Levosimendan improved the function of stunned myocardium without obvious impairment of diastolic function.
Levosimendan has been developed for the treatment of decompensated heart failure and is used intravenously when patients with heart failure require immediate initiation of drug therapy. It increases cardiac contractility and induces vasodilatation. The pharmacokinetics of levosimendan are linear at the therapeutic dose range of 0.05-0.2 microg/kg/minute. The short half-life (about 1 hour) of the parent drug, levosimendan, enables fast onset of drug action, although the effects are long-lasting due to the active metabolite OR-1896, which has an elimination half-life of 70-80 hours in patients with heart failure (New York Heart Association functional class III-IV). Although levosimendan is administered intravenously, it is excreted into the small intestine and reduced by intestinal bacteria to an amino phenolpyridazinone metabolite (OR-1855). This metabolite is further metabolised by acetylation to N-acetylated conjugate (OR-1896). The circulating metabolites OR-1855 and OR-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. The haemodynamic effects after levosimendan seem to be similar between fast and slow acetylators despite the fact that the enzyme N-acetyltransferase-2, which is responsible for the metabolism of OR-1855 to OR-1896, is polymorphically distributed in the population. Levosimendan reduces peripheral vascular resistance and has direct contractility-enhancing effects on the failing left ventricle. It also improves indices of diastolic function and seems to improve the function of stunned myocardium. Despite an improvement in ventricular function, levosimendan does not increase myocardial oxygen uptake significantly. An increase in coronary blood flow and a reduction in coronary vascular resistance have been observed. Levosimendan reduces plasma brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) levels substantially, and a decrease in plasma endothelin-1 has been observed. Levosimendan also exerts beneficial effects on proinflammatory cytokines and apoptosis mediators. The effects of a 24-hour levosimendan infusion on filling pressure, ventricular function and BNP, as well as NT-proBNP, last for at least 7 days.
BackgroundDental general anaesthesia (DGA) is a very efficient treatment modality, but is considered only in the last resort because of the risks posed by general anaesthesia to patients’ overall health. Health services and their treatment policies regarding DGA vary from country to country. The aims of this work were to determine the reasons for DGA in the Helsinki Public Dental Service (PDS) and to assess the role of patient characteristics in the variation in reasons and in the treatments given with special focus on preventive care.MethodsThe data covered all DGA patients treated in the PDS in Helsinki in 2010. The data were collected from patient documents and included personal background: age (<6, 6–12, 13–17, 18–68), gender, immigration, previous conscious sedation and previous DGA; medical background; reasons for DGA and treatments provided. Chi-square tests, Fisher’s exact test, and logistic regression modelling were employed in the statistical analyses.ResultsThe DGA patients (n=349) were aged 2.3 to 67.2 years. Immigrants predominated in the youngest age group (p<0.001) and medically compromised patients among the adults (p<0.001) relative to the other age groups. The main reason for DGA was extreme non-cooperation (65%) followed by dental fear (37%) and an excessive need for treatment (26%). In total, 3435 treatments were performed under DGA, 57% of which were restorations, 24% tooth extractions, 5% preventive measures, 5% radiography, 4% endodontics and the remaining 5% periodontics, surgical procedures and miscellaneous. The reasons for DGA and the treatments provided varied according to age, immigration, previous sedation and DGA and medical background. The logistic regression model showed that previous sedation (OR 2.3; 95%CI 1.3-4.1; p=0.005) and extreme non-cooperation (OR 1.7; 95%CI 0.9-3.2; p=0.103) were most indicative of preventive measures given.ConclusionsExtreme non-cooperation, dental fear and an excessive need for treatment were the main reasons for the use of comprehensive, conservative DGA in the Helsinki PDS. The reasons for the use of DGA and the treatments provided varied according to personal and medical background, and immigration status with no gender-differences. Preventive measures formed only a minor part of the dental care given under DGA.
Skin blood flow of 30 healthy volunteers (age 17-58 years) was measured at a number of sites and in different ways using laser Doppler flowmetry (Periflux) to establish reference values. The interindividual and spatial variations were great. The long-term variation in skin blood flow was studied in five subjects from the above group, both at 2-h intervals on the same day and on five different days within 2-3 weeks. No significant variation between the values recorded at different times was observed. Forehead was the best measurement site showing the lowest coefficient of variation (CV) of 20-21%, all mean values recorded at different times falling within the 95% confidence limits of the reference values. Forearm skin blood flow was also followed in another 12 healthy volunteers (age 21-24 years) after administration of 0.5 mg of sublingual nitroglycerin. A rapid and transient increase of about 40% in blood flow, which peaked at 3-4 min was observed (P less than 0.05). It is concluded that laser Doppler flowmetry is very sensitive in measuring acute changes in skin blood flow, and may also be applicable in long-term studies on factors affecting microcirculatory flow.
Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Calcium sensitization of the myofilaments might increase inotropy without influencing cardiac electrophysiology unless modified by ancillary properties of the drugs. Electrophysiologic effects of a calcium sensitizer inotrope levosimendan were examined in short-term intravenous administration in humans. Variables were determined in 10 patients with normal cardiac function during a preceding control phase and levosimendan infusion yielding a high therapeutic concentration of 110 (+/-22) microg/L. Levosimendan increased heart rate by 9 beats/min (p < 0.01) on average and shortened the sinus node recovery time and AH interval. At the tested cycle lengths, levosimendan shortened the effective refractory periods in the atrioventricular node by 40-63 ms (p < 0.05), in the atrium by 22-33 ms (p < 0.001), and in the ventricle by 5-9 ms (p < 0.005) on average. Levosimendan increased ventricular monophasic action potential duration by 9-17 ms at 50% (p < 0.001) and by 5-15 ms (p = 0.07) at 90% levels of repolarization on average. The QT interval during spontaneous rhythm and atrial pacing remained unchanged although increased slightly when corrected to sinus rate (p < 0.001). The observations indicate that levosimendan in short-term administration facilitates impulse formation and conduction in cardiac slow-response tissue, enhances recovery of excitability in the myocardium, and may delay ventricular repolarization. The effects on the ventricle were not substantial, and therefore the likelihood of provoking serious cardiac arrhythmias is not estimated to be high.
Levosimendan is a new calcium-sensitiser intended for the treatment of congestive heart failure. The results of preclinical studies indicate it has positive inotropic and vasodilator effects. In the open study reported here up to 5 mg levosimendan and vehicle were administered to 8 healthy male volunteers at one- to 2-week intervals. Efficacy was evaluated using M-mode echocardiography, and by measuring systolic time intervals, recording ECG and measuring blood pressure. For almost all haemodynamic parameters except heart rate (HR) the maximum effect was seen 10 or 20 min after drug infusion. Effects 10 min after infusion of drug and vehicle were compared. HR was significantly increased 10 min only after infusion of 5 mg: significant increases were seen 60 min after infusions of 2, 3 and 5 mg (4, 8 and 17 beats.min-1, respectively). Diastolic blood pressure was significantly lower after doses of 1 mg or more. The decrease after 5 mg was 17 mmHg. Systolic blood pressure tended to increase. Fractional shortening (FS) and ejection fraction (EF) increased significantly after doses of 1 mg and higher. EF 10 min after infusion of vehicle was 54%. It increased to 73% after 5 mg. Decreases in electromechanical systole (QS2i) 10 min after 2, 3 and 5 mg were significant. There were no clinically significant adverse events or changes in laboratory safety values. The changes in QS2i, FS, EF and blood pressure indicate that levosimendan has positive inotropic and vasodilator effects in healthy subjects.
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