Eur J Cardiothorac Surg 2007;32:629-633. doi:10.1016/j.ejcts.2007.07.010
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
Efficacy and safety of perioperative infusion of levosimendan in patients with compromised cardiac function undergoing open-heart surgery: importance of early use
Androniki Tasoulia,*,
Kirillos Papadopoulosa,
Theophanie Antonioub,
Ioannis Kriarasa,
Georges Stavridisc,
Dimitrios Degiannisd,
Stephanos Geroulanosa
a ICU, Onassis Cardiac Surgery Center, Athens, Greece
b Department of Anaesthesiology, Onassis Cardiac Surgery Center, Athens, Greece
c 1st Department of Cardiac Surgery, Onassis Cardiac Surgery Center, Athens, Greece
d Department of Immunopathology & Histocompatibility, Onassis Cardiac Surgery Center, Athens, Greece
Received 10 April 2007;
received in revised form 6 July 2007;
accepted 9 July 2007.
* Corresponding author. Address: Marathonomahon 18, 14572 Athens, Greece. Tel.: +30 210 8133257. (Email: atacard{at}hotmail.com).
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Abstract
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Objective: Levosimendan is a promising new inotrope. We investigate the proper time for its infusion during or after open-heart surgery to avoid complications related with low-output syndrome and high dosage of inotropes. Methods: Forty-five consecutive patients were randomised to receive levosimendan in addition to the conventional therapy, its infusion starting in the operating theatre (Group OT) or in the ICU (Group ICU) when low-output syndrome was certified and were consequently dependent on classical inotropic support and IABP. Levosimendan was infused at a rate of 0.1 µg/kg min without loading dose, the infusion being for at least 24 h to a maximum 48 h. Results: Levosimendan was well tolerated, with the simultaneous infusion of norepinephrine if required. Its efficacy was identical in both groups with improvement in the haemodynamic and functional status of patients (amelioration of stroke volume, cardiac index and mixed venous blood oxygen saturation, increase of left ventricular ejection fraction by echo study, de-escalation of traditional inotropes, subtraction of IABP and reduction in BNP plasma levels). The ICU stay and hospital stay were significantly decreased in patients of Group OT, compared to patients of Group ICU. Four patients died because of multiple organs dysfunction syndrome (MODS) due to sepsis (all patients of Group ICU). Conclusion: Levosimendan is a safe and efficient choice in the management of low-output syndrome during and after open-heart surgery. The shortening of hospitalisation and the trend for better outcome confirm its clear superiority when the infusion starts from the operating theatre.
Key Words: Levosimendan • Perioperative infusion • Open-heart surgery • Low-output syndrome
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1. Introduction
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Levosimendan (LS) is an effective new agent that acts via two complementary mechanisms. It enhances cardiac contractility by improving the response of the myofilaments to intracellular calcium [1–4] and it reduces the cardiac workload by opening the adenosine triphosphate dependent potassium channels for the dilation of blood vessels [5–8]. LS had been recognised as having a long acting metabolite with a half-life of 80 h [9–12]. Accordingly, the pharmacologic effects of this metabolite may persist for approximately 1 week. In humans, LS improved the function of stunned myocardium in patients with acute myocardial infarction undergoing angioplasty [13]. In studies of heart failure, infusion of LS did not cause elevations in troponin T, a sensitive marker of myocardial damage [14]. No tolerance to the effects of LS has been observed, despite infusions lasting as long as 7 days [9]. No rebound decline in haemodynamic variables has been observed after withdrawal of LS. On the other hand, following cardiac surgery, the occurrence of low-output syndrome is relatively common, ranging from 3 to 10% incidence, depending on patient age, procedure performed and co-morbidities (ITACTA 2001). To prevent or lessen these adverse outcomes, a post-surgical low-output state should be reversed whenever possible. Instead of traditional inotropes, such as epinephrine, dobutamine and milrinone, which are recognised as improving contractility, but at the cost of increased myocardial oxygen demand with consequent risk for ischaemia and arrhythmia [15], LS is a promising alternative inotropic agent with possible clinical indication after open-heart surgery [16–20]. We intend to estimate the proper time for its infusion to avoid clinical complications related with low-output syndrome and high dosage of conventional inotropes and consequent prolonged hospitalisation.
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2. Methods—study design
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The study population consists of 45 consecutive patients with compromised cardiac function [New York Heart Association (NYHA) III–IV preoperatively, left ventricular ejection fraction (LVEF) < 35% by echo study], who underwent open-heart surgery. Haemodynamic data measured by a pulmonary artery catheter (cardiac index CI < 2.0 l/min m2, pulmonary capillary pressure wedge PCWP > 18 mmHg) confirm the low cardiac output syndrome in the operating theatre. Patients were prospectively selected to receive LS in addition to conventional inotropic support (epinephrine 0.08–0.1 µg/kg min, dobutamine 8–10 µg/kg min) and intraaortic balloon pump (IABP). They were randomised to receive LS in the operating theatre during the operation (Group OT) or in the ICU the second postoperative day (Group ICU), correspondingly. Twenty-five men (55.56%) and 20 women (44.44%) participated in the study. According to the type of cardiac procedure, 16 patients (35.56%) were submitted to coronary artery bypass surgery (CABG), 7 patients (15.56%) to multiple valve replacement (multi-VR) and 22 patients (48.89%) to combined open-heart surgery (CABG + other). They were all patients of high risk because of NYHA III–IV class and low left ventricular function preoperatively, need for increased inotropic support and IABP dependence, as already mentioned. The median age for the total sample was 65 years (interquartile range: 53–72 years). Basic characteristics are described in Table 1
. LS was infused at a rate of 0.1 µg/kg min without loading dose for at least 24 h to the maximum 48 h. Simultaneous infusion of norepinephrine was added, when required, to maintain mean arterial pressure (MAP) > 70 mmHg. We investigate the haemodynamic profile, the echocardiographic estimation of LVEF, the B-type natriuretic peptide (BNP) plasma levels 48 h after the beginning of LS infusion, the duration of IABP and classical inotropic support, the weaning success from mechanical ventilation and the patients’ outcome. The principal aim of the study is to compare the LS effect in ICU and hospital stay in association with the timing of its infusion.
The institutional ethics committee approved the study and written consent was given by each patient.
2.1 Statistical analysis
Variables were first tested for normality using the Kolmogorov–Smirvov criterion. Normal variables are expressed as mean ± standard deviation; while variables with skewed distribution are expressed as median (interquartile range). Qualitative variables are expressed as absolute and relative frequencies. The parametric paired Student's t-test and the non-parametric Wilcoxon signed rank test were used in order to evaluate any possible differences within the two time periods’ measurements. For the comparison of all measurements between the two groups (ICU vs OT) the parametric independent Student's t-test was used when the normality assumption was satisfied and the non-parametric Mann–Whitney test when it was not. Fischer's exact test was used for the comparison of proportions. P values reported are two-tailed. Statistical significance was set at 0.05 and analysis was conducted using SPSS, version 13.00 (SPSS Inc, Chicago, IL).
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3. Results
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LS was well tolerated, with the simultaneous infusion of norepinephrine, if required. Seventeen patients received norepinephrine (37.78%), nine patients in the operating theatre (40.91% of patients receiving LS in the operating theatre) and eight patients in ICU (34.78% of patients receiving LS in ICU). The values of haemodynamic and other data before and 48 h after the infusion of LS are summarised in Table 2
for both groups. In the same table we demonstrate the changes of haemodynamic and other parameters within the two groups of patients, but principally, we compare the efficacy of LS between Group ICU and Group OT, according to the beginning of its infusion in the operating theatre or in the ICU, respectively. Cardiac index (CI), stroke volume (SV), mixed venous oxygen saturation (SvO2), coronary arteries perfusion pressure (DAP-PCWP), LVEF and BNP decreased significantly after the infusion of LS, in both groups. Patients receiving LS from the operating theatre were independent of the classical inotropic support and IABP at the latest the fourth postoperative day with the start of de-escalation of epinephrine and dobutamine from the first postoperative day and IABP subtraction until the third postoperative day. On the other hand, patients receiving LS on the second postoperative day become independent of the classical inotropic support and IABP at the latest from the sixth postoperative day with the start of de-escalation of epinephrine and dobutamine from the third postoperative day and IABP subtraction after the fourth postoperative day.
Re-intubation occurred in only five patients (21.74%) of Group ICU but in Group OT none required re-intubation. We also have to note that the ICU stay and the duration of hospitalisation were significantly decreased in patients receiving LS from the operating theatre, compared to patients in whom infusion of LS was started in ICU. In addition, peak value of serum CRP levels was significantly lower in the Group OT in comparison to the Group ICU. Finally, four patients died because of multiple organs dysfunction syndrome (MODS) due to sepsis; they were all patients who started receiving LS in ICU. The median ICU stay for the four patients was 7 days and not significantly different compared to the median ICU stay of the rest of the patients. We do not however observe deaths in patients receiving LS from the operating theatre. The rest of the patients had a good in-hospital outcome without readmission within the first postoperative month. The results concerning the impact of LS in morbidity postoperatively are summarised in Table 3
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4. Discussion
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The interpretation of the role of LS as an alternative or supplementary inotropic agent is still a challenge for clinical study [19–24]. It has been officially recognised as Class of recommendation IIa, level of evidence B inotrope, versus dobutamine (Class of recommendation IIb, level of evidence C), according to the Guidelines of the European Society of Cardiology (2005) in patients with acutely decompensated severe chronic heart failure. Labriola et al. proposed the use of LS in patients with low-output syndrome following cardiac surgery [18] in agreement with their findings in a pilot study of 11 postsurgical patients with evidence of severely impaired cardiac output and haemodynamic compromise. Labriola et al. delivered LS as a loading dose of 12 µg/kg over 10 min followed by a continuous infusion of 0.1 µg/kg/min over 12 h. After having completed another pilot study which included 15 patients prospectively selected to receive LS after open-heart surgery, we have been convinced for the extension of the use of LS in patients with low cardiac output syndrome after open-heart surgery [19]. In the present study we investigate the possible role of the early infusion of LS and compare its relative efficacy between the two groups, namely those patients receiving the agent, in addition to the conventional inotropic support and IABP from the operating theatre (Group OT) and those receiving it on the second postoperative day in ICU (Group ICU). We confirm that LS constitutes a new promising treatment for low cardiac output syndrome during and after open-heart surgery. The proofs of amelioration of left ventricular function are derived from the improvement of the haemodynamic profile and the agreement of echocardiographic estimation 48 h after the start time of LS infusion. Increase of cardiac index (CI) in accordance with augmentation of stroke volume (SV), increase of mixed venous oxygen saturation (SvO2), a sensitive and reliable marker for the cardiac function and the sufficient tissue oxygenation, decrease of systemic (SVR) and pulmonary vascular resistance (PVR), diminution of central venous pressure (CVP) and wedge pressure (PCWP) in a statistically significant level represent indisputable proofs of the positive effect of LS in cardiac output. We also observe a significant increase in LVEF 48 h later, with a constant effect even after 1 week, in both patients’ groups. It is of great importance that the patients of both groups became independent of IABP and high doses of epinephrine and dobutamine improving their clinical status within a period of approximately 3 days after the initiation of LS infusion. Urine flow amelioration was also present, which recertifies the haemodynamic stabilisation of these patients. Therefore, we confirm the efficacy of LS in improving the haemodynamic and functional situation of patients. LS had been recognised as responsible for the clinical improvement, this being demonstrated by the fact that its addition, independent of the timing of its infusion, causes similar haemodynamic alteration. Preventing the aggravation of low cardiac output syndrome, LS exerts its action without capture of receptors, with additive effect to the classical inotropic support. Thus, when the receptors down-regulation happens, as this is a limitation for the action of epinephrine or dobutamine, LS still offers its action in an independent, efficient and constant way. Furthermore, LS allows the avoidance of high doses of conventional inotropes, which are implicated in negative consequences and complications in accordance to the exaggerated effect of vasoconstriction. Besides, with prolongation of LS infusion for 48 h and avoidance of loading dose we succeed better tolerance of the agent and improvement of its dose dependent beneficial effect in the myocardium contractility. Therefore, LS affords a therapeutic solution when other inotropes become inefficient or even dangerous, if they are used in high dosage. In addition, LS decreases the incidence of low-output syndrome related sepsis, a fact that is widely expressed in the population of Group OT with concomitant contribution in the significant decrease of CRP peak value in comparison to the Group ICU. CRP, which remains the inflammatory marker that presently seems more suitable to assess inflammation, constitutes an important factor associated with in-hospital prognosis. Thus, the significantly decreased peak value of CRP in patients of Group OT may reflect the beneficial effect of LS infusion starting from the operating theatre and recertifies the better prognosis of the patients of Group OT in comparison to the patients of Group ICU. It has been shown from previous studies [25] that elevated plasma concentration of BNP constitutes excellent independent predictor of mortality and readmission in heart failure patients. If BNP does not fall after aggressive treatment, this is indicative of a very poor prognosis. In the present study we evaluate the effect of LS infusion in BNP levels. Forty-eight hours after the start time of LS infusion, we confirmed a statistically significant decrease in plasma BNP levels indicative of improvement of short-term outcome. Consequently, relative changes in BNP value during treatment with LS predict short-term outcome and appear to perform even better as a prognostic marker and even as a therapeutic target in patients with low cardiac output syndrome who receive LS during or after open-heart surgery. Moreover, precise improvement of indexes of postoperative morbidity is confirmed. Improvement of clinical status is a finding that becomes more impressive and significant in patients in whom LS infusion starts from the operating theatre, immediately after the recognition of low cardiac output syndrome. We did not observe any significant difference in the weaning from mechanical ventilation between the two groups. On the other hand, avoidance of re-intubation, diminution of ICU and hospital stay provides evidence against reservation for the earlier infusion of this new agent. According to our data, the mortality rate is higher in Group ICU (17.39% in Group ICU, 4.55% in Group OT), as a consequence of increased incidence of sepsis in this group of patients. It is incontestable that the earlier infusion of LS protects not only myocardium but also the other organ targets and preserves the tissue oxygenation. At the same time, LS may constitute a cost effective option as it decreases significantly ICU and hospital stay and consequent risk of complications after open-heart surgery in high risk patients with compromised cardiac function.
In conclusion, we recertify that LS is a new promising inotropic agent with a particular place in the therapeutic management of low cardiac output syndrome during and after open-heart surgery. Under these circumstances, LS constitutes a safe and efficient choice according to its beneficial effect in the haemodynamic, echocardiographic and biochemical markers. We also confirm a significant impact of LS infusion in morbidity factors according to the time of commencement of its use. The immediate and constant action related to the metabolite of this particular agent with prolonged half life period may contribute to the avoidance of prolonged hospitalisation and the derived complications. Consequently, in patients with compromised cardiac function, we adopt the clear superiority of the early infusion of LS, immediately after the confirmation of low-output syndrome, from the operating theatre, as is demonstrated by improved in-hospital outcome.
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Abstract
1. Introduction
