Adel Abdel Fattah Saleh, MD Professor of cardiothoracic anesthesiology Cairo University adelafsaleh@yahoo.com adelafsaleh@gmail.com
12/7/2012
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Klabunde, R, Cardiovascular Physiology Concepts (2007) 12/7/2012
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A. Calcium mobilizers B_receptors stimulate the formation of cAMP from ATP via adenyl cyclase. Phosphodieestrase inhibitors reduces the conversion of cAMP, the two agents acting synergistically. The increased cAMP promotes intracellular calcium availability and hence the contractile force generated.
A 2
B. Calcium sensitizers
A 1
(pyridazinonelevosimendan) binds
B
and stabilizes the Ca2-bound TnC, allowing unopposed interaction between actin and myosin filaments and enhancing the rate and extent of myocyte contraction, while allowing Ca2 to dissociate from the protein during diastole.
A 3 12/7/2012
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Hemodynamic response to calcium is critically dependent on pre
administration plasma ionized calcium.
In the presence of normal calcium conc, SVR is only increased. Elevation of calcium is detrimential to ischemic myocardium. The myocyte is unable to generate sufficient high energy phsphate to
permit normal reuptake of cytoplasmic calcium following contraction.
The ischemic heart is unable to relax and contracture develops. Calcium accumulation in mitochondria will lead to cell death. 12/7/2012
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The importance of initial calcium concentration on left ventricular response to calcium infusion a. Initial normocalcemia . Calcium infusion produces hyperclacemia associated with only a small upward and left shift of the ventricular function curve. b. Initial hypocalcemia calcium infusion is associated with a much greater shift of the function curve to the left and upward. Drop LJ et al Am J Cardiol.1981; 47:1043-51 12/7/2012
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Epinephrine is the most powerful cardiotonic agent, with
peripheral a vasoconstrictor effect. It is occasionally useful, when high systemic BP is required.
Dopamine and dobutamine stimulate local
catecholamine release from myocardium. It reduces catecholamine stores in the failing ventricle, and limits its action. Dopamine is commonly used to support CO after CBP. Dobutamine has a more adrenergic action. •Hardy JF, Belisle S. Inotropic support of the heart that fails to successfully wean from cardiopulmonary bypass. the
Montreal Heart Institute experience. J Cardiothorac Vasc Anesth 1993;7(suppl 2):33-39.
•Bohn DJ, Poirier CS, Edmonds JF, Barker GA. Hemodynamic effects of dobutamine after cardiopulmonary bypass in
children Crit Care Med 1980;8:367-371
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Increase in myocardial oxygen consumption. Increase in heart rate (HR)?.
Increase in Systemic afterload. Increase the risk of arrhythmia. Ravishankar C, Tabbutt S, Wernovsky G. Critical care in cardiovascular medicine Curr Opin Pediatr 2003;15:443-453 12/7/2012
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Catecholamines stimulate B receptors with the formation of cAMP from ATP via adenyl cyclase.
Phosphodieestrase inhibitors reduces the conversion of cAMP.
The increased cAMP promotes intracellular calcium availability
and hence the contractile force generated. The two agents acting synergistically. A combination of dobutamine and amrinone produces greater improvement in the cardiac index.
These drugs are potent arterial, venous, and pulmonary dilators. 12/7/2012
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It Produces deleterious effects of raised intracellular calcium
as well as neurohormone levels on the failing myocardium, in patients suffering from chronic heart failure.
In 21 trials (8408 patients),4 specific PDI derivatives have been considered.
Results reported 1) As compared with placebo, treatment was found to be associated with a significant 17% increased mortality rate. (95% confidence interval 1.06 to 1.30; p<0.001).
2) In addition, PDIs significantly increase cardiac death, sudden death, arrhythmias
•Amsallem E, Kasparian C, Haddour G, Boissel JP, Nony P. Phosphodiesterase III
inhibitors for heart failure Cochrane Database Syst Rev 2005;1. •Raja SG, Nayak SH. Sildenafil. emerging cardiovascular indications. Ann Thorac Surg 2004;78:1496-1506. 12/7/2012
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ď ˝ Calcium sensitizers increase myocardial
contractility without increasing intracellular calcium.
ď ˝ levosimendan has been shown to exert potent dose dependent positive inotropic and vasodilatory activity.
ď ˝ Can be an alternative to conventional inotropic agents for patients with decompensated heart failure.
Frishman WH. Advances in positive inotropic therapy. levosimendan. Crit Care Med 2003;31:2408-2409 Figgitt DP, Gillies PS, Goa KL. Levosimendan Drugs 2001;61:613-627 12/7/2012
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On the contractile apparatus of myocardial cell: Increases cardiac contractility
So improves the circulation of the blood throughout the body
On the vascular smooth muscle cells: Enhances vasodilatation via K ATP channel opening (pulmonary, systemic, coronary)
So improves the filling of the heart with blood, and improves oxygen and nutrient supply to organs
On the mitochondria of the cardiomyocyte: activation through opening ATP K channels (positive lusitropic effects) .
Levosimendan does not impair diastolic function or lusitropy. McBride BF, White CM. Levosimendan. implications for clinicians. J Clin Pharmacol 2003;43:1071-1081 12/7/2012
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Increased cardiac output. Decreased systemic vascular resistance.
Lowered capillary wedge pressure. No increase in cardiac work or myocardial oxygen demand.
The risk of proarrhythmic events is low. *Lepran I, Papp JG. Effect of long-term oral pretreatment with levosimendan on cardiac arrhythmias during coronary artery occlusion in conscious rats. Eur J Pharmacol 2003;464:171-176. du Toit EF, Muller CA, McCarthy J, Opie LH. Levosimendan: effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langendorff perfused guinea pig heart. J Pharmacol Exp Ther 1999;290:505-514. 12/7/2012
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Feature
Comparison between Levosimendan Milrinone
Drug class
Calcium sensitizer
intracellular calcium No effect
Phosphodiesterase III inhibitor
Increases
Dobutamine Catecholamine Increases
Inotrope
Yes
Yes
Yes
Vasodilator
Coronary, systemic & pulmonary No effect
Pulmonary & systemic
Mild systemic
No effect
Increases
Arrhythmogenic
None seen yet
Ventricular (12%) and supraventricular arrhythmias (4%)
Ventricular ectopic activity (5%)â&#x20AC;&#x201D;less than milrinone
Administration with β- blockers
Yes
Yes
Yes
Adverse effects
Hypotension
Ventricular arrhythmias, hypotension,
Tachycardia, hypertension
Effect on myocardial oxygen demand
Raja SC, Rayen et al: Levosimendan in cardiac surgery: Ann Thorac 12/7/2012 Surg.2006 Apr;81(4):1536-46
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Studies Reporting Levosimendan Use in Cardiac Surgery Tasouli and colleagues
2005
Harjola and colleagues
2004
Barisin and colleagues
2004
Pilot study
Adult postcardiac surgery patients with CI<2.0 L/min/m2, LVEF<35% and PCWP>18 mm Hg Case series 75% highrisk adult patients a
15
0.1–0.2 µg/kg/min
Successful weaning of IABP and high doses of 2 other inotropes in 80% patients
16
0.1 µg/kg/min after a bolus of 12–24 µg/kg for 10 min
Increased CI in all patients with successful weaning from CPB
RCT
31
12 µg/kg or Significant 24 µg/kg increase in CO, LVEF, SV, and decrease in SVR with both doses
Adult OPCAB patients with good preop LV function
Shahzad G. Raja, MRCS*, Benson S. Rayen, DCH Levosimendan in cardiac surgery: current best available evidence. Ann. Thorac Surg.2006 Apr;81(4):1536-46.
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Orion sponsored study 12/7/2012
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started after induction of anaesthesia.
Epinephrine was added at he second weaning attempt.
Orion sponsored study 12/7/2012
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Orion sponsored study 12/7/2012
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Orion sponsored study 12/7/2012
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Levosimendan has the ability to augment systolic function without
increasing MOD, with less incidence of arrhythmias, and augment the diastolic function (positive lusitropic effects).
It may be a promise in elective therapy for: Cardiac surgical patients with high perioperative risk. Compromised left ventricular function. Difficult weaning from cardiopulmonary bypass. Maintenance of hemodynamic stability in OPCAB, However hypotension should be considered.
Data are limited for determination of an optimum dosage, and start time in cardiac surgery.
It has been studied only as a short-term therapy, generally infused for 6 to
24 hours. There is nothing in the literature to suggest an optimum duration of therapy.
However for based clinical evidence, further randomized clinical trials is considered the best approach to ascertain the value of a 19 levosimendan therapy 12/7/2012
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Increasing myocardial concentrations of calcium. Calcium. Catecholamines stimulate B1adrenoceptors on the myocardial
cells, causing increases in cAMP. Phosphodiesterase inhibitors prevent the breakdown of cAMP by phosphodiesterase.
The increase in cAMP causes an up-regulation in the activity of protein kinase C, which increases the calcium current into myocytes during systole to cause an increased inotropic effect
Calcium sensitizers (pyridazinone-dinitrite), increase myocardial contractility without increasing intracellular calcium.
McBride BF, White CM. Levosimendan. implications for clinicians. J Clin Pharmacol 2003;43:10711081.
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Relaxation
Contraction MyCa
TnC
Tnl
2+
TnT
Troponin complex Tropomyosin Actin Myosin head Myosin 12/7/2012
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ď ˝
When Ca++ binds to TN-C, there is a conformational change in the troponin complex such that TN-I moves away from the myosin binding site on the actin, thereby making it assessable to the myosin head. When Ca++ is removed from the TN-C, the troponin complex resumes its inactivated position, thereby inhibiting myosin-actin binding. TN-I is important in clinical practice because it is used as a diagnostic marker for myocardial infarction (it is released into the circulation when myocytes die). 12/7/2012
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In high perioperative risk patients with severely compromised myocardial function.
Previous MI. Chronic valvular disease. Following myocardial ischemia and reperfusion injury. Following cardioplegia and aortic cross clamping. 12/7/2012
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ď ˝ Pharmacological in the form of inotropic and vasodilator therapy.
ď ˝ Mechanical in the form of: IABP or assisted devices 12/7/2012
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To achieve improvement of tissue perfusion in the perioperative period.
To support weaning from cardiopulmonary bypass.
To support weaning from IABP.
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ď ˝ To compare different cardiotonic agents used to support the circulation in the perioperative period.
ď ˝ To spot light on what seems to be the ideal
inotropic agent, that can achieve improvement of perfusion with minimal side effects, in the perioperative period.
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Mechanisms of action of levosimendan and other cardiotonic agents
Na+/Ca2+exchanger Ca2+-induced Ca2+ release ryanodine receptor [SR Ca2+release channel] dihydropyridine receptor [L-type Ca2+ channel]
SR Ca2+pump ATPase phospholamban
Raja S. G. et al.; Ann Thorac Surg 2006;81:1536-1546 12/7/2012
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Labriola and colleagues [50]
2004
Pilot study
Adult postsurgical patients with severely impaired CO
11
Lehmann and colleagues [52]
2004
Case series
Adult highrisk patients for emergency CABG on CPB
10
Rajek and colleagues [53]
2003
Case series
Adult patients with LVEF 19 ± 5% for elective cardiac surgery on CPB
8
0.1 µg/kg/min for 12 hrs after a bolus of 12 µg/kg over 10 min
Significant increase in CI, SV, and significant decrease in MAP, SVR, RAP, MPAP, and PCWP 6 µg/kg Succesful followed by weaning from 0.2 CPB on first µg/kg/min attempt in all infusion with patients with catecholamine decreased s duration of critical care 0.6 µg/kg over 10 min followed by 0.2 µg/kg/min
Shahzad G. Raja, MRCS*, Benson S. Rayen, DCH Levosimendan in cardiac surgery: current best available evidence. Ann. Thorac Surg.2006 Apr;81(4):1536-46. 12/7/2012
CO stayed more than 5 L/min on postop day 1 with reduced catecholamine requirements and decreased duration of critical care
29
B_receptors stimulate the formation of cAMP from ATP via adenyl cyclase. Phosphodieestrase inhibitors reduces the conversion of cAMP, the two agents acting synergistically. The increased cAMP promotes intracellular calcium availability and hence the contractile force generated. 12/7/2012
30
Levosimendan binds to the regulatory protein troponin C (TnC) and stabilizes the Ca2-bound conformation of TnC, thereby allowing unopposed interaction between actin and myosin filaments and enhancing the rate and extent of myocyte contraction.
Levosimendan-tnc binding is its dependence on intracellular Ca2
concentration that facilitates the interaction between TnC and Ca2
while simultaneously allowing Ca2 to dissociate from the protein during diastole. •Haikala H, Kaivola J, Nissinen E, et al. Cardiac troponin C as a target for a novel calcium during systole,
sensitizing drug, levosimendan. J Mol Cell Cardiol 1995;27:1859–66. •Haikala H, Levijoki J, Linden IB. Troponin C-mediated calcium sensitization by levosimendan accelerates the proportional development of isometric tension. J Mol Cell Cardiol 1995;27:2155– 65. •Haikala H, Nissinen E, Etemadzadeh E, et al. Troponin C-mediated calcium12/7/2012 sensitization induced 31 by levosimendan does not impair relaxation. J Cardiovasc Pharmacol 1995;25:794–801.
levosimendan A drug with a mechanism of action does not increase demand on the already-failing heart
SUPPLY SUPPLY
DEMAND DEMAND
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Orion sponsored study
In a placebo-controlled study levosimendan 18 or 36 μg/kg loading dose followed by 0.2 or 0.3 μg/kg/min 15 min before the start of CPB and continued for 6 h after CPB in randomized 18 patients with normal preoperative cardiac function Showed: Increased cardiac output and stroke volume significantly and reduced SVR. Less hypotension and tachycardia, was associated with the lower dose. It did not affect arterial oxygenation or cause arrhythmogenic effects.
•Nijhawan N. et al. 1999 Levosimendan enhances cardiac performance
after cardiopulmonary bypass: a prospective, randomized placebo12/7/2012 controlled trial. J Cardiovasc Pharm; 34(2): 219-28.
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Control of interaction between actin and myosin Myosin is a mechanochemical enzyme, converting the energy stored in the high-energy phosphate bond of ATP to useful work, at the cost of hydrolysis of the ATP. As mentioned, the principle controlling mechanism of actin:myosin interaction is [Ca ++]i . Calcium binds to the thin filament, and tiny changes in calcium concentration profoundly alter the interaction between actin and myosin. No contraction occurs with depletion of intracellular calcium, there is about a 50% response at concentrations of 2 micromol/l, and doubling this results in about 90% activation. {Technically, a Hill coefficient of over 3}. The regulatory molecules are tropomyosin and troponins C, I and T.
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A thin filament Troponin C has four metal-binding sites, but it is site II that primarily regulates cardiac contraction in heart muscle. Troponin C inhibits the interaction of actin and myosin, provided there is no Ca ++ around. Once calcium concentrations rise, the inhibition decreases, and the two interact to cause motion. This inhibition does not only depend on Troponin C. Tropin I must also be present. Troponin T is the glue that holds the whole system together. There are several differences between skeletal and cardiac muscle: myocardial troponin T is shorter than that in skeletal muscle, cardiac troponin I also differs slightly, and sites I and II are both active in skeletal troponin C. Troponin binding to actin+tropomyosin is usually modelled using the "two-site model", although a "three-state model" has been postulated.
The tropomyosin molecule seems to mediate the long range effect of troponin, as there is only one troponin for every seven actin molecules. Tropomyosin spans seven actins!
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Cardiac contraction occurs when calcium binds the troponin complex (subunits C, I, and T) and Îątropomyosin, making possible the myosin-actin interaction. Actin stimulates ATPase activity in the globular myosin head and results in the production of force along actin filaments. Cardiac myosin-binding protein C, arrayed transversely along the sarcomere, binds myosin and, when phosphorylated, modulates contraction.
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Importantly, levosimendan does not impair
relaxation during diastole when intracellular calcium concentration is decreased.89,91
Levosimendan has been shown to increase
contractility considerably with only a modest increase in intracellular calcium, even in ventricular muscle strips from end-stage failing human hearts.82,98
This finding is significant in relation to clinical effect in that levosimendan does not increase energy consumption96,99 and
The risk of proarrhythmic events is low.93,101 12/7/2012
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ď ˝ Levosimendan does not impair diastolic function or lusitropy.
ď ˝ The mechanism for the positive lusitropic effects can be attributed to PD III inhibition. This leads to
1. Increased cAMP levels, 2. Augmented phosphorylation of phospholamban. 3. Thus enhanced removal of cytosolic calcium by the sarcoplasmic-endoplasmic reticulum ATPase pump, resulting in accelerated relaxation of the myofilaments.
McBride BF, White CM. Levosimendan. implications for clinicians. J Clin Pharmacol 2003;43:1071-1081 Lehtonen L. Levosimendan. a parenteral calcium-sensitising drug with additional vasodilatory properties. Expert Opin Investig Drugs 2001;10:955-970. 12/7/2012
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ď ˝ In contrast, levosimendan reduces the
calcium-binding coefficient of troponin C by stabilizing the conformational shape of the protein in its active form.
ď ˝ This enhances myocardial contraction
similar to traditional agents but with lower intracellular calcium concentration requirements.
McBride BF, White CM. Levosimendan. implications for clinicians. J Clin Pharmacol 2003;43:1071-1081.
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Levosimendan selectively binds to calcium-saturated cardiac troponin C (Figure 3).19,83,84,85,86,87 By binding to troponin C and stabilising the troponin C-Ca2+ complex, levosimendan enhances the sensitivity of the myofilament and facilitates the actin–myosin crossbridge formation.18,19,82 The calcium sensitisation effect of levosimendan has been demonstrated both in skinned fibres,80,89,90 intact cardiac myocytes,97 muscle strips, and isolated hearts.88,97,98,99 The formation of the troponin C-Ca2+–levosimendan complex is calcium-dependent, and calcium sensitivity is enhanced 12/7/2012
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ď ˝ Levosimendan-induced systemic, pulmonary, and
coronary vasodilation as a result of at least three distinct mechanisms.:
1. It opens potassium (K) channels (ATP-sensitive, and 2.
3.
Ca2-activated forms) and reduces intracellular Ca2 concentration in vascular smooth muscle (11). It induces Ca2 desensitization of the contractile apparatus in vascular smooth muscle that does not contain TnC independent of intracellular Ca2 concentration (12). PDE inhibition may also play a role in vasodilation produced by higher doses of the drug. 12/7/2012
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Tasouli and colleagues
Studies Reporting Levosimendan Use in Cardiac Surgery 2005
Pilot study
Adult postcardiac surgery patients with CI<2.0 L/min/m2, LVEF<35% and PCWP>18 mm Hg 75% high-risk adult patients
15
0.1–0.2 µg/kg/min
Successful weaning of IABP and high doses of 2 other inotropes in 80% patients
Harjola and colleagues
2004
Case series
16
2004
Open, single- Children (3 dose study months to 7 yrs) with CHD
13
0.1 µg/kg/min after a bolus of 12–24 µg/kg for 10 min 12 µg/kg over 10 min
2004
RCT
31
Increased CI in all patients with successful weaning from CPB Pharmacokine tic profile of levosimendan in children with CHD is similar to that in adult patients with CHF Significant increase in CO, LVEF, SV, and decrease in SVR with both doses45
Turanlahti and colleagues]
Barisin and colleagues
a
Adult OPCAB patients with good preop LV function
Shahzad G. Raja, MRCS*, Benson S. Rayen, DCH Levosimendan in cardiac surgery: current best available evidence. Ann. Thorac Surg.2006 Apr;81(4):1536-46.
12 µg/kg or 24 µg/kg
12/7/2012
Fig 1. Mechanisms of action of levosimendan and other cardiotonic agents. Mechanisms of action of cardiotonic agents are classified in the upper row in relation to the site of action on cardiac excitation-contraction (EC) coupling in the lower row. Horizontal lines with arrows in the middle of a myocardial cell surrounded by half-tone broad line represent the main stream of cardiac EC coupling. Modulation of Ca2+路 troponin (Tn) 路 tropomyosin complex is reflected either to class I or to class II Ca2+ sensitizing action. Dotted lines indicate the feedback regulation of Ca2+ binding affinity to troponin C induced by tension development (crossbridge cycling). (CICR = Ca2+-induced Ca2+ release; DHPR = dihydropyridine receptor [L-type Ca2+ channel]; NCX = Na+/Ca2+exchanger; SERCA2, SR Ca2+pump ATPase; PLB = phospholamban; RyR = ryanodine receptor [SR Ca2+release channel]; SR = sarcoplasmic reticulum.) (Reproduced with permission from Endoh M. Mechanisms of action of novel cardiotonic agents. J Cardiovasc Pharmacol 12/7/2012
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Relaxation
Enhances contractility of cardiac muscle cells by amplifying the trigger for contraction; does not increase total intracellular calcium levels ď&#x201A;ŽImproves pumping of blood around the body with no increased risk of deathContraction ď ˝
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•The mean duration of cardiopulmonary bypass (CPB) to primary weaning attempt was 104±25 min in the levosimendan group and 109±22 min in the placebo group. •Primary weaning was successful in 22 patients (73%) in the levosimendan group and in 10 (33%) in the placebo group (p=0.002). •Four patients (13%) in the placebo group failed the second weaning and underwent intra-aortic balloon pump (IABP), compared with none in the levosimendan group (p=0.112).
Note: The percentages in the slides are cumulative. Thus the reason that ‘only’ 27% of patients treated with levosimendan were successfully weaned at the second attempts is that only 27% needed a second weaning attempt. Everyone else was successfully weaned first time. Source Eriksson HI et al. Ann Thorac Surg 2009;87:448–54 12/7/2012
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•Here are details of a more recent appraisal of levosimendan in cardiac surgery. •The LEWE study was a prospective, randomized, placebo-controlled, double-blind study that enrolled 60 patients who had left ventricular ejection fraction (LVEF) <50% and who were scheduled to undergo cardiac surgery to correct three-vessel coronary disease. •The mean±SD pre-operative left ventricular ejection fraction (LVEF) was 36±8% in both groups; baseline cardiac index (CI) was 1.8±0.3 l/min/m2 in the levosimendan group and 1.9±0.4 l/min/m2 in the placebo group. •Levosimendan was started immediately after induction anaesthesia using this protocol: 12 mcg/kg bolus, followed by an infusion of 0.2 mcg/kg/min) for 24 h. Strict predefined haemodynamic criteria were used to assess the success of weaning. If weaning was not successful, CPB was reinstituted and an adrenaline infusion was started. If the second weaning attempt failed, intra-aortic balloon pumping (IABP) was initiated. •Source •Eriksson HI et al. Ann Thorac Surg 2009;87:448–54 12/7/2012
49
•
Levosimendan (administered in addition to standard of care) increased cardiac index numerically more than placebo (also given on top of standard of care) in the LEWE study but the difference was not statistically significant.
•
However, as you can see in the graph, post-operative serum lactate levels were significantly lower in the levosimendan group than in the placebo group. This is relevant because high serum lactate levels are signifiers of poor tissue perfusion and are associated with increased mortality.
•
The lower levels attained in the levosimendan-treated patients may therefore be seen as a benefit of therapy. Source Eriksson HI et al. Ann Thorac Surg 2009;87:448–54 12/7/2012
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Levosimendan was compared with placebo in a randomised doubleblind study in 60 patients with 3-vessel coronary disease and LVEF of less than 50%.141 Levosimendan administration (12 μg/kg bolus followed by an infusion of 0.2 μg/kg/min) was started immediately after induction anaesthesia. The primary endpoint was successful primary weaning from cardiopulmonary bypass. Primary weaning was successful in 22 patients (73%) in the levosimendan group and in 10 (33%) in the placebo group (p = 0.002). The odds ratio for failure in primary weaning was 0.182 (95% CI, 0.060 to 0.552) (Figure 28). Four patients in the placebo group failed the second weaning and underwent intraaortic balloon pump (IABP) compared with none in the levosimendan group (p=0.112).
Figure 28. Weaning from cardiopulmonary bypass. Epinephrine was added at he second weaning attempt.141 Levosimendan treatment was associated with lower levels of lactate indicating a better tissue perfusion (Figure 29) and a lesser increase in troponin T, indicating less myocardial damage (Figure 30). 51 12/7/2012 Weaning
Table 1 Comparison of Levosimendan with Milrinone and Dobutamine Feature Levosimendan Milrinone Dobutamine Drug class Calcium sensitizer Phosphodiesterase III inhibitor Catecholamine Effect on intracellular calcium levels No effect Increases Increases Inotrope Yes Yes Yes Vasodilator Coronary, systemic & pulmonary Pulmonary & systemic Mild systemic Effect on myocardial oxygen demand No effect No effect Increases Arrhythmogenic None seen yet Ventricular (12%) and supraventricular arrhythmias (4%) Ventricular ectopic activity (5%)—less than milrinone Available formulations Intravenous Intravenous, oral Intravenous Drug interactions None significant Few significant None significant Administration with β- blockers Yes Yes Yes Adverse effects Headache, hypotension Ventricular arrhythmias, hypotension, headache Tachycardia, hypertension
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•The mechanisms by which levosimendan enhances the inotropic state and produces vasodilation have been extensively studied (1). Briefly, levosimendan binds to the regulatory protein troponin C (TnC) (6) and stabilizes the Ca2-bound conformation of TnC, thereby allowing unopposed interaction between actin and myosin filaments and enhancing the rate and extent of myocyte contraction (7). •A unique feature of levosimendan-TnC binding is its dependence on intracellular Ca2 concentration that facilitates the interaction between TnC and Ca2 during systole, while simultaneously allowing Ca2 to dissociate from the protein during diastole (8). •This Ca2-dependence of TnC binding prevents deleterious abnormalities in relaxation that would otherwise be expected to occur (9). •Preservation of lusitropic function is also facilitated by the PDE-inhibiting properties of levosimendan that occur at higher doses of the drug (10). •Levosimendan-induced systemic, pulmonary, and coronary vasodilation occurs as a result of at least three distinct mechanisms. Levosimendan opens several types of potassium (K) channels (including voltagedependent, ATP-sensitive, and Ca2-activated forms) in conductance and resistance vessels, actions that reduce intracellular Ca2 concentration in vascular smooth muscle (11). •Levosimendan induces Ca2 desensitization of the contractile apparatus in vascular smooth muscle that does not contain TnC independent of intracellular Ca2 concentration (12). PDE inhibition may also play a role in vasodilation produced by higher doses of the drug. (Pagel Vol. 104, No. 4, April 2007 © 2007 International Anesthesia Research Society 12/7/2012
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What is the key clinical evidence to support Simdax? LIDO study
p=0.048
1.0
0
1.09
0.8 0.6
0.8 0.4 0.2
0
n=103 n=100 DO LS
Change in PCWP (mmHg)
Change in CO (L/minute)
1.2
DO LS n=103 n=100
-1 -2
-3.0
-3 -4 -5 -6 -7
-6.5
p=0.03 LS, levosimendan; DO, dobutamine
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What is the key clinical evidence to support Simdax? LIDO study Kaplan–Meier curves showing all-cause mortality
Proportion of patients alive
1.00
Levosimendan
0.90 0.80
0.70
Dobutamine
0.60
● Levosimendan has a comparative Hazard Ratio of 0.57 (95% CI 0.34-0.95; p=0.029) 0.50 0
30
60
90
120
150
180
Days 12/7/2012 Follath F et al. Lancet 2002; 360: 196–202.55
What is the key clinical evidence to support Simdax? RUSSLAN study Kaplan-Meier survival curves
Proportion of patients alive
1.0
0.9
Levosimendan
0.8
Placebo 0.7
â&#x2014;? Levosimendan has a comparative Hazard ratio of 0.67 (95% CI 0.45-1.00; p=0.053) 0.6 0
50
Time (days)
100
150
180
56 Moiseyev V et al. 2002.12/7/2012 Eur Heart J 23: 1422-1432.
How is Simdax administered? Sample calculation of amount of Simdax infusion solution required:
Patients > 90 kg require opening a 2nd vial of Simdax 10 min loading infusion at 259 mL/h = 43 mL 24 h continuous infusion at 22 mL/hr = 528 mL 43 mL + 528 mL = 571 mL
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Weight, kg
Total infusion, mL
40
259
50
312
60
365
70
442
80
494
90
571
100
624
110
677
120
754 57
No treatment
Levosimendan infusion
% change in mean PCWP from baseline
0 -5
n=98
n=94
n=42
-10
-15 -20
-24%
-25
-31%
-30
-35%
-35 -40
6 hours
24 hours
48 hours
p<0.001 12/7/2012
58 Slawsky MT et al. 2000. Circulation 102: 2222-2227.
Concentration (ng/ml)
80 70
Levosimendan OR-1855 OR-1896 (active metabolite)
60 50
40 30
20
10 24 h infusion 0
0
1
2
3
4
5
6
7
8
9
10 11 12 13
Time (days) 59 Kivikko et al, Int 12/7/2012 J Clin Pharm & Ther 2002
Is Simdax safe to use? RUSSLAN study Kaplan-Meier survival curves
Proportion of patients alive
1.0
0.9
Levosimendan
0.8
Placebo 0.7
â&#x2014;? Risk for death is lowered by one-third 0.6 0
50
Time (days)
100
150
180
60 Moiseyev V et al. 2002.12/7/2012 Eur Heart J 23: 1422-1432.
Can Simdax be used for heart failure patients taking -blockers? 1.5
Change in cardiac output
1.0
+ - p=0.01
0.5 0 0
Change in PCWP
+ Levosimendan
Dobutamine
-2 -4
-
p=0.03
Patients on -blockers do not have lessened Simdax effects, as is the case with dobutamine.
Although -blockers interfere with the action of a -agonist (dobutamine), there is no such effect with Simdax because it acts as a calcium sensitiser.
-6 -8 61 12/7/2012 Follath F et al. 2002. Lancet 360: 196-202.
Levosimendan was compared with placebo in 28 patients with pulmonary hypertension. The initial 24-hour levosimendan infusion produced a significant decrease in pulmonary vascular resistance (Figure 31). Importantly, in the same study, levosimendan was administered intermittently every 2 weeks (altogether 5 times) and this repeated administration was found to be safe.142
Figure 31. Mean change in pulmonary vascular resistance (±SEM) during 24-hour and 6-hour infusions at day 0 and week 8, respectively.142 12/7/2012
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On the contractile apparatus of myocardial cells.
On the vascular smooth muscle cells. On the mitochondria of the cardiomyocyte.
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ď ˝ Increases cardiac contractility So improves the circulation of the blood throughout the body
ď ˝ Enhances vasodilatation via potassium ATP channel opening
So improves the filling of the heart with blood, and improves oxygen and nutrient supply to organs
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ď ˝
Levosimendan offers the advantage of increasing systolic force without compromising coronary perfusion due in part to a synergistic mechanism of action attributed to opening of the adenosine triphosphate-sensitive potassium channels [11, 12, 14â&#x20AC;&#x201C;16]. The opening of adenosine triphosphate-sensitive potassium channels by adenosine triphosphate (ATP) produces peripheral vasodilation, coronary artery dilation, and myocyte mitochondrial activation [13]. All these beneficial effects work synergistically with calcium sensitization to improve myocardial performance.
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ď ˝
Unlike classic inotropes, levosimendan does not impair diastolic function or lusitropy. In vitro studies have consistently demonstrated either a neutral or a positive lusitropic effect [13]. It is hypothesized that the neutral effect on diastolic function is secondary to the calcium-dependent binding to troponin C [13]. The mechanism for the positive lusitropic effects can be attributed to PD III inhibition at higher concentrations [12]. Phosphodiesterase inhibition leads to increased cAMP levels, augmented phosphorylation of phospholamban, and thus enhanced removal of cytosolic calcium by the sarcoplasmic-endoplasmic reticulum ATPase pump, resulting in accelerated relaxation of the myofilaments [12].
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ď ˝
Catecholamines such as dobutamine stimulate beta-1 adenoceptors on the myocardial cells, causing increases in cAMP, while phosphodiesterase inhibitors such as milrinone prevent the breakdown of cAMP by phosphodiesterase.
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Levosimendan was administered as an 18 μg/kg loading dose followed by 0.2 μg/kg/min for 6 hours, or 36 μg/kg followed by 0.3 μg/kg/min after cardiopulmonary bypass in patients with normal pre-operative cardiac function in a placebo-controlled study.138 Both doses increased cardiac output and stroke volume significantly and reduced peripheral vascular resistance. Levosimendan did not affect arterial oxygenation or cause arrhythmogenic effects and was well tolerated. The lower dose of levosimendan was as effective as the higher dose, but was associated with less hypotension and tachycardia, and was therefore considered to be a potential dose for use in this patient population. Another placebo-controlled study with 2 bolus doses of levosimendan(8 and 24 μg/kg) in patients after cardiopulmonary bypass showed that levosimendan transiently increased cardiac output, reduced systemic and pulmonary vascular resistances, and did not adversely affect myocardialmetabolism.136,139
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ď ˝ Thus, whether the theoretical advantages of levosimendan will ultimately translate into improved outcome in cardiac surgical patients with LV dysfunction is unknown and will require additional investigation to define.
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Here are some more early data. Nijhawan et al. randomized 18 patients to receive levosimendan (loading dose 18 or 36 mcg/kg, followed by 0.2 or 0.3 mcg/kg/min infusion, respectively) or placebo. Treatment was initiated 15 min before the start of cardiopulmonary bypass (CPB) and continued for 6 h after CPB. As shown in the slide, use of levosimendan was associated with a significant early increase in cardiac output (CO) (p<0.05 vs. placebo). Mean arterial pressure early after the start of treatment was lower in patients randomized to levosimendan than in the placebo group (p<0.05). Systemic vascular resistance was also lower in patients receiving levosimendan than in the placebo group (data not shown in slide). Later in the study, CO in the placebo group increased and narrowed the initial gap between the study groups (see top graph). High-dose levosimendan was associated with higher heart rate (vs. placebo) immediately after CPB. No differences in arterial oxygenation and perioperative cardiac arrhythmias were observed between any of the groups. These results were interpreted as another indication that levosimendan can enhance cardiac performance after CPB in humans. Source Nijhawan N et al. J Cardiovasc Pharmacol 1999;34:219–28
Orion sponsored study
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ď ˝
Another placebo-controlled study with 2 bolus doses of levosimendan (8 and 24 Îźg/kg) in patients after cardiopulmonary bypass showed that levosimendan transiently increased cardiac output, reduced systemic and pulmonary vascular resistances, and did not adversely affect myocardial metabolism.136,139
Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol 2004; 43:635-41 Lilleberg J, Nieminen MS, Akkila J, et al. 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 1998; 19(4): 660-8. 12/7/2012
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ď ˝
Current best available evidence (grade A/level 1b) suggests that levosimendan enhances cardiac performance and reduces left ventricular afterload after CPB in patients with normal preoperative left ventricular function. Furthermore, in addition to being effective in postoperative rescue therapy for patients with difficult weaning from CPB, elective preoperative initiation of levosimendan in patients with high perioperative risk or compromised left ventricular function appears to reduce catecholamine requirements, the need for mechanical circulatory support, and the duration of critical care. It has a favorable pharmacokinetic profile and is well-tolerated by adult as well as pediatric postoperative cardiac surgical patients. However, these encouraging preliminary results with levosimendan in cardiac surgical patients need to be verified by a larger, multicenter RCT, evaluating the optimum dosage and duration of therapy, its role in specific subgroups of patients (such as by etiology and age), its combination with other vasoactive intravenous therapy, and finally its long-term effects on symptomology, duration of hospitalization, and mortality as well as its cost-effectiveness.
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Why is calcium sensitisation the best approach? â&#x2014;? Simdax does not increase risk for cardiac arrhythmias.
Properties of acute HF treatment drugs Dobutamine
Milrinone
Simdax
Sinus tachycardia
++
+++
-
Supraventricular tachycardia
+
+
-
Ventricular arrhythmia
++
+++
-
Singh BN et al. 1999. Am J Cardiol 83: 16-20. 12/7/2012
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only when intracellular calcium concentration is elevated.18 As a result of this unique property, levosimendan increases contractile force during systole when intracellular calcium concentration is increased. Importantly, levosimendan does not impair relaxation during diastole when intracellular calcium concentration is decreased.89,91 Levosimendan has been shown to increase contractility considerably with only a modest increase in intracellular calcium, even in ventricular muscle strips from end-stage failing human hearts.82,98 This finding is significant in relation to clinical effect in that levosimendan does not increase energy consumption96,99 and the risk of proarrhythmic events is low.93,101 Other agents shown to improve cardiac output, such as milrinone, have different 12/7/2012
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Increase in oxygen consumption (%)
● Simdax does not cause oxygen wasting. 70
60
p=0.047
50
58%
40
30 20 10
Dobutamine caused 5-fold greater increase in O2 consumption vs levosimendan (in healthy volunteers). Simdax was neutral for myocardial O2 consumption vs placebo (in decompensated CHF patients).
12%
0 Dobutamine Levosimendan Ukkonen et al. 1997 Clin Pharmacol Ther 61:596-607; Ukkonen et al 2000 Clin Pharmacol Ther 68: 522-31.
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Calcium sensitisation with levosimendan offers increased cardiac contractility without:Increasing i • ntracellular calcium97• Increasing oxygen consumption95 Affecting cardiac rhythm93,101 and relaxation89,91 Opening of ATP-sensitive potassium channels on the sarcolemma of smooth muscle cells in the vasculature Vasodilation with levosimendan results from the opening of ATPsensitive potassium channels; it reduces preload and afterload, and improves oxygen supply to the myocardium. Vasodilation with levosimendan has been demonstrated in both arterial21 and venous22 vascular beds, and in the coronary arteries.23 Opening of ATP-sensitive potassium channels has also been observed in ventricular myocytes—an effect that may help to protect ischaemic myocardium.104 12/7/2012
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The opening of ATP-sensitive potassium (KATP) channels by levosimendan was both electrophysiologically21 and pharmacologically23 demonstratedin arterial and venous preparations and in coronary arteries.105 It was also shown that the venodilatory effect of levosimendan on the noradrenalin-constricted human portal vein22 or serotonin-constricted human saphenous vein106 was also mediated by the opening of KATP channels. In addition, some pharmacological findings indicate that levosimendan may open the calcium-dependent potassium channels in arteries and veins106 as well as voltagedependent potassium channels in coronary arteries.107 In light of the above-mentioned studies, it seems that levosimendan may preferentially stimulate KATP channels in small resistance vessels.24 In large conductance vessels the vasodilatation appears to be mediated mainly through opening of voltage as well as calcium dependent potassium channels. In addition, at high concentrations of levosimendan, PDE III inhibition might contribute to the vasodilatory effect.108 12/7/2012
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Opening of ATP-sensitive potassium channels in the mitochondria of the cardiomyocytes
By opening mitochondrial ATP-sensitive potassium (mitoKATP) channels, 28,78 levosimendan protects the heart against ischemia-reperfusion damage.95 The demonstration that levosimendan can prevent or limit myocyte apoptosis via the activation of mitoKATP channels provides a potential mechanism whereby this agent might protect cardiac myocytes during episodes of acute heart failure.109,110,27
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