levosimendan is recognized as an inotropic drug used in acute or decompensated chronic heart failure with innovative characteristics . it is not a -adrenergic agonist which would have energy - consuming and proarrhythmic effects . it is rather a mild pde inhibitor in clinical relevant doses   and mainly a ca - dependant troponine - i sensitizer resulting in energetically beneficial contractility of the cardiac muscle . furthermore , there is also an atp - dependant k - channel activation which causes peripheral vasodilation . a cardioprotective mechanism via the atp - k channels and the phenomenon of preconditioning is also under research . pharmacokinetically , levosimendan acts for prolonged time , since its two major metabolites or-1855 and or-1896 have half - life time of 7080 hours . this pharmacological profile offers an ideal medical option in acute heart failure with preserved or borderline systolic blood pressure . standard pattern of infusion consists of a loading dose and a continuous 24-hour i.v . infusion . in some cases , the vasodilatory action causes an early hypotension resulting in withdrawal of drug or coadministration with a -agonist with all the possible risks of this combination . the goal of this observational study was primarily to determine whether a prolonged and beyond the 24-hour infusion pattern without the loading dose could be efficient and safe for patients in acute or decompensated heart failure . for this reason , we administrated a prolonged levosimendan infusion for 24 , 48 , or 72 hours creating three subgroups . clinical and neurohormonal responses were measured with simple bedside parameters derived from physical examination   and serial measurements of bnp   and saecg . safety was determined by the presence of major or minor complications and onset of new arrhythmias . study population consisted of patients admitted to hospital between march 2003 and december 2006 suffering from acute heart failure or decompensated chronic heart failure . the clinical status of those patients was iii or iv according to the nyha classification . all patients were resistant to optimal medical therapy and did need support of an inotropic agent . diagnosis of heart failure was confirmed by the contribution of physical examination , previous history , but mainly by transthoracic echocardiography and thoracic x - rays . retrospective analysis of the heart failure aetiology was performed . as for the exclusion criteria , patients with an acute coronary syndrome , cardiac shock with systolic blood pressure under 85  mmhg resistant to volume administration , hypertrophic cardiomyopathy , benign or life - threatening tachyarrhythmias with heart rate over 120/min , and electrolytic abnormalities did not participate . the study protocol included quantitative analysis in three different subgroups of main population determined by clinical evaluation after 24-hour intervals . all participants took next to their standard medication ( diuretics , oxygen , aces or arbs , digoxin , and -blockers in minor dose ) an infusion of levosimendan of 0.05  g / min / kg uptitrated in two hours to 0.1  g / min / kg for 24 hours . in the interval , if there was no contraindication , the uptitration could achieve the dose of 0.2  g / min / kg . it should be decided if levosimendan could be stopped or continued according to bedside clinical criteria . the subjective criterion of patient 's well - being and the absence of pathologic signs on auscultation of the pneumonal areas or the absence of s3 gallop were cut points for the discontinuation of levosimendan infusion . patients , who continued the infusion , did so for a duration of 72 hours . the exclusion criteria of recruitment had the same power during the infusion time , so that management could be safe . in some complications , like hypotension or tachyarrhythmia , it was up to investigator to treat the complication and to decide for the next step of the study . blood pressure and heart rate were determined at baseline and at 24 , 48 , and 72 hours ,   respectively . a resting ecg was performed at the above - mentioned time points confirming also the possible arrhythmogenic complications . in cases a confirmation of heart failure was needed , a transthoracic echo was performed . as far for the neurohormonal response of the therapy , we used measurements of brain natriuretic peptide ( bnp ) by means of the microspheric elisa analysis ( meia ) method . blood samples of 6  ml were taken at the beginning time point of the infusion , at 48 hours and at 72 hours independently on the subgroup a patient belonged to . after an addition of 0.1  ml transylol for preserving protein molecules , these samples were centrifuged at 3000  cycles / min for 5 minutes . bnp normal range was assumed under the value of 100 pg / ml . on the study , a signal averaged ecg was used ( marquette model 5000 ) . p - wave filtered , qrs filtered duration , root mean square voltage , the last 40  msec , and the duration of voltage < 40  v at 40  hz were determined at baseline , 48 and 72 hours , respectively . normal ranges of the above mentioned variables are qrs filtered duration < 120  msec , rms the last 40  msec > 20  v , and duration of low voltage at 40  hz < 38  msec . confirming an assumption of bnp response changes in qrs - filtered duration observed in this clinical study were evaluated with the assumption that variations in qrs complex duration could represent respective variations in left ventricular dimensions . so , decreases in qrs - filtered duration > 10  msec were regarded as good response . increases in qrs - filtered duration were evaluated as no response and the values in between as moderate ones . the well - being status was evaluated by means of clinical examination and subjective confirmation of the patient at 24 and 48 hours of infusion . major complications were confirmed for the whole duration of the study and a period of a month followed . countable variables were demonstrated with minimum , maximum , mean , and standard deviation values . differences in countable variables were evaluated with the nonparametric paired t - test of wilcoxon . correlation between countable variables was evaluated with linear regression analysis . to confirm a comparison between the subgroups uncountable variables were evaluated in a descriptive manner and the correlation between them with the chi - square test accompanied by the phi or cramer 's v test . in all the tests the protocol was approved by the institutional review board of our center and was performed in accordance with institutional guidelines and the declaration of helsinki . the population consisted mainly of male participants ( 82.9% ) , not allowing to perform adequate sex - related statistical analysis . regarding the aetiology of the heart failure , we observed a population with 64.3% suffering from coronary artery disease and with 35.7% from nonischemic dilated cardiomyopathy . bnp mean baseline value was 1105  pg / ml , confirming a study population with severe heart failure with low mean ejection fraction at baseline ( 33.5  6.3% ) and   high mean enddiastolic left ventricular diameter ( 6.81  0.81  mm ) . mean p wave was elevated at baseline ( 180  9.5  msec ) and mean qrs duration filtered ( 149  4.1  msec ) was quite higher than normal range , even if bundle branch block was present . relative bnp difference and qrs duration filtered at 72 hours   are shown below   ( table 2 ) . it is obvious by the data derived that using the specific infusion pattern , there was a 68.6% of good or moderate bnp and a 45.7% of good or moderate qrs response . considering the two main end - point parameters overall , there was a statistically significant bnp decrease at 48 hours after baseline ( p < .001 ) , which continued at 72 hours , and a significant decrease of qrs filtered duration at 72 hours ( p = .04 ) . however , crosstabulation of the qrs duration and the bnp response did not show any statistically significant correlation ( p > .1 ) . there were established three subgroups depending on the duration of infusion of 24 hours ( n = 14 ) , 48 hours ( n = 35 ) , or 72 hours ( n = 21 ) .   the 24-hour infusion subgroup had a mean percentage relative difference on bnp at 72 hours of 15.3% and mean difference on qrs duration at 72 hours of 0.8  msec per patient . there were no statistical significance in any measured parameter ( p > .1 ) according to the wilcoxon test for paired differences ( table 3 ) . patients with 48-hour infusion had a statistically significant decrease on bnp beginning at 48 hours ( p < .0001 ) , which continued at 72 hours ( p < .0001 ) . this finding indicates an enormous neurohormonal response with 48-hour infusion of levosimendan without loading dose . the mean percentage relative difference of bnp at 72 hours showed a decrease of 43% , which is a quite acceptable percent . qrs duration had on average a borderline significant decrease at 72 hours of 10.96  msecs per patient ( p = .065 ) , which might indirectly indicate a decrease of left ventricular dimensions . patients with 72-hour infusion had a borderline significant decrease on bnp beginning at 48 hours ( p = .039 ) and a statistically significant decrease at 72 hours ( p < .004 ) . this finding shows a good neurohormonal response with 48-hour infusion of levosimendan without loading dose with the necessity to follow 24-hour infusion additionally , so that the decrease could achieve a significant range . qrs filt duration had on average a borderline significant decrease at 72 hours of 7.4  msecs per patient ( p = .049 ) . trying a general correlation between the countable parameters of difference of qrs filtered duration at 72 hours and bnp relative difference at 72 hours , there was a linearity only in cases with adverse response for the two variables ( r - squared = 0.01 ) . crosstabulation analysis of the two 48- and 72-hour infusion patterns demonstrated that at 48-hour infusion there was an obvious correlation between good qrs responders and good bnp responders ( p value of -square test = .05 ) . this statistical result was determined by the respective adjusted residuals of the data analysis .   at 72-hour infusion , the correlation was biased with non - bnp responders to have also a moderate qrs filtered duration response ( p > .1 ) . according to the kolmogorov - smirnov test and the mann - whitney analysis , the demographics of two subgroups of the population were compared . without differences on the characteristics , those who have taken 48-hour infusion demonstrated at least good or moderate qrs filtered duration  at acceptable bnp response , representing a subpopulation with good neurohormonal profile ( figure 3 ) . as for the complications , there were not patients who had to discontinue the study due to hypotension or other minor complication . new onset of atrial flutter , atrial fibrillation or ventricular tachycardia was not observed , indicating a study population with low short - term arrhythmogenic profile according to the continuous ecg monitoring . all patients survived achieved a weaning status by inotropic agents without the necessity of withdrawal until their discharge . within a period of a month , one patient was presented with acute renal exacerbation , and three others needed to be rehospitalised for exacerbated heart failure . in this study , we tried to demonstrate efficiency and safety of an alternative infusion pattern of levosimendan in acute heart failure . the critically ill patients of this condition have most of the time a borderline preserved systolic pressure . so , it is important to prevent the patient from hypotension , which could induce hypoperfusion . levosimendan has on start an enormous peripheral vasodilatory effect , which causes hypotension . in this view , participants were not given the loading dose at the beginning , but a continuous dose was administrated up to 72 hours depended on the clinical response . bnp is widely recognized as a therapeutic tool of responsiveness in patients with heart failure . in our study , we used bnp as a reliable marker of efficiency . it was obvious from the data analysis that those patients who were given 72-hour infusion had the necessity for such a long infusion . they did not achieve clinical improvement at 48 hours , so they had to continue with another 24-hour infusion . the population studied were patients with advanced heart failure , since mean value was generally above 1000  pg / ml . this means that the percent of decrease of bnp was , respectively , not so enormous like in other trials , in which the mean value was about 500800  pg / ml . we think that the achieved mean values of 3143% are acceptable improvement , concerning that all patients survived did not have symptoms or re - exacerbation of their clinical status . the other basic bound of our study was the investigation of safety of such infusion patterns . as for the complications the two deaths were due to advanced heart failure and could be accepted by the condition of acute heart failure . the signal averaged ecg is an examination which has a good specificity in predicting monomorphic ventricular tachycardia in patients with chronic heart failure . there are also studies with patients of dilated cardiomyopathy , which mention the role of signal - averaged ecg . however , in the last years , the role of this examination has diminished . the scope was to show that levosimendan did not at least change the parameters of this examination , so that a neutral effect could be confirmed . indeed , the study showed that in good bnp responders there was a subpopulation whose qrs filtered duration not only was unchanged but also decreases . the finding of this observation can not be evaluated exactly but indicates a subpopulation with good clinical and neurohormonal response . further studies should be conducted to investigate the correlation between bnp and filtered qrs duration variations . considering the results of this study , it could be said that levosimendan is an inotropic drug , which allows an infusion of more than 24 hours . there is also an opposed opinion , which supports that there is no need of prolonged infusions , since the metabolites of levosimendan have long half - life period . the problem is that sometimes patients admitted are critically ill and the target of treating them efficiently is difficult to achieve . we need an inotropic agent like levosimendan with an acceptance of -blocker coadministration , or at least at low doses , with non--agonist effect and energetically beneficial . furthermore , at this clinical condition , a drug - induced hypotension could be unnecessary . limitations of the study are its design , which does not have perspective analysis and randomization of groups in an objective manner . it is an observational study with the additional limitation of small period of followup of the variables measured . another limitation is the absence of hemodynamic data [ 19 , 20 ] , which could support adequately the scope of the study . this could be the goal of a future study in the same way of using alternative infusion patterns . the subgroup observed in this study with the beneficial profile should be followed in time with the hope to stratify the cumulative risk of mortality or morbidity in heart failure .
background . 
 levosimendan is an inotropic drug with unique pharmacological advantages in patients with acute heart failure . 
 scope of this study is to determine whether longer infusion patterns without the hypotension - inducing loading dose could justify an effective and safe alternative approach 
 . methods . 
 70 patients admitted to the emergencies with decompensated chronic heart failure received intravenously levosimendan without a loading dose up to 72 hours . 
 clinical parameters , bnp ( brain natriuretic peptide ) and signal - averaged - ecg data ( saecg ) were recorded up to 72 hours . 
 results . the 48-hour group demonstrated a statistically significant bnp decrease ( p < .001 ) after 48 hours , which also maintained after 72 hours . 
 the 72-hour group demonstrated a bordeline decrease of bnp after 48 hours ( p = .039 ) , necessitating an additional 24-hour infusion to achieve significant reduction after 72 hours ( p < .004 ) . 
 saecg data demonstrated a statistically significant decrease after 72 hours ( p < .04 ) . apart from two deaths due to advanced heart failure , no major complications were observed . 
 conclusion . 
 prolonged infusion of levosimendan without a loading dose is associated with an acceptable clinical and neurohumoral response .