Open Access Scientific Reports

Evaluating the Prophylactic use of Levosimendan Versus Milrinone in Open Heart Surgery Patients with Myocardial Dysfunction

Research Article Open Access
Gamal T Saad1,2* and Mahmoud F Fawzy3
1Aneshesiology and intensive care, Umm Al- Qura university, Makkah, KSA
2Aneshesiology and intensive care. Zagazig university, Zagazig, Egypt
3Cardiothoracic surgery, National heart institute
*Corresponding authors: Dr. Gamal Tohami Ali Saad Associate. Professor of anesthesia and intensive care Faculty of public health and health informatics Umm Al-Qura University, Makkah, KSA Tel: 00966564068661 E-mail: drgamal43@yahoo.com
Received January 28, 2012; Published July 30, 2012
Citation: Saad GT, Fawzy MF (2012) Evaluating the Prophylactic use of Levosimendan Versus Milrinone in Open Heart Surgery Patients with Myocardial Dysfunction. 1: 218. doi:10.4172/scientificreports.218
Copyright: © 2012 Saad GT, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Levosimendan is a promising new inotrope.
Objective: The aim of this prospective study is to evaluate the prophylactic administration (start after anesthesia induction) of levosimendan compared with milrinone to wean patients from a heart lung machine and to avoid complications related with low-output syndrome and high dosage of conventional inotropes and consequent prolonged hospitalization in open heart surgery patients with a preoperative compromised cardiac function.
Methods: thirty consecutive patients with compromised cardiac function who underwent open-heart surgery with CBP were randomised to receive levosimendan (0.1 μg/kg min without loading dose) or milrinone (0.5 μg/kg/ min without loading dose) after anesthesia induction. The 2 groups received dobutamine 5 μg/kg/min started after aortic cross clamp release. Hemodynamic profile and Blood were obtained for before anesthesia and on arrival to ICU, after 6, 12 and 24 hours.
Results: Cardiac output after surgery was initially higher than at baseline in both groups but was significantly higher in levosimendan group versus milrinone group. Cardiac output declined 12 hours after surgery in milrinone group but not in Levosimendan group (p < 0.05 between groups), despite similar filling pressures. Levosimendantreated patients had lower postoperative troponin- I concentrations than milrinone group. The intubation time, reintubation, ICU stay and hospital stay were significantly decreased in Levosimendan Group. Postoperative atrial fibrillation was observed in 8 patients in milrinone group and only 1 in levosimendan group (p < 0.05).
Three patients died because of multiple organs dysfunction syndrome (MODS) due to sepsis in milrinone group.
Conclusion: prophylactic levosimendan infusion after anesthesia induction was associated with a higher postoperative cardiac output and additional myocardial protection, as manifested by a better haemodynamic recovery, lower postoperative Troponin-I levels and a lower incidence of postoperative atrial fibrillation than prophylactic milrinone infusion. Levosimendan is a safe and efficient choice in the prophylaxis of low-output syndrome during and after open-heart surgery. The shortening of hospitalisation and the trend for better outcome confirm its clear superiority.
Introduction
The incidence of a low-output syndrome (LOS) after cardiac surgery with cardiopulmonary bypass (CPB) in patients with depressed ventricular function is approximately 30 % [1]. Patients, who have LOS require more monitoring, more medication. LOS causes delayed recovery, organ failure, prolonged intensive care unit (ICU) stays, increased hospital costs and adds to the risk of early postoperative mortality [2,3]. To prevent or lessen these adverse outcomes, a postsurgical low-output state should be prevented whenever possible. Instead of traditional inotropes, such as epinephrine, dobutamine and milrinone (phosphodiesterase inhibitor), which are recognised as improving contractility, but at the cost of increased myocardial oxygen demand with consequent risk for ischaemia and arrhythmia [4], The myofilament calcium sensitizer levosimendan is a promising alternative inotropic agent with possible clinical indication after open-heart surgery [5-9]. levosimendan improves cardiac muscle contractile force, vascular smooth muscle relaxation ,coronary blood flow and cardiac output through calcium sensitization of the myocardial contractile filaments and opening of potassium channels without increasing oxygen consumption of the heart muscle cells. In addition to its favorable hemodynamic effects,Levosimendan acts on the mitochondrial KATP channels,a mechanism by which preconditioning is induced,thereby reducing the extent of myocardial ischemia-reperfusion injury [10-12]. levosimendan had been recognised as having a long acting metabolite with a half-life of 80 h [13-16]. Levosimendan improved the function of stunned myocardium in patients with acute myocardial infarction undergoing angioplasty [17]. Tritapepe, et al found that a short infusion of Levosimendan before start of CBP in patients undergoing coronary artery surgery was not only associated with a higher cardiac index but also with lower postoperative troponin-1 concentrations and related these cardio protective actions to a possible preconditioning effect [18].
The aim of this randomized controlled clinical study was to investigate whether prophylactic (immediatly after anesthesia induction) levosimendan infusion is superior to milrinone in preventing clinical complications related with low-output syndrome, postcardiotomy myocardial dysfunction and high dosage of conventional inotropes and consequent prolonged hospitalization in open heart surgery patients with a preoperative compromised cardiac function and to evaluates the efficacy of intravenous levosimendan infusion started during open heart operation to wean patients from a heart lung machine.
Methods
This prospective, randomized trial was conducted at national heart institute, Egypt and all patients gave written informed consent. The study population consists of 30 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 with CBP (elective CABG surgery or valve surgery). LOS was defined as cardiac index (CI) ≤2.2 L/min/m2, pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, mean arterial pressure (MAP) ≤50 mmHg, and systemic vascular resistance (SVR) ≥1,500 dynes/sec/cm-5. Exclusion criteria were symptomatic congestive heart failure (CHF) while the patient was on bed rest, preoperative LOS, preexisting renal failure, preoperative cardiopulmonary resuscitation, preoperative use of milrinone or Levosimendan. All patients were premedicated with midazolam 0.1 mg / kg orally on the night before surgery and scopolamine 8 ug / kg i.m and morphine sulphate 0.1 mg / kg one hour before surgery .Two hours before surgery an equipotent dose of oral metoprolol was given for patients who were on preoperative B-blockers.
Monitoring: The hemodynamic measurements included leads II and V5 on the electrocardiogram with ST-segment and arrhythmia monitoring capability, a continuous cardiac output pulmonary artery catheter (Edwards Lifesciences, Irvine, CA), and a radial artery catheter. After induction of anesthesia, a urinary bladder catheter with a temperature probe was inserted for temperature and urine-output monitoring.Intraoperative transesophageal echocardiography was used.
Anesthetic and surgical techniques: A standard anesthetic technique for all patients was performed. All patients were induced with midazolam (0.05 mg/kg), fentanyl (0.5 μg/kg), propofol (1.0 mg/ kg), and an intubating dose of rocuronium. Anesthesia was maintained with air/O2, sevoflurane (0.5-1.0â„…) and supplemental propofol 50- 100 ug/kg/min throughout the surgery and fentanyl 1-2 ug /kg i.v as required (total dose 20-50 ug/kg all over the surgery) .All operations were performed through a median sternotomy using a standard surgical technique. Before aortic canulation, the patients were anti coagulated with heparin 4 mg/kg to reach ACT > 400. The CPB was conducted with a flat sheet membrane oxygenator using non-pulsatile flow. The circuit prime consisted of ringer's solution 1800 ml, 25% manitol 100 ml and heparin 600 IU. The pump flow was maintained at 2.0-2.5 litre/min/m2. Cold cardioplegic solution was given after aortic cross- clamping for myocardial protection. After weaning from CPB, maintenance of anesthesia was with oxygen and sevoflurane and protamine sulphate was infused slowly over 20 min to neutralize heparin effect. After skin closure, all patients were transferred to ICU, intubated and mechanically ventilated. Upon arrival in the ICU, the patient’s condition was evaluated and further sedation was administered by propofol (infusion 2-3 mg/kg/h) and intermittent boluses of morphine (2-4 mg every 30 minutes as needed).
Study design and measurement: Hemodynamic profile (HR, arrhythmias, MAP, PCWP, CO,CVP, SVR , ) were obtained after the induction of anesthesia and before starting the assigned pharmacologic treatment(base) , 20 minutes after separation from CBP, after sternal closure and in ICU on arrival (T0), 6 (T6), 12 (T12), 24 (T24) hours later. Blood was obtained for analysis of troponin-1, CK-MB, creatinine, SGOT, SGPT before anesthesia and on arrival to ICU, after 6, 12 and 24 hours . During and after surgery, norepinephrine infusions were administered to maintain MAP ≥70 mmHg. The norepinephrine infusion was started for hypotension with SVR ≤600 dynes/sec/cm-5.
After anesthesia inductionThe patients were randomized by sealed envelopes to receive levosimendan (levosimendan group) or milrinone( the milrinone group) as 24 hour continous infusion. Levosimendan (Simdax; Orion Corp, Espoo, Finland) was infused at a rate of 0.1 μg/ kg min without loading dose and milrinone (Primacore; Sanofi, Paris, France) was infused at a rate of 0.5 μg/kg/min without loading dose. The 2 groups received dobutamine 5ug/kg/min started after aortic cross clamp release. Simultaneous infusion of norepinephrine was added, when required, to maintain mean arterial pressure (MAP) > 70 mmHg. Pulmonary capillary wedge pressure was kept in all patents between 12 and 18 with fluid administration. Heart rate was kept constant by atrioventricular sequential pacing at a rate of 90 beats/min unless spontaneous underlying rhythm was higher. Weaning from inotropic support was based on hemodynamic profile and patient physical status in ICU.
The primary outcomes were to compare proportion of successful primary weanings and cardiac output. The hemodynamic and relevant biochemical profiles of the 2 groups for 48 hours after starting treatment. The study also documented the need for other catecholamines.
Statistical Analysis
The data were collected and analyzed by paired sample t test and expressed as mean ± standard deviation. The statistical difference was done by 2-tailed test. P value was significant if < 0.05 .These statistics were done by using SPSS 10 software.
Results
Preoperative and surgical patient characteristics are summarized in Table 1. There were no differences among groups in the pre- or intraoperative data except that 94% of patients in the levosimendan group and only 67% in the milrinone group could be weaned from CPB at first attempt (p <0.05). Hemodynamic data are listed in Table 2. HR, CVP, PCWP, and MAP were not different among groups as a result cardiac pacing and adherence to the protocol for maintaining these variables within specified ranges. Cardiac output after surgery was initially higher than at baseline in both groups but was significantly higher in levosimendan group versus milrinone group. Cardiac output declined 12 hours after surgery in milrinone group but not in Levosimendan group (p < 0.05 between groups), despite similar filling pressures. This difference was observed throughout the remainder of the observation period. SVR was significantly lower in levosimendan –treated patients than in milrinone-treated patients starting from + post-CBP. Cardiac isoenzyme levels and other biochemical data are listed in (Table 3). Levosimendan-treated patients had lower postoperative troponin- I concentrations than milrinone group starting from post-CBP but statistically significant differences were observed postoperatively at T24 andT48 (P<0.05) .Except for the creatinine, all values measured after surgery were significantly increased compared with baseline measurements. This increase was significantly higher in milrinone group. Inotropic and vasoactive medication and postoperative outcome data are listed in (Table 4). The duration of the study drug administration was 21 ±3 hours in levosimendan group compared with 77 ± 41 hours in milrinone group (p < 0.05). In all patients in the levosimendan group, the drug could be stopped within the first 24 h after the start of the infusion .The total dose and duration of administration of dobutamine and norepinephrine were higher in milrinone group than Levosimendan group (Table 4). The duration of tracheal intubation and mechanical ventilation was longer in milrinone group. Re-intubation occurred in only five patients of milrinone group but in levosimendan group none required re-intubation. We also have to note that the ICU stay and the duration of hospitalisation were significantly decreased in levosimendan group, compared to milrinone group. In both groups, atrial fibrillation was the cause of all the postoperative arrhythmias, the incidence of postoperative atrial fibrillation was significantly lower in levosimendan group. Finally, three patients in milrinone group died because of multiple organs dysfunction syndrome (MODS) due to sepsis; they were all patients who started receiving LS in ICU. We do not however observe deaths in Levosimendan group.
Table 1: Preoperative and Surgical Characteristic.
Table 2: Peri- and Postoperative Hemodynamic Changes Over Time.
Table 3: Biochemical Data.
Table 4: Inotropic and Vasoactive Medication and Postoperative Outcome Events.
Discussion
This study demonstrates that in cardiac surgery patients with low preoperative ejection fraction, prophylactic levosimendan infusion after anesthesia induction before CPB was associated with a higher postoperative cardiac output and additional myocardial protection beyond that provided by cardioplegia alone, as manifested by a better haemo dynamic recovery and lower postoperative Troponin-I levels than prophylactic milrinone infusion. Also levosimendan prophylaxis was associated with better weaning from CBP.
Variable degrees of postoperative myocardial stunning occur after cardiac surgery, even with the use of contemporary cardioprotective strategies. This may result in transient myocardial dysfunction, which is more pronounced in patients with impaired left ventricular function before surgery, resulting in the need for postoperative inotropic support [19,20]. In the present study we investigate the possible role of the prophylactic infusion of levosimendan in comparison with milrinone infusion. We confirm that Levosimendan constitutes a new promising prophylaxis and 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, augmentation of stroke volume and cardiac output (CO), decrease of systemic vascular resistance (SVR), in a statistically significant level represent indisputable proofs of the positive effect of levosimendan in cardiac output. In both groups, the study drug was combined with a continuous administration of dobutamine. In this institution, separation from CPB is typically performed with combined inotropic support with dobutamine and milrinone. Both dobutamine and milrinone enhance myocardial contractility by increasing the concentration of cyclic adenosine monophosphate and thereby intracellular calcium. This action results in a rise in myocardial oxygen consumption. In contrast, levosimendan improves myocardial contractility primarily by enhancing myocardial contractile protein sensitivity to calcium without increasing its intracellular concentration.This action does not result in an increase in myocardial oxygen consumption [21-23]. Levosimendan 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, levosimendan still offers its action in an independent, efficient and constant way. Furthermore, levosimendan 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. Therefore, levosimendan affords a therapeutic solution when other inotropes become inefficient or even dangerous, if they are used in high dosage. levosimendan may have a more advantageous profile than phosphodiesterase II inhibitors, especially in patients with a compromised myocardial oxygen balance. Our results indicated better postoperative cardiac function and less need for adjuvant hemodynamic support with levosimendan. It should be noted that levosimendan has an active metabolite which has similar hemodynamic effects [24-26] and has a long elimination halflife on the order of 70 to 80 hours [26,27] This might explain why the positive hemodynamic effects lasted even after the 24-hour infusion, whereasmilrinone had to be continued for about 3 days. De Hert, et al. [28] have recently shown that Levosimendan in combination with dobutamine maintained stroke volume better than another inodilator, milrinone, in combination with dobutamine in cardiac surgery patients with a preoperative ejection fraction <30%.
In the present study there was lower postoperative Troponin-I levels with levosimendan prophylaxis indicating additional protection against myocardial injury .This is in agreement with the study of Tritapepe, et al [18] who observed that a short 10-minute infusion of levosimendan before the start of CPB In coronary artery surgery patients with a good preoperative cardiac function, was associated with lower postoperative troponin I concentrations and higher cardiac indexes. The authors attributed this protective effect to a preconditioning-like action of levosimendan. Levosimendan opens both mitochondrial and sarcolemmal KATP channels, channels implicated in the mediation ischemic preconditioning [29]. Levosimendan may protect the ischemic myocardium when administered before and during myocardial ischemia [30]. Experimental evidence that levosimendan pretreatment is capable of reducing ischemia related cardiac damage was endorsed by recent clinical findings, indicating that early treatment with the drug might be associated with a trend for better outcome [31] .
Postoperative levels of CK-MB, SGOT and SGPT were significantly lower in the levosimendan-treated patients. These effects may be related to a direct organprotective action of the drug or are the consequence of the better postoperative cardiac function, resulting in improved early organ perfusion. Experimental reports have observed increased blood flow with levosimendan to various tissues including the gastric mucosa, renal medulla, small intestine, and liver [32,33] Levosimendan also seems to be superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation, [33,34] and it increases portal venous blood flow and oxygen delivery in experimental septic shock [35]. Finally, in patients with low output heart failure, improvement of renal function was observed with levosimendan compared with dobutamine [36,37]. In the present study, however, no differences in postoperative creatinine levels were observed among the 2 groups.
The results of this study indicate that the incidence of postoperative atrial fibrillation was significantly lower in the Levosimendan group. It is not clear what possible underlying mechanisms might be responsible for this observation. A recent review presented evidence that suggested an antiarrhythmic effect for levosimendan. The proposed mechanism was the activation of the myocardial KATP-channel, which mediated a protective role against lethal ventricular arrhythmias [38].
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, less incidence of intubation, and shorter ICU and hospital stays. Baggish and colleagues [39] 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. The mortality rate is higher in milrinone Group as a consequence of increased incidence of sepsis in this group of patients. It is incontestable that the earlier infusion of Levosimendan protects not only myocardium but also the other organ targets and preserves the tissue oxygenation. At the same time, levosimendan 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.
Conclusion
In cardiac surgery patients with low preoperative ejection fraction, prophylactic levosimendan infusion after anesthesia induction before CPB was associated with a higher postoperative cardiac output and additional myocardial protection, as manifested by a better haemodynamic recovery, lower postoperative Troponin-I levels and a lower incidence of postoperative atrial fibrillation than prophylactic milrinone infusion. Also levosimendan prophylaxis was associated with better weaning from CBP. Levosimendan is a safe and efficient choice in the prophylaxis of low-output syndrome during and after open-heart surgery. The shortening of hospitalisation and the trend for better outcome confirm its clear superiority.
References
	Chernov SA (2002) Early postoperative complications and prevention of them in ischemic heart disease patients after direct myocardial revascularization, Ter Arkh 74: 45-49. Avery GJ 2nd, Ley SJ, Hill JD, Hershon JJ, Dick SE (2001) Cardiac surgery in the octogenarian Evaluation of risk, cost and outcome, Ann Thorac Surg; 71: 591-596. Nemec P, Bedanova H, Necas J, Meluzin J, Stetka F, et al. (2001) Coronary artery bypass grafting in patients with left ventricular ejection fraction of 30% or less, Bratisl Lek Listy; 102: 15-21. Dupuis JY, Bondy R, Cattran C, Nathan HJ, Wynands JE (1992) Amrinone and dobutamine as primary treatment of low cardiac output syndrome following coronary artery surgery: a comparison of their effects on haemodynamics and outcome. J Cardiothorac Vasc Anesth 6: 542-553. Lilleberg J, Nieminen MS, Akkila J, Heikkilä L, Kuitunen A, et al. (1998) Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting, Eur Heart J; 19: 660–668. Nijhawan N, Nicolosi AC, Montgomery MW, Aggarwal A, Pagel PS, et al. (1999) Levosimendan enhances cardiac performance after cardiopulmonary bypass: a prospective, randomized placebo-controlled trial, J Cardiovasc Pharmacol 34: 219–228. Labriola C, Siro-Brigiani M, Carrata F, Santangelo E, Amantea B (2004) Hemodynamic effects of levosimendan in patients with low-output heart failure after cardiac surgery. Int J Clin Pharmacol Ther 42: 204-211. Tasouli A, Papadopoulos K, Kriaras J, Georgiadis M, Geroulanos S (2005) Safety and Efficacy of the novel calcium sensitizer Levosimendan after open heart surgery: our experience from a pilot study. Interact Cardiovasc Thorac Surg 4: 556. Raja SG, Rayen BS (2006) Levosimendan in cardiac surgery: current best available evidence. Ann Thorac Surg; 81: 1536–1546. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N (1997) The novel calcium sensitizer levosimendan activates the ATP-sensitive K_ channel in ratventricular cells. J Pharmacol Exp Ther 283: 375-383. Kersten JR, Montgomery MW, Pagel PS, Warltier DC (2000) Levosimendan, a new positive inotropic drug, decreases myocardial infarction size via activation of K (ATP) channels. Anesth Analg 90: 5-11. Yapici D, Altunkan Z, Ozeren M, Bilgin E, Balli E, et al. (2006) Effects of Levosimendan on myocardial ischaemia-reperfusion injury. Eur J Anaesthesiol 25: 8-14. Takahashi R, Talukder MA, Endoh M (2000) Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium. J Cardiovasc Pharmacol 36: 118–125. Takahashi R, Talukder MA, Endoh M (2000) Inotropic effects of OR-1896, an active metabolite of levosimendan, on canine ventricular myocardium. Eur J Pharmacol 400: 103–112. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikäinen PJ (2002) Pharmacodynamics and safety of a new calcium sensitizer, levosimendan and its metabolites during an extended infusion in patients with severe heart failure. J Clin Pharmacol 42: 43–51. Kivikko M, Lehtonen L, Colucci WS (2003) Sustained haemodynamic effects of intravenous levosimendan, Circulation 107: 81–86. Sonntag S, Sundberg S, Lehtonen LA, Kleber FX (2004) The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia, J Am Coll Cardiol; 43: 2177–2182. Tritapepe L, De Santis V, Vitale D, Santulli M, Morelli A (2006) Preconditioning effects of levosimendan in coronary artery bypass grafting- A pilot study. Br J Anaesth 96: 694-700. Mangano DT (1985) Biventricular function after myocardial revascularization in humans: deterioration and recovery patterns during the first 24 hours. Anesthesiology 62 :571–577. Eagle KA, Guyton RA, Davidoff R, Edwards FH, Ewy GA, et al. (2004) ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 110:340–437. Ukkonen H, Saraste M, Akkila J, Knuuti MJ, Lehikoinen P, et al. (1997) Myocardial efficiency during calciumsensitization with levosimendan: A noninvasive study with positron emission tomography and echocardiography in healthy volunteers. Clin Pharmacol Ther ;61: 596-607. Lilleberg J, Nieminen MS, Akkila J, Heikkilä L, Kuitunen A, et al. (1998) Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 19: 660-668. Ukkonen H, Saraste M, Akkila J, Knuuti J, Karanko M, et al. (2000) Myocardial efficiency during levosimendan infusion in congestive heart failure. Clin Pharmacol Ther 68: 522-531. Takahashi R, Talukder MA, Endoh M (2000) Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium. J Cardiovasc Pharmacol 36: 118-125. Takahashi R, Talukder MA, Endoh M (2000) Effects of OR-1896, an active metabolite of levosimendan, on canine ventricular myocardium. Eur J Pharmacol 400:103-112. Kivikko M, Lehtonen L, Colucci WS (2003) Sustained hemodynamic effects of intravenous levosimendan. Circulation 107: 81-86. Kivikko M, Antila S, Eha J, Lehtonen L, Pentikäinen PJ (2003) Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. J Clin Pharmacol 42: 43-51. De Hert SG, Lorsomradee S, Cromheecke S, Van der Linden PJ (2007) The effects of levosimendan in cardiac surgery patients with poor left ventricular function. Anesth Analg 1004: 766-773. Gross GJ, Fryer RM (2003) KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol 285: 921–930. Kersten JR, Montgomery MW, Pagel PS, Warltier DC (2000) Levosimendan, a new positive inotropic drug, decreases myocardial infarction size via activation of KATP channels. Anesth Analg 90: 5–11. Tasouli A, Papadopoulos K, Antoniou T, Kriaras I, Stavridis G, et al. (2006) Efficacy and safety of perioperative infusion of levosminendan in patients with compromised cardiac function undergoing open-heart surgery: Importance of early use. Eur J Cardiothor Surg 32: 629-633. Pagel PS, Hettrick DA, Warltier DC (1996) Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs. Br J Pharmacol 119: 609-615. Schwarte LA, Picker O, Bornstein SR, Fournell A, Scheeren TW, et al. (2005) Levosimendan is superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation in dogs. Crit Care Med 33:135-142. Morelli A, De Castro S, Teboul JL, Singer M, Rocco M, et al. (2005) Effects of Levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med 31: 638-644. Oldner A, Konrad D, Weitzberg E, Rudehill A, Rossi P, et al. (2001) Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med 29: 2185-2193. Follath F, Cleland JG, Just H, Papp JG, Scholz H, et al. (2002) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe lowoutput heart failure (the LIDO study): A randomized double-blind trial. Lancet 360: 196-202. Yilmaz MB, Yalta K, Yontar C, Karadas F, Erdem A, et al. (2006) Levosimendan improves renal function in patients with acute decompensated heart failure: Comparison with dobutamine. Cardiovasc Drug Ther ;21: 431-435. Polleselloa P, Mebazaab A (2004) ATP-dependent potassium channels as a key target for the treatment of myocardial and vascular dysfunction. Curr Opin Crit Care 10: 436–441. Baggish AL, MacGillivray TE, Hoffman W, Newell JB, Lewandrowski KB, et al. (2004) Postoperative troponin-T predicts prolonged intensive care unit length of stay following cardiac surgery. Crit Care Med 32:1866–1871.