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Acute decompensated heart failure (ADHF) is a common clinical problem associated with a high mortality rate. Because ADHF has various aetiologies, there are a range of therapeutic options, among others, positive inotropes (inotropic drugs). As an inotropic agent whose mechanism is different than that of “classical” medicines, levosimendan (LSM) is one of the most common therapeutic options. Despite many publications on LSM, some issues related to its application remain unclear. The authors of this paper have attempted to summarise expert recommendations and reports available in the literature.

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.

Current therapeutic strategies for acute heart failure (AHF) are based on traditional inotropic agents that are often associated with untoward effects; therefore, finding new effective approaches with a safer profile is dramatically needed. Istaroxime is a novel compound, chemically unrelated to cardiac glycosides, that is currently being studied for the treatment of AHF. Its effects are essentially related to its inotropic and lusitropic positive properties exerted through a dual mechanism of action: activation of the sarcoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a) and inhibition of the Na+/K+-ATPase (NKA) activity. The advantages of istaroxime over the available inotropic agents include its lower arrhythmogenic action combined with its capability of increasing systolic blood pressure without augmenting heart rate. However, it has a limited half-life (1 hour) and is associated with adverse effects including pain at the injection site and gastrointestinal issues. Herein, we describe the main mechanism of action of istaroxime and we present a systematic overview of both clinical and preclinical trials testing this drug, underlining the latest insights regarding its adoption in clinical practice for AHF.

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.

Nitroxyl (HNO), the one-electron reduced form of nitric oxide (NO), shows a distinct chemical and biological profile from that of NO. HNO is currently being viewed as a vasodilator and positive inotropic agent that can be used as a potential treatment for heart failure. The ability of HNO to react with thiols and thiol containing proteins is largely used to explain the possible biological actions of HNO. Herein, we summarize different aspects related to HNO including HNO donors, chemistry, biology, and methods used for its detection.

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.

Background: Intra-aortic balloon pump (IABP) had a pivotal role in the therapy of cardiogenic shock (CS), but recent studies have questioned its effects on patients' outcome. Aim of this study is the description of a "real world" series of patients in which IABP was used as a primary mechanical circulatory support (MCS). Methods: All patients who received IABP in our institution during 1 year were prospectively enrolled in our study. The outcomes were: ICU mortality, length of ICU stay, factors associated with mortality and complications of IABP. A logistic regression model was developed to estimate the effect of several risk factors on mortality. Results: A total of 119 patients were enrolled, 54 patients underwent IABP placement for CS unrelated to cardiac surgery (medical CS) and 65 after open-heart surgery. There was no significant difference for mortality between medical CS [12/54 (22.2%)] and cardiac surgery [7/65 (10.8%)] (P=0.09). The morbidity rate related to IABP was 11.3%. Multivariable analysis identified AKI (OR =9.3; 95% CI, 2.0-40.0; P=0.004), inotropic score at the time of IABP implantation (OR =1.06; 95% CI, 1.01-1.11; P=0.009) and history of myocardial revascularization (OR =4.7; 95% CI, 1.1-20.2; P=0.036) as independent predictors for early death (P < 0.05). A ROC curve analysis for inotropic score at time of implantation and mortality was performed in the overall population [AUC=0.78 (95% CI, 0.66-0.90)]. A cutoff of 20 has a specificity =72% and sensitivity=74% in this population. Conclusions: Mortality is similar in medical and postcardiotomy CS. The benefits of IABP are limited if the amount of inotropes and the severity of shock are too high.

A Cu-catalyzed regio- and enantioselective hydroboration of 1,2-dihydroquinolines with high yields and excellent enantioselectivities (up to 98% ee) was presented. This method could be applied in the asymmetric synthesis of the important intermediates used in the enantioselective synthesis of the potential agent Sumanirole for the treatment of Parkinson’s disease and of the potentially interesting positive inotropic agent (S)-903.

Chrysosplenol C (4',5,6-trihydroxy-3,3',7-trimethoxyflavone) isolated from Miliusa balansae has unique structural features as a reversible inotropic agent independent of β-adrenergic signaling and with selective activation of cardiac myosin ATPase. Hence, a series of chrysosplenol analogues were synthesized and explored for identification of pharmacophore that is essential for the increasing contractility in rat ventricular myocytes. Analogue 7-chloro-2-(3-hydroxyphenyl)-3-methoxy-4H-chromen-4-one showed highly potent contractility (54.8% at 10 μM) through activating cardiac myosin ATPase (38.7% at 10 μM). Our systematic structure-activity relationship study revealed that flavonoid nucleus of chrososplenol C appears to be an essential basic skeleton and hydrophobic substituent at position 7 of chromenone such as methoxy or chloro enhances the activity. Additionally, our ATPase study suggested that these chrysosplenol analogues have selectivity toward cardiac myosin activation. Thus, the novel flavonone with 3-/7-hydrophobic substituent and 3'-hydrogen bonding donor function is a novel scaffold for discovery of a new positive inotropic agent.

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.

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.

Aim: Colistin’s parenteral use was limited due to nephrotoxicity related to decreased renal perfusion, nephrotoxins and ischemia-reperfusion injury. Colistin became popular again because of multiple drug resistance (1, ). This study aimed to retrospectively evaluate the characteristics of intensive care patient groups with and without colistin-induced acute kidney injury. Material and Methods: Following approval of local ethics committee, information of the patients, who were treated in the anesthesia and surgical intensive care units between 01/01/2016 and 30/06/2017, were analyzed retrospectively. Results: Twenty patients (59%) developed acute kidney injury during colistin treatment. No statistically significant difference was observed between the groups with and without acute kidney injury in terms of age, gender and duration of stay in the intensive care unit, however, patients with acute kidney injury were found to be older and stayed in the intensive care unit for a longer period of time. The comparison made between the groups in terms of inotropic agent use showed that the duration of inotropic agent use was statistically longer in the acute kidney injury group. Discussion: Rate of colistin-induced acute kidney injury varies between 5-55%. In addition, fluid balance of patients is important in acute kidney injury development. Fluid therapy, hourly urine output and central venous pressure trends of the patients should be closely monitored particularly when nephrotoxic medicines are used. There is a need for large-scale studies with more advanced methodologies for the early detection and prevention of colistin-induced nephrotoxicity.

Positive inotropic agents should be used judiciously when managing surgical patients with acute myocardial ischemia–reperfusion injury, as use of these inotropes is not without potential adverse effects.

Inotropic agents induce changes in the contraction amplitude and frequency of cardiomyocytes (CMs). However, it is unknown how local contractions of CMs treated by inotropic agents behave spatiotemporally. In this study, the effect of isoproterenol, a positive inotropic agent, on local contractions of isolated neonatal rat CMs was explored by atomic force microscopy (AFM). We observed that changes in local contraction amplitude of CM in the presence of isoproterenol were heterogeneous; they were unchanged or increased, at different positions, with respect to the amplitude of untreated CMs. Interestingly, spatial heterogeneities of local contraction amplitude of CM in the presence of isoproterenol did not obviously correlate with the local elasticity, indicating that the local contractions were facilitated by cooperative dynamics of the cytoskeletal structure in relatively large regions, rather than those just under AFM indentation. Moreover, local contraction amplitude of CM in the presence of isoproterenol was not proportional to that in the control condition, showing that the former change was no longer additive in local scales.

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.

Possible arrhythmogenic side-effects of the positive inotropic agent prenalterol were studied in conscious dogs, three to four days after coronary artery ligation. Prenalterol showed a propensity to cause arrhythmias in one out of eight dogs, thereby confirming published data from clinical studies.

A concise enantioselective synthesis of (S)-903, an inotropic agent, is described in nine linear steps and 95% ee based on asymmetric dihydroxylation of cinnamate ester and Co-catalyzed multifunctional reduction of several functional groups leading to the construction of core tetrahydroquinolin-3-ol, as the key steps.

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.

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.

Dopamine is a commonly used positive inotropic agent for the treatment of hypotension in small animals. Two dogs that had undergone surgery, under isoflurane anaesthesia, developed a sudden and profound bradycardia when a dopamine infusion was administered. Bradycardia was attributed to the activation of the Bezold-Jarisch reflex, an inhibitory reflex, characterised by bradycardia and hypotension.

Background: Mesenchymal stem cell (MSC)-treatment has shown clinical benefits in various diseases, however the poor viability of engrafted MSC limits therapeutic potential. Apelin-13 is a potent inotropic agent that, when administered in conjunction with MSCs treatment, improves survival and

Introduction Traumatic subarachnoid hemorrhage (SAH) is a common intracranial lesion after traumatic brain injury (TBI). As in aneurysmal SAH, cerebral vasospasm is a common cause of secondary brain injury and is associated with the thickness of traumatic SAH. Unfortunately, there is limited literature on an effective treatment of this entity. The vasodilatory and inotropic agent, Milrinone, has been shown to be effective in treating vasospasm following aneurysmal SAH. The authors hypothesized that this agent could be useful and safe in treating vasospasm following tSAH. Case descriptions Case reports of 2 TBI cases from a level 1 trauma centre with tSAH and whom developed delayed ischemic neurological deficits (DINDs) are presented. Intravenous Milrinone treatment was provided to each patient following the “Montreal Neurological Hospital Protocol”. Discussion and evaluation Both patients had an improvement in their DINDs following the treatment protocol. There were no complications of treatment and the Glasgow Outcome Scores of the patients ranged from 4 to 5. Conclusion This is the first report of the use of intravenous Milrinone to treat cerebral vasospasm following traumatic SAH. This treatment option appeared to be safe and potentially useful at treating post-traumatic vasospasm. Prospective studies are necessary to establish Milrinone’s clinical effectiveness in treating this type of cerebral vasospasm.

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.

Myocardial injury due to acute carbon monoxide intoxication is often refractory to standard resuscitation methods. Levosimendan is a new inotropic agent that is used in the treatment of acute and chronic heart failure. We report a case of severe cardiopulmonary compromise after exposure to carbon monoxide in a 40-year-old woman who was monitored using transthoracic echocardiography and the arterial pulse contour analysis system (FloTrac) and successfully treated with levosimendan.

The effect of the cardiotonic sensitizing drug EMD 57033 was studied in frog skinned skeletal muscle fibres at 12 degrees C to provide a baseline for skeletal muscle studies and for comparison with cardiac fibres. The activation and relaxation of fibres were induced by laser flash photolysis of the caged calcium NP-EGTA, and caged calcium chelator diazo-2 respectively. EMD 57033 (10 microM) slightly increased the rate of relaxation (rate constant k1 changing from 24.0 +/- 2.9 s-1 in control to 28.1 +/- 3.2 s-1) but had no significant effect on the rate of activation (k1 = 9.6 +/- 0.9 s-1 in control conditions, 9.7 +/- 1.6 s-1 with EMD 57033). The effect of the optical isomer of EMD 57033, EMD 57439, was examined on steady-state force and relaxation rate. EMD57439 (10 microM) slowed the rate of relaxation (k1 = 20.5 +/- 2.4 s-1) but had no effect on the maximal calcium-activated force whereas EMD 57033 increased it by 16.5 +/- 5.7%. These results are compared to earlier results from this laboratory in guinea-pig skinned trabeculae, and a possible model for the action of EMD 57033 whereby the drug enhances force per cross-bridge is discussed.

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.

肝膵同時切除術13例において輸液量として術中15ml/kg/hr, 0病日は5ml/kg/hrを目標とした管理を行い術中肝静脈血酸素飽和度 (ShvO2) と循環動態を検討した. 術後全身循環は酸素運搬能600ml/min/m2以上, 酸素消費量135ml/min/m2以上で推移しShvO2の低下も認めなかった. 動脈血中ケトン対比は術中0.53±0.16であったが, 1病日以後は1.0以上で推移した. 術中ShvO260%以下低下時間は術後総ビリルビンとIL-6最高値との間におのおのr=0.938, r=0.740の有意な相関を認め, ShvO2モニタリングは肝虚血侵襲の把握に有用と考えられた. 本研究対象症例に肺合併症は認めず, 肝不全は1例7.7%で手術死亡は認めなかった. HPDにおける積極的な輸液投与とinotropic agentの併用, ShvO2モニタリングの有用性を示す結果と考えられた.

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.

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.

Conformationally restricted analogues of the positive inotropic agent 1 have been synthesized in order to determine its biologically active conformation. Comparison of the distance maps (as a tool for the allowed conformations) with the biological activity give new insights in the biologically active conformation of this class of positive inotropic agents.

The synthesis of ethyl or methyl esters of 2-substituted 5-acetyl-1,6-dihydro-6-oxo-3-pyridinecarboxylic acids 2a-d, f and 5 by reaction of sodium acetoacetamide with ethyl or methyl 2-dimethylaminomethylene-3-oxoalkanoates and ethyl 2-ethoxymethylene-4,4,4-trifluoro-3-oxobutanoate, respectively, has been described. These esters routinely gave the corresponding carboxylic acids by alkaline hydrolysis followed by acidification. As milrinone analogues, the above compounds were tested on contractile activity and frequency rate of spontaneously beating atria and on contractile activity of electrically-driven left atrium from reserpinetreated guinea pigs. Among the tested compounds, ethyl 5-acetyl-1,6-dihydro-6-oxo-2-phenyl-3-pyridinecarboxylate was found to be more potent and more effective than milrinone as a positive inotropic agent, while only marginally affecting the frequency rate.

Putative 5-HT 4 receptors were investigated in isolated piglet left atria and papillary muscles. In atrial tissues, 5-hydroxytryptamine (5-HT) was a potent positive inotropic agent with a pD 2 of 6.7. Its effects were antagonised in a selective and competitive manner by the 5-HT 4 receptor antagonist, SDZ 205-557, with a pA 2 of 7.3. In contrast to atrial tissues, piglet papillary muscles were virtually unresponsive to 5-HT 10 −8 −10 −3 M, suggesting that functional cardiac 5-HT 4 receptors are not present in ventricular tissue.

The influence of temperature on the myocardial inotropic response to norepinephrine was studied in rats of different ages. Right papillary muscles isolated from 3-, 12-, and 24-month-old rats were superfused at two temperatures (29 degrees C and 37 degrees C) with progressively larger doses of norepinephrine. At 29 degrees C, the contraction duration was longer and the inotropic effect of norepinephrine was significantly smaller in 24-month muscles than in 3- and 12-month preparations. In muscles superfused at 37 degrees C, these age-related differences in the contraction duration and in the response to norepinephrine disappeared. Analysis of variance and covariance showed that temperature, but not age, is responsible for the differences in the inotropic response to norepinephrine observed. These results show that experimental conditions, among which temperature may play a major role, deeply affect the responsiveness of cardiac preparations to beta-adrenergic agonists.

Triiodothyronine is an important regulator of cellular metabolism and may have potential use as an inotropic agent The aim of this study was to determine the effects of cardiopulmonary bypass on thyroid function in infants weighing less than 5 kg. Serial measurements of triiodothyronine, thyroxine, and thyroid-stimulating hormone were made in 10 infants and corrected for the effects of hemodilution. We demonstrated a fall in triiodothyronine and thyroxine levels, with some recovery after 3 to 6 hours. An additional decrease then occurred, reaching a trough at 48 hours (representing a fall of 78% for triiodothyronine and 57% for thyroxine) before hormone levels returned to normal at 5 to 7 days. Thyroid-stimulating hormone concentrations increased and decreased, predating and complementing exactly the changes in triiodothyronine and thyroxine. These results are quantitatively and, for thyroid-stimulating hormone, qualitatively different from those previously reported in adults. In two patients who died, however, and in one who had a particularly difficult postoperative course, no increase in triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations was found after a trough had been reached at 48 to 72 hours, which suggests abnormal function at the hypothalamopituitary level. (J T horac C ardiovasc S urg 1992;103:800-5)

The effects of DPI 201-106 (a novel, cyclic AMP-independent positive inotropic agent with Ca(2+)-sensitizing and Na(+)-channel agonistic mechanisms) on myocardial mechanics and energetics were assessed in the excised cross-circulated dog left ventricle. In the first protocol, the relation between left ventricular oxygen consumption (VO2) and systolic pressure-volume area (PVA) was analyzed before and during administration of DPI 201-106. The reciprocal of the slope of the VO2-PVA relation has been shown to reflect the contractile efficiency, and the VO2-intercept consists of the oxygen cost of contractility-dependent excitation-contraction coupling and basal metabolism. DPI 201-106 increased Emax (contractility index) and elevated the VO2-PVA relation in a parallel manner, i.e., the VO2-intercept increased without a change in the slope. In the second protocol, the increase in the VO2-intercept of the VO2-PVA relation for a unit increase in Emax (i.e., oxygen cost of enhanced contractility) was compared between DPI 201-106 and epinephrine in a paired manner in each heart. Epinephrine significantly abbreviated the time to end systole, whereas DPI 201-106 did not, suggesting that the mechanism of inotropic action differed between the two drugs. However, the oxygen cost of enhanced contractility was the same between the two drugs in each heart. Therefore, DPI 201-106 did not alter the contractile efficiency nor spare the oxygen cost of enhanced contractility as compared to epinephrine under the present experimental conditions. This suggests that the Ca(2+)-sensitizing effect of DPI 201-106, if any, is too small to spare the oxygen cost of contractility in the blood-perfused, non-failing dog heart.

The contractile response to Endothelin-1 (ET-1) has been investigated in electrically stimulated single cardiac myocytes isolated from hearts of young and senescent rats. ET-1 (0.1-10 nM) exhibited a marked negative inotropic effect in both age groups. ET-1 (1.0 nM) also reduced the occurrence of spontaneous contractile oscillations in young myocytes, suggesting depletion of sarcoplasmic reticulum-Ca(2+) stores. The possibility that ET-1 may have opposite effects on myocardial contractility is discussed.

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.

Shock is a situation of circulatory failure characterized by a generalized and severe decrease of tissue oxygen and nutrient delivery. Shock, whatever the etiology, induces reversible and later irreversible cell lesions.