Prompt coronary revascularization, which reduces ischaemic time in patients with acute coronary syndromes (ACSs), prevents cardiomyocyte apoptosis and improves long-term survival [1-3]. Coronary revascularization can be achieved by fibrinolysis, percutaneous coronary intervention or coronary artery bypass grafting (CABG). Emergency CABG should be considered in patients with ACS when percutaneous intervention has failed and pain and/or haemodynamic instability persist . In such high-risk CABG patients, cardioprotective strategies to prevent or attenuate apoptosis will improve short-term and long-term outcome. These strategies include intra-aortic balloon counterpulsation, assist devices, avoidance of catecholamine-induced cardiotoxicty and myocardial preconditioning . Activation of the mitochondrial adenosine triphosphate-dependent potassium (KATP) channels in cardiac myocytes is the main step in preconditioning and represents a potent cardioprotective mechanism .
Levosimendan is a calcium sensitizer with a dual mechanism of action. It exerts positive inotropic effects by prolonging the effective cross-bridging time. Levosimendan stabilizes the calcium-induced conformational change of troponin C by binding in a calcium-dependent manner to troponin C during systole only. It avoids an increase of intracardiomyocyte calcium [6,7]. Levosimendan is also a potent opener of KATP channels, thus exerting cardioprotective and vasodilating effects. It has been shown to reduce experimental infarct size and protect myocytes from apotosis [5,8,9]. Therefore, patients with ACS requiring inotropic support should benefit from treatment with levosimendan.
The primary objective of this matched pair analysis was to assess the influence of levosimendan in comparison to standard therapy on mortality and morbidity in patients with ACSs undergoing emergent CABG. A secondary aim was to study changes in haemodynamics.
Between January 2005 and December 2006, a total of 2587 patients underwent cardiac surgery at our institution. Immediate CABG was indicated in 96 patients (3.7%) with ACSs. In this subset, 27 patients were treated with levosimendan whereas 69 patients were not. A case-matched cohort drawn from these 69 patients was created according to age, EuroSCORE [10,11] and presence of cardiogenic shock. Of these 69 patients, 25 were matched to the 27 patients treated with levosimendan and were suitable for analysis in this report. Cardiogenic shock was defined as a continued state of hypotension, in the absence of hypovolaemia or arrhythmia, leading to hypoperfusion [12,13]. Systolic blood pressure (BP) was <90 mmHg for more than 30 min or drug and/or mechanical support was needed to maintain a systolic BP >90 mmHg [12,13].
Haemodynamic therapy was started in all these critically ill patients as soon as possible. The haemodynamic goals to be achieved were a cardiac index (CI) >2 L min−1 m−2 and a mean arterial pressure (MAP) >60 mmHg. When MAP decreased to less than 60 mmHg, and right and left ventricular filling pressures (central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP), respectively) were below 12 mmHg, hydroxyethyl starch (MW 130 000 D) was infused. Dobutamine, up to 10 μg kg−1 min−1, was the first-choice positive inotropic drug. If dobutamine failed to increase CI, epinephrine was administered. Norepinephrine was used to increase MAP, if MAP was <60 mmHg despite adequate CI. In patients additionally treated with levosimendan, the infusion of this drug was started as early as possible. A bolus of 6 μg kg−1 levosimendan was infused within 15 min, followed by a continuous infusion of 0.2 μg kg−1 min−1 . The infusion rate was halved to 0.1 μg kg−1 min−1 if MAP was <60 mmHg, while norepinephrine was infused at a rate >0.5 μg kg−1 min−1 and volume load was adequate. If hypotension persisted, levosimendan was stopped. A maximum dose of 12.5 mg of levosimendan was infused and the infusion was abruptly stopped. No repeated doses of levosimendan were given.
Haemodynamic monitoring consisted of a five-lead electrocardiogram, radial or femoral artery cannulation, and a thermodilution pulmonary artery catheter (Explorer 7.0, Baxter, Irvine, CA, USA) placed via the right internal jugular vein. Heart rate (HR), MAP, CVP, mean pulmonary artery pressure (MPAP) and PCWP were recorded. Cardiac output (CO) was determined as the mean of three values obtained by the thermodilution technique. CI, stroke volume (SV), systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were calculated from standard formulae. Cardiopulmonary bypass (CPB) was performed using mild hypothermia (core temperature 32.5-33.5°C), alphastat acid-base management and non-pulsatile flow (2.4 L min−1 m−2). MAP was adjusted to 50-80 mmHg using a vasopressor (norepinephrine) or vasodilator (nitroglycerin) as needed. The transfusion trigger was a haemoglobin level of <70 g L−1 during CPB and <95 g L−1 after CPB. An intra-aortic balloon pump (IABP) was inserted if the haemodynamic goals (CI <2 L min−1 m−2 and MAP >60 mmHg) were not achieved with adequate volume load, and with infusion of epinephrine <0.4 μg kg−1 min−1 and norepinephrine <0.5 μg kg−1 min−1.
After surgery, all patients were transferred to the ICU. Controlled mechanical ventilation was continued. FiO2 and ventilation patterns were adjusted to keep PaO2 between 10.5 and 16.0 kPa and PaCO2 between 5.0 and 6.0 kPa. The patients were extubated when no major blood loss occurred and haemodynamic and respiratory parameters had remained stable for at least 2 h. The time to extubation was documented. No fast-track procedures were performed in these high-risk patients. The patients were discharged from ICU when they had been haemodynamically stable without inotropic or vasopressor support, and could maintain a PaO2 >9.3 kPa with oxygen <4 L min−1 via face mask for more than 12 h. The times to discharge from ICU and from hospital were documented. Dialysis was initiated when serum creatinine increased >250 μmol L−1 or oliguria <600 mL 24 h−1 resulted in fluid retention.
Following the accumulation of data, statistical models were formed and analysed using MedCalc 4.30 statistical software (MedCalc Software, Mariakerke, Belgium). The χ2 test was used for categorical univariate tests, and stepwise logistic regression was used for multivariate analysis. The risk of death was plotted by the Kaplan-Meier technique; Cox's proportional-hazard model was used to assess the significance of any noted differences between the treatment groups. Haemodynamics were analysed using two-factorial analysis of variance (ANOVA) for repeated measurements. For significant findings, post hoct-tests were applied at the end-point of each measurement. In case of multiple comparisons, P-values were corrected according to Bonferroni. Fisher's exact test and non-paired t-tests were also used when appropriate. Results are expressed as mean ± SD unless otherwise indicated.
Patient characteristics and preoperative EuroSCORE are summarized in Table 1. In the levosimendan group (n = 27), 14 patients (52%) had cardiogenic shock at arrival in the operation theatre, two patients were transferred under resuscitation for left main stem occlusion, one patient had post-infarct septal rupture and one patient had an ischaemic acute mitral regurgitation. In the control group (n = 25), 13 patients (52%) were in cardiogenic shock when they arrived in the operation theatre, one patient was under resuscitation for left main stem occlusion, two patients had post-infarct septal rupture and two patients had an ischaemic acute mitral regurgitation.
Perioperative data are presented in Table 2. Of the patients, 89% in the levosimendan group and 88% in the control group could be weaned from CPB at first attempt. One levosimendan patient could not be weaned from CPB and the patient died intraoperatively.
Seven patients (26%) in the levosimendan group died within 30 days postoperatively compared with 11 patients (44%) in the control group (P > 0.05). Interestingly, the differences in survival were observed only after the 10th postoperative day (Fig. 1). An IABP was inserted in nine patients (33%) in the levosimendan group and 19 patients (76%) in the control group (P < 0.05). Three patients (11%) in the levosimendan group required dialysis, compared to eight patients (32%) in the control group (P > 0.05). The need for ventilatory support was significantly prolonged in the control group (Table 3). The length of stay in the ICU and in the hospital did not differ between the two groups (Table 3).
Haemodynamic data are presented in Table 4. No significant differences were found between the two groups, or between values before CPB and after CPB. The need for additional dobutamine was similar in the two groups (levosimendan 30%; control 48%, P > 0.05). The use of epinephrine (levosimendan 74%; control 88%) and norepinephrine (levosimendan 96%; control 88%) did not differ between the two groups. In four patients, levosimendan was stopped in the early postoperative period (4-6 h) because of vasodilation and hypotension. In the remaining 23 patients, 12.5 mg of levosimendan were infused.
The term ‘acute coronary syndrome' includes unstable angina, ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI). It is a clinically useful definition because the initial presentation and early management of unstable angina, STEMI and NSTEMI are often similar. It represents a shift from a definite diagnosis to a clinical strategy as a rapid working diagnosis . Reperfusion within the first 3 h after onset of symptoms improves long-term outcome in these patients [12,15-18]. Percutaneous coronary intervention (PCI) is the preferred reperfusion technique if it can be performed by experienced staff within 90 min after first medical contact [15,18]. Patients in cardiogenic shock had significantly better survival at 6 months with early revascularization (49.7%) as compared with initial medical stabilization (36.9%) . Emergency or urgent CABG should be considered in suitable patients with ACSs if PCI fails or if pain or haemodynamic instability persists after PCI .
Cardioprotection can be achieved by activation of mitochondrial KATP channels in cardiac myocytes [5,19] by ischaemia or drugs, i.e. ischaemic or pharmacologic preconditioning. Potassium channel openers of clinical interest are nicorandil and levosimendan . In patients with acute myocardial infarction undergoing PCI, treatment with nicorandil resulted in better myocardial perfusion and better functional and clinical outcome than PCI alone. In these patients, left ventricular function was better preserved at 3 months follow-up . Nicorandil seems to enhance the myocardial protective effect of cold hyperkalaemic cardioplegia in patients undergoing cardiac surgery .
Levosimendan is a drug with a dual mechanism of action. First, it binds in a calcium-dependent manner to cardiac troponin C [6,7]. It increases myocardial contractility without increasing intracellular calcium content, thus avoiding the undesired side-effects of other positive inotropic drugs, e.g. increased oxygen consumption and increased incidence of arrhythmia. An interesting review on the positive inotropic effects of levosimendan was recently published by Toller and Stranz . Secondly, levosimendan is a KATP-channel opener . In cultured cardiac myocytes, levosimendan opposed myocyte apoptosis at concentrations below the therapeutic range in humans . This effect was prevented by inhibiting the KATP channels . In dogs, levosimendan has been shown to reduce experimental infarct size while simultaneously enhancing ventricular contractile function . The cardioprotective effect, but not the positive inotropic effect, can be blocked by inhibition of the KATP channels . In patients with acute myocardial ischaemia undergoing PCI, levosimendan improved the function of stunned myocardium . In congestive heart failure patients, levosimendan has been shown to exert anti-inflammatory, anti-oxidant and anti-apoptotic effects [24,25]. This might explain the favourable long-term effects of levosimendan, as compared to dobutamine, reported in these studies. In patients undergoing CABG, pre-treatment with levosimendan resulted in lower postoperative troponin I concentrations and a higher CI as compared to a control group .
We observed lower morbidity in the levosimendan group than in the control group. However, the benefit in survival did not reach statistical significance probably due to the limited number of patients. Interestingly, mortality in the first 10 days was equal in both groups. The patients dying later, between postoperative days 10 and 30, suffered from multiple organ failure. Levosimendan reduced perioperative morbidity and prevented organ failure.
Mitochondrial KATP channels are not specific to the heart; they are found in any organ of the body . In mice, levosimendan had marked protective effects against experimental endotoxaemic renal failure . KATP channel opening was reported to mediate hypoxic tubular injury . The beneficial effects of levosimendan seen in our study do not seem to be a result of improved haemodynamics, as there were no major differences in haemodynamics between the two groups. The favourable long-term effects of levosimendan might be mediated by its anti-inflammatory, anti-oxidant and anti-apoptotic effects [24,25]. Opening of mitochondrial KATP channels seems to have a key role in protecting the organism against the deleterious effects of severe congestive heart failure resulting in hypoperfusion and hypoxia [5,9,19,24,25].
There is a severe limitation to the study presented - it is not a prospective, randomized trial. In the particular setting, levosimendan was used as an off-label prescription in critically ill patients. The drug is not approved in Germany. Despite using a matched pair analysis, there might be a bias in patient selection. The data presented have to be confirmed in a prospective, randomized controlled trial. In a recent editorial of this journal, Feneck  discussed the increasing difficulties in performing large-scale randomized controlled trials in patients undergoing cardiac surgery. The costs for insuring research in these patients are immense.
In this retrospective matched pair analysis of patients undergoing emergent CABG for acute myocardial ischaemia, levosimendan reduced morbidity. Patients treated with levosimendan needed fewer IABPs and were ventilated postoperatively for shorter periods. Mortality and the need for dialysis were reduced without reaching statistical significance. These beneficial effects did not translate into a shorter length of stay in hospital. The cardioprotective effects of levosimendan should be confirmed in a randomized, controlled trial with a larger number of patients. Based on our observational data only, it is not appropriate to recommend levosimendan in patients with acute ischaemia undergoing cardiac surgery.
The study was completely financed by the Department of Anaesthesiology and Intensive Care Medicine of the Klinikum der Stadt Ludwigshafen, Germany. Dr Lehmann was member of the advisory board of levosimendan, which was financed by Orion Pharma, Espoo, Finland.
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