a b s t r a c t

Aneurysmal subarachnoid hemorrhage (aSAH) is one of the leading causes of neurologic disability accounting for dismal long term survival rates. aSAH leads to a sudden increase in intracranial pressure and a massive sympathetic discharge. Excessive sympathetic stimulation leads to catecholamine mediated myocardial dysfunction and hemodynamic instability which may critically hamper brain perfusion and oxygenation. In the setting of acute aSAH, administration of Vasoactive drugs aims at stabilizing impaired hemodynamics. However, studies have shown that Conventional treatment with vasoactive drugs that lead to Ca⁺² overload and increase myocardial oxygen consumption, fail to restore hemodynamics and decrease cerebral blood flow. Levosimendan is a non- adrenergic inotropic Ca⁺² sensitizer with not only beneficial hemodynamic properties but also pleiotropic effects, contributing to its cardioprotective and neuroprotective role. Although there have been limited data available regarding the use of levosimendan in patients with aSAH, current evidence suggests that levosimendan may have a role in the setting of post-aSAH cardiomyopathy and decreased cerebral blood flow both in the emergency departments and in intensive care units. The purpose of this review is to provide an overview of studies of levosimendan therapy for aSAH, and describe current knowledge about the effects of levosimendan in the management of aSAH.

(C) 2015

Introduction

aneurysmal subarachnoid hemorrhage is one of the leading causes of neurologic disability accounting for permanent Neurological deficits of survivors [1]. The prognosis of aSAH remains poor, with mortality rates as high as 33% [2].

aSAH leads to a sudden increase in intracranial pressure and a massive sympathetic discharge. Excessive sympathetic stimulation leads to catecholamine mediated myocardial dysfunction and hemody- namic instability which may critically hamper brain perfusion and oxy- genation [3]. In the setting of acute aSAH, administration of vasoactive drugs aims at stabilizing impaired hemodynamics. However, several studies [4,5] have shown that conventional treatment with vasoactive drugs [6] that lead to Ca⁺² overload and increase myocardial oxygen consumption, fail to restore hemodynamics and decrease cerebral blood flow [7]. Although there has been limited data available regarding the use of levosimendan in patients with aSAH, levosimendan appears

? Disclosure: The authors declare no conflicts of interest.

* Corresponding author at: 11 Rodopis Street, 14561, Athens, Greece. Tel.: +30 6938495109; fax: +30 213 20 86 000.

E-mail address: gvarvarousi@yahoo.gr (G. Varvarousi).

¹ University of Athens, Medical School, Greece, 75 Mikras Asias street, 11527, Athens, Greece.

² KAT Hospital, 2 Nikis street, 14561, Athens, Greece.

to be an emerging tool for the treatment of post -aSAH cardiomyopathy and decreased cerebral blood flow both in the emergency departments (EDs) and in intensive care units [8-11]. It is a non-adrenergic inotropic Ca⁺² sensitizer that allows rapid restoration of cardiac output without increasing myocardial oxygen consumption and also optimizes cerebral perfusion [9]. Moreover, its antioxidant and anti-inflammatory effects contribute to its cardioprotective and neuroprotective role [10].

The purpose of this review is to provide evidence of levosimendan therapy for aSAH, and describe current knowledge about the effects of levosimendan in the management of aSAH.

Post-aSAH neurogenic stunned myocardium

Approximately 20-30% of aSAH patients manifest neurogenic stunned myocardium, which is associated with high mortality. Its onset occurs within 72 hours after aSAH and its prognosis depends on the degree of neurological rather than Cardiac damage [12]. neurogenic-stunned myocardium is a reversible myocardial injury with a severely depressed left ventricular (LV) systolic function which leads to a decreased cardiac output during the Acute stage of aSAH [13]. The classic triad of clinical findings includes transient LV Wall motion abnormality, electrocardiographic abnormalities, such as QT prolongation, T-wave and ST-segment changes, and elevation in

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0735-6757/(C) 2015

myocardial enzymes in the absence of coronary artery disease [14]. LV wall motion abnormality is characterized by either hypokinesis of the basal and mid-ventricular segments with sparing of the apex or global LV hypokinesis [14]. In the neurogenic stunned myocardium, myocyte injury results in nonvascular territory patterns of abnormality, specifically contraction band necrosis, coupled with Normal coronary arteries. Myocardial contraction band necrosis is characterized by hypercontracted sarcomeres, dense eosinophilic transverse bands, and an interstitial mononuclear inflammatory response [15]. The range of myocardiac dysfunction in the early phase after aSAH extends from asymptomatic minor elevations in cardiac enzymes to severe complica- tions such as pulmonary edema, Malignant arrhythmias, and cardiogenic shock [16]. Therefore, it requires prompt recognition and proper interven- tion both in the ED and in the intensive care unit.

aSAH leads to a sudden increase of ICP, a decrease in cerebral perfusion pressure (CPP) and consequently to a reduction in cerebral blood flow [3]. The compensatory mechanism in order to increase cardi- ac output and mean arterial pressure (MAP) and therefore to restore CPP includes an intense neuronal sympathetic activation. The sympa- thetic stimulation of adrenoceptors in the ventricular myocardium is achieved through a local release of catecholamines by sympathetic nerve terminals directly innervating the myocardium [17]. This leads to an interaction with stimulatory G proteins (Gs), which in turn acti- vates adenylyl cyclase to enhance cyclic adenosine monophosphate (cAMP) formation. Elevated cAMP concentrations activate protein kinase A (PKA) [18], which phosphorylates several downstream intra- cellular targets, resulting in an increased contractile response [19]. However, an excessive release of catecholamines from sympathetic nerve terminals triggered by aSAH leads to Ca⁺² overload of the myocyte and prolonged contraction and structural damage to the myocardium [20]. All the above result in a depletion of high-energy phosphates, Mitochondrial dysfunction, and Myocardial stunning [21]. Grad et al have shown that increased levels of catecholamines and their metabolites have been noted in the urine and serum of patients with aSAH and were associated with direct myocardial toxicity [22]. Moreover, Melville et al reported that ablation of cardiac sympathetic nerves in animal models of SAH prevented early myocardial dysfunc- tion [23].

b-Adrenoreceptors couple predominantly to Gs proteins but also

couple to G-inhibitory (Gi) proteins [24]. High levels of circulating catecholamines trigger a switch in intracellular signal trafficking in ven- tricular cardiomyocytes, from Gs protein to Gi Protein Signalling via the b2-adrenoreceptors [25]. b2-AR-Gi mediated signalling in ventricular myocytes leads to a negative inotropic effect through inhibition of Gs- cAMP production [26] and alters myofilament sensitivity to Ca⁺². In this way, the myocardium is protected from the effects of Gs-cAMP- PKA overstimulation [27]. Moreover, this effect is greatest at the basal myocardium than in the apical, in which the b-adrenoreceptor density is greatest [26]. Furthermore, increased catecholamine levels may result in desensitization and down-regulation of b1-adrenoreceptors. The above leads to a reduced contractile response to the activation of b1-adrenoreceptors and to aSAH related myocardial dysfunction [28].

Acute aSAH is accompanied by neurometabolic cardiac abnormali- ties which may lead to metabolic stunning [29]. Studies have shown that depression of myocardial lipid and glucose metabolism may be in- volved in the pathogenesis of neurogenic stunned myocardium. Catecholamine-mediated increased output of glucose from the liver leads to lactate production and hyperglycemia [30]. Moreover, sympa- thetic stimulation leads to insulin resistance and inhibition of insulin re- lease. The above lead to reduced glucose uptake by the myocardium, depression of glucose metabolism, and intramyocardial lipid accumula- tion [31]. Hyperglycemia may be associated with denudation of the en- dothelial glycocalyx and deleterious effects on the microcirculation [32]. Moreover, hyperglycemia and lipid accumulation exacerbates aSAH- induced myocardial and brain injury by enhancing the mitochondrial dynamic imbalance, apoptosis and inflammation [33]. Dilsizian et al

showed a direct correlation between catecholamine-induced segmental dysfunction, lipid accumulation and glycogen exhaustion as well as a reduced uptake of lipid and glucose in the akinetic segments of the myocardium in aSAH patients during the acute phase [34].

In the acute phase of aSAH auto-oxidation of catecholamines results in the generation of highly toxic cytotoxic free radicals [35]. An expo- sure of the normal myocardium to Reactive oxygen species \(ROS\) in- duces oxidative damage [36]. Free radicals initiate the peroxidation of membrane-bound fatty acids, damaging the membrane integrity lead- ing to both functional and structural myocardial injury [36]. Moreover, the excessive production of ROS directly inhibits the respiratory chain complexes activities and thus may lead to mitochondrial dysfunction and myocardial cell death [37]. There is also accumulating evidence that a sympathetic overstimulation in the setting of aSAH induces cytokine expression. Studies have shown increased circulating levels of pro-inflammatory cytokines, such as tumor necrosis factor-? (TNF-?) and interleukines 6 and 8 to 10 [38] in cerebrospinal fluid and serum of patients with aSAH. In addition, the activation of various cytokine cascades not only triggers proapoptotic signalling pathways and therefore aggravates cardioVascular injury but also contributes to the refractoriness to inotropic drugs and to high mortality [15].

Rhythm and conduction disturbances are common during the first 48 hours after aSAH. Repolarization abnormalities after SAH include T-wave inversions, ST depression, and QT prolongation [39]. Excessive sympathetic stimulation triggered by aSAH elevates intracellular Ca⁺² concentration, leads to arrhythmiogenesis, and may exacerbate myo- cardial Ischemic injury [40]. Moreover, in the setting of aSAH, vagal nerve reflexes are disturbed due to the ischemic insult, which may lead to heart rhythm irregularities [41]. Early assessment of electrocardio- graphic abnormalities in the ED is important as they are independently associated with the in-hospital mortality of patients with aSAH [42].

Sympathetic over-stimulation induces pulmonary venous constric- tion and microembolus formation and leads to increases in pulmonary capillary pressure [43]. Furthermore, sympathetic activation aggravates myocardial dysfunction due to Peripheral vasoconstriction and in- creased left ventricular afterload. Papanikolaou et al have shown that in aSAH, aortic stiffness may further increase left ventricular afterload, reduce diastolic Coronary blood flow and induce subendocardial ischemia [44]. Aortic stiffness and associated LV dysfunction might play a role in the pathogenesis of neurologic sequelae in aSAH because they may affect cerebral blood flow adversely [44] (Fig. 1).

Levosimendan and post-aSAH neurogenic stunned myocardium

Neurogenic stunned myocardium in the setting of aSAH commonly results in hemodynamic instability and decreased cerebral blood flow [2]. The treatment of post-aSAH neurogenic stunned myocardium war- rants the use of inotropic drugs, aiming at increasing organ perfusion and tissue oxygen delivery [45]. Although data regarding the optimal vasoactive drug therapy of neurogenic stunned myocardium in aSAH patients is limited, treatment includes primarily cAMP-mediated Ca² in- crease by either b1-adrenergic stimulation or phosphodiesterase inhibi- tion. However, in the setting of acute aSAH in which adrenergic stimulation is already maximal, further increase in intracellular Ca⁺² and myocardial oxygen consumption with conventional inotropes would no longer be beneficial [46]. Several studies have shown that neurogenic stunned myocardium may be refractory to conventional treatment [4,9]. cAMP-dependent inotropes may have a negative ino- tropic effect in the already compromised myocardium and increase mortality [47], despite their rapid onset of action. They may not only aggravate the vicious cycle of catecholamine-induced cardiotoxicity by augmenting the already increased circulating catecholamine levels but also induce themselves stress cardiomyopathy in the late period post- aSAH [48,49].

Levosimendan is a non-adrenergic inotropic calcium sensitizer [8] that exerts its inotropic effect principally via binding to the Ca⁺²

Fig. 1. Pathophysiology of neurogenic stunned myocardium in aSAH. SAH, subarachnoid hemorrhage; b2-AR, b2-adrenoreceptors.

saturated troponin C of the myocardial thin filament [40]. Levosimendan increases Ca⁺² sensitivity of contractile regulatory pro- teins, causing an increase in myocardial contractility with no impact on myocardial energy consumption [50]. It does not impair diastolic re- laxation or cardiac rhythm and has less harmful effects on myocardial energetics [51,52]. Levosimendan has a favourable pharmacokinetic profile, providing both rapid and sustained effects in acute aSAH [53]. Levosimendan has a short half-life (approximately 1 hour) and is char- acterized by a fast onset of drug action. Early administration of levosimendan in the acute setting of aSAH may rapidly increase cardiac output and cerebral blood flow, avoiding excessive administration of exogenous catecholamines [4,51]. Therefore, it may be a safe and effec- tive therapeutic option for the early treatment of acute aSAH in hospital EDs [11]. Furthermore, persistent beneficial hemodynamic effects are due to the presence of a pharmacologically active metabolite with a prolonged elimination half-life [50]. Neurogenic stunned myocardium as it onset occurs within 72 h after aSAH. In this respect, long-lasting effects of levosimendan may have certain advantages [4,54]. Although levosimendan has been recently recommended in European Society of Cardiology guidelines, as inotropic therapy for the short-term treatment of acute severe heart failure, data are limited regarding its use in pa- tients with aSAH [52]. Further time-related studies must be undertaken in order to determine the effects of levosimendan in aSAH.

Levosimendan may induce hemodynamic stability after the failure of

standard treatment in refractory aSAH related cardiomyopathy. A case report presented a woman with cardiogenic shock associated with neurogenic cardiomyopathy. Hemodynamics could not be restored after a prolonged resuscitation effort with high doses of dobutamine and milrinone. Although the patient died due to neurological status deterioration, the administration of levosimendan infusion improved systemic hemodynamics and peripheral organ perfusion [10]. The administration of levosimendan also resulted in relatively greater cardiac performance enhancement than dobutamine and milrinone in SAH-related heart failure, which may relate to the fact that it is a calcium sensitizer, and thus may be able to bypass the cardiac Ca⁺² overload that is known to occur with myocardial stunning [10]. In addition,

levosimendan, a cAMP-independent inotrope, may be effective in re- versing the negative inotropic effect of epinephrine. In a study, the ad- ministration of levosimendan at the point at which cAMP-dependent, inotrope-negative effects were beginning was effective in preventing further decline in cardiac output and improved survival [55] (Table).

Levosimendan is presently not recommended in the presence of hy- potension and cardiogenic shock due to its vasodilatory properties [56]. However, studies have shown that administration of levosimendan increased MAP and organ blood flow and that the hypotension from levosimendan is dose related [57]. Therefore, a flexible dose of levosimendan depending on the hemodynamic status of the patient could ameliorate hypotension [11]. In a study by Busani, a 38-year-old woman was admitted to the intensive care unit due to severe aSAH. After the embolization of the aneurysm, the patient suffered from car- diogenic shock which was refractory to conventional treatment with dopamine, dobutamine and norepinephrine and high amounts of fluids. Levosimendan infusion, without a loading dose resulted in a rapid and significant improvement of organ blood flow. In addition, MAP was ele- vated, which probably led to the favorable neurological outcome [8]. Furthermore, Papanikolaou et al described a case series of 2 women with aSAH complicated by neurogenic stress cardiomyopathy and con- comitant severe hemodynamic instability. After surgical clipping of the ruptured aneurysms both patients presented with neurogenic stress cardiomyopathy and hemodynamic instability refractory to conven- tional treatment. Early administration of levosimendan without a load- ing dose led to the stabilization of CPP [4]. Initial bolus or loading dose of levosimendan may lead to hypotension, such that patterns without loading dose could be beneficial [58]. Moreover, a flexible dose of levosimendan depending on the hemodynamic status of the patient could ameliorate hypotension [11]. Levosimendan could be adminis- tered for the management of acute aSAH in the ED, under continuous hemodynamic monitoring and ensuring sufficient volume status of the patient, due to its vasodilating properties. However, evidence is extremely limited and further comparative studies are warranted in order to determine the effects of levosimendan in aSAH related hemo- dynamic instability (Table).

Table

Studies regarding the use of levosimendan in aSAH

Study	Type of study	Material	Outcomes
Konczalla et al 97	Experimental	Rat	There was no vasospastic potential for levosimendan in cerebral arteries after aSAH
Cengiz et al 84	Experimental	Rabbit	Levosimendan prevented cerebral vasospasm induced by SAH
Busani et al 8	Case report	One patient	Administration of levosimendan in post-SAH cardiogenic shock improved cardiac function and neurological outcome
Papanikolaou et al 4	Case series	Two patients	Administration of levosimendan in aSAH complicated by neurogenic stress cardiomyopathy improved hemodynamics
Taccone et al 10	Case report	One patient	Administration of levosimendan in cardiogenic shock following SAH, improved cardiac function and

peripheral organ perfusion

Levosimendan has also vasodilatory and anti-stunning effects medi- ated by the opening of ATP-sensitive potassium (KATP) channels in the sarcolemmal membrane of vascular smooth muscle cells. It induces va- sodilation in systemic, pulmonary and coronary circulation and lowers both preload and afterload, improving tissue perfusion [59]. In that way levosimendan reduces LV filling pressure, improves cardiac output and normalizes LV wall motion [59]. Furthermore, levosimendan in- creases the responsiveness of myofilament to Ca⁺², with no effect in cy- tosolic Ca⁺² concentrations [60]. These effects may account for the reductions in myocardial ischemia, as well as the improved function of stunned myocardium. The anti-stunning effects of levosimendan were also shown in other studies. In a study by Sonntag, the total number of hypokinetic segments was significantly decreased with levosimendan treatment in 24 patients with acute coronary syndrome [60]. Wu et al have shown that continuous infusion of levosimendan significantly im- proved myocardial function as compared to placebo in patients with acute myocardial infarction who experienced myocardial stunning [61]. Levosimendan exerts antioxidant effects in comparison to conven- tional inotropes [62] and improves long-term benefit by the opening of mitochondrial KATP channels in cardiomyocytes [63]. The stimula- tion of K⁺ flux through mitochondrial KATP has been demonstrated to maintain cellular energy homeostasis and to protect mitochondria from oxidative injury [64]. Parissis et al reported that levosimendan administration decreases oxidative stress by decreasing free radical pro- duction in the myocardium and by the suppression of lipid peroxidation

and protein oxidation [65].

Levosimendan also has pre-conditioning and anti-inflammatory effects [66], which protect mitochondria from Ischemia-reperfusion injury. The opening of KATP channels in the mitochondria attenuates Ca⁺² accumulation in the mitochondria and stabilizes the mitochondrial inner membrane permeability [67]. Levosimendan decreases the expres- sion of pro-Inflammatory mediators, indicating a diminished progression of injury [59]. Paris et al reported that levosimendan treatment caused a significant reduction in interleukin 6 and TNF-? [67]. The anti- inflammatory effects of levosimendan, combined with the absence of in- tracellular Ca⁺² overloading in cardiomyocytes, also lead to the down- regulation of apoptosis signalling pathways in the neurogenic stunned myocardium (Fig. 3).

aSAH and brain injury

Spontaneous rupture of an Intracranial aneurysm in SAH leads to a increase in ICP, a decrease in CPP and Early brain injury. Early brain injury which occurs within the first 72 hours following SAH [68], results from significant pathophysiological mechanisms, including blood-brain barrier (BBB) dysfunction, microcirculation disturbance, acute vaso- spasm, and neuronal apoptosis. It is associated with severe functional disability and high mortality after aSAH and participates in the patho- genesis of delayed ischemic injury and cerebral vasospasm [69].

In the setting of acute aSAH, the maintenance of an adequate CPP is a major goal, in order to increase cerebral blood flow. However, during the early brain injury period, the increase in ICP leads to BBB dysfunction, Brain edema and dysfunction of auto-regulation. Impaired auto-regulation raises the critical threshold for CPP and cerebral blood flow may fall in response to only minor decreases in blood pressure

[70]. Neurogenic stunned myocardium may reduce CPP and cerebral blood flow in aSAH [71]. Zug et al, have shown that left ventricular dysfunction and low cardiac output are independent risk factors for vasospasm and cerebral ischemia [72]. Moreover, the use of sympatho- mimetic compounds to achieve desired CPP may aggravate both myo- cardial function and cerebral blood flow [73]. Liu et al have shown that norepinephrine-induced myocardial dysfunction is associated with a dramatic decrease in cardiac output, which not only results in systemic hypoperfusion but also in insufficient maintenance of MAP during cerebral ischemia [74]. Furthermore, sympathomimetic com- pounds may induce not only cerebral vasoconstriction [73] but also global edema in the brain with lost auto-regulation, which is an independent risk factor for mortality and poor outcome after SAH [75]. Studies have shown that a-adrenergic-mediated effects of norepi- nephrine not only lead to vasoconstriction of the proximal large cerebral vessels but also impair microcirculation [73,75].

intracranial arteries possess extensive sympathetic innervations

that participate in the modulation of cerebrovascular tone and auto- regulation by inducing constriction [76]. Baset et al have shown a prominent role for the sympathetic nervous system in the development of vasospasm [77]. Sympathetic stimulation leads to the elevation of intracellular Ca⁺² levels in the cerebral artery. The above results in sustained contraction of smooth muscle cells and decreased cerebral blood flow [78]. Moreover, catecholamines potentiate the activation of endothelin, a potent vasoconstrictor, which plays a role in the develop- ment of cerebral vasospasm following aSAH [79]. Ogura et al reported that in aSAH elevated levels of circulating catecholamines, coupled with an abnormal sensitivity of the cerebral vasculature to these catecholamines, predispose patients to cerebral ischemia and to neuro- logical deterioration [80].

KATP channels, which are present in both large cerebral arteries and microvessels, regulate cerebrovascular tone and mediate cerebrovasodilation through Nitric oxide [81]. NO is a potent vascular relaxant and has been well characterized in SAH-induced vasospasm. Endothelial injury of cerebral arteries after aSAH impairs vasodilator mechanisms [82]. After aSAH, KATP channel dysfunction leads to decreased NO production and impaired responses to endothelium-dependent vasodilators. The above KATP may lead to cerebral vasospasm and ischemic injury [83,84].

Ischemia due to aSAH leads to a primary energy failure that is ac- companied by the dysfunction of ATP-dependent channels and an in- creased intracellular Ca⁺² concentration [84]. Massive neuronal influx of Ca⁺² triggers a cascade of pathophysiological processes that lead to further neuronal degeneration [85]. Ca⁺² is taken up into the mitochon- dria and can cause generation of ROS [86]. In aSAH, ROS are mostly gen- erated during lipid peroxidation and hemoglobin auto-oxidation and induce oxidative stress that contributes to early and delayed ischemic injury. ROS induce damage to the vascular smooth muscle and the endothelium and disruption of BBB [87]. Moreover, oxidative stress leads to the release of apoptotic mediators such as cytochrome c [87]. Endothelial cell apoptosis has been implicated in breakdown of the BBB, edema formation, and secondary brain injury following aSAH [88]. Furthermore, a prominent inflammatory reaction is noted following aSAH and it is characterized by release of pro-inflammatory mediators, endothelial expression of adhesion molecules and migration and activation of leukocytes. Inflammation accompanying aSAH may be

Fig. 2. Pathophysiology of brain injury in a SAH. SAH; subarachnoid hemorrhage.

a critical pathway that is underlying to the development of cerebral vasospasm [75]. Studies have shown that elevated levels of cytokines in CSF are correlated with neurological damage and contribute to brain injury [89,90] (Fig. 2).

Levosimendan and aSAH related brain injury

In the setting of aSAH, rapid restoration of depressed cardiac output may prevent further cerebral damage by preserving cerebral blood per- fusion and reversing vasospasm-induced cerebral flow deficits. There is a lack of randomized clinical trials on hemodynamic therapy and clinical outcome. To increase cerebral blood flow different combinations of he- modilution, hypervolemia and hypertension have been used for many years [6,91]. Although this combination treatment has been associated with a reduction in mortality from vasospasm and cerebral ischemia, it is in many ways the opposite of the normal treatment for neurogenic stunned myocardium. Neurogenic stunned myocardium precludes the above aggressive therapy for cerebral vasospasm and impairs cerebral blood flow and subsequent neurological recovery. Recent evidence sug- gests that this treatment combination may decrease oxygen delivery to the myocardium, exposing the myocardium to further injury [46,48].

Levosimendan may successfully decrease left ventricular afterload, increase cardiac output and allow an adequate CPP to be restored with- out affecting the already compromised myocardium [92]. In a study by Busani, a woman suffered from a cardiogenic shock which was refracto- ry to conventional treatment with dopamine, dobutamine, and norepi- nephrine and high amounts of fluids. Levosimendan infusion increased cardiac output and MAP, which probably led to the favorable neurolog- ical outcome. However, a limitation of the study is that there was no measurement of intracranial pressure [8]. Moreover, studies have dem- onstrated that increases in the cardiac output can increase cerebral blood flow (CBF) independently of changes in MAP [92,93]. More stud- ies are warranted in order to find the effect of levosimendan on cardiac output.

laboratory investigations suggest that levosimendan, in contrast to other inotropes, does not have a vasospastic action in cerebral arteries [83,94]. In a study by Konczalla et al [94], levosimendan did not affect the endothelin-1 system or the pathway of endothelial nitric oxide in cerebral arteries, which both play an important role in the development of cerebral vasospasm after aSAH. Moreover, levosimendan caused sig- nificant and dose-dependent relaxation in cerebral circulation affecting the prostaglandin system [94]. Levosimendan demonstrated significant neuroprotective properties in a rabbit model of SAH by preventing

Fig. 3. Cardioprotective role of levosimendan in the post-aSAH period.

cerebral vasospasm. Cengiz et al has shown that intravenous adminis- tration of levosimendan was effective by increasing the pathological lu- minal area and reducing muscular wall thickness measurements in the rabbit model of SAH [83]. However, data are limited, and clinical studies would be helpful to determine the role of administration of levosimendan in post-SAH vasospasm in patients following aSAH (Table).

Levosimendan increases cerebral blood flow through activation of KATP channels [95] and it also interferes with nitric oxide (NO) pathway through the opening of KATP channels and directly contributes to re- ducing vasospasm in aSAH. Cenzig et al, have shown that the activation of KATP channels and the increase of NO release in the vessels by levosimendan led to vasodilation in the brain [83]. In an experimental cardiac arrest model, levosimendan increased cerebral blood flow, reduced neuronal injury and improved neurological outcome [95]. Low oral levosimendan doses induced an increase in cerebral blood flow velocities, assessed by transcranial Doppler method [96]. Bravo et al showed improved cerebral perfusion and oxygenation with intravenous levosimendan in critically ill infants [97].

Levosimendan through KATP channels not only causes vasodilata- tion of the cerebral microcirculation [6], but also maintains cerebral auto-regulation intact. By balancing and optimizing the vascular tone of cerebral vessels, it increases blood flow to the under-perfused cere- bral parenchyma and ameliorates secondary reperfusion injuries [6]. Levosimendan significantly attenuates the SAH-induced alteration in BBB permeability through activation of KATP channels and reduces edema formation [86,98].

Levosimendan has anti-inflammatory effects that may ameliorate ce- rebral vasospasm. It may decrease the expression of pro-inflammatory mediators. In a study of ischemia-reperfusion injury, Levosimendan reduced the inflammatory response 24 hours after reperfusion and the expression of TNF-? [99]. In another study, Levosimendan decreased in- flammatory response in the spinal cord and improved function after transient ischemia [100]. Levosimendan, by inhibiting neutrophil infil- tration with subsequent release of inflammatory mediators that induce lipid peroxidation, has also anti- oxidant effects. Via its anti-lipid perox- idation action, it mediates membrane stabilization and free radical scav- enging. Activation of mKATP channels regulates neuronal excitation,

Fig. 4. Neuroprotective role of levosimendan in the post-aSAH period.

neuronal degeneration and minimizes neuronal loss [83]. Levosimendan reduces intracellular Ca⁺² influx and has anti-apoptotic properties. However, clinical studies are still needed to evaluate the extent of levosimendan’s antioxidant effects.

Levosimendan may have direct Neuroprotective effects by reducing reperfusion Cerebral injury [104,105]. It has also been reported to exhib- it a neuroprotective profile by reducing neuronal injury in a model of traumatic brain injury [101]. Levosimendan also improved function and reduced neurological injury in the spinal cord of the rabbit. The reduction of the infarct size was associated with a partial inhibition of mitochondrial permeability transition pore opening, a key mediator of reperfusion injury [105]. Moreover, levosimendan has been shown to reduce cell death and inflammatory responses and to improve function after transient ischemia of the spinal cord in rabbits [101]. In a model of transient brain ischemia by intraluminal occlusion of the middle cerebral artery in 40 male Wistar rats, intravenously administered levosimendan limited the infarct size and Brain swelling [99] (Fig. 4).

Conclusion

The poor prognosis of patients with neurogenic stunned myocardium and Cerebral hypoperfusion in the setting of aSAH remains a major issue re- sponsible for mortality. Current evidence suggests that levosimendan may have a role in the setting of acute aSAH, not only due to its beneficial hemo- dynamic properties, but also due to its pleiotropic effects, contributing to its cardioprotective and neuroprotective role. However, data are limited and clinical studies would be helpful to determine the role of administration of levosimendan in post-aSAH neurogenic stunned myocardium and brain injury.

Authorship

GV, EK, and PS contributed in the literature review, data collection, writing of the manuscript, writing of the table, as well as obtaining and editing of the images and references. TX, IP, and ME participated in revising critically the manuscript. All authors read and approved the final manuscript.

Acknowledgement

None.

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