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Background: Levosimendan (LEVO), is an inotropic agent which has been shown to be associated with better myocardial performance, and higher survival rate in cardiac surgical patients. However, preliminary clinical evidence suggested that LEVO increased the risk of post-operative bleeding in patients undergoing valve surgery. Currently, there has been no randomized controlled trials (RCTs) designed specifically on this issue. Therefore, we performed present systemic review and meta-analysis. Methods: Electronic databases were searched to identify all RCTs comparing LEVO with Control (placebo, blank, dobutamine, milrinone, etc). Primary outcomes include post-operative blood loss and re-operation for bleeding. Secondary outcomes included post-operative transfusion of red blood cells (RBC), fresh frozen plasma (FFP) and platelet concentrates (PC). For continuous variables, treatment effects were calculated as weighted mean difference (WMD) and 95% confidential interval (CI). For dichotomous data, treatment effects were calculated as odds ratio (OR) and 95% CI. Results: Search yielded 15 studies including 1,528 patients. Meta-analysis suggested that, LEVO administration was not associated with increased risk of reoperation for bleeding post-operatively (OR = 1.01; 95%CI: 0.57 to 1.79; p = 0.97) and more blood loss volume (WMD = 28.25; 95%CI: –19.21 to 75.72; p = 0.24). Meta-analysis also demonstrated that, LEVO administration did not increase post-operative transfusion requirement for RBC (rate: OR = 0.97; 95%CI: 0.72 to 1.30; p = 0.83 and volume: WMD = 0.34; 95%CI: –0.55 to 1.22; p = 0.46), FFP (volume: WMD = 0.00; 95%CI: –0.10 to 0.10; p = 1.00) and PC (rate: OR = 1.01; 95%CI: 0.41 to 2.50; p = 0.98 and volume: WMD = 0.00; 95%CI: –0.05 to 0.04; p = 0.95). Conclusion: This meta-analysis suggested that, peri-operative administration of LEVO was not associated with increased risks of post-operative bleeding and blood transfusion requirement in cardiac surgical patients.

Background Heart failure with preserved ejection fraction ( HF p EF ) is an increasingly prevalent form of heart failure, representing half of the total burden of heart failure. We hypothesised that modulation of the phosphodiesterase type 3/cyclic AMP using a novel oral formulation of milrinone might exert favorable effects HF p EF via pulmonary and systemic vasodilation and enhancement of ventricular relaxation. We assessed the safety and efficacy of oral milrinone on quality of life and functional outcomes in patients with HF p EF . Methods and Results The Mil HFPEF (Extended Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction) study was a randomized, double‐blind, placebo‐controlled pilot study in 23 patients with symptomatic HF p EF . Efficacy end points included changes from baseline in Kansas City Cardiomyopathy Questionnaire summary score and 6‐minute walk distance. The primary safety end point was the development of clinically significant arrhythmia. The Kansas City Cardiomyopathy Questionnaire score improved significantly in milrinone‐treated patients compared with placebo (+10±13 versus −3±15; P =0.046). Six‐minute walk distance also tended to improve in the treatment group compared with placebo (+22 [−8 to 49] versus −47 [−97 to 12]; P =0.092). Heart rate (−1±5 versus −2±9 bpm; P =0.9) and systolic blood pressure (−3±18 versus +1±12 mm Hg; P =0.57) were unchanged. Early filling velocity/early mitral annular velocity (−0.3±3.0 versus −1.9±4.8; P =0.38) was unchanged. One patient in the placebo arm was hospitalized for heart failure. Holter monitoring did not demonstrate evidence of a proarrhythmic effect of milrinone. Conclusions In this novel pilot study, extended release oral milrinone was well tolerated and associated with improved quality of life in patients with HF p EF . Further longer‐term studies are warranted to establish the role of this therapeutic approach in HF p EF . Registration URL : https://www.anzctr.org.au/ ; Unique identifier: ACTRN 12616000619448.

Background Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent form of heart failure, representing half of the total burden of heart failure. We hypothesised that modulation of the phosphodiesterase type 3/cyclic AMP using a novel oral formulation of milrinone might exert favorable effects HFpEF via pulmonary and systemic vasodilation and enhancement of ventricular relaxation. We assessed the safety and efficacy of oral milrinone on quality of life and functional outcomes in patients with HFpEF. Methods and Results The MilHFPEF (Extended Release Oral Milrinone for the Treatment of Heart Failure With Preserved Ejection Fraction) study was a randomized, double‐blind, placebo‐controlled pilot study in 23 patients with symptomatic HFpEF. Efficacy end points included changes from baseline in Kansas City Cardiomyopathy Questionnaire summary score and 6‐minute walk distance. The primary safety end point was the development of clinically significant arrhythmia. The Kansas City Cardiomyopathy Questionnaire score improved significantly in milrinone‐treated patients compared with placebo (+10±13 versus −3±15; P=0.046). Six‐minute walk distance also tended to improve in the treatment group compared with placebo (+22 [−8 to 49] versus −47 [−97 to 12]; P=0.092). Heart rate (−1±5 versus −2±9 bpm; P=0.9) and systolic blood pressure (−3±18 versus +1±12 mm Hg; P=0.57) were unchanged. Early filling velocity/early mitral annular velocity (−0.3±3.0 versus −1.9±4.8; P=0.38) was unchanged. One patient in the placebo arm was hospitalized for heart failure. Holter monitoring did not demonstrate evidence of a proarrhythmic effect of milrinone. Conclusions In this novel pilot study, extended release oral milrinone was well tolerated and associated with improved quality of life in patients with HFpEF. Further longer‐term studies are warranted to establish the role of this therapeutic approach in HFpEF. Registration URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12616000619448.

The overexpression of ABCB1 in cancer cells is a major factor contributing to the development of multidrug resistance (MDR) and treatment failure in cancer patients. Therefore, re-sensitization of MDR cancer cells to anticancer drugs remains an important aspect in chemotherapy. The progress in developing clinically applicable synthetic inhibitors of ABCB1 has been slow, mostly due to complications associated with intrinsic toxicities and unforeseen drug-drug interactions. Here, we explored the drug-repositioning approach for cancer therapy by targeting ABCB1-mediated MDR in human cancer cells. We found that DPI-201106, a positive inotropic agent, selectively inhibits the drug efflux function of ABCB1, and in doing so, re-sensitizes ABCB1-overexpressing MDR cancer cells to conventional anticancer drugs. Furthermore, the ATPase activity of ABCB1 and docking analysis of DPI-201106 in the drug-binding pocket of ABCB1 were determined to confirm the interaction between DPI-201106 and ABCB1 protein. In summary, we revealed an additional action and a potential clinical application of DPI-201106 to reverse ABCB1-mediated MDR in human cancer cells, which may be beneficial for cancer patients who have developed multidrug resistance and no longer respond to conventional chemotherapy, and should be further investigated.

Background: There is currently no consensus on the appropriate selection of inotropic therapy in ventricular dysfunction. The objective of the study was to detect the effects of different inotropes on the hemodynamics of patients who developed low cardiac output. Methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched (all updated December 31, 2017). The inclusion criteria were as follows: low cardiac index (CI

In heart failure patients, hemodynamics can be regulated by therapeutic drugs. Although the cardiovascular responses to these drugs usually include nonlinearity and drug interactions, it is difficult to identify the characteristics of the dynamics under such conditions. This study, therefore, was aimed at evaluating the technique used for nonlinear system identification based on convolutional neural networks (CNN). As an image i.e., pixel values corresponding to time-course data), CNN can be used to treat the complicated relation between previous inputs (i.e., drug infusions) and outputs i.e., hemodynamics). To compare the accuracy of CNN, traditional methods based on the standard neural networks (NN) and fast Fourier transformation FFT were applied to nonlinear system identification with drug interactions. The cardiac output and arterial blood pressure under heart failure were modulated by the drug infusions of an inotropic agent and a vasodilator. CNN accurately predicted the dynamic system responses regardless of the inclusion of nonlinearity and drug interactions. Based on the findings of this study, CNN to carry out nonlinear system identification could clarify complicated pharmacodynamics, and thus could be useful for in appropriate cardiac treatment with multiple therapeutic agents.

Prospective observational study was conducted in a tertiary care hospital of India over 8 months to measure blood pressure (BP) in healthy term and preterm neonates using oscillometric method and explore the associations with gestational age and birth weight. Consecutive BP measurements were taken by standard oscillometric method on 1617 neonates on day 4, 7 and 14 of life. Mean birth weight was 2.7 ± 0.46 kg, and mean gestational age was 38.2 ± 2.12 weeks. The mean arterial pressure (MAP) on day 4, 7 and 14 were 59.3 ± 7.33, 63.2 ± 6.55 and 66.4 ± 6.13 mmHg, respectively. Larger and mature newborns had significantly higher BP than those who were smaller and premature. Birth weight more strongly correlated with MAP than gestational age. Predictive equations linking MAP with gestational age and birth weight were deduced, which can be used for judicious fluid inotrope management.

Levosimendan is a pyridazinone-dinitrile derivative with positive inotropic and vasodilatory effects that has beneficial effects on myocardial performance.In previous randomized studies levosimendan improved hemodynamics and clinical course, but its effect on prognosis is still unclear. This important issue has limited its use. Although primarily used in the management of acute heart failure syndromes, this new inotropic agent may play a role in other clinical conditions.This review aims to summarize current knowledge on levosimendan and to present future prospects for the use of this drug. Resumo: O levosimendan é um derivado da piridazinona-dinitrilo que induz um efeito inotrópico positivo e vasodilatador, exercendo efeitos benéficos sobre o desempenho do miocárdio.Em estudos aleatorizados prévios o levosimendan melhorou a hemodinâmica e a evolução clínica dos doentes, com um significado ainda pouco definido no prognóstico. Esta questão importante tem condicionado o seu uso. Embora seja utilizado principalmente no tratamento da insuficiência cardíaca aguda, este novo agente poderá desempenhar um papel importante em outras condições clínicas.Esta revisão pretende resumir o conhecimento atual sobre o levosimendan e mostrar perspetivas futuras no uso deste fármaco. Keywords: Levosimendan, Heart failure, Inotropes, Palavras-chave: Levosimendan, Insuficiência cardíaca, Inotrópicos

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Is it possible to predict the risk of ischaemic bowel after cardiac surgery?' Altogether 80 papers were found as a result of the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. This best evidence topic presents 68 214 cardiac surgical patients from seven major cardiothoracic centres dated from 1980 to 2011. The incidence and mortality rates of bowel ischaemia after cardiac surgery range from 0.07-0.5 and 59-64%, respectively. Advanced age and peripheral vascular disease are the common preoperative risk factors, which were reported by 3 papers each. The most common intraoperative risk factors were prolonged cross-clamp and cardiopulmonary bypass time, which were reported by 3 papers each. Five of 7 papers reported that the use of intra-aortic balloon pump was a significant risk factor. The use of inotropes, postoperative blood loss and postoperative renal failure were reported by 3 of 7 papers, each to be a significant risk factor for postoperative bowel ischaemia in cardiac surgery patients. We, therefore, conclude that these are probably the most significant and useful predictive risk factors for bowel ischaemia after cardiac surgery. Thus, careful intraoperative management to minimize cardiopulmonary bypass and cross-clamp time and optimal care of patients' postoperative haemodynamic status, particularly in elderly patients with severe atherosclerotic disease, are useful in preventing this rare but lethal postoperative complication. Besides that, a heightened clinical suspicion in patients with these risk factors may lead to prompt diagnosis of bowel ischaemia, allowing intervention to prevent mortality. The variability of the study design and risk factors studied in each paper impose limitation to summarize the predicting risk factors.

Shock is a common presentation to the ED, with the incidence of septic shock increasing in Australasia over the last decade. The choice of inotropic agent is likely dependent on previous experience and local practices of the emergency and other critical care departments. The relatively short duration of stay in the ED before transfer leaves little room for evaluating the appropriateness of and response to the agent chosen. Delays in transfer to inpatient facilities means that patients receive advanced critical care within the ED for longer, requiring initiation and titration of vasoactive agents in the ED. This article discusses the general concepts of shock and the indicators for inotrope and vasopressor use, revises the various agents available and reviews the current evidence for their use.

Purpose of review To critically examine the mortality rates of septic shock over the last 25 years to determine if significant improvements have been accomplished. Recent findings A gradual and progressive improvement in mortality rates associated with septic shock has been realized over the few decades. These improvements in outcome are quantitatively small but significant and they primarily represent improvements in supportive care, and the recognition that well meaning and seemingly logical treatments have been overused and probably contributed to excess mortality rates in the past. Summary Survival rates for patients in septic shock have gradually improved in critical care units worldwide over the last 25 years. Further improvement will be predicated on the discovery of new therapies to disrupt the underlying pathophysiology of sepsis and the development of improved rapid, diagnostic testing and immune monitoring of individual patients.

Objective: The goal of this study was to develop a national database of patients hospitalized in Turkey with acute heart failure (AHF) using evaluations of diagnostic and therapeutic approaches. Methods: Patient data was collected using an Internet-based survey. Total of 588 patients were enrolled from 36 participating medical centers from across the country. Results: Mean age was 62±13 years and 38% of the patients were female. Ratio of de novo AHF to study cohort was 24%. Coronary heart disease and hypertension were found in 61% and 53% of the patients, respectively. Valvular heart disease was underlying cause in 46% of heart failure patients. Most frequent factor associated with decompensation was noncompliance with treatment, observed in 34% of patients. Systolic blood pressure was 125±28 mmHg and heart rate was 93±22 beats/minute in the cohort. Most common fndings on physical examination were inspiratory fne crackles (84%), peripheral edema (64%), and cold extremities in 34%. Mean ejection fraction (EF) measured at admission was 33±13%. Preserved EF (=%40) was present in 20% of patients. At admission, 60%, 46%, and 40% of patients were using angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, or aldosterone antagonist, respectively. Death, stroke, and myocardial infarction were reported with frequency of 3.4%, 1.6%, and 2%, respectively, as in-hospital events. Conclusion: Compared to some other research data collected around the world, AHF patients in Turkey were younger, more frequently had valvular heart disease as underlying cause, and were more noncompliant with medical treatment, but overall mortality was lower. Drugs shown to reduce mortality, and which also form the backbone of guideline-directed medical therapy, are still used inadequately. © 2016 Turkish Society of Cardiology.

YILMAZ, MEHMET BIRHAN/0000-0002-8169-8628; YILMAZ, MEHMET BIRHAN B/0000-0002-8169-8628; Demirbag, Recep/0000-0001-7831-2715; Guvenc, Tolga Sinan/0000-0002-6738-266X; YILMAZ, Mehmet Birhan/0000-0002-8169-8628; Basarici, Ibrahim/0000-0003-4435-337X; Celebi, Aksuyek savas/0000-0002-3637-0711 WOS: 000392634300003 PubMed: 28045409 Objective: The goal of this study was to develop a national database of patients hospitalized in Turkey with acute heart failure (AHF) using evaluations of diagnostic and therapeutic approaches. Methods: Patient data were collected using an Internet-based survey. A total of 588 patients were enrolled from 36 participating medical centers across the country. Results: Mean age was 62 +/- 13 years and 38% of the patients were female. Ratio of de novo AHF to study cohort was 24%. Coronary heart disease and hypertension were found in 61% and 53% of the patients, respectively. Valvular heart disease was the underlying cause in 46% of heart failure patients. The most frequent factor associated with decompensation was noncompliance with treatment, observed in 34% of patients. Systolic blood pressure was 125 +/- 28 mmHg and heart rate was 93 +/- 22 beats/minute in the cohort. The most common findings on physical examination were inspiratory fine crackles (84%), peripheral edema (64%), and cold extremities in 34%. Mean ejection fraction (EF) measured at admission was 33 +/- 13%. Preserved EF (>=%40) was present in 20% of patients. On admission, 60%, 46%, and 40% of patients were using angiotens-in-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, or aldosterone antagonist, respectively. In-hospital events were reported as 3.4% death, 1.6% stroke and 2% myocardial infarction. Conclusion: Compared to previous data collected around the world, AHF patients in Turkey were younger, had more frequently valvular heart disease as the underlying cause, and were more noncompliant with medical treatment, but overall mortality was lower. Drugs shown to reduce mortality, and which also form the basis of guideline-directed medical therapy, are still used inadequately. Turkish Society of Cardiology Turkish Society of Cardiology

Leptospirosis is a re-emerging spirochetal zoonosis with a worldwide distribution affecting both animals and humans. The clinical syndromes may vary from a subclinical infection to a severe illness. Although it may potentially have a fulminant and fatal course, leptospirosis usually remains as an underdiagnosed cause of multiorgan failure. In this study, we report a patient with leptospirosis who presented with a fulminant course of diffuse alveolar haemorrhage and hepatorenal failure. His clinical condition deteriorated, despite appropriate antibiotic therapy and haemodialysis. However, he showed prompt clinical improvement when corticosteroids and plasma exchange were instituted in addition to the original therapy. We conclude that leptospirosis should be considered in any case presenting with pulmonary haemorrhage and hepatorenal failure. Plasma exchange and corticosteroids may be a choice of treatment in selected patients unresponsive to conventional therapy. Potential benefits of plasma exchange and corticosteroids may be based on a toxin- and/or cytokine-mediated pathogenesis of the disease. © 2007 The Authors Journal compilation 2007 Blackwell Publishing Ltd.

Milrinone is an inotropic agent with vasodilating properties used in the treatment of ventricular dysfunction. Milrinone is predominantly eliminated by the kidneys and accumulates in the setting of acute kidney injury (AKI). The purpose of this study was to evaluate milrinone pharmacokinetics in children with AKI with or without continuous renal replacement therapy (CRRT).Retrospective collection of milrinone therapeutic drug monitoring data in patients with AKI, including those requiring CRRT, through chart review from January 2008 to March 2014. Pharmacokinetic (PK) data were analyzed by Bayesian estimation using a pediatric population PK model (MW/Pharm). Clearance estimates were allometrically scaled to body weight.Data on 11 patients were available for analysis. Three patients required CRRT. Milrinone concentrations during continuous infusion varied 30-fold and ranged from 44 to 1343 ng/mL. Of the 33 samples obtained in 11 patients, 24 were outside the target range (72.7%), with 16 (48.5%) above and 8 (24.2%) below. Patients with AKI had significantly lower milrinone clearance (4.72 ± 2.26 L/h per 70 kg) compared with published data in patients without AKI. There was large between-patient variability in milrinone clearance (range: 2.91-13.6 L/h per 70 kg). Clearance in patients on CRRT ranged from 2.8 to 7.19 L/h per 70 kg. A significant correlation between milrinone clearance and estimated creatinine clearance was observed (r = 0.70, P = 0.0097). Allometrically scaled milrinone clearance was lower in the youngest patients (younger than 2 years), suggestive of ongoing renal maturation and existing AKI.Pediatric patients with AKI have significantly lower milrinone clearance compared with published data in patients without AKI. Large variability was noted in milrinone concentrations, and they were frequently outside the target range. The large between-patient variability in milrinone concentrations suggests that dosing regimens should be individualized in this population of critically ill patients. Evaluation of PK model-based milrinone dose optimization and the use of biomarkers as predictors of changes in clearance warrant further study.

In the present study of mitral valve replacement, we investigated whether complete preservation of both leaflets (that is, the subvalvular apparatus) is superior to preservation of the posterior leaflet alone. Seventy patients who underwent mitral valve replacement in our clinic were divided into 2 groups: MVR-B (n=16), in whom both leaflets were preserved, and MVR-P (n=54), in whom only the posterior leaflet was preserved. The preoperative and postoperative clinical and echocardiographic findings were evaluated retrospectively. No signs of left ventricular outflow tract obstruction were observed in either group. In the MVR-B group, no decrease was observed in left ventricular ejection fraction during the postoperative period, whereas a significant reduction was observed in the MVR-P group (P=0.003). No differences were found between the 2 groups in their need for inotropic agents or intra-aortic balloon pump support, or in cross-clamp time, duration of intensive care unit or hospital stays, postoperative development of new atrial fibrillation, or mortality rates. Bileaflet preservation prevented the decrease in left ventricular ejection fraction that usually followed preservation of the posterior leaflet alone. However, posterior leaflet preservation alone yielded excellent results in terms of decreased left ventricular diameter. Bileaflet preservation should be the method of choice to prevent further decreases in ejection fraction and to avoid death in patients who present with substantially impaired left ventricular function.

Background: There are currently many on-going clinical trials assessing therapies for the treatment of patients with heart failure. Aims: The purpose of this series of papers is to present concise summaries of current randomised trials in the field of heart failure and myocardial infarction (MI). Methods: Data from large double-blind, placebo-controlled trials, which are on-going or have only recently been published, are given in a format allowing easy comparison. Where appropriate, data from smaller studies are included. Results: Major studies which are examined in this issue include CIBIS II, MERIT-HF, RESOLVD, SPICE, VEST, MACH-1, ATLAS, RALES, CIDS and CASH. These trials assess the efficacy and safety of beta-blocker, angiotensin-II-receptor blocker, positive inotropic agent, calcium antagonist, angiotensin-converting enzyme (ACE) inhibitor, aldosterone receptor blocker, and antiarrhythmic interventions in the treatment of heart failure. Conclusions: The presentation of data from these on-going trials should allow an up-to-date assessment, by physicians, of the most appropriate and effective treatment for patients with heart failure. It is evident that some therapies may play no further role in the treatment of heart failure, due to the increased risk of mortality associated with their administration, whilst others may convey significant benefits.

The history began in the 19th century with Ascanio Sobrero (1812-1888), the discoverer of glycerol trinitrate (nitroglycerine, NTG), and with Angelo Angeli (1864-1931), the discoverer of sodium trioxodinitrate (Angeli's salt). It is likely that Angeli and Sobrero never met, but their two histories will join each other more than a century later. In fact, it has been discovered that both NTG and Angeli's salt are able to induce a preconditioning effect. As NTG has a long history as an antianginal drug its newly discovered property as a preconditioning agent has also been tested in humans. Angeli's salt properties as a preconditioning and inotropic agent have only been tested in animals so far.

The authors report a case where four novel strategies were successfully used in the management of advanced right ventricular failure with severe pulmonary hypertension and complex adult congenital heart disease. These included combination and optimisation of three advanced therapies for pulmonary hypertension, therapeutic abdominal paracentesis, correction of underlying metabolic/endocrine disturbance and a new inotropic agent.

Although international guidelines for hemodynamic support of pediatric septic shock suggest considering the potent calcium sensitizer inodilator levosimendan as a second-line inotropic agent to treat cold hypodynamic shock resistant to catecholamines, clinical experience in septic infants is lacking. We report the beneficial effects of levosimendan infusion in 2 infants (39 and 64 days old) with low cardiac output septic shock (ejection fraction, 29% and 33%; fractional shortening, 10% and 16% respectively) refractory to volume replacement and to the catecholamines dopamine and dobutamine. Levosimendan infusion (0.15 µg/kg/min) promptly increased both patients' myocardial contractility and improved tissue perfusion, thereby reducing lactate levels and increasing urine output. The only adverse effect was moderate hypotension in one infant, who reversed by adding norepinephrine to levosimendan. This clinical experience confirms the potential beneficial effects of levosimendan infusion to restore hemodynamics in infants with low cardiac output septic shock resistant to catecholamines.

In order to compare the acute hemodynamic effects of digoxin (0.01 mg/kg) and enoximone (1 mg/kg), a phosphodiesterase inhibitor inotropic agent, in severe chronic congestive heart failure, 8 patients (male, mean age 56.7 years, sinus rhythm) were investigated with a randomized cross-over study. Peak effect of enoximone (30 min) in comparison to that of digoxin (90 min) resulted in a similar reduction of left-ventricular filling pressure (-27 vs. -28%) and mean pulmonary artery pressure (-23 vs. -24%). Pulmonary (-39 vs. -16%; p0.01) and systemic vascular resistance (-27 vs. -4%; p0.001) were significantly lowered by enoximone. Cardiac index (+30 vs. +6%; p0.001) and heart rate (+11 vs. -3%; p0.05) were increased significantly more by enoximone than by digoxin. Since enoximone resulted in an enhancement of cardiac performance greater than that produced by digoxin, enoximone could be a useful and powerful substitute for digoxin in the acute therapy of severe chronic congestive heart failure with sinus rhythm.

The present study was designed to evaluate the significance of echocardiography versus cardiac troponin I levels in early detection of anthracycline dependent cardiotoxicity in acute lymphoblastic leukemia (ALL) patients. A total of 276 pediatric ALL patients were included in the study prospectively along 3 phases of data collection lasted from 2002 to 2009; including phase I (March 2002 to February 2003; n = 25; 53.3% females), phase II (September 2003 to April 2004; n = 35; 57.1% females), and phase III (January 2005 to June 2009; n = 216; 52.7% females) with respect to cumulative anthracycline doses applied. Anthracycline was administered in accordance with berlin-Franfurt-Munich (BFM)-2000 protocol in doses of 30 to 350 mg/m(2) (in the first phase) and 30 to 240 mg/m(2) (in the following phases). Evaluation of cardiotoxicity was performed via echocardiography and measurement of cardiac troponin I levels. Patients in each phase were homogenous in terms of gender and age. Diastolic dysfunction determined via reduction E/A ratio below the cutoff value was demonstrated to deteriorate earlier than systolic functions and alteration in cardiac enzymes. Being similar between dose groups, cTnI levels were shown to rise in the presence of congestive heart failure. In conclusion, anthracycline cardiotoxicity appears to be detected in an earlier stage by using diastolic parameters compared to systolic parameters and cardiac enzymes.

The hyperadrenergic condition following surgical stress and inotropic drugs have been identified as leading causes for postoperative atrial fibrillation (AF). Smokers are characterized by higher catecholamine levels and tolerance. We tested the hypothesis that smoking patients are less prone to develop postoperative AF.A total of 3,245 coronary artery bypass and valvular procedures were reviewed. Predictors of AF and interaction between variables were explored by multivariable logistic regression. AF-predictive scores were created and validated for goodness of fit, and receiver operating characteristic curves were created.Postoperative AF occurred in 26% of patients. Smokers accounted for 15% of the study population and demonstrated a reduced incidence of postoperative AF compared with nonsmoking individuals (20% vs. 27%, p.001). Multivariate analysis revealed a significant interaction between smoking status and inotropic support requirement. The AF-protective effect of smoking was confounded by inotropic drugs. However, when we excluded from analysis the patients with inotropic support, smoking conferred a 46% risk reduction of AF (odds ratio [OR] = 0.54, 95% CI = 0.34-0.87, p = .011). In addition, age, valvular surgery, and hypertension were independently associated with AF. Postoperative AF increased the length of hospitalization, without affecting hospital mortality. AF was associated with an increased 1-year mortality (p = .002).Current smokers are less prone to develop AF after cardiac surgery. Our data support the hypothesis that hyperadrenergic state and catecholamines are key mechanisms in the pathophysiology of postoperative AF.

The clinical heterogeneity of acute heart failure and the low number of controlled trials, to date, are the main causes of the lack of agreement on therapeutic objectives, uncertainty on the most appropriate management, and difficulties to obtain robust evidence for the treatment of this syndrome. The inappropriate use of inotropic agents is one the most common pitfalls shown by registries. Two to 10% of patients admitted for acute heart failure present with a low output syndrome, a clinical profile associated with high mortality, where inotropes may be a rational therapeutic choice. Crucial points for an effective use of inotropes are an accurate evaluation and selection of patients, tailoring of therapeutic schemes and strict patient monitoring. Beta-adrenergic agonists and phosphodiesterase inhibitors increase myocardial oxygen demand, favor arrhythmias and may cause peripheral vasodilation with a secondary decrease in coronary perfusion pressure. These effects may translate in myocardial ischemia, loss of cardiomyocytes and accelerated ventricular remodeling with worse prognosis. Levosimendan, a novel inotropic agent studied according to the principles of evidence-based medicine, augments myocardial contractility without changes in intracellular calcium concentrations, and with minimal impact on myocardial oxygen consumption. This paper, based on an expert consensus, aims to suggest criteria for the appropriate use of inotropic agents in acute heart failure, based on a critical appraisal of the existing evidence and clinical experience. © 2009 AIM Publishing Srl.

The aim of this study was to determine whether early administration (2 hours after the first surfactant dose) of the second surfactant dose would be superior to late surfactant treatment (6 hours after the first surfactant dose) in preterm infants with severe respiratory distress syndrome. Between June 2003 and March 2005, 40 newborns born with respiratory distress syndrome in Uludag University Hospital were investigated in this prospective study. The inclusion criteria for the recruitment of the infants were: age = 0.4 and mean airway pressure >= 7 cm H(2)O to obtain arterial pressure of oxygen between 70-80 mmHg. Infants with lethal congenital anomalies or being treated with high-frequency oscillatory ventilation were excluded from the study. Birth weight, gestational age, gender, and Apgar scores were recorded and complications of the surfactant therapy were examined. Twenty boys and 20 girls were enrolled in the study. The first surfactant dose was administered in the first hour of life in all infants. The second surfactant dose was given 2 hours after the first dose in 20 of them and 6 hours after the first dose in the other 20. Infants in both groups (early versus late) were similar with respect to gestational age, birth weight, gender, and the rate of prenatal corticosteroids. There were also no significant differences between the two groups in terms of the response to surfactant therapy and complications. The results of this study show that administration of the second surfactant dose earlier is as effective as late administration, and it may be suggested that the second surfactant dose can be applied earlier in severe respiratory distress syndrome.

To assess whether an inotropic agent may affect quality of life in severe heart failure, a double-blind, placebo-controlled crossover study was performed in 10 patients over three periods of 3 weeks, including an initial control period of 3 weeks and periods on placebo or enoximone, 150 mg t.d.s. Quality of life was assessed by a questionnaire following initial training of patients to evaluate their symptoms after certain stresses, by visual analogue scales of symptoms, and by objective assessments during graded exercise. Daily dyspnoea score decreased from 33.2 +/- 2 (placebo) to 27.7 +/- 4 (enoximone) (P less than 0.01) and daily fatigue score decreased from 14.8 +/- 2.5 (placebo) to 12.6 +/- 2 (enoximone) (P less than 0.05). There were also significant beneficial responses in the mean daily NYHA class and in the duration of a walking test. Self-assessed global quality of life score increased from 2.7 +/- 0.6 (placebo) to 3.6 +/- 0.8 (enoximone) (P less than 0.05). It was concluded that over periods of 3 weeks, enoximone significantly improved self-assessed quality of life.

Diuretics and angiotensin-converting enzyme inhibitors currently are the mainstay of both acute and chronic heart failure management. They have earned their place by bringing measurable and reliable clinical benefit to patients with all grades and types of heart failure. Other treatments--digoxin, vasodilators and inotropes--offer less secure efficacy and their clinical role is at times controversial. The need for new remedies is inescapable. Despite current therapy, heart failure causes a distressing reduction in both quality and quantity of life. As knowledge of the pathophysiology of heart failure is gained, more selective treatment options may become available offering hitherto unknown specificity but demanding remarkable levels of diagnostic accuracy.

Looking back reveals how the direction of therapy for heart failure has changed since the inception of the first large clinical trial of vesnarinone, an inotropic agent, in April 1990. At that time...

Background: Preinfarction angina (PA) and early reperfusion of infarct-related arteries have been shown to reduce infarct size in patients with acute myocardial infarction (AMI). The beneficial effects of PA on infarct size have been attributed to the development of ischemic preconditioning and faster coronary recanalization in patients treated with thrombolytic therapy (TT). Objective: To evaluate the effect of PA on clinical coronary reperfusion time in patients with AMI receiving successful TT. Methods: Seventy-five patients presenting with AMI (within 6 h after the initial onset of symptoms) were studied. All patients received TT and were evaluated with coronary angiography (CA) at predischarge. The patients were divided into two groups: group 1 (PA-positive) comprised those who experienced a new onset of prodromal angina within 72 h before the onset of AMI. Group 2 (PA-negative) comprised those who had a sudden onset of AMI without the preceding angina. The successful myocardial reperfusion criteria after TT were ST segment resolution of 50% or greater, the appearance of reperfusion arrhythmias and the resolution of chest pain. The time of reperfusion criteria was recorded after TT. CA was performed in all patients at predischarge. Patients with no patent infarct-related arteries on CA and clinical failure of reperfusion were excluded from the study. Results: Clinical characteristics, risk factors and angiographic findings did not differ significantly between the groups. The time interval from the start of continuous chest pain to TT was also similar between the groups. The left ventricular ejection fraction was higher and there were less frequent ventricular arrhythmias in patients with PA than in those without PA (47.9±7.4 versus 44.4±8.1, P=0.041, and 17.1% versus 37.5%, P=0.043, respectively). The clinical reperfusion time was significantly shorter in the patients with PA than in those without PA (68.2±24.5 min versus 81.4±19.3, P=0.012). The clinical reperfusion time was positively correlated with age and the time interval from the start of continuous chest pain to TT but inversely related to the presence of PA. Conclusions: In patients with AMI preceded by PA, TT resulted in more rapid clinical reperfusion than in patients without PA. Thus, earlier myocardial reperfusion may account for smaller infarct size and better prognosis in patients with PA. © 2005 Pulsus Group Inc. All rights reserved.

The aim of this study was to compare the positive inotropic effects of 3 different agents with 3 different mechanisms of actions-levosimendan, rolipram, and dobutamine-on human atrial trabecular muscles. Samples of right atrial appendage (1 cm, 500-1000 mg) were removed and immersed in preoxygenated and modified Tyrode solution. In oxygenated Tyrode solution, preparations were used to investigate the concentration-effect relationship of levosimendan, dobutamine, and rolipram on percentage developed tension (DT), from 10 to 10 M, each concentration for 15 minutes. All 3 agents produced concentration-dependent increments in DT. We found that levosimendan was the most efficacious positive inotropic agent on isolated human atrial trabeculae. Both the sensitivity (pD2) and maximum response (Emax) of human atrial trabeculae to levosimendan (6.711 +/- 0.26 and 23.2 +/- 2.2 mN, respectively) were significantly greater than those of dobutamine (6.663 +/- 0.19 and 17.6 +/- 2.8 mN) and rolipram (6.497 +/- 0.18 and 15.0 +/- 1.0 mN). pD2 and Emax values for dobutamine were significantly higher than those for rolipram. It was suggested that because of its potential to enhance cardiac performance without predisposition to calcium-induced arrhythmias, levosimendan might be more useful as a positive inotropic agent in clinical practice.

Objective: To determine whether glutamat and aspartat enriched cold crystalloid cardioplegia which was given in antegrade way has any effect on the myocardial protection during cardiopulmonary bypass. Material and Methods: Thirty-four patients who were electively undergone open heart surgery at Osmangazi University Faculty of Medicine, thoracic and cardiovascular surgery department, between March 2001 and May 2001 were included in this study. The patients were divided in two groups, each consisting of 17 patients. In group 1 coronary artery bypass surgery (CABG) was performed in 11 patients, mitral valve replacement (MVR) in 3 patients, aortic valve replacement (AVR) in 1 patient and AVR and MVR in 2 patients. While in group 2 CABG was performed in 13 patients and MVR was done in 4 patients. Group 1 patients received antegrade glutamat and aspartat (15 mmol/L) enriched cold crystalloid cardioplegia and group 2 patients were given cold crystalloid cardioplegia by antegrade route. Age, gender, diabetes mellitus, hypertension, preoperative myocardial infarction, smoking, ejection fraction, aortic cross-clamp time, need to defibrillation, inotropic support, and intraaortic balloon pump were recorded. The levels of cardiac troponin I (cTI) and creatine kinase myocardial band fraction (CK-MB) were measured in arterial blood samples at five different times. Statistical analysis was performed using Student's t-test and Chi-square test. Results: There were no statistically significant differences in cTI and CK-MB values in blood samples taken at 5 different times pre and postoperatively between group 1 and group 2. Conclusion: It is concluded that glutamat and aspartat enriched cold crystalloid cardioplegia does not have any effect on myocardial protection.

Objective: To determine whether glutamat and aspartat enriched cold crystalloid cardioplegia which was given in antegrade way has any effect on the myocardial protection during cardiopulmonary bypass. Material and Methods: Thirty-four patients who were electively undergone open heart surgery at Osmangazi University Faculty of Medicine, thoracic and cardiovascular surgery department, between March 2001 and May 2001 were included in this study. The patients were divided in two groups, each consisting of 17 patients. In group 1 coronary artery bypass surgery (CABG) was performed in 11 patients, mitral valve replacement (MVR) in 3 patients, aortic valve replacement (AVR) in 1 patient and AVR and MVR in 2 patients. While in group 2 CABG was performed in 13 patients and MVR was done in 4 patients. Group 1 patients received antegrade glutamat and aspartat (15 mmol/L) enriched cold crystalloid cardioplegia and group 2 patients were given cold crystalloid cardioplegia by antegrade route. Age, gender, diabetes mellitus, hypertension, preoperative myocardial infarction, smoking, ejection fraction, aortic cross-clamp time, need to defibrillation, inotropic support, and intraaortic balloon pump were recorded. The levels of cardiac troponin I (cTI) and creatine kinase myocardial band fraction (CK-MB) were measured in arterial blood samples at five different times. Statistical analysis was performed using Student's t-test and Chi-square test. Results: There were no statistically significant differences in cTI and CK-MB values in blood samples taken at 5 different times pre and postoperatively between group 1 and group 2. Conclusion: It is concluded that glutamat and aspartat enriched cold crystalloid cardioplegia does not have any effect on myocardial protection.

The aim of this study was to investigate and determine whether patients with significant (greater than or equal to%50) left main coronary artery stenosis could undergo coronary bypass on the beating heart and compare the results to those obtained using the conventional method. Prospectively collected data of patients with significant left main coronary artery disease who had undergone coronary bypass on the beating heart (group A, n=100) or with the conventional method (group B, n=100) were evaluated retrospectively. EuroSCORE values, preoperative and operative details, postoperative morbidity and mortality, and early results were compared. Groups were similar in terms of EuroSCORE, demographics, and preoperative variables. Number of distal anastomoses per patient was 3.1+/-0.9 in the beating heart group while it was 3.3+/-0.9 in the conventional group (P=0.09). Patients operated on with the conventional method had higher levels of peak creatine kinase-myocardial band, blood and blood product transfusions, and inotropic requirements, while mechanical ventilation times and hospital stay were longer. The incidence of postoperative atrial fibrillation, mediastinitis, and intra-aortic balloon usage were comparable between the groups. There was no neurological complication in group A whereas five major neurological complications (three transient ischemic attacks, two strokes) occurred in group B (P=0.06). Thirty-day mortality occurred in one patient in the beating heart group whereas five early deaths were observed in the conventional group (P=0.21). In significant left main coronary artery stenosis coronary bypass on the beating heart is a safe and effective alternative to the conventional method with the same or better early results. The long-term results need to be evaluated.

Background: This study was conducted to compare the effect of histidine-triptophanketoglutalate solution (HTK) with that of cold blood cardioplegic solution (CBC) in mitral valve surgery. Method: Forty-six patients who underwent mitral valve replacement between January 1994 and December 1996 were enrolled in this study. Twenty patients received HTK (HTK group), while 27 patients had CBC (CBC group) as myocardial protection. HTK was given as a single high dose, whereas CBC was used in the usual multidose format. Result: The doses of inotropic agent at the end of extracorporeal circulation did not differ between the HTK group and the CBC group. Creatine kinase values (units) on day 1 and day 2 were 1140 ± 412, 921 ± 436 for the HTK group and 904 ± 335,816 ± 420 for the CBC group, respectively (p = NS). Spontaneous defibrillation occurred in 26% of the CBC group and 90% of the HTK group (p < 0.05). Pacing was temporarily used in 20% of the HTK group and 44% of the CBC group after extracorporeal circulation (p < 0.05). Conclusions: These results suggest that HTK provided more adequate myocardial protection in mitral valve surgery. (J Card Surg 1998; 13:43–47)

In a prospective, randomized, controlled study, we have investigated the effect of forced air warming on the rate of change of nasopharyngeal and rectal temperatures in 20 patients after coronary artery bypass grafting. All patients had nasopharyngeal temperatures less than 36 degrees C on arrival in the intensive care unit and received an infusion of glyceryl trinitrate 15 mg h-1, but none received inotropes. Ten patients were warmed under an aluminized plastic "space" blanket (control group) and 10 were warmed under a "Bair Hugger" blanket connected to its power unit on "high" setting (Bair Hugger group). The rates of increase in nasopharyngeal temperature were 0.4 and 0.95 degrees C h-1, respectively, in the control and Bair Hugger groups (P0.01) during the first 2 h after operation. Over the same period of time, rectal temperatures increased at a rate of 0.25 and 0.75 degrees C h-1 in the control and Bair Hugger groups, respectively (P0.01).

Milrinone has been studied in a variety of situations. In experimental dogs it has been documented to increase contractility to a similar degree as beta-receptor agonists and to produce mild arteriolar dilation in dogs. In canine patients with heart failure, milrinone produces demonstrable improvement in echocardiographic ventricular function and hemodynamic variables. In addition, it improves clinical signs in these patients, improving their quality of life. Milrinone is superior to digoxin as evidenced by the improvement in clinical signs noted in dogs that were unresponsive or no longer responding to digoxin administration. There is no doubt that milrinone improves short-term prognosis and in so doing prolongs life. Many of the patients that the author has observed would not have gone home without the benefits of milrinone. Milrinone's effects on long-term survival cannot be assessed, but its effects on survival time are certainly not dramatic enough to be evident without a comparison population. Therefore, milrinone administration should be considered palliative, as is administration of all other cardiovascular medications for heart failure. In addition to its beneficial effects, milrinone also appears to be relatively safe when compared with the alternative of digoxin administration. Fatal events attributable to milrinone administration are rare, and those directly attributable to enhanced ventricular arrhythmia can generally be avoided by monitoring an electrocardiogram after initial milrinone administration commences. Milrinone does not increase the incidence of sudden death in Doberman Pinschers. It is possible that a small number of dogs with mitral regurgitation may develop mitral chordal rupture. For this reason and possibly others, milrinone probably will not be indicated in early heart failure due to mitral regurgitation when heart failure is readily responsive to diuretic administration. The risk-to-benefit ratio turns markedly in the favor of milrinone administration in the dog with mitral regurgitation that is partially or completely refractory to other cardiovascular drugs. Milrinone appears to be a more effective and safer positive inotrope for long-term treatment of dogs with congestive heart failure than drugs currently available. The author and all the investigators involved in the milrinone clinical trials hope that it will soon be available for use by the veterinary community.

The choice of inotropic agent, particularly in catecholamine-resistant septic shock, remains an area of debate. Here we discuss a recent trial examining the use of vasopressin in a carefully controlled trial setting. Yet more data on the use of drotrecogin alfa (activated) in septic shock are described, as are novel but as yet experimental approaches to the treatment of sepsis. Finally, it is important not to forget to read the latest surviving sepsis guidelines.

The belief that a depression of cardiac contractility is the fundamental defect in patients with chronic heart failure has led to the development during the past 20 years of nearly 100 new drugs wi...

A new inotropic agent, TA-064, (-)-alpha-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzylalcohol, was shown to have strong effects in experimental animals. Its effectiveness and associated adverse effects were tested in humans invasively (n = 6) and noninvasively (n = 17). Increasing doses of intravenous infusion (1, 2, and 4 micrograms/kg/min) increased plasma levels to 15, 35, and 82 ng/ml, respectively, resulting in marked increases in the peak rate of left ventricular pressure rise (dP/dt) (1,450 +/- 63 to 3,042 +/- 349 mm Hg/s) (mean +/- standard error of the mean [SEM], p less than 0.01) and the ratio of dP/dt to left ventricular pressure at a developed pressure of 40 mm Hg (25 +/- 3 to 39 +/- 2 s-1) (p less than 0.01), with a reduction in left ventricular end-diastolic pressure (12 +/- 2 to 4 +/- 1 mm Hg) (p less than 0.01). Minimal or no changes were seen in heart rate and left ventricular systolic pressure. After a single oral dose (10 mg), the plasma level reached its peak at 90 minutes (16 +/- 9 ng/ml, n = 17). A positive inotropic effect was confirmed echocardiographically in both healthy volunteers (n = 8) and patients with congestive heart failure (CHF) (n = 9) who were maximally treated with conventional regimens: increase in mean velocity of circumferential fiber shortening (healthy volunteers: 1.29 +/- 0.05 to 1.60 +/- 0.11 circ/s [p less than 0.05]; patients with CHF: 0.69 +/- 0.08 to 0.93 +/- 0.09 circ/s [p less than 0.01]), ejection fraction (healthy volunteers: 68 +/- 2 to 75 +/- 2% [p less than 0.05], patients with CHF: 37 +/- 4 to 45 +/- 5% [p less than 0.01]) without change in heart rate. The cardiac index was increased only in the CHF group (2.71 +/- 0.22 to 3.21 +/- 0.24 liters/min/m2) (p less than 0.05). No significant untoward effects were observed. Thus TA-064 is a potent inotropic agent and can be used either parenterally or orally. Salutary effects can be expected in patients with congestive heart failure who are treated with digitalis and diuretic agents.

1. UK 14,275 (Pfizer) an inotropic agent with cardiac phosphodiesterase inhibitory activity, was administered to ten healthy male volunteers. 2. The inotropic activity was assessed by non-invasive measurement of systolic time intervals (STI). 3. The compound had significant inotropic activity in the doses administered, as judged by the shortening of pre-ejection period (PEP), without any significant chronotropic activity. 4. The inotropic effect was abolished when measurements were repeated following beta-adrenoceptor blockade with oral propranolol. 5. The inotropic activity was compared to that of intravenous isoprenaline.

The hemodynamic and neurohumoral effects of cummulative intravenous doses of piroximone (MDL 19205), a noncatecholamine, nonglycoside, imidazole derivative with positive inotropic and vasodilating properties, were studied in eight patients with severe congestive heart failure. A dose of 1.25 mg/kg in seven patients and 1.75 mg/kg in one patient increased cardiac index by 75% from 1.96 to 3.41 liters/min per m2 and decreased systemic vascular resistance (-41%), right atrial (-66%) and pulmonary wedge pressure (-35%) (all p less than 0.005). Mean arterial pressure was slightly reduced from 78 to 71 mm Hg (p less than 0.05) and forearm blood flow increased by 42%. Plasma norepinephrine decreased from 830 to 542 pg/ml (p less than 0.05) and plasma renin activity tended to increase. In four patients, dobutamine (15 micrograms/kg per min) produced a comparable increase in cardiac index (+100%), but less decrease in pulmonary wedge pressure (-21 versus -41%, p less than 0.05 versus piroximone) and, unlike piroximone, significantly increased heart rate (+22%, p less than 0.05 versus piroximone) and heart rate-blood pressure product (+30%, p less than 0.01 versus piroximone). In four other patients, a single intravenous dose of piroximone (1 mg/kg) resulted in a 35% increase in the first derivative of left ventricular pressure (dP/dt) from 796 to 1,068 mm Hg/s (p less than 0.01). Thus, piroximone is a potent inotropic agent with an acute hemodynamic profile that may be more favorable than that of dobutamine. Because the drug is orally absorbed, clinical trials of chronic efficacy are indicated.

The effects of DPI, a new inotropic agent, were compared in trabeculae carneae from control and myopathic human hearts loaded with aequorin, a bioluminescent calcium indicator that emits light when it combines with calcium, and in saponin-skinned trabeculae carneae from the same hearts. The force-pCa curves in saponin-skinned fibers and the peak force-peak Ca2+ curves in aequorin-loaded preparations were not significantly different between the control and myopathic tissues. The force-pCa curve in the skinned and aequorin-loaded preparations from the same control hearts displayed no significant shifts with the addition of DPI. In contrast, a leftward shift was present in the force-calcium relationship in the presence of DPI in aequorin-loaded and skinned muscles from myopathic hearts, indicating an increase in the sensitivity of the myofilaments to calcium. These differences in the modulation of calcium activation between myopathic and control tissues indicate that pharmacological agents may produce differential effects in normal and diseased hearts.

The ideal inotropic agent should be available for both parenteral and oral administration and be potent and effective long term without significant adverse effects. In recent years, numerous new agents have been developed in an attempt to find a more potent, less toxic alternative to digoxin. beta-Agonists, while useful when given parenterally short term, appear to have their long term oral application limited by adverse effects and the development of tolerance. A number of other non-catecholamine agents, most of which have both inotropic and vasodilator actions, have also been studied. Adverse effects have been relatively frequent and occasionally severe. Of these newer agents none has yet been proven in clinical trials to be safe and effective in the long term.

1 BM 10.188 (Doxaminol, Boehringer Mannheim, GmbH) is a recently developed beta-sympathomimetic agent which has shown promising positive inotropic activity in experimental animal models. It is a dibenzoxepine derivative. 2 The effects of 20 mg oral BM 10.188 on systolic time intervals and standard echocardiographic parameters have been studied in six normal healthy male volunteers. 3 When assessed by repeated measured analysis of variance, QS2 and LVET shortened significantly (P less than 0.005) in the 8 h period following BM 10.188. Mean maximum shortening values were: QS2, 25.7 +/- 25.6 (s.d.) ms at 155 min and LVET, 10.7 +/- 9.5 (s.d.) ms at 155 min. There was a corresponding small but significant increase of 4.2 +/- 3.9 (s.d.) ml in stroke volume at 6 h (P less than 0.025). 4 These results indicate that in normal volunteers, BM 10.188 exhibits effects on noninvasive cardiological indices similar to those observed after cardiac glycosides.

Piperanometozine (OPC-8212) is a new, orally effective inotropic agent. To evaluate the efficacy of this agent on systemic hemodynamics and clinical symptoms in patients with congestive heart failure, a multicenter study was performed. Thirty four patients with New York Heart Association (NYHA) functional classes II to IV and initially treated with digitalis were enrolled from ten centers. After a washout period of one or two weeks (placebo period), digitalis was replaced by piperanometozine (30 or 60 mg/day) for four weeks, while other drugs were continued. Clinical symptoms, routine physical findings, electrocardiogram, chest roentgenogram, echocardiogram, exercise tolerance time, and routine laboratory data were obtained in 34 patients. Four patients were withdrawn from the study before completion. After the withdrawal of digitalis, heart rate was increased and ejection fraction was decreased. Exercise tolerance time was increased while other parameters were unchanged. At the end of the treatment period with piperanometozine, ejection fraction significantly (p less than 0.05) increased with a decrease in LV end-systolic volume (p less than 0.05), whereas heart rate and blood pressure remained unchanged. Systolic blood pressure/LV end-systolic volume (P/V index) tended to decrease after the withdrawal of digitalis and increase during piperanometozine therapy. Exercise tolerance time was further increased (p less than 0.01) and NYHA functional class was improved in 11 patients, whereas it worsened in only one patient. No major adverse effects were observed. These results indicate that a short-term therapy of oral piperanometozine restored the depressed cardiac performance of the heart and improved clinical symptoms in patients with congestive heart failure. Thus, this promising agent deserves further clinical study in long-term trials.

A patient with severe cardiac failure due to idiopathic congestive cardiomyopathy resistant to conventional therapy, responded to amrinone, a new non-glycosidic non-catecholamine positive inotropic agent. Amrinone produced significant haemodynamic improvement during both intravenous and oral administration. Thrombocytopaenia, however, was induced, necessitating cessation of the drug. Amrinone is a promising, orally effective inotropic agent for patients with refractory congestive cardiac failure, but is limited by its tendency to cause thrombocytopaenia.