractile dysfunction is a fre-quent 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 vasodilatory6and anti-ischaemic effects mediated by the opening of ATP-sensitive potassium (KATP) channels.7
The KATPchannel 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.
In clinical studies to date, levosimendan has improved cardiac performance in left ventricular failure8 – 10and in myocardial stunning after percutaneous coronary interven-tion.11 In a randomized, placebo-controlled study of 24 patients undergoing CABG, we demonstrated lower post-operative troponin I concentrations (P,0.05) and a higher cardiac index in those randomized to receive a short dur-ation infusion of levosimendan before the initidur-ation of
car-diopulmonary bypass (CPB).12 This pilot study
encouraged us to see whether this improvement in post-operative 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 elec-tive CABG surgery into our double-blind, single-centre, pro-spective, randomized, placebo-controlled trial. The study was approved by the local research ethics committee, and all patients provided written informed consent. Inclusion cri-teria were age18 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 aminotransfer-ase or aspartate aminotransferaminotransfer-ase.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
identical-appearing 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
cap-nography. Anaesthesia was induced with a
target-controlled 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 estab-lished with the cannulation of the right atrium and ascend-ing 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 cardiople-gic solution was delivered for 1 min. Warm-blood retro-grade cardioplegia was administered at the end of cross-clamping. A standard coronary artery bypass oper-ation 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 ventricu-lar tachyarrhythmias were treated with internal cardiover-sion 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 kg21min21), 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
resist-ance (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 kg21h21and pro-pofol 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 output0.5 ml kg21h21. After 15 min, sufentanil was titrated down at 30 min intervals. The tracheal tube was removed when the fol-lowing criteria were achieved: adequate response to command, arterial oxygen saturation measured by pulse
oxi-metry (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: SpO290% at an FIO20.5
by facemask, adequate cardiac stability with no haemody-namically significant arrhythmia, chest tube drainage ,50 ml h21, urine output0.5 ml kg21
h21, no i.v. inotropic or vasopressor therapy, and no seizure activity. The cri-teria for eligibility for hospital discharge were haemo-dynamic 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.
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
thermodilu-tion 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
quantifi-cation 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 ml21and 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 hos-pital stay, tracheal intubation time and reduction in inotro-pic 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
non-parametric 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
fre-quencies and percentages. Differences were assessed using x2or 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 corre-lation type was used to account for unequally spaced time occasions during follow-up. P-values ,0.05 were con-sidered statistically significant. All analyses were per-formed using SAS Statistical Package Release 9.1 (SAS Institute, Cary, NC, USA).
Results
One hundred and forty patients were assessed for eligi-bility, of whom 106 were randomly assigned to levosimen-dan (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 intuba-tion 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 levo-simendan 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 sig-nificantly higher in the control group (18.0% vs 3.8%; P¼0.02). The groups were similar with respect to fre-quency 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 transi-ent myocardial dysfunction. Differtransi-ent cardioprotective strategies have been tested to reduce myocardial injury during cardiac surgery, including short-term precondition-ing usprecondition-ing ischaemia,17 volatile anaesthetic agents18 – 20and opiates.21 To our knowledge, the current study using a short-term infusion of levosimendan before CPB in patients undergoing first-time surgical myocardial revascu-larization is the first to demonstrate a reduction in the ICU stay in addition to reduced tracheal intubation time and inotropic support requirements.
A considerable body of experimental and clinical evi-dence indicates that levosimendan pre-treatment induces protection against subsequent ischaemic stress through its KATP channel-opening properties.22 The opening of
mito-chondrial KATP channel protects the heart against
ischaemia – reperfusion damage.23The 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
140 subjects screened for eligibility
34 excluded (20 refused to participate, 14 did not meet inclusion criteria)
53 assigned to receive levosimendan 53 assigned to receive placebo 52 received levosimendan 50 received placebo 1 withdrawn as surgery was cancelled 3 withdrawn as surgery was cancelled 106 randomized
Fig 1 Study flow diagram.
Table 1Baseline characteristics. Data are reported as mean (range) for age, mean (SD), median (range) or frequencies and percentages. P-values refer to x2or the Fisher exact test for categorical variables and Mann – Whitney U-test
for continuous ones
Variable Control Treatment P-value
n 50 52
Age, yr 66.5 (54.0 – 87.0) 64.0 (54.0 – 86.0) 0.2 Sex: male, n (%) 39 (78.0) 43 (82.7) 0.6 Body mass index, kg m22 28.8 (2.3) 28.1 (2.5) 0.07 EuroSCORE 3.5 (1.0 – 7.0) 2.5 (1.0 – 7.0) 0.1 Ejection fraction, % 44.1 (9.8) 41.6 (10.7) 0.2 Aortic cross-clamp time, min 53.6 (7.1) 54.6 (6.7) 0.4 CPB time, min 83.2 (12.4) 85.8 (10.2) 0.3 Number of bypasses 3.0 (2.0 – 4.0) 3.0 (2.0 – 4.0) 0.2 ACE-inhibitor, n (%) 20 (40.0) 17 (32.7) 0.4 b-Blockers, n (%) 40 (80.0) 43 (82.7) 0.7 Calcium channel blockers, n (%) 17 (34.0) 16 (30.8) 0.7 Antiarrhythmic drugs, n (%) 5 (10.0) 4 (7.7) 0.7
Diuretics, n (%) 10 (20.0) 9 (17.3) 0.7
Nitrates, n (%) 18 (36.0) 16 (31.4) 0.6
Platelet inhibitor therapy, n (%) 24 (48.0) 26 (51.0) 0.8
Statins, n (%) 39 (78) 41 (79) 0.9
Table 2Postoperative results. Data are reported as mean (SD), or frequencies and percentages. P-values refer to x2or the Fisher exact test for categorical
variables and Mann – Whitney U-test for continuous ones
Variable Control Treatment P-value
n 50 52 Thirty-day mortality 0 0 NS MI, n 1 0 0.5 Atrial fibrillation, n (%) 10 (20.0) 12 (23.1) 0.7 Time on ventilator, h 13.6 (4.5) 11.3 (2.5) 0.02 Received inotropes, n (%) 17 (34.0) 9 (17.3) 0.053 Received inotropes .12 h, n (%) 9 (18.0) 2 (3.8) 0.02 Postoperative serum
creatinine .130 mmol litre21, n (%)
4 (8) 2 (3.8) 0.4
ICU stay, h 32.7 (12.9) 24.8 (7.1) 0.002
Hospital stay, days 12.0 (2.5) 11.1 (2.3) 0.09 Re-admission to ICU, n (%) 1 (2.0) 0 0.5 Re-exploration for bleeding, n (%) 1 (2.0) 1 (1.9) 0.9
and in one of the two multi-centre studies of patients with acute decompensation of chronic heart failure.25 26To our knowledge, this study is the first to confirm improved cardiac function (haemodynamics, and inotropic require-ments), 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.27This may be influenced by the type of surgery,28the choice of cardioplegic solution and its mode of delivery.29 However, after accounting for the complexity of the surgery and other potential confound-ing factors, cTnI levels at 24 h remain independent
predic-tors of short, medium, and long-term outcome.30 An
increased cTnI (.13 ng/ml) in adults undergoing cardiac surgery is associated with major postoperative compli-cations31with 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 poten-tially, at the risk of more adverse events such as hypoten-sion. 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.
CPI is a relatively novel haemodynamic parameter, which was the strongest haemodynamic correlate of in-hospital mortality in patients admitted with cardiogenic
68 72 76 80
Mean arterial pressure (mm Hg)
1.5 2.0 2.5 3.0 3.5
Cardiac index (litre min–1 m–2)
10 12 14 16
Pulmonary artery wedge pressure (mm Hg)
1800 1900 2000 2100
Systemic vascular resistance index (dyne s–1 cm–5 m–2)
0.3 0.4 0.5 0.6
Cardiac power index (Wm–2)
Control Levosimendan
0 6 24
h Baseline
Fig 3Longitudinal 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.
Troponin I (ng/ml) 0 6 24 48 h 0 2 4 6 Baseline Control Levosimendan
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.
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 con-tractility contributes to the increase in CI, rather than a reduction in SVRI alone. Reported kinetics for
levosimen-dan37 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 cardio-protective 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 metab-olite, 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,
levosi-mendan will produce vasodilatation and, potentially, sig-nificant 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 dur-ation of ICU stay. Further studies should investigate patients undergoing high-risk cardiac surgery and pro-cedures 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.
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