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Inoprotection: the perioperative role of levosimendan.

SUMMARY

Levosimendan is emerging as a novel cardioprotective inotrope. Levosimendan augments myocardial contractility by sensitising contractile myofilaments to calcium without increasing myosin adenosine triphosphatase activity or oxygen consumption. Levosimendan activates cellular adenosine triphosphate-dependent potassium channels, a mechanism which is postulated to protect cells from ischaemia in a manner similar to ischaemic preconditioning. Levosimendan may therefore protect the ischaemic myocardium during ischaemia-reperfusion as well as improve the contractile function of the heart. Adenosine triphosphate-dependent potassium channel activation by levosimendan may also be protective in other tissues, such as coronary vascular endothelium, kidney and brain. Clinical trials in patients with decompensated heart failure and myocardial ischaemia show levosimendan to improve haemodynamic performance and potentially improve survival. This paper reviews the known pharmacology of levosimendan, the clinical experience with the drug to date and the potential use of levosimendan as a cardioprotective agent during surgery.

Key Words: levosimendan, heart failure, cardiac surgery, inotropy, cardioprotection, ischaemic preconditioning

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Ischaemic preconditioning is an adaptive cellular response to ischaemia which protects the cell from further ischaemic insult, slows the rate of cell death and preserves organ functions (1,2). Recent interest has focused on how pharmacological agents (such as the volatile anaesthetics) can similarly preserve organ function during surgery (3). Levosimendan, a new inotropic agent with novel cardioprotective effects, is emerging as a therapeutic option for both intraoperative cardiac support as well as organ protection. Levosimendan appears to mimic ischaemic preconditioning and confer protection to the heart during ischaemia-reperfusion states, as well as improve the haemodynamic state in heart failure. However the role of levosimendan in the perioperative period remains undefined.

The multiple but complimentary pharmacological actions of levosimendan make it attractive as a therapeutic agent in the treatment of perioperative heart failure (Figure 1). Levosimendan enhances myocardial contraction by sensitising myofilaments to intracellular calcium (4), as well as causing vasodilatation via activation of adenosine triphosphate-dependent potassium channels ([K.sub.ATP]) (5-7). [K.sub.ATP], channels are also present in tissues apart from the myocardium, includingvascular endothelium (8), brain (9) and kidney (10). In blood vessels, [K.sub.ATP] channel activation results in systemic and pulmonary vasodilatation with improvement of haemodynamic performance (11). In heart failure, levosimendan reduces pulmonary capillary wedge pressure and improves diastolic function (12,13).

Importantly, [K.sub.ATP] channel activation is a central mediator in the mechanism of ischaemic preconditioning (14,15), the reduction of myocardial infarct size (16) and recovery of stunned myocardiums (17). Two types of [K.sub.ATP] channels have been implicated in cellular preconditioning, the sarcolemmal membrane [K.sub.ATP] channel (s[K.sub.ATP]) and the mitochondrial [K.sub.ATP], channel (m[K.sub.ATP]). Activation of the m[K.sub.ATP] by levosimendan results in potassium influx into cardiac mitochondria, a postulated mechanism of cardioprotection (18).

The European Heart Associations (19) has recommended the use of levosimendan in the short-term treatment of acute heart failure when there is a need for inotropic support. In recent large prospective trials (20), the addition of levosimendan to standard inotropic therapy improved cardiac performance and may have improved long-term survival compared to dobutamine (21). Additionally, reports of patient survival with levosimendan in catecholamine-resistant sepsis, or in patients unresponsive to conventional therapy (22,23) have been published, drawing attention to a unique mechanism of action and survival potential. In cardiopulmonary resuscitation, there is evidence that levosimendan improves survival through activation of [K.sub.ATP] channels (24).

[FIGURE 1 OMITTED]

A positive inotropic agent that simultaneously activates intracellular [K.sub.ATP], channels is potentially protective of patients at risk of myocardial ischaemia. Such 'inoprotection' is particularly relevant to patients in cardiogenic shock, evolving myocardial infarction, perioperative ischaemia and emergence from cardiopulmonary bypass. The question remains whether the multiple pharmacological actions of levosimendan occur over a similar range of plasma concentrations. The intracellular mitochondrial effect, for example, may be a more subtle action and occur only at specific plasma concentrations. Investigation of individual concentration effects at the cellular level provides a basis for understanding the clinical response to this drug. This review investigates the known pharmacology of levosimendan, the clinical experience to date and the potential use of levosimendan as a cardioprotective agent during surgery.

PERIOPERATIVE CARDIAC DYSFUNCTION

During anaesthesia, patients may experience induced vasodilatation, volume shifts and blood loss, pain and hypothermia. In addition the perioperative state is associated with increased myocardial work, the release of inflammatory mediators and catecholamines, a hypercoagulopathic state and sympathetic nervous system activation, all of which impact on the patient with limited myocardial reserve. Pre-existing coronary artery disease may predispose patients to myocardial ischaemia during anaesthesia, or from ischaemia-reperfusion injury following cardiopulmonary bypass. Perioperative ischaemia resulting in myocardial infarction and cardiac arrest is associated with a high incidence of mortality (25).

As for the non-surgical patient, management of perioperative heart failure is similarly directed to afterload reduction, maintenance of coronary perfusion and augmentation of contractility. The monitoring of intracardiac filling pressures and cardiac function by intraoperative echocardiography is required. Infusion of vasodilator agents (glyceryl trinitrate) may have pronounced effects during anaesthesia and requires careful titration. Maintenance of an adequate mean arterial pressure with volume loading and use of vasoconstrictor agents is essential for maintaining coronary perfusion, particularly when intracardiac pressures are elevated. When ejection fraction remains low and is inadequate for organ perfusion, short-term infusion of inotropic drugs can restore circulatory homeostasis.

The short-term infusion of inotropic drugs, however, is not associated with improved long-term prognosis (26). On the contrary, the long-term use of these agents is limited since they are associated with arrhythmia, sudden death and increased mortality (27-31). Most inotropic drugs increase cardiac contractility by increasing the level of intracellular cyclic adenosine monophosphate (cAMP) (32). Catecholamine-based [beta]-adrenoceptor agonists increase cAMP formation by activation of adenyl cyclase, mediated via guanine nucleotide binding proteins (G-proteins) coupled to the [beta]-adrenoceptor. Cyclic nucleotide phosphodiesterase (PDE) inhibitors act by decreasing the breakdown of cAMP This mechanism of action, though effective, is limited by intracellular calcium overload resulting in increased myocardial oxygen consumption, arrhythmogenesis and myocardial cell death (apoptosis).

Research continues for novel inotropic drugs that can increase contractility independent of cAMP, thereby avoiding intracellular calcium loading. Such drugs may increase contractility by affecting sarcolemmal ion pumps, sarcoplasmic reticular function (flosequinan) or myofilament sensitivity to calcium (levosimendan). The calcium sensitisers in particular are an attractive class of drug since their inotropic action is unique and not dependant on increased cAMP levels, or associated with increased energy expenditure. However, some drugs of this class may exhibit a mixed action, for example pimbomendan, having both calcium sensitising and PDE inhibitory effects (33).

The question remains whether inotropic augmentation of myocardial contractility is a valid approach in heart failure (34). Heart failure therapy currently centres on modulating the neurohumoral activation that arises from myocardial dysfunction. Antagonists of the renin-angiotensin system for example, provide cardiac protection by unloading the ventricle, reducing oxygen consumption and attenuating cardiac remodelling and hypertrophy. Recent trials have also shown that [beta]-adrenoceptor antagonists, which can act as negative inotropes, cause beneficial effects on cardiac contractility, remodelling and survival (35). Similarly, levosimendan has been shown to improve survival in hypertensive Dahl/Rapp rats by attenuating cardiac remodelling and cardiomyocyte apoptosis (36).

Alterations in intracellular calcium cycling and adrenergic signalling are hallmarks of depressed myocardial contractility in chronic heart failure. The traditional 'cardiocentric' approach in heart failure management has been to further stimulate the impaired myocardium with inotropic drugs. Therapy may be more appropriately targeted to include support of other organ function rather than focussing primarily on myocardial contractility per se.

PHARMACOLOGY OF LEVOSIMENDAN

Levosimendan (Simdax[R], (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl] hydrazono]propanedinitrile) is the active enantiomer of simendan, a pyridazinone-dinitrile derivative (Figure 1). The drug is presented as a clear yellow liquid for intravenous infusion and an oral formulation is under development (37,38). Clinical experience (Table 2) indicates that administration of levosimendan at a loading dose of 6 to 24 [micro]g.[kg.sup.-1] followed by infusion of <0.4 [micro]g.[kg.sup.-1].[h.sup.-1] will cause a haemodynamic response. A 24-hour infusion of 0.05 to 0.2 [micro]g.[kg.sup.-1].[h.sup.-1] is associated with therapeutic plasma levels of 10 to 100 ng.[ml.sup.-1], i.e. 0.035 to 0.32 [micro]M(39).

Pharmacokinetics

Levosimendan has complex pharmacokinetics and its clinical effects are prolonged due to its active metabolites. The metabolite OR-1896 has a half-life of 80 h, reaches peak plasma concentration at two days and results in a haemodynamic effect lasting seven to nine days after cessation of the parent infusion (39,40). Since OR-1896 potentiates the haemodynamic effects of levosimendan after cessation of the parent drug, short-term infusions of six to 24 hours have been used clinically. No specific interaction with commonly used cardioactive drugs has been reported.

MECHANISM OF ACTION

Racemic simendan was initially isolated by stereoselective binding to troponin C using an affinity column (4). Levosimendan, the levorotatory form, was shown to exert a positive inotropic effect in isolated cardiac preparations (41), with greater potency than the dextrorotatory isomer, dextrosimendan (42). The concentration producing 50% maximal inotropic effect ([EC.sub.50]) has been recently described in guinea pig papillary muscle as 60 nM and 2.3 [micro]M, for levosimendan and dextrosimendan respectively (43). The property of calcium sensitisation is based on skinned fibre experiments (40,41,71), demonstration of positive inotropy without increases in calcium transient or PDE inhibition (40,88) and NMR mapping studies demonstrating specific stereo-selective binding of levosimendan to troponin C(TnC) (68). Levosimendan has also been studied in human isolated tissue preparations (44-47).

Levosimendan has multiple effects on the circulatory system as shown by in vitro and in vivo preclinical studies and in clinical trials. Despite differences in tissue preparation, species and experimental design, specific pharmacological actions of levosimendan have been defined (Table 1). Inotropy from calcium sensitisation occurs at concentrations well below 1 [micro]M, while PDE III inhibition may contribute to inotropic effect at concentrations above 1 [micro]M. This positive inotropic effect has been demonstrated by integrative experiments using isolated cardiomyocytes, ventricular muscle and perfused heart with simultaneous monitoring of the [beta]-adrenoceptor cAMP signalling cascade to indicate active PDE inhibition. Measurements have included L-type calcium transient using the voltage patch clamp technique, phosphorylation of signalling proteins cAMP, cGMP and phospholamban concentrations, PDE isoform inhibition and calcium transient amplitude using aquorin immunoflurescence (57,88,92).

From these data levosimendan appears to have a positive inotropic effect with an [EC.sub.50] of around 60 to 100 nM. Pharmacokinetic studies (40,48-50) indicate a positive haemodynamic effect associated with vasodilatation at plasma concentrations of around 50 ng.[ml.sup.-1] (i.e. 180 nM), correlating with the experimental work.

Less clear however, is whether the actions of inotropy, vasodilatation and cardioprotection all occur at similar plasma concentrations in vivo and whether there is a differential effect between tissues. Table 1 indicates a wide variability in concentration at which levosimendan exerts its pharmacological effects. Plasma concentrations of levosimendan that are positively inotropic are speculated to also confer cellular protection against ischaemia-reperfusion injury via mitochondrial [K.sub.ATP] channel activation (51). Levosimendan activates [K.sub.ATP] channels in rat isolated cardiac mitochondria (52) (Figure 2) and ventricular cells (6) with [EC.sub.50] values of 0.83 and 4.7 [micro]M, respectively; values which are different from those required for inotropism. Further, during ischaemia, as the intracellular ADP: adenosine triphosphatase (ATP) ratio increases, the potency of levosimendan may be potentially enhanced. However it is important not to over-interpret in vitro data to the clinical setting, but understand levosimendan has a spectrum of actions at any given plasma level (Figure 3).

[FIGURE 2 OMITTED]

Excitation-contraction coupling

Levosimendan exerts its inotropic effect without increasing the intracellular calcium transient (53). With excitation, cytosolic calcium concentration increases from [10.sup.-7] to [10.sup.-5] M to initiate contraction movement (54). Calcium binds TnC inducing a conformational change in the molecule (55) which enables interaction between actin and myosin filaments powered by ATP (56). During diastole cytosolic calcium levels fall, predominantly due to calcium re-uptake by the sarcoplasmic reticulum ATPase (SERCA) and myofilament activation subsides, enabling myocardial relaxation and ventricular filling to occur. In human isolated myocardium, levosimendan had a similar effect on contraction force to milrinone (49% and 58% increase respectively), but increased the calcium transient by only 15% compared to milrinone 49% (46). As PDE inhibition increases, so too will the amplitude of the calcium transient. In the guinea pig isolated hearts (57), levosimendan increased inotropy with a lower calcium transient and less energy consumption.

Catecholamines cause a greater amount of calcium to enter the cell at each excitation and a larger fraction of the cytosolic calcium pool to be taken up by the sarcoplasmic reticulum during relaxation. The calcium transient peak is increased (58) which initiates an increased positive inotropic response. [beta]-adrenergic stimulation also influences the pacemaker current [I.sub.f] resulting in a more rapid diastolic membrane repolarisation and increased contraction frequency (59). In heart failure, sympathetic overstimulation (60) results in [beta]-adrenoceptor uncoupling and tolerance (61), increased oxygen consumption, metabolic changes, alteration of cardiac output distribution and cellular apoptosis. Excitation-contraction coupling is abnormal, characterised by elevated diastolic intracellular calcium, blunted calcium transients and slow decay. Abnormal calcium cycling is believed to be responsible not only for contractile dysfunction but also arrhythmogenesis (62-65).

[FIGURE 3 OMITTED]

Calcium sensitization

Levosimendan binds to troponin C, stabilises the calcium-bound conformation and prolongs the systolic actin-myosin interaction (66). Nuclear magnetic resonance mapping studies have demonstrated levosimendan binding to the regulatory domain of cTnC, inducing a chemical shift (67). This calcium sensitising effect of levosimendan is postulated to occur in a calcium-dependent manner (68,69) with enhancement of the contractile effect at lower calcium concentrations.

Effect on lusitrophy

Diastolic dysfunction is recognised as a major component of heart failure and is present in up to 50% of patients (70). A potential risk of calcium sensitisers is worsening of diastolic dysfunction by increasing the sensitivity of myofilaments to calcium during diastole. Calcium sensitisers such as EMD 53998, EMD 57033 and Org 30029 have impaired diastolic relaxation in human isolated myocardium (71) and in experimental animals (72,73), though not in some preparations (74,75). Varying degrees of PDE inhibition may account for these differences.

Levosimendan does not appear to worsen lusitrophy and this relates to its stabilising action of the calcium-troponin C complex rather than increasing the binding affinity of calcium to troponin C. In vitro studies have shown levosimendan to bind to troponin C in a calcium-dependent manner, with decreased binding at lower calcium levels and unimpaired relaxation (76). During diastole, as calcium levels fall, levosimendan molecules are postulated to dissociate from the binding site of cTnC, thereby preventing an increase in calcium sensitivity. Levosimendan and OR-1896 appear to have a positive or neutral lusitrophic effect (53-77). In patients with severe low-output heart failure, levosimendan has been shown to maintain diastolic function and reduce left atrial filling pressure (12,13). Few studies however, have attempted to further quantify this effect on diastolic function (78).

Phosphodiesterase inhibition

Four phosphodiesterase isoforms exist in the human myocardium (79,80) and inhibition of the isoforms III and IV is necessary for increased contractility (81). Phosphodiesterase enzymes break down cAMP to maintain an intracellular homeostatic balance and limit the effect of PKA phosphorylation (82). Myocyte contraction force increases when L-type calcium channels are phosphorylated by cAMP-dependent PKA and inward calcium current ([I.sub.Ca]) is increased (83).

Levosimendan has a molecular structure with similarities to phosphodiesterase inhibitors. Early studies have consistently shown levosimendan to inhibit the phosphodiesterase PDE III isoenzyme particularly at higher concentrations. This initially suggested an alternative mechanism of inotropy rather than calcium sensitisation (84-86). At concentrations greater than 0.3 [micro]M, levosimendan inhibits PDE III in vitro (41,87) and this questions the role of a cAMP effect in the clinical action of increased heart rate and cardiac performance seen with levosimendan. In clinical practice, plasma levels less than 100 ng/ml have been recommended to avoid a PDEI effect (88).

The question of whether levosimendan has parallel PDE inhibitory activity at higher concentrations remains. It has been argued that a positive inotropic effect from PDEI only occurs when the two isoforms (PDE III and IV) are inhibited simultaneously (89-91). PDE inhibitors with poor selectivity are more likely to inhibit both isoforms and increase cAMP Levosimendan (and OR-1896) however, has one of the highest selectivity factors (92) (10,000 fold compared with milrinone 14 fold for PDE III:IV inhibition) indicating a marked differential effect in the inhibition of the III and IV isoforms. This implies the two isoforms are not simultaneously inhibited and that PDE inhibition is unlikely to be the primary mechanism of action (93).

Cardiovascular effects

The effects of levosimendan on the regional distribution of cardiac output compared to pimobendan and milrinone have been studied in anaesthetised dogs (94). All three agents caused similar increases in heart rate, cardiac output, left ventricular dP/dt and decreases in end-diastolic pressure and systemic vascular resistance. Levosimendan notably increased blood flow to the renal medulla and small intestine. Gastric mucosal oxygenation was more improved with levosimendan infusion compared to milrinone and dobutamine (95).

Intracoronary injection of levosimendan (12 and 24 [micro]g.[kg.sup.-1]) in anaesthetised pigs increased coronary blood flow by 26 to 41% and this effect was inhibited by nitric oxide antagonism (96). In male volunteers, non-invasive assessment of cardiac function using dynamic positron emission tomography showed levosimendan to have a neutral effect on oxygen consumption compared to dobutamine which increased oxygen requirement (97). In a follow-up study of heart failure patients (NYHA III/IV) levosimendan enhanced cardiac output and right ventricular function without an increase in myocardial oxygen consumption. This was associated with coronary, pulmonary and systemic vasodilatation (98).

Clinical experience has shown a dose-dependent increase in heart rate and decrease in mean arterial pressure and systemic vascular resistance (88).

Significant hypotension has the potential to impact on regional circulation and this may be a limiting factor in the use of higher doses in individual patients. Hypotension can result in reduced coronary perfusion pressure, particularly in the presence of a critical coronary artery stenosis. In a porcine model of coronary artery ligation, levosimendan reduced systemic vascular resistance by 21% and reduced blood flow through a stenotic left anterior descending coronary by 7%, whereas flow in the non-ligated circumflex artery increased by 15% (99). Additionally levosimendan increased heart rate in these animals. Positive chronotropy is reported in both human and isolated tissue studies.

The role of [K.sub.ATP] channel activation

Mitochondrial [K.sub.ATP] channels appear to be pivotal in ischaemic preconditioning, and specific mitochondrial channel openers have been proposed as the mechanism for cardioprotection during surgery (100-102). Pharmacological activators of [K.sub.ATP] channels include levosimendan, nicorandil, cromakalim, diazoxide, minoxidil and pinacidil, while glibenclamide and tolbutamide both inhibit [K.sub.ATP] channels non-specifically. In patients with angina (IONA Trial) (103), nicorandil was shown to have a protective effect, possibly mediated by activation of the m[K.sub.ATP] channel (104).

Recent molecular cloning (105) has characterised the [K.sub.ATP] channel to consist of subunits of the sulfonylurea receptor SUR, coupled with subunits of the inward rectifier Kir6.x. These ion channels are essentially molecular pores in cell membranes allowing ionic flow and generation of pico-currents across the cell membrane (106). The structure of [K.sub.ATP] isoforms vary between tissues and, within the cell, myocyte sarcolemmal channels differ in structure to channels located in mitochondria. The sarcolemmal [K.sub.ATP] channel acts as a metabolic sensor coupled to intracellular processes, such as creatine kinase and adenyl cyclase, linking cellular metabolism to surface membrane electrical activity. When intracellular ATP falls during ischaemia, these channels are activated to hyperpolarise the membrane, shorten the action potential, reduce calcium influx and conserve energy (107).

Mitochondrial [K.sub.ATP] channels are believed to act as "guardians of cellular integrity" by stabilising mitochondrial metabolism during ischaemia (100,108,109). These organelles play a major role in the process of both apoptosis and necrotic cell death and are believed to play a central role in the mechanism of preconditioning. Mitochondrial [K.sub.ATP] channels are involved in the regulation of mitochondrial matrix volume, matrix calcium, oxidative phosphorylation and nuclear calcium transient and gene expression (110). The opening of a non-specific pore in the inner mitochondrial membrane, called the mitochondrial permeability transition pore (mPTP), in response to ischaemic stress is a central mechanism in cell damage (111). Prevention of mPTP opening is believed to be the primary effector of cardioprotection in the heart (100,112,113). Levosimendan has been shown to open m[K.sub.ATP] channels and cause depolarisation in the respiring rat mitochondria (52): this presumably stabilises the organelle and is the postulated mechanism of mitochondrial inoprotection (Figure 4).

[FIGURE 4 OMITTED]

Levosimendan and vasodilatation

Levosimendan has been shown to activate sarcolemmal channels in arteries, arterioles and veins (5,114-116) acting as an active vasodilator agent on systemic vasculature and the microcirculation94117. Sarcolemmal [K.sub.ATP] channels play a key role in maintaining the basal tone of the coronary vasculature (118). Evidence also indicates other K channels may also be activated (119) accounting for differences in response between large conductance and smaller resistance vessels. Channel activation leads to potassium ion efflux and membrane hyperpolarisation. This is postulated to inhibit the inward L-type calcium current, lower intracellular calcium and induce vasodilatation (120). Vasodilatation leads to increased coronary arterial flow, lowered systemic and pulmonary vascular resistance and improved organ microcirculation (11,121,122). With additional cellular protective properties, the concept of vascular protection by levosimendan is a promising area of research.

Arrhythmogenesis

Unlike other positive inotropic agents that increase intracellular cAMP, levosimendan is not associated with an increased incidence of arrhythmia leading to cardiovascular mortality. A direct effect on heart rate was observed in animal experiments (41,85), while in vivo vasodilatation may also contribute to reflex tachycardia. Clinically, heart rate tends to be increased in a dose-dependent manner in both healthy volunteers and in heart failure patients (88). Levosimendan administered in lower doses (loading dose LD <25 [micro]g.[kg.sup.-1], infusion <0.2 [micro]g.[kg.sup.-1].[h.sup.-1]) to patients with normal cardiac function and receiving 24 h Holter monitoring was not associated with increased incidence of arrhythmia or significant alteration of the QT interval (123,124). A second Holter study also confirmed no increased frequency of atrial fibrillation, supra- or ventricular tacchycardia in heart failure patients receiving levosimendan (125). However, at higher doses (LD 24 and 36 [micro]g.[kg.sup.-1], infusion 0.4 to 0.6 [micro]g.[kg.sup.-1].[h.sup.-1]) and prolonged infusion, levosimendan prolonged the QT interval in heart failure patients (39,88). Despite these electrophysiological changes there is no evidence of associated morbidity. In a canine model of ischaemia, levosimendan has recently been shown to significantly reduce the risk of arrhythmia and improve survival rate (126).

Levosimendan in ischaemia-reperfusion injury

Levosimendan has been shown to reverse the effects of myocardial stunning (127) and improve contractile force in models of ischaemia-reperfusion. Levosimendan has the potential to reverse myocardial depression induced by acidosis in the stunned myocardium because of its mode of action on the myofilaments (128). During ischaemia, acidosis decreases calcium sensitivity in the failing heart by interacting with the N-terminus of cardiac troponin I, at a site different from levosimendan action (129). In vitro models of acidosis demonstrate levosimendan to have positive inotropy (130,131). In view of its unique myofilament action, levosimendan has the potential to preserve contractile function during such times of stress.

Most ischaemia-reperfusion studies have shown levosimendan to have protective effects following reperfusion injury. In anaesthetised dogs (132) undergoing coronary artery occlusion, administration of intracoronary levosimendan improved myocardial function following reperfusion. A similar 'anti-stunning effect' has been demonstrated in guinea pig isolated heart model of global ischaemia-reperfusion (133-135). This effect was maintained in the presence of calcium and [beta]-adrenoceptor antagonists (136) and was not associated with increased ATP utilisation (137). Using a global ischaemic guinea pig model, post-ischaemic contractility was enhanced by levosimendan, whereas dobutamine worsened it (138. Similarly, in patients undergoing angioplasty for acute myocardial ischaemia, levosimendan reduced myocardial stunning and improved LV pressure-volume parameters without impairing diastolic function (13). In contrast, two studies showed treatment with levosimendan impaired contractile function and was associated with an increased incidence of arrhythmia on reperfusion (99,135).

CLINICAL APPLICATION

Levosimendan in heart failure

Studies in patients with advanced heart failure show that levosimendan improves stroke volume, reduces left atrial filling pressure and is less arrhythmogenic when compared to dobutamine or placebo (Table 2A). Short-term infusion of levosimendan is safe, without tolerance and with haemodynamic effects persisting after discontinuation. In an early dose range trial in 151 patients with stable heart failure (NYHA III), a loading dose of levosimendan (3 to 36 [micro]g.[kg.sup.-1]) followed by infusion (0.05 to 0.6 [micro]g.[kg.sup.-1].[min.sup.-1]) was compared to dobutamine and placebo (88). Improved haemodynamic endpoints were seen in 50% (lowest dose) to 88% (highest dose) in patients receiving levosimendan compared with dobutamine (70%) and placebo (14%). The minimum effective dose required for haemodynamic effect in heart failure patients was a loading dose of 0.6 [micro]g.[kg.sup.-1] followed by infusion of 0.05 to 0.1 [micro]g.[kg.sup.-1].[min.sup.-1].

Levosimendan is clinically effective in patients with acutely decompensated heart failure when compared to placebo (139-141) and to dobutamine (LIDO study) (11). Importantly, levosimendan had beneficial effects on survival compared to dobutamine at 31 and 108 days (11). Levosimendan is also effective in patients with left ventricular failure from acute myocardial infarction requiring inotropic therapy (RUSSLAN study) (122).

Two recent large prospective trials (20) have evaluated the survival advantage of levosimendan. The REVIVE II study showed that patients who received levosimendan in addition to standard inotropic therapy were more likely to show clinical improvement and less likely to deteriorate than patients on standard therapy alone. The SURVIVE trial studied 1327 patients with acutely decompensated heart failure and randomised patients to dobutamine (minimum 5 [micro]g.kg.[min.sup.-1]) or levosimendan bolus (12 [micro]g.[kg.sup.-1]) followed by a stepped dose regimen of levosimendan (0.1 to 0.2 [micro]g.[kg.sup.-1].[min.sup.-1] over 24 h), with survival as the primary endpoint. Even though levosimendan resulted in fewer deaths compared with dobutamine alone, SURVIVE failed to meet its primary goal of reducing mortality by 25% at six months. However, it demonstrated levosimendan to be an effective alternative to current therapies for heart failure.

Levosimendan in sepsis

In septic shock the inflammatory response to infection results in a complex interaction between pathological vasodilatation, relative hypovolaemia, direct myocardial depression, altered blood flow distribution and microvascular abnormalities. Cardioactive agents are often used in combination and there are few comparative clinical trials investigating outcome. Guidelines for the management of severe sepsis and septic shock have been formulated (142). Noradrenaline or dopamine are commonly used as vasopressor agents during initial fluid resuscitation and dobutamine is often the first choice inotrope, with vasopressin reserved for salvage therapy. Clinical reports of the use of levosimendan in septic shock are limited, with case reports describing survival in septic patients unresponsive to standard therapy (143-144).

However the efficacy of levosimendan in septic myocardial depression has been studied in a porcine model of endotoxaemias (145). Cardiac output and oxygen delivery were improved and pulmonary vasoconstriction reduced. Other animal studies (146,147) also indicate levosimendan has potential benefit in the treatment of circulatory failure in sepsis. Levosimendan may be protective in sepsis where severe vasoconstriction may predispose to ischaemic acute renal failure (148).

Levosimendan in cardiac surgery

Despite cardioplegic protection during cardio-pulmonary bypass (CPB), a variable degree of ischaemia and myocardial stunning usually follows cardiac surgery (149). Multiple additives to cardioplegic solution, including potassium channel openers, have been proposed as therapies to reduce reperfusion injury (101). Separation from CPB is a critical event during cardiac surgery, where cardiac performance must be optimised at a time of relative ischaemia and reperfusion injury. The development of a low cardiac output syndrome post-CPB can result in a failure to wean a patient from cardiopulmonary support, or to frank post-cardiotomy cardiogenic shock. Cardiogenic shock has associated high mortality and is a major indication for inotropic and mechanical support (150).

Anaesthetists commonly administer [beta]-adrenergic agonists (dobutamine, dopamine or adrenaline) as first-line inotropic therapy, with secondary addition of milrinone or enoximone before the institution of mechanical support. The choice of inotrope is however, dependent on institutional protocol (151-153) as well as individual preference. The evidence to support the use of one inotrope over another has not been rigorously studied and choice is often made on the basis of a more favourable side-effect profile (154,155), a profile which is dose-dependant.

Impairment of diastolic relaxation is a common feature after separation of CPB (156) and recently both dobutamine and milrinone have been shown to have favourable effects on the rate of myocardial relaxation post-CPB (157,158) resulting in improved diastolic and systolic cardiac performance. For this reason dobutamine is viewed by many as a favourable initial inotropic therapy. Combination therapy using a catecholamine with a PDEI such as milrinone is an established clinical approach for biventricular dysfunction (159,160). However, acute [beta]-adrenoceptor desensitisation and uncoupling occurs after CPB (161,162), which can result in altered responses to catecholamine inotropic infusions.

Levosimendan

Experience with levosimendan in human heart surgery is limited, with small clinical studies involving patients with both normal and impaired ventricular function (163) (Table 2B). In low output states following cardiac surgery, levosimendan may provide inotropic support and may have an added cardioprotective benefit, reducing further myocardial damage. Levosimendan given to cardiac surgical patients before CPB is associated with lower troponin I concentrations (164). In the perfused guinea pig heart model employing normothermic cardioplegic arrest, levosimendan has a positive inotropic and chronotropic effect during reperfusion (165).

When given as a loading dose followed by continuous infusion before separation from CPB, levosimendan produces sustained increases in cardiac output and heart rate, and reductions in mean arterial pressure, systemic vascular resistance and pulmonary capillary wedge pressure in patients with normal ventricular function. The increase in cardiac output is due to increased stroke volume and reduced systemic vascular resistance (48). Haemodynamic improvement occurs without increased oxygen consumption or substrate utilization (48, 121). Levosimendan does not affect arterial oxygenation or cause arrhythmia and is well tolerated in postoperative cardiac surgery patients. The increase in heart rate is a combination of baroreceptor reflex activation and direct chronotropic effects on the myocardium (166).

Levosimendan has been used to wean high-risk patients from CPB after failure to wean the patient with catecholamines (167). Continuous levosimendan infusion was given before or after CPB and increased cardiac index significantly without a change in mean arterial pressure or pulmonary capillary wedge pressure. Noradrenaline and adrenaline were used in combination with levosimendan without adverse effect. Further, levosimendan can be used concomitantly with other inotropic drugs, reducing their requirement (168), and may attenuate any adverse effect on diastolic function (169). Recently, the use of levosimendan in combination with dobutamine has been shown to augment stroke volume to a greater degree than milrinone-dobutamine combination therapy in cardiac surgical patients with low ejection fraction (170).

In patients with low-output syndrome following cardiac surgery, haemodynamic improvement occurred within a few hours after commencement of levosimendan infusions (171). Cardiac index and stroke volume increased, while mean arterial pressure, systemic vascular resistance and pulmonary capillary wedge pressure decreased. In critically-ill patients with cardiogenic shock requiring catecholamines, levosimendan has been shown to be safe and effective in improving the haemodynamic state (172). Similarly in patients with acute ischaemia and cardiogenic shock requiring immediate surgical revascularisation, levosimendan improved contractility and appeared to protect the myocardium from ischaemia (173). In a study of 38 patients, levosimendan improved the medium term survival in patients requiring mechanical-assist support for post-cardiotomy heart failure (174). The nine patients who received levosimendan were all weaned successively, required less adrenaline dosage, had lower plasma lactate levels and required less renal support. In off-pump coronary artery bypass grafting, levosimendan given at either low dose (12 [micro]g.[kg.sup.-1]) or high dose (24 [micro]g.[kg.sup.-1]) or placebo was administered to 31 patients (175). Significant increases in cardiac output and left ventricular ejection fraction occurred with both low and high doses of levosimendan.

Thus far, experience with levosimendan in cardiac surgery confirms it to have potential for reducing myocardial dysfunction following CPB. The chronotropic and vasodilatory effects of levosimendan may contribute partially to the haemodynamic improvement observed. However levosimendan has a unique myofilament inotropic action, is not associated with increased myocardial oxygen consumption or arrhythmia at low doses and stabilises cellular function, all of which contribute to its efficacy during reperfusion. These effects are dose-dependent and loading doses <36 [micro]g.[kg.sup.-1] followed by infusion 0.1 to 0.4 [micro]g.kg.[min.sup.-1] appear safe and effective. Higher doses however, may contribute to PDE inhibition and arrhythmia (48,88). The optimal time to administer levosimendan during cardiac surgery and duration of infusion post-surgery have not been defined. The haemodynamic effects of the active metabolite, OR-1896 would be expected to persist well after CPB, though this is not known.

CONCLUSION

Levosimendan has multiple pharmacological effects on the circulation and organ function. As a positive inotrope levosimendan overcomes the disadvantages of current inotropic agents, being less likely to induce arrhythmia, cause intracellular calcium overload and cell death.

In cardiac surgery, administration of levosimendan may potentially stabilise myocyte mitochondria before ischaemia-reperfusion injury. Intraoperative indications could include the use of levosimendan before, during or after CPB when ventricular function is impaired; as an add-on therapy when current inotropes are ineffective, and in right heart failure and transplantation. Larger studies are required to define this role of levosimendan in cardiac surgery, with outcome based on measures such as primary wean, the need for inotropic rescue, biochemical markers of injury and apoptosis, and survival.

At the cellular level, evidence suggests that the mechanism of inoprotection is to maintain closure of the mitochondrial permeability pore, through activation of the m[K.sub.ATP] channel. [K.sub.ATP] channels are present in tissues apart from the myocardium, including vascular endothelium, brain and kidney. Similarly, pharmacological manipulation of these channels may lead to preservation of these organs during stress. Clinical outcome may be dependent on the effects new drugs have on systemic vasculature and regional perfusion rather than enhancement of cardiac contractile force. This pharmacological action may be the most important property of such therapy. Ultimately, the endpoint of such therapy will be improved survival.

Accepted for publication on July 18, 2007.

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P. F. SOEDING *, C. E ROYSE [[dagger]], C. E. WRIGHT [[double dagger]], A. G. ROYSE [[section]], J. A. ANGUS **

Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia

* M.B., B.S, F.A.N.Z.C.A., Postgraduate Student, Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne and Consultant Anaesthetist, Department of Anaesthesia and Pain Medicine, Royal Melbourne Hospital.

[[dagger]] M.B., B.S., M.D., F.A.N.Z.C.A., Associate Professor, Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne and Department of Anaesthesia and Pain Medicine, Royal Melbourne Hospital.

[[double dagger]] Ph.D., Associate Professor,

[[section]] M.B., B.S., M.D., F.R.A.C.S., Associate Professor, Cardiovascular Therapeutics Unit, Department of Pharmacology, University of Melbourne and Department of Cardiothoracic Surgery, Royal Melbourne Hospital.

** Ph.D., Professor.

Address for reprints: Dr P. F. Soeding, Cardiovascular Therapeutics Unit, Department of Pharmacology. University of Melbourne. Melbourne, Vic. 3010.
TABLE 1
Pharmacological actions and potency of levosimendan in isolated
cardiac and vascular tissues

Action Species Tissue Potency
 E[C.sub.50]
 (nM)

Positive Guinea pig Cardiomyocyte 9
inotropy
 Cardiomyocyte 8

 Skinned fibre * 100

 Skinned fibre * 300

 Skinned fibre 300

 Atrium * 100

 Papillary muscle 60

 Isolated perfused * 100
 heart

 Isolated perfused * 100
 heart

 Isolated perfused * 100
 heart

 Isolated perfused 15
 heart

 Isolated perfused 8
 heart

 Isolated perfused 460
 heart

 Rabbit Papillary muscle 300

 Dog Left ventricle * 300

 Human Left atrium 120

 Left ventricle 380

 End-stage ([dagger]) 62
 ventricle

 End-stage * >100
 ventricle

Vasodilatation Guinea pig Isolated perfused * 100
 heart

 Isolated perfused * 100
 heart

 Isolated perfused * 100
 heart

 Pig Coronary artery 100000
 ([dagger][dagger])

 Human Coronary artery 7070
 [phi]

PDE inhibition Guinea pig Cardiomyocyte [DELTA]> 100

 Cardiomyocyte [DELTA]> 1000

 Cardiomyocyte PDEIII 3

 PDEIV 2500

 Rabbit Cardiomyocyte [DELTA]>300

 Isolated perfused PDEIII 8
 heart

[K.sub.ATP] Rat Cardiomyocyte 4700
activation
 Rat Arterial myocyte 2900

 Cat Pulmonary artery * >300

 Pig Coronary artery 410

 Human Pulmonary vein 281

Action Species Tissue Reference

Positive Guinea pig Cardiomyocyte Lancaster et al
inotropy 1997 (89)

 Cardiomyocyte Szilagyi et al
 2004 (96)

 Skinned fibre Edes et al
 1995 (41)

 Skinned fibre Haikala et al
 1995 (71)

 Skinned fibre Sorsa et al
 2004 (42)

 Atrium Boknik et al
 1997 (87)

 Papillary muscle Kaheinen et al
 2006 (43)

 Isolated perfused Kristof et al
 heart 1998 (91)

 Isolated perfused Kaheinen et al
 heart 2001 (121)

 Isolated perfused Kaheinen et al
 heart 2004 (57)

 Isolated perfused Szilagyi et al
 heart 2004 (96)

 Isolated perfused Szilagyi et al
 heart 2005 (97)

 Isolated perfused Toiler et al
 heart 2005 (134)

 Rabbit Papillary muscle Sato et al
 1998 (53)

 Dog Left ventricle Takahashi et al
 2005 (135)

 Human Left atrium Usta et al
 2004 (44)

 Left ventricle Brixius et al
 2002 (45)

 End-stage Brixius et al
 ventricle 2002 (45)

 End-stage Hasenfuss et
 ventricle al 1998 (46)

Vasodilatation Guinea pig Isolated perfused Haikala et al
 heart 1997 (92)

 Isolated perfused Kaheinen et al
 heart 2001 (121)

 Isolated perfused Kaheinen et al
 heart 2004 (57)

 Pig Coronary artery Gruhn et al
 ([dagger][dagger]) 1998 (120)

 Human Coronary artery Montes et al
 [phi] 2006 (47)

PDE inhibition Guinea pig Cardiomyocyte Edes et al
 1995 (41)

 Cardiomyocyte Boknik et al
 1997 (87)

 Cardiomyocyte Szilagyi et al
 2004 (96)

 Rabbit Cardiomyocyte Sato et al
 1998 (53)

 Isolated perfused Kaheinen et al
 heart 2004 (57)

[K.sub.ATP] Rat Cardiomyocyte Yokoshiki et
activation al 1997 (6)

 Rat Arterial myocyte Yokoshiki et
 al 1997 (5)

 Cat Pulmonary artery De Witt et al
 2002 (119)

 Pig Coronary artery Pataricza et al
 2003 (123)

 Human Pulmonary vein Pataricza et al
 2000 (118)

E[C.sub.50]=concentration producing 50% maximal effect, * =estimate from
data, ([dagger]) =isoprenaline prestimulation/elevated calcium,
([dagger][dagger])=prostaglandin F2 pre-treatment, [phi]=noradrenaline
pre-treatment, [DELTA]=estimate of inhibitory concentration based on
cAMP increase. PDEIII, PDEIV phosphodiesterase isoenzymes.

TABLE 2
Clinical studies of levosimendan

Study Patient group LVEF (%)

2A Studies in heart failure
Niemenan et al 2000 (90) ADHF n=151 <40

Slawsky et al 2000 (143) ADHF n=146 <25

Follath et al 2003 ADHF n=203 <35
(LIDO) (11)

Moiseyev et a1 2002 AMI/ADHF n=504 NA
(RUSSLAN) (126)

Cleland et a1 2004 ADHF n=299 <35
(CASINO) (145)

Johansson et a1 2004 ADHF n=100 <55
(REVIVE I) (144)

Cleland et a1 2006 ADHF n=600 <35
(REVIVE II) (20)

Cleland et a1 2006 ADHF n=1327 <30
(SURVIVE) (20)

2B Studies in cardiac surgery
Lilleberg et al 1998 (48) CAGS n=23 >30

Nijhawan et al 1999 (125) CAGS n=18 >30

Sandell et al 2002 (167) Cardiac surgery n=18 >35

Plochl et a1 2004171 Cardiac surgery n=8 <20

Lehmann et al 2004 (176) Emergent CAGS n=10 CS

Labriola et a1 2004 (174) Cardiac surgery n=11 CPB-LOS

Delle Karth et a1 2003 (175) ICU/Post surgery n=10 CS

Siriila-Waris et al 2005 (170) Cardiac surgery n=16 14-75

Braun et al 2006 (177) Cardiac surgery n=41 CPB-LOS
 Assist Device

Barisin et al 2004 (178) OPCAGS n=31 56-58

Tritapepe et al 2006 (168) CAGS n=12 >50

De Hert et al 2007 (173) CAGS n=15 <30

Study Loading dose Infusion
 ([micro]g/kg) ([micro]g/
 kg/min)
2A Studies in heart failure
Niemenan et al 2000 (90) 3 to 36 0.05-0.6/24 h

Slawsky et al 2000 (143) 6 0.1-0.4/24-48h

Follath et al 2003 24 0.1/24 h
(LIDO) (11)

Moiseyev et a1 2002 6 to 24 0.1-0.4/24 h
(RUSSLAN) (126)

Cleland et a1 2004 16 0.1-0.2/24 h
(CASINO) (145)

Johansson et a1 2004 12 0.1-0.2/24 h
(REVIVE I) (144)

Cleland et a1 2006 6, 12 0.1-0.2/24 h
(REVIVE II) (20)

Cleland et a1 2006 12 0.1- 0.2/24 h
(SURVIVE) (20)

2B Studies in cardiac surgery
Lilleberg et al 1998 (48) 8, 24 Pre CPB -

Nijhawan et al 1999 (125) 18, 36 Pre CPB 0.2, 0.3

Sandell et al 2002 (167) 18, 36 Pre CPB 0.2, 0.3

Plochl et a1 2004171 0.6 Pre CPB 0.2

Lehmann et al 2004 (176) 6 Pre CPB 0.2

Labriola et a1 2004 (174) 12 0.1

Delle Karth et a1 2003 (175) - 0.1

Siriila-Waris et al 2005 mostly 12 0.1
(170)

Braun et al 2006 (177) 20 in ICU 0.1-0.2/48 h

Barisin et al 2004 (178) 12, 24 -

Tritapepe et al 2006 (168) 24 -

De Hert et al 2007 (173) - 0.1

Study Comments

2A Studies in heart failure
Niemenan et al 2000 (90) Dose effect study
 Compared to P, Db

Slawsky et al 2000 (143) Symptomatic hypotension
 Compared to P

Follath et al 2003 Levosimendan superior to Db
(LIDO) (11) Lower 31, 180 day mortality

Moiseyev et a1 2002 0.1-0.2[micro]g/kg/min favourable
(RUSSLAN) (126) Lower 14, 180 day mortality

Cleland et a1 2004 Trial stopped
(CASINO) (145) Clear survival benefit over Db

Johansson et a1 2004 Reduced length of stay
(REVIVE I) (144) Reduction in B-ANP

Cleland et a1 2006 Hypotension, arrhythmia
(REVIVE II) (20) Compared to P

Cleland et a1 2006 Similar survival to Db
(SURVIVE) (20)

2B Studies in cardiac surgery
Lilleberg et al 1998 (48) Haemodynamic improvement
 No increase in Mv[0.sub.2]

Nijhawan et al 1999 (125) Haemodynamic improvement
 No increase in arrhythmia
 Low dose efficacious

Sandell et al 2002 (167) Haemodynamic improvement

Plochl et a1 2004171 Reduced inotropic requirement
 Reduced length of stay

Lehmann et al 2004 (176) Haemodynamic improvement
 Concomitant inotropic agents
 Successful wean

Labriola et a1 2004 (174) Haemodynamic improvement

Delle Karth et a1 2003 (175) MAP maintained

Siriila-Waris et al 2005 (170) Successful CPB wean

Braun et al 2006 (177) Less inotrope, renal support
 Improved 180 day survival

Barisin et al 2004 (178) MAP maintained

Tritapepe et al 2006 (168) Decreased troponin I levels

De Hert et al 2007 (173) Improved SV compared to Mil
 Combination therapy with Db

ADHF=acutely decompensated heart failure, AMI=acute myocardial
infarction, LVEF=left ventricular ejection fraction, CAgS=coronary
artery bypass surgery, CPB=cardiopulmonary bypass, Mvo2=myocardial
oxygen consumption, LOS=low output syndrome, MAP=mean arterial
pressure, SV=stroke volume, BNP=B-type natriuretic peptide,
P=placebo, Db=dobutamine, Mil=milrinone, CS=cardiogenic shock.

TABLE 3
Clinical studies of levosimendan in cardiac surgery

Study Patient group LVEF (%)

Lilleberg et al CAGS n=23 >30
1998 (48)

Nijhawan et al CAGS n=18 >30
1999 (125)

Sandell et al Cardiac surgery n=18 >35
2002 (167)

Plochl et al Cardiac surgery n=8 <20
2004 (171)

Lehmann et al Emergent CAGS n=10 Cardiogenic shock
2004 (175)

Labriola et al Cardiac surgery n=11 Post CPB-LOS
2004 (173)

Delle Karth et al ICU/ Post surgery n=10 Cardiogenic shock
2003174

Siriila-Waris Cardiac surgery n=16 14-75
K et al
2005 (170)

Braun et al Cardiac surgery n=41 CPB-LOS Assist
2006 (176) Device

Barisin et a1 OPCAGS n=31 56-58
2004 (177)

Tritapepe et al CAGS n=12 50
2006 (168)

Study LD ([micro]g/kg) Infusion
 ([micro]g/kg/min)

Lilleberg et al 8, 24 Pre CPB -
1998 (48)

Nijhawan et al 18,36 Pre CPB 0.2, 0.3
1999 (125)

Sandell et al 18, 36 Pre CPB 0.2, 0.3
2002 (167)

Plochl et al 0.6 Pre CPB 0.2
2004 (171)

Lehmann et al 6 Pre CPB 0.2
2004 (175)

Labriola et al 12 0.1
2004 (173)

Delle Karth et al - 0.1
2003174

Siriila-Waris mostly 12 0.1
K et al
2005 (170)

Braun et al 20 in ICU 0.1-0.2/48 h
2006 (176)

Barisin et a1 12, 24 -
2004 (177)

Tritapepe et al 24 -
2006 (168)

Study Comment

Lilleberg et al Haemodynamic improvement
1998 (48) No increase in Mv[O.sub.2]

Nijhawan et al Haemodynamic improvement
1999 (125) No increase in arrhythmia
 Low dose efficacious

Sandell et al Haemodynamic improvement
2002 (167)

Plochl et al Reduced inotropes
2004 (171) Reduced length of stay

Lehmann et al Haemodynamic improvement
2004 (175) Concomitant inotropes
 Successful wean

Labriola et al
2004 (173)

Delle Karth et al MAP maintained
2003174

Siriila-Waris Successful CPB wean
K et al
2005 (170)

Braun et al Less inotrope, renal support
2006 (176) Improved 180 day survival

Barisin et a1 MAP maintained.
2004 (177)

Tritapepe et al Decreased troponin I levels
2006 (168)

MAP=mean arterial pressure, ICU=intensive care unit.
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Author:Soeding, P.F.; Royse, C.F.; Wright, C.E.; Royse, A.G.; Angus, J.A.
Publication:Anaesthesia and Intensive Care
Article Type:Drug overview
Geographic Code:8AUST
Date:Dec 1, 2007
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