acute heart failure is a condition that is characterised by impaired myocardial function , whereby the heart can not supply sufficient o2 to the body tissues .
the common causes of heart failure include hypertension , coronary artery disease ( including previous myocardial infarction ) , atrial fibrillation , valvular heart disease , and cardiomyopathy [ 1 , 2 ] .
heart failure can also be triggered by surgical procedures , generally in the more elderly patients with limited cardiopulmonary reserve .
all surgical procedures can lead to systemic inflammatory reactions , with the resultant increase in heart rate .
stress and inadequate postoperative analgesia can prompt elevated systemic blood pressure , tachycardia and increased afterload , thereby raising myocardial o2 requirements .
the strategies commonly used focus not only on improvement of the symptoms , but also on prevention of the transition from asymptomatic to symptomatic heart failure , as well as on mortality reduction through slowing disease progression . however , once haemodynamic support is required , there is a relative scarcity of effective therapies .
-adrenergic - receptor - stimulating drugs including dobutamine , dopamine and adrenaline are used in this setting .
all of these act via the adrenergic receptors on the myocyte cell membranes , to intensify the production of the second messenger adenosine 3,5-cyclic monophosphate , which leads to increases in ca influx and increased contraction force .
in addition , these drugs tend to cause arrhythmia , which can further impair cardiac function .
more recently , the phosphodiesterase inhibitors drugs were developed , which reduce the degradation of adenosine 3,5-cyclic monophosphate , thereby leading to increased influx of ca .
the inodilator levosimendan is a ca sensitiser that has been approved for short - term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not suffcient , and in cases where inotropic support is considered appropriate .
levosimendan has a number of pharmacological effects , which include increased cardiac contractility mediated by ca sensitisation of troponin c , vasodilation based on the opening of k channels in the vasculature , and cardioprotection due to the opening of mitochondrial k channels in the cardiomyocytes .
clinical data obtained in patients with heart failure has confirmed that these pharmacological effects translate into improved haemodynamics .
contrary to other inotropes , o2 consumption is not increased to a significant extent during treatment with levosimendan [ 20 , 21 ] .
symptoms of acute heart failure have been shown to be diminished by levosimendan treatment [ 17 , 18 , 22 , 23 ] .
levosimendan pre - treatment can decrease infarct size in an ischaemia - reperfusion model and improve recovery of cardiac function following global ischaemia .
this beneficial effect is not believed to be mediated through inhibition of ventricular hypertrophy , dilation or alterations in late - phase healing of the infarct , but primarily through ca sensitisation of contractile proteins .
levosimendan has an active metabolite , known as or-1896 , which ensures sustained efficacy for at least 7 days [ 24 , 27 ] .
in contrast to dobutamine , the effects of levosimendan are not attenuated by concomitant administration of -blockers .
levosimendan also offers a predictable safety profile [ 17,18,19 , 23 ] , and no impairment of diastolic function has been demonstrated with levosimendan [ 29 , 30 ] . also , there is no development of tolerance to levosimendan .
the most common adverse events of levosimendan treatment include hypotension , headache , atrial fibrillation , hypokalaemia and tachycardia [ 22 , 23 , 31 ] . in recent years
, the use of levosimendan has broadened to treatment of heart failure in different settings .
these include advanced chronic heart failure , and other scenarios where haemodynamic stability is sought , such as pre - operative treatment of patients at risk of low cardiac output syndrome or peri - operative heart failure .
the aims of this presentation of four case reports were to compare the use of levosimendan in different settings , and to highlight differences and similarities in the effects obtained , with the purpose of defining common guidance on the use of levosimendan .
we retrospectively reviewed the records of patients with heart failure in the registries of our wards , and identified four cases where the patients had received levosimendan in four different settings .
we describe here the clinical management of these four cases . according to the local laws and regulations , due to the retrospective nature of data collection
case 1 . in 2002 , a 71-year - old , non - smoker male with a history of lymphoma , hypertension and long - standing diabetes was diagnosed with enlargement of the left ventricle and pronounced impairment of systolic function , with mitral insufficiency and pulmonary hypertension .
over the course of the next 18 months , the patient was repeatedly hospitalised due to congestive heart failure , and his medication was adjusted several times .
apart from treatments with angiotensin - converting enzyme inhibitors and diuretics , he also received an aldosterone antagonist , an angiotensin receptor blocker , and a -blocker . in april 2003
, he had new york heart association ( nyha ) class iiib heart failure , coronary angiography showed no significant arterial stenosis and the findings suggested biventricular failure . based on the electrocardiogram , the patient did not meet the criteria for cardiac resynchronisation therapy ( failure ) pacemaker implantation . in the spring of 2004 , medical treatment of this patient had effectively reached a dead end , and no further clinical improvement was seen .
the decision was then taken to initiate treatment with levosimendan . in late april 2004 ,
the first dose of levosimendan was applied , followed by further levosimendan doses every 4 weeks .
since the start of this treatment , the patient has not needed any further emergency admissions . in july 2004 ,
another echocardiograph that was performed in october 2004 showing only mildly impaired lv function with just minor mi and insignificant ti .
patient s condition was markedly improved with no symptoms , absence of oedema and improved quality of life .
simdax treatment was discontinued . at recheck to the cardiology clinic in march 2005 , the patient remained asymptomatic and his quality of life had further improved with increased physical activity , such as dancing and 3-km long daily walks .
anticoagulants were replaced with asa and the dosage of diuretics was reduced since there was no longer any fluid retention . at a follow up in september 2005 ( three year after the first hospitalization ) the patient was still asymptomatic .
a 73-year - old male had myocardial infarction in 1994 , which was followed by bypass surgery .
he was suffering from paroxysmal atrial fibrillation and chronic heart failure . in spring 2005 , the patient was hospitalised because of heart failure ( nyha class iiib ) . in august 2005 ,
echocardiography showed impaired left - ventricular systolic function with a left - ventricular ejection fraction ( lvef ) of 10% to 15% .
he also showed mild mitral and moderate tricuspid insufficiency , with a maximum velocity of tricuspid regurgitation flow of 4.2 m / s .
the patient was admitted to the internal medicine ward , and treatment with intravenous diuretics initiated .
he experienced less dyspnoea , but was still dizzy , with blood pressure of 80/60 mmhg .
after transfer to the cardiology - internal medicine ward , levosimendan treatment was started at a loading dose of 12 g / kg over 10 min , followed by continuous infusion with 0.2 g / kg / min for 24 h. the condition of the patient had already dramatically improved on the day after the levosimendan infusion .
his blood pressure rose to 95/65 mmhg , his diuresis recovered , and the following day he was able to walk on the ward without dyspnoea .
laboratory results showed improved renal function with decreasing creatinine values , and normalised liver function tests .
coronary angiography revealed proximal occlusion of the left anterior descending artery , and proximal stenosis of the circumflex artery .
he was completely symptom - free during surgery , and experienced no problems when lying flat on the operating table .
he showed improved left - ventricular function , with lvef of 20% to 25% . at the latest regular telephone follow up in 2008 ( three year after the previous hospitalization )
he had had a myocardial infarction approximately 7 years previously , had undergone coronary artery bypass surgery the same year , but had had no cardiac issues since that time .
he showed an inflammatory response with vasodilation during the procedure , and required infusion of substantial amounts of both crystalloid and colloid fluids .
support with phenylephrine was needed to maintain his mean arterial pressure ( map ) > 65 mmhg .
surgery revealed a perforated diverticulum of the small intestine and an abscess that required small bowel resection .
successful cardioversion was performed after 6 h of fibrillation . on the morning of the first postoperative day
, the patient showed normal sinus rhythm and heart rate , with map > 65 mmhg .
however , he reported shortness of breath , and his o2 saturation was 90% on 8 l / min supplemental o2 , using a mask .
laboratory results showed mild elevation of troponin t , but there were no electrocardiogram changes .
this was interpreted as heart failure , which had perhaps been triggered by a small myocardial infarction .
treatment with levosimendan was initiated with a loading dose for 10 min , which was followed by continuous infusion with 0.1 g / kg / min .
a couple of hours after the start of levosimendan treatment , the patient began to produce increasing amounts of urine . during the night , his o2 supplementation was reduced .
serial analysis of his troponin levels suggested a small myocardial infarction . repeated blood - gas evaluation showed a gradual increase in central venous o2 saturation ( scvo2 ) , to 68% .
after 24 h , the patient was discharged from the intensive care unit , and 10 days later he left for rehabilitation at another hospital . at one month after the operation the patient was asymptomatic .
case 4 . a 94-year - old male with known heart failure ( lvef , 15%-20% ; mild elevation of pulmonary artery pressure with moderate tricuspid insufficiency ; atrial fibrillation with normal heart rate ) presented at the emergency room with a two - day history of abdominal pain .
following various radiographic investigations , he was referred for an emergency laparotomy with suspected intestinal perforation . given his advanced age and cardiac status
it was believed that the perioperative inflammatory response , the negative inotropic effects of anaesthesia , and the positive - pressure ventilation might tip the balance and trigger manifest heart failure .
his cardiac index was 1.7 l / min / m , and scvo2 was 59% .
after treatment was begun with colloid administration , his cardiac index increased a little , to approximately 2 l / min / m , and his scvo2 to just over 60% . to further optimise treatment ,
the patient was started on levosimendan infusion ( loading dose 12 g / kg , followed by continuous infusion at 0.1 g / kg / min ) .
after 4 h of levosimendan treatment , the heart function of the patient improved , with a cardiac index of 3 l / min / m , and scvo2 of almost 70% .
small bowel resection was performed because of a perforated diverticulum . during the entire procedure ,
he was completely stable throughout the peri - operative course , and was extubated immediately after surgery .
then the patient was transferred to the postoperative ward for 24 h. five days later , the patient was discharged from hospital . at one month after the operation the patient was asymptomatic .
in this case series , we have presented four patients who required haemodynamic support in various settings of a failing heart .
three patients ( cases 1 - 3 ) experienced acute cardiac decompensation , while one patient ( case 4 ) appeared stable at low lvef , but needed to undergo abdominal surgery , which raised concerns as to probable cardiac failure during the course of the intervention .
the first patient developed persistent symptomatic heart failure on the basic of chronic ventricular dysfunction , with frequent emergency admissions to hospital .
customary heart - failure medication only temporarily relieved these symptoms . when it was felt that no further progress could be made , levosimendan treatment was administered over a total of four sessions , which produced a pronounced and rapid improvement at both the subjective and objective levels .
the second patient showed signs of severe biventricular failure after chronic heart failure had been present for many years .
he experienced hypotension , with signs of renal hypo - perfusion . in this patient with ischaemic heart disease and susceptibility to ventricular arrhythmia , levosimendan was the obvious choice .
biventricular pacing and levosimendan proved to be a well - chosen combination . for the third patient
rhythm regularisation and diuretic therapy were not sufficiently effective , but the condition of the patient improved with levosimendan treatment .
dobutamine can be considered as an alternative inotropic in this setting , although it can increase myocardial o2 consumption and the risk of arrhythmia . as both a small myocardial infarction and atrial fibrillation were present in this patient
the last case report describes the perioperative management of a 94-year - old man with known impairment of left - ventricular function .
levosimendan was deemed more appropriate than treatment with an adrenergic agonist , all the more so because the patient had chronic atrial fibrillation .
the administration of levosimendan produced rapid improvements to cardiac function , thus enabling the surgery to go ahead .
a large amount of data from many clinical trials has been published describing the effects of levosimendan in different clinical settings .
our narrative should be considered as anecdotic as any set of case reports , but our aim was to collect cases in which the same inodilator was used in different settings .
the description of the hemodynamic and symptomatic effects of the drug in parallel in such different patients may offer a new view point .
one clear limitation is that the patients undergoing surgery were followed up only for one month after operation . in our own clinical experience
, the use of a loading dose could be harmful if : the baseline pressure is too low;the diuretic dose is too high;the patient is hypokalemic .
the baseline pressure is too low ; the diuretic dose is too high ; the patient is hypokalemic . in this case
another point to be discussed is the cost of the drug : since at the moment no large mrct are published to support the beneficial effect of levosimendan over comparator on long term outcome , it appears difficult to justify a premium price over cheap generic such as dobutamine . some pharmaco - economic studies , however , were published which justify the use of this drug in the settings which we described in our manuscript .
we have presented a case series that shows that the administration of the ca sensitiser levosimendan can greatly improve heart failure in different settings .
the ca - sensitising effects of levosimendan are demonstrated here to remarkably improve cardiac output .
levosimendan , however , also has a pronounced vasodilatory effect , which contributes to lowering the pre - load and after - load . on the bases of our own experience , due to its vasodilatory effect
, levosimendan should be given cautiously to patients with low blood pressure , especially in the case of hypovolaemia .
the use of lower infusion rates without the loading bolus should be considered for such patients .
finally , we present here three recommendations for dosing of levosimendan treatment based on our own experiences on the ward : use a loading dose ( 6 - 12 g / kg over 10 min ) only if an immediate effect is needed and if systolic blood pressure is 100 mmhg;use a maintenance infusion rate of  < 0.2  g / kg / min , with individualised dosing  regimen;avoid hypovolaemia before and during the treatment ( fluid as needed ; intravenous diuretics with caution ) .
guidance on the repetitive use of levosimendan in chronic advanced heart failure , and on the perioperative use of levosimendan was provided recently by nieminen et al .   and toller et al .
use a loading dose ( 6 - 12 g / kg over 10 min ) only if an immediate effect is needed and if systolic blood pressure is 100 mmhg ; use a maintenance infusion rate of  < 0.2  g / kg / min , with individualised dosing  regimen ; avoid hypovolaemia before and during the treatment ( fluid as needed ; intravenous diuretics with caution ) .
guidance on the repetitive use of levosimendan in chronic advanced heart failure , and on the perioperative use of levosimendan was provided recently by nieminen et al .   and toller et al .
 introductionthe inodilator levosimendan was developed as a treatment for acutely decompensated severe chronic heart failure . in recent years 
 , its use has broadened to treatment of heart failure in different settings . 
 these include advanced chronic heart failure , and other scenarios where haemodynamic stability is sought , such as pre - operative treatment of patients at risk of low cardiac output syndrome or peri - operative heart failure . 
 the aims of this presentation of four case reports were to compare the use of levosimendan in different settings , and to highlight differences and similarities in the effects obtained , with the purpose of defining common guidance on the use of levosimendan.methodswe retrospectively reviewed the records of patients with heart failure in the registries of our wards , identified and described four cases where levosimendan was received in four different settings . 
 we provide here a systematic report on these four cases.resultsone patient suffered from acutely worsened chronic heart failure , one from advanced chronic heart failure , with repetitive treatment needed , one experienced acute ventricular failure as a result of a perioperative myocardial infarction , and one with left - ventricular function impairment and planned surgery.conclusionsheart failure arising from different aetiologies and occurring in different settings is amenable to successful treatment with levosimendan . 
Introduction
Methods
Results
Discussion
Conclusion