BJA Advance Access originally published online on April 4, 2006
British Journal of Anaesthesia 2006 96(6):694-700; doi:10.1093/bja/ael082
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Preconditioning effects of levosimendan in coronary artery bypass grafting—a pilot study
1 Department of Anesthesiology and Intensive Care, University of Rome ‘La Sapienza’ Rome, Italy
2 Department of Cellular Biotechnology and Haematology, University of Rome ‘La Sapienza’ Rome, Italy
3 Department of Experimental Medicine and Pathology, University of Rome ‘La Sapienza’ Rome, Italy
4 VOC di Biotecnologie Applicate alle Malattie Cardiovasculari, Department of the Heart and Great Vessels ‘Attilio Reale’, University of Rome ‘La Sapienza’ Rome, Italy
5 Bloomsbury Institute of Intensive Care Medicine, University College London London, UK
*Corresponding author: Via Clementina 11, 00184 Rome, Italy. E-mail: vincenzo.desantis{at}uniroma1.it
Accepted for publication March 7, 2006.
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Abstract |
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Background. The calcium sensitizer levosimendan protects against myocardial ischaemia and reperfusion injury in animal models.
Methods. The present pilot study investigated whether a short infusion before coronary artery bypass grafting (CABG) would protect the myocardium and improve postoperative haemodynamics. Twenty-four patients with stable angina undergoing elective CABG surgery were randomized to receive either placebo or levosimendan (24 µg kg–1) infused i.v. over a 10 min period just before placing the patient on cardiopulmonary bypass.
Results. Perioperative haemodynamic variables, concentrations of cardiac troponin I over the 48 h postoperative period, and clinical outcomes were assessed. There were no adverse effects related to levosimendan. Compared with control patients, levosimendan-treated patients had lower postoperative troponin I concentrations (P<0.05) and a higher cardiac index (P<0.05).
Conclusion. Patients receiving a short infusion of levosimendan before CABG showed evidence of less myocardial damage, suggestive of a preconditioning effect. Larger outcome studies are thus indicated to confirm benefit.
Keywords: anaesthesia, cardiac; complications, myocardial infarction; heart, ischaemia; heart, myocardial function; muscle cardiac, contractility
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Introduction |
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Levosimendan is a calcium sensitizer that enhances myocardial contractility and produces both coronary and peripheral vasodilatation. Its inotropic mechanism is based on calcium sensitization of myofilaments by binding to cardiac troponin C in a calcium-dependent manner.1 Its vasodilatory action is related to activation of ATP-sensitive (KATP) channels in myocytes.2 3 The KATP channel is an important mediator of cardioprotection and its role in ischaemic preconditioning has been demonstrated in animal studies.4 Levosimendan has also been shown to activate KATP channels in rat ventricular myocytes.5 In an ischaemia–reperfusion animal model, levosimendan reduced infarct size via activation of KATP channels.3 To our knowledge, no studies exist that have investigated levosimendan-induced perioperative cardioprotection in humans. If these reported cardioprotective effects of levosimendan in animals3 were relevant to patients, it should have beneficial effects on perioperative myocardial function and postoperative markers of myocardial tissue damage (cardiac troponin I).
To test this hypothesis, we undertook a pilot study in patients undergoing coronary artery bypass grafting (CABG) to assess the potential benefits of a short duration infusion of levosimendan before the initiation of cardiopulmonary bypass (CPB) on postoperative myocardial injury and performance.
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Methods |
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The study was approved by the Ethics Committee of the University of Rome ‘La Sapienza’. Patients with multiple-vessel coronary artery disease and stable angina undergoing elective coronary artery bypass graft surgery were enrolled after written informed consent had been obtained. Patients were consecutively randomized into placebo (n=12) and levosimendan (n=12) groups. Randomization was performed using computer-generated random numbers. Surgeons, perfusionists, research assistants and medical, and nursing staff in the intensive care unit (ICU) and on the ward were blinded to the group assignments.
Patients with unstable angina, valvular disease, diabetes mellitus treated with sulphonylurea drugs, renal failure (plasma creatinine >120 µmol litre–1), severe hepatic disease (alanine aminotransferase or aspartate aminotransferase >100 u litre–1), severe chronic obstructive pulmonary disease (forced expired volume in 1 s <50% of predicted or <2.0 litre), or those who having undergone prior CABG surgery or suffered recent myocardial infarction (<1 month) were deemed ineligible.
Study protocol
Levosimendan group patients received levosimendan 24 µg kg–1 as a slow i.v. bolus through the central venous port of a pulmonary artery catheter over the 10 min before initiation of CPB. Control patients received a placebo (0.9% sodium chloride) infusion of equivalent volume over the same time interval. If systolic blood pressure decreased by more than 20% compared with pre-infusion values, a 50 µg phenylephrine bolus was infused.
Anaesthesia and surgical technique
A radial arterial cannula and a pulmonary artery catheter were inserted before operation to enable continuous haemodynamic monitoring. Midazolam premedication (0.03 mg kg–1) was administered i.v. 10 min before induction of anaesthesia with a target-controlled infusion of propofol (site effect 1.6–1.8 µg ml–1), sufentanil (0.35–0.8 µg kg–1) and rocuronium (0.6 mg kg–1). After tracheal intubation, the lungs were mechanically ventilated with an oxygen–air mixture (
40%). Anaesthesia was maintained with propofol (site effect 1.6–2.2 µg ml–1), sufentanil (0.35 µg kg–1 h–1) and supplemental boluses of rocuronium. If the patient developed pre-bypass hypertension [mean arterial pressure (MAP) 
85 mm Hg], urapidil 25–50 mg was administered as an i.v. bolus. If MAP remained above 85 mm Hg, a glyceryl trinitrate infusion was started at 0.5 µg kg–1 min–1 and increased in 0.25 µg kg–1 min–1 increments until a mean pressure 
65 mm Hg was achieved. A standard coronary artery bypass operation was undertaken using one internal thoracic artery, and 1–3 peripheral vein grafts taken from the lower limbs. CPB was established with the cannulation of the right atrium and the ascending aorta, and mild hypothermia (32°C). A retrograde coronary sinus cannula was inserted transatrially for cardioplegia infusions (cold-blood cardioplegia 6–8°C). The first cardioplegia infusion was given antegradely for 2 min, and then retrograde cardioplegia was given for a further 2 min. The potassium concentration of the induction cardioplegia was 20 mmol litre–1. After each distal anastomosis, additional cardioplegic solution was delivered for 1 min. Warm-blood retrograde cardioplegia was administered at the end of cross-clamping. After weaning from CPB, dobutamine was administered if the cardiac index (CI) fell below 2.0 litre min–1m–2 with a pulmonary artery wedge pressure (PAWP) above 15 mm Hg and a mean arterial blood pressure below 65 mm Hg. Dobutamine was initiated as an i.v. infusion starting at 5 µg kg–1 min–1 and increasing in 1 µg kg–1 min–1 increments until haemodynamic targets were achieved (CI 2.3–2.5 litre min–1 m–2).
Haemodynamic monitoring
Haemodynamic monitoring consisted of heart rate, MAP, central venous pressure, PAWP and cardiac output measurements. Derived cardiovascular variables, namely CI and systemic vascular resistance index, were calculated using standard formulae. Output measurements were based on the bolus thermodilution technique using the mean of five consecutive 5 ml injectates of 5% glucose. Haemodynamic data were serially collected at the following time points: (i) at baseline, after induction of anaesthesia; (ii) 45 min after the end of CPB (end surgery); (iii) on admission to the ICU (postop 1); (iv) 6 h post-ICU admission (postop 6); and (v) 24 h after ICU admission (postop 24).
Standard 12-lead ECG recordings were obtained before operation, and at postoperative times end surgery, postop 6, postop 12 and postop 24. All ECGs were subsequently evaluated by an experienced cardiologist blinded to all other data. The axis, PQ, QRS, QT and RR intervals were determined on each recording. A new onset inverted T wave, ST segment depression, and/or elevation >0.2 mV in one or more leads was considered to be electrocardiographic evidence of myocardial ischaemia. For each recording, the cardiologist made a yes/no decision concerning myocardial ischaemia. Perioperative myocardial infarction was diagnosed by the presence of a new Q wave on a postoperative 12-lead ECG, according to the Minnesota Code criteria.6
Extubation and discharge protocols
While in the ICU, patients were routinely kept sedated with a continuous infusion of sufentanil 0.3 µg kg–1 h–1 and propofol 0.5 µg kg–1 h–1, until CI was above 2.2 litre min–1 m–2, no significant dysrhythmias were present, temperature exceeded 36°C, haemoglobin 8.0 g dl–1 and no signs of excessive bleeding (>150 ml h–1) were present. The extubation regimen was commenced with discontinuation of propofol when body temperature exceeded 36°C, haemodynamic stability was maintained, chest tube drainage was less than 100 ml h–1 and urine output exceeded 0.5 ml kg–1 h–1. Patients were extubated when they showed an adequate response to verbal commands, their arterial oxygen saturation measured by pulse oximetry (
) was 95%; with a fractional inspired oxygen () 0.5, arterial pH 7.3, carbon dioxide tension (
) was 50 mm Hg, and adequate, spontaneous respiratory efforts were being maintained.
Patients were eligible to transfer out of the ICU when the following criteria were met: 90% at an 0.5 by a facemask, adequate cardiovascular stability with no haemodynamically significant arrhythmia, chest tube drainage <50 ml h–1, urine output >0.5 ml kg–1 h–1, no i.v. inotropic or vasopressor therapy and no seizure activity.
Criteria for eligibility for hospital discharge were haemodynamic and rhythm stability, the presence of clean and dry wounds, apyrexia, the ability to void and open bowels, and independent ambulation and feeding.
Biological markers
Blood levels of troponin I (TnI), a biochemical marker of cardiomyocyte injury, were serially measured by an immunoassay technique (Dimension CCS; Dade Behring Limited, Walton Manor, UK). Blood samples were obtained from peripheral vessels after the induction of anaesthesia (baseline), on arrival in the ICU (postop 1), and at 6 h (postop 6), 24 h (postop 24) and 48 h (postop 48). The limit of quantification of cardiac TnI determination was 0.04 ng ml–1. 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 ml–1, 6% for values between 0.47 and 1.44 ng ml–1 and 5% for values above 1.44 ng ml–1.
Postoperative results
Total inotropic drug requirements during the first 72 h after operation, plus postoperative electrocardiographic changes, complications, time on a ventilator, length of intensive care and hospital stay (ICU and hospital LOS) were recorded.
Statistical analysis
Cumulative doses of anaesthetic agents, pre and postoperative data were compared using Fisher's exact test and unpaired t-test analysis where appropriate.
Data were analysed for normality with the Kolmogorov–Smirnov test. Because values of TnI and haemodynamic variables do not have a Gaussian distribution, data are expressed as median with 25 and 75% percentiles. To evaluate the differences in medians for each variable of interest between the two groups we used the Mann–Whitney non-parametric sum rank test. To evaluate the differences within one group we used the Friedman repeated-measures ANOVA on ranks followed by the Wilcoxon non-parametric sum rank test. Statistical significance was accepted at P-values below 0.05. Statistical analysis was performed using SPSS software package version 10 (SPSS, Chicago, IL, USA).
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Results |
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The patients' characteristics and perioperative data are presented in Table 1. Preoperative patient characteristics were similar for both groups. There were no significant inter-group differences with regard to age, gender, ejection fraction, preoperative medication, number of grafted vessels, CPB and cross-clamping times. There were no major complications in either group and all survived to hospital discharge. The cumulative doses of propofol and sufentanil did not significantly differ between the two groups (Table 2). One patient in the levosimendan group developed hypotension treated with phenylephrine, while one control patient suffered postoperative myocardial ischaemia. Treatment for pre-bypass hypertension was required for one patient of the control group. The incidence of atrial fibrillation and the need for pacing did not significantly differ between the two groups. No electrical cardioversion was needed after operation. Inotropic support was required for one of the levosimendan group and for three control patients. The dose of dobutamine used was 5 µg kg–1 min–1 except for one control patient who required 7 µg kg–1 min–1.
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Figure 1 illustrates the evolution of the cardiac TnI levels over the first 48 h after operation. TnI release was significantly lower in the levosimendan group than in controls, while the peak value recorded 6 h after surgery was also lower (postop 1: P=0.026; postop 6: P=0.005; postop 24: P=0.044; postop 48: P=0.006; Mann–Whitney non-parametric sum rank test).
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At the end of the operation and at postop 1, CI was decreased in the control group but not in the levosimendan group (Table 3). Levosimendan-treated patients had significantly higher postoperative values of CI compared with placebo group (end surgery: P=0.031; postop 1: P=0.005; postop 6: P=0.004; postop 24: P=0.013; Mann–Whitney non-parametric sum rank test) and compared with baseline (baseline–postop 1: P=0.012; baseline–postop 6: P=0.005; baseline–postop 24: P=0.002; Wilcoxon non-parametric sum rank test). The values of SVRI were significantly lower in the levosimendan group compared with baseline (baseline–end surgery: P=0.028; baseline–postop 1: P=0.041; baseline–postop 6: P=0.008; baseline–postop 24: P=0.012; Wilcoxon non-parametric sum rank test). No differences were seen between groups in duration of mechanical ventilation (P=0.22) ICU stay (P=0.09) or hospital stay (P=0.07) (Table 4).
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Discussion |
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This pilot study demonstrates that pharmacological preconditioning with a short duration infusion of levosimendan in cardiac surgical patients before commencing CPB appears to confer additional myocardial protection beyond that provided by cardioplegia alone, as manifested by a better haemodynamic recovery and lower postoperative TnI levels.
Preconditioning is classified into two distinct components: classic, early preconditioning and delayed or late preconditioning. Each has its own biological mechanism. Early cardioprotection is highly effective but relatively short-lived, whereas the delayed form of adaptation is manifested sub-acutely approximately 24 h following the preconditioning stimulus; its degree of protection is usually less than that achieved by early preconditioning, but its duration is considerably longer (72 h). Recent evidence suggests that in addition to enhanced tolerance to lethal ischaemic injury, delayed preconditioning confers protection against other end-points of ischaemia–reperfusion injury including ventricular arrhythmias7 and post-ischaemic myocardial dysfunction (stunning).8 9
The ATP-sensitive potassium (KATP) channel has been shown to be an important mediator and/or end-effector of cardioprotection. Its role in early and late preconditioning has been demonstrated in whole animals, isolated hearts and in cardiac myocytes. Although some data suggest a critical role for the sarcolemmal KATP channel,10 most evidence to date is consistent with mitochondrial rather than surface channels as being more important.11
Evidence derived from animal models3 12 13 demonstrates that levosimendan, through its KATP channel opening properties,14 can mimic ischaemic preconditioning, and improve cardiac function and cell viability. The above-mentioned animal models have the limitation of being a partial ischaemia–reperfusion model; thus, a protective anti-ischaemic effect related to a levosimendan-induced increase in coronary blood flow cannot be excluded. Moreover, in such studies, a major confounding factor is the acute recruitment of collateral vessels. Aortic cross-clamping performed during CABG induces a period of global ischaemia that excludes the recruitment of collateral vessels.
Ours is the first study, albeit preliminary, that has investigated levosimendan-induced myocardial protection in humans with ischaemic heart disease undergoing a major cardiac and circulatory insult. Cardiac TnI release is a recognized marker of myocardial damage.15 Some studies suggest that troponin could be an early marker of postoperative myocardial ischaemia and infarction in cardiac surgery;16 17 although, in this setting, the use of cardiac specific markers for diagnosis and quantitation of myocardial damage is still debated. In our study, TnI was lower in the levosimendan group, a finding consistent with a beneficial cardioprotective effect. In the control group TnI levels are, however, similar to those previously reported in patients classified as having minor myocardial damage after coronary bypass grafting.16 The peak value (6.3 ng ml–1) observed at 6 h after operation in our series is much lower than the cut-off value (13.4 ng ml–1) that could differentiate between patients with myocardial infarction or ischaemia.17 Nevertheless, even in the perioperative scenario of limited myocardial damage, levosimendan appeared to offer cardioprotection.
Myocardial stunning plays a pivotal role in postoperative myocardial dysfunction. It represents a prolonged post-ischaemic contractile dysfunction of myocardium salvaged by reperfusion.18 Studies have demonstrated contractile dysfunction over the first few hours after myocardial revascularization19 that generally resolves spontaneously over 24–48 h and is independent of preload and afterload.20 Our results do not reflect this phenomenon. The CI increased over time in both groups (control after postop 6), albeit more so in the levosimendan group. As preload and afterload indicators were almost identical between the two groups, the haemodynamic improvement brought about by levosimendan was mostly related to myocardial protection. There is a limitation in using CI to evaluate the benefit derived from preconditioning as this variable could be influenced by the patient's preload and afterload, and inotropic requirements.21 Three of the twelve control patients required inotropes as opposed to one patient in the levosimendan group. Reported kinetics for levosimendan22 would exclude the haemodynamic benefit being derived from its calcium-sensitizing effect. The dosage used and the mode of administration in our study would not achieve either a minimum effective concentration of the drug nor appreciable amounts of its active metabolite OR-1896.23 Kinetic models have not yet considered the potential influences of hypothermia or CPB; however, this low dose of levosimendan (or its metabolite) is very unlikely to exert any haemodynamic effect at 24 h.
This pilot study was designed to provide preliminary data to test the hypothesis that levosimendan has a preconditioning effect in patients. It was not fully blinded for logistical reasons; although the medical and nursing staff caring for the patients, and the research assistants collecting data were unaware of the randomization schedule. Our study provides no information on the dose-range of levosimendan relative to its cardioprotective effects. Previous studies suggest that a minimum duration of ischaemia is required to activate the endogenous preconditioning response,24 25 and that a certain threshold of stimulation has to be reached. Our study shows that a 24 µg kg–1 i.v. bolus of levosimendan may reach this preconditioning threshold. Further investigation is required to discover whether lower doses have the same efficacy in myocardial protection.
The general trend of reduced postoperative complications with levosimendan include a lower incidence of atrial fibrillation, less need for inotropic support, less time on the ventilator, and shorter ICU and hospital stays. Statistical significance was not achieved because of the small sample size, though this study was a hypothesis-generating pilot trial and not designed to assess outcome benefit, as has been reported with prolonged infusion of levosimendan in patients with decompensated heart failure.26 27 De Hert and colleagues28 demonstrated that the use of a cardioprotective halogenate-based anaesthetic regimen resulted in shorter intensive care and hospital length of stays. This seems to be related to better preservation of early postoperative myocardial function. Similar protective effects were obtained using sevoflurane in patients undergoing on-pump CABG.29 30 Garcia and colleagues29 found that preconditioning CABG patients may improve long-term cardiovascular outcomes, while Julier and colleagues30 also found improved renal function in a similar group of high-risk patients. The anaesthetic regimen and amounts used in our study were well-matched between levosimendan and control groups.
Baggish and colleagues31 showed a positive correlation between postoperative troponin T levels and intensive care length of stay. The beneficial trends seen in outcome variables and lower TnI concentrations recorded in our levosimendan-treated patients are in agreement with the aforementioned studies and could be used to adequately power future trials. A power analysis performed on the basis of this study suggests a sample size requirement of 96 patients (48 in each group) would be needed to detect a reduction in median ICU length of stay from 35 h in the control group to 24 h in the protocol group (
=0.05, power 0.9). This further trial is currently underway in our hospital.
In conclusion, this pilot study indicates that a short, 10 min infusion of levosimendan before commencing CPB, in patients with stable angina undergoing revascularization, results in improvements in haemodynamic performance and a reduction in TnI release. These data are consistent with a preconditioning effect in humans.
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Footnotes |
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Declaration of interest. M.S. has sat on advisory boards for levosimendan on behalf of Orion, the manufacturer, and Abbott, the distributor. He has also received honoraria for chairing/speaking at satellite symposia and for co-editing a website, failinghears.com, supported by an unrestricted educational grant from Abbott. 
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