Use Of Positive Inotropic Agents Research Articles

Machine Learning-Driven Models to Predict Prognostic Outcomes in Patients Hospitalized With Heart Failure Using Electronic Health Records: Retrospective Study.

BackgroundWith the prevalence of cardiovascular diseases increasing worldwide, early prediction and accurate assessment of heart failure (HF) risk are crucial to meet the clinical demand.ObjectiveOur study objective was to develop machine learning (ML) models based on real-world electronic health records to predict 1-year in-hospital mortality, use of positive inotropic agents, and 1-year all-cause readmission rate.MethodsFor this single-center study, we recruited patients with newly diagnosed HF hospitalized between December 2010 and August 2018 at the First Affiliated Hospital of Dalian Medical University (Liaoning Province, China). The models were constructed for a population set (90:10 split of data set into training and test sets) using 79 variables during the first hospitalization. Logistic regression, support vector machine, artificial neural network, random forest, and extreme gradient boosting models were investigated for outcome predictions.ResultsOf the 13,602 patients with HF enrolled in the study, 537 (3.95%) died within 1 year and 2779 patients (20.43%) had a history of use of positive inotropic agents. ML algorithms improved the performance of predictive models for 1-year in-hospital mortality (areas under the curve [AUCs] 0.92-1.00), use of positive inotropic medication (AUCs 0.85-0.96), and 1-year readmission rates (AUCs 0.63-0.96). A decision tree of mortality risk was created and stratified by single variables at levels of high-sensitivity cardiac troponin I (<0.068 μg/L), followed by percentage of lymphocytes (<14.688%) and neutrophil count (4.870×109/L).ConclusionsML techniques based on a large scale of clinical variables can improve outcome predictions for patients with HF. The mortality decision tree may contribute to guiding better clinical risk assessment and decision making.

Treatments targeting inotropy.

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.

Clinical outcomes associated with catecholamine use in patients diagnosed with Takotsubo cardiomyopathy

BackgroundRecent hypotheses have suggested the pathophysiological role of catecholamines in the evolution of the Takotsubo syndrome (TTS). The extent of cardiac and circulatory compromise dictates the use of some form of supportive therapy. This study was designed to investigate the clinical outcomes associated with catecholamine use in TTS patients.MethodsOur institutional database constituted a collective of 114 patients diagnosed with TTS between 2003 and 2015. The study-patients were subsequently classified into two groups based on the need for catecholamine support during hospital stay (catecholamine group n = 93; 81%, non-catecholamine group = 21; 19%). The primary end-point of our study was all-cause mortality.ResultsPatients receiving catecholamine support showed higher grades of circulatory and cardiac compromise (left ventricular ejection fraction (LVEF) 39.6% vs. 32.7%, p-value < 0.01) and the course of disease was often complicated by the occurrence of different TTS-associated complications. The in-hospital mortality (3.2% vs. 28.5%, p < 0.01), 30-day mortality (17.2% vs. 51.4%, p < 0.01) as well as long-term mortality (38.7% vs. 80.9%, p < 0.01) was significantly higher in the group of patients receiving catecholamine support. A multivariate Cox regression analysis attributed EF ≤ 35% (HR 3.6, 95% CI 1.6–8.1; p < 0.01) and use of positive inotropic agents (HR 2.2, 95% CI 1.0–4.8; p 0.04) as independent predictors of the adverse outcome.ConclusionRates of in-hospital events and short- as well as long-term mortality were significantly higher in TTS patients receiving catecholamine support as compared to the other study-patients. These results need further evaluation in pre-clinical and clinical trials to determine if external catecholamines contribute to an adverse clinical outcome already compromised by the initial insult.

Heart Rate Modification of Cardiac Output Following Cardiac Surgery: The Importance of Cardiac Time Intervals.

Inadequate cardiac output is associated with a poor outcome following cardiac surgery and is generally modified by the use of positive inotropic agents, volume resuscitation, and pacing. Echocardiography-guided pacemaker optimization is used in the outpatient setting, using different variables including total isovolumic time and the Tei index. We sought to determine the acute impact of heart rate on cardiac electromechanics, cardiac output, and stroke volume in the perioperative setting. Observational study. Cardiothoracic adult intensive care department. Twenty-four sequential patients admitted after cardiac surgery. Patients with pacemaker set by the treating anesthesiologist using hemodynamic parameters in theatre, within 4 hours of returning to intensive care, they were reassessed using transthoracic echocardiography. A comprehensive baseline echocardiographic study was performed at the clinician set RR interval and at heart rates from 70 to 110 beats/min, in increments of 10 beats/min. Pearson correlation coefficients were used to assess relationships between the measurements. Cardiac output and cardiac index were increased significantly in 79% patients using echocardiography-guided pacemaker optimization (2.21 L/min [± 0.97] and 1.2 L/min/m [± 0.52]). The echocardiography-driven cardiac output optimization protocol led to a significant reduction of total isovolumic time with concurrent increase of cardiac output and cardiac index in the overall population (p < 0.001). There was no consistent correlation between changes in RR interval and stroke volume, cardiac output, or cardiac index in the overall population. A strong negative correlation was found between the left ventricular total isovolumic time and stroke volume, cardiac output, and cardiac index in all groups. Echocardiography-guided heart rate optimization results in a significant increase in cardiac output when compared with clinically derived pacing settings in the postoperative period. The optimal heart rate should be individualized for each patient, and total isovolumic time is the echocardiographic index with the highest sensitivity to determine the optimal hemodynamic profile.

Inotropic agents use in patients hospitalized with acute decompensated heart failure: a retrospective analysis from a 22-year registry in a Middle-Eastern Country (1991-2013).

BackgroundData about the use of positive inotropic agents in patients hospitalized with acute decompensated heart failure (ADHF) is limited.MethodsThe records of 8066 patients with ADHF who were hospitalized at Hamad Medical Corporation, Qatar from 1991 to 2013 were analyzed to explore demographics and clinical characteristics of the patients according to inotropic agents use.ResultsEight hundred fifty eight patients [10.6 %, 95 % CI (10 to 11.3 %)] received intravenous inotropic support. Patients receiving inotropes were more likely to be female and have preserved ejection fraction when compared to those not receiving inotropic agents. Comorbidities associated with higher likelihood of receiving inotropic treatment included acute myocardial infarction, chronic renal impairment, dyslipidemia, hypertension, obesity and hyperglycemia. Patient on inotropes were more likely to undergone percutaneous coronary intervention (PCI), intra-aortic balloon pump support and intubation. There were no differences in the mean plasma BNP and CK-MB levels between the 2 groups. Heart failure patients receiving inotropes also were more likely to have complications including ventricular tachycardia (2.0 % vs. 0.9 %, p = 0.003), prolonged hospital stay (8.0 vs. 5.0 days, p = 0.001), cardiac arrest (14.6 % vs. 3.2 %, p = 0.001) and in-hospital mortality (30.8 % vs. 9.1 %, p = 0.001). Over the study period there was an increase use of inotropic agents and decreased mortality rates.ConclusionInotropic use increased over the period whereas; female gender and conventional cardiac risk factors were predictors of inotropic agents use in the study.

HFpEF: Cardiovascular Abnormalities Not Just Comorbidities

Twenty-five years ago, the understanding of heart failure (HF) was straightforward. HF was a clinical syndrome due to left ventricular (LV) systolic dysfunction apparent as a reduced ejection fraction (EF). Based on this understanding, large randomized trials were conducted using an EF<0.30 or 0.35 as a key entry criterion. These studies demonstrated that the use of angiotensin-converting enzyme inhibitors, β-adrenergic blockers, aldosterone blockers, and cardiac resynchronization improved morbidity and mortality in patients with HF and a reduced EF (HFrEF).1 The benefit of these interventions (except for aldosterone blockade) was associated with reversal of the LV dilation (eccentric remodeling) present in HFrEF.2 In contrast, the use of positive inotropic agents to improve systolic function was either of no benefit or actually detrimental in HFrEF.1 This suggested that there was more to HF than just systolic dysfunction. Article see p 710 The concept that all HF was due to systolic dysfunction apparent as a reduced EF was further challenged by the subsequent recognition that HF occurs in patients with the entire range of EFs, including EF>0.50, an EF that is in the normal or near-normal range (ie, preserved EF).3 Many features of the HF syndrome are similar across the EF spectrum including elevated left atrial pressure, abnormal LV filling dynamics, neurohormonal activation, dyspnea, impaired exercise tolerance, frequent hospitalization, and reduced survival.4,5 There are also clear clinical differences between HF with a preserved EF (HFpEF) and HFrEF. Patients with HFpEF are older, more likely to be women, less likely to have ischemia, and there is a very strong association with systolic hypertension. In addition, there are differences in cardiac structure and function.6,7 In HFrEF, the LV is dilated with eccentric remodeling. In contrast, the LV end-diastolic volume is not increased relative to the …

Hospital Patterns of Use of Positive Inotropic Agents in Patients With Heart Failure

This study sought to determine hospital variation in the use of positive inotropic agents in patients with heart failure. Clinical guidelines recommend targeted use of positive inotropic agents in highly selected patients, but data are limited and the recommendations are not specific. We analyzed data from 376 hospitals including 189,948 hospitalizations for heart failure from 2009 through 2010. We used hierarchical logistic regression models to estimate hospital-level risk-standardized rates of inotrope use and risk-standardized in-hospital mortality rates. The risk-standardized rates of inotrope use ranged across hospitals from 0.9% to 44.6% (median: 6.3%, interquartile range: 4.3% to 9.2%). We identified various hospital patterns based on the type of agents: dobutamine-predominant (29% of hospitals), dopamine-predominant (25%), milrinone-predominant (1%), mixed dobutamine and dopamine pattern (32%), and mixed pattern including all 3 agents (13%). When studying the factors associated with interhospital variation, the best model performance was with the hierarchical generalized linear models that adjusted for patient case mix and an individual hospital effect (receiver operating characteristic curves from 0.77 to 0.88). The intraclass correlation coefficients of the hierarchical generalized linear models (0.113 for any inotrope) indicated that a noteworthy proportion of the observed variation was related to an individual institutional effect. Hospital rates or patterns of use were not associated with differences in length of stay or risk-standardized mortality rates. We found marked differences in the use of inotropic agents for heart failure patients among a diverse group of hospitals. This variability, occurring in the context of little clinical evidence, indicates an urgent need to define the appropriate use of these medications.

Management of Acute Decompensated Heart Failure

Acute decompensated heart failure is the most common cause for hospitalization among patients over 65 years of age. It may result from new onset of ventricular dysfunction or, more typically, exacerbation of chronic heart failure symptoms. In-hospital mortality remains high for both systolic and diastolic forms of the disease. Therapy is largely empirical as few randomized, controlled trials have focused on this population and consensus practice guidelines are just beginning to be formulated. Treatment should be focused upon correction of volume overload, identifying potential precipitating causes, and optimizing vasodilator and beta-adrenergic blocker therapy. The majority of patients (>90%) will improve without the use of positive inotropic agents, which should be reserved for patients with refractory hypotension, cardiogenic shock, end-organ dysfunction, or failure to respond to conventional oral and/or intravenous diuretics and vasodilators. The role of aldosterone antagonists, biventricular pacing, and novel pharmacological agents including vasopressin antagonists, endothelin blockers, and calcium-sensitizing agents is also reviewed.

Stem cells in acute myocardial infarction: the good, the bad, and the ugly

Any new form of treatment, when based on solid experimental observations, initially generates a lot of enthusiasm among researchers as well as among patients (when media get involved). If the initial positive results in observational studies are then confirmed in small randomized trials with surrogate endpoints and finally in large randomized trials with clinical endpoints, the new treatment gains momentum and becomes common practice when incorporated in guidelines (for instance, the use of ACE inhibitors in patients with heart failure). At the other extreme, if the initial positive results are not confirmed in controlled randomized trials, the new treatment is quickly forgotten (for instance, the use of positive inotropic agents in patients with heart failure). As clinicians, we know, however, that we have to accept the grey area where things can remain uncertain for years or even decades. A good example is offered by lipid-lowering drugs: in spite of compelling evidence in the sixties that hypercholesterolaemia is a key atherogenic stimulus, statins have entered guidelines in the nineties only. The simple reason for this prolonged hovering in the grey area is that lipid-lowering drugs used prior to statins were able to significantly reduce cholesterol levels, but this reduction was not large enough to translate into a significant reduction of clinical endpoints. More recently, growing attention has been paid to the issue of safety. For instance, non-steroidal anti-inflammatory drugs are under close scrutiny because of an increased risk of thrombotic complications which went unnoticed during the last few decades. The interpretation of the growing number of trials of cell-based therapy following acute myocardial infarction (AMI) has to be considered in this broad context. After the seminal observation in 2001 by Anversa et al .1 that the human heart is not a post-mytotic organ, several studies in experimental models have confirmed that … *Corresponding author. Tel: +39 630154187; fax: +39 63055535. E-mail address : filippo.crea{at}rm.unicatt.it

Nesiritide for heart failure: impact on costs and complications

Decompensated heart failure accounts for approximately 1 million hospitalizations in the USA each year with an estimated cost of US$11,000 per hospitalization. Despite this prevalence and cost burden, relatively few therapies for decompensated heart failure have been developed over the past 30 years. Although once the mainstay of treatment of decompensated heart failure, the use of positive inotropic agents has fallen into disfavor. Although these agents improve hemodynamics and ejection fraction, there is evidence that the positive inotropes increase the risk of adverse clinical outcomes and mortality. Nesiritide is a naturetic peptide that produces balance vasodilation, inhibits sympathetic nervous system activity, and promotes diuresis and naturesis. At the time the drug received Food and Drug Administration approval for marketing in the USA, it had been shown to produce hemodynamic improvements to an extent greater than placebo or nitroglycerin. However, evidence of benefit in terms of clinical improvement and other outcomes was lacking. Recent trials have found that nesiritide reduces hospital length of stay (although not statistically significant in all trials) and healthcare resource utilization in patients admitted to hospital with decompensated heart failure. In a randomized, controlled trial, nesiritide given in the emergency room reduced hospital admissions for heart failure compared with placebo/usual care. Prelimary data from an outpatient intermittent infusion trial of nesiritide found that patients receiving nesiritide had fewer hospital admissions than patients randomized to standard care. There is currently little objective evidence that therapies used routinely in the management of patients with decompensated heart failure are associated with improved outcomes. Data with positive inotropic agents suggest that they do more harm than good. There is a growing body of evidence that nesiritide is associated with improvements in clinical outcomes in decompensated heart failure including fewer complications, less healthcare resource utilization, and lower costs when compared with standard therapy. Despite this evidence, larger, prospective trials demonstrating the impact of nesiritide on the costs and complications in decompensated heart failure are needed.

Models of dilated cardiomyopathy in small animals and novel positive inotropic therapies.

Several randomized clinical trials of vesnarinone and milrinone in patients with heart failure left disappointing results in the 1990s. Thereafter, use of positive inotropic agents has been avoided. Exceptions are the use of digitalis glycosides to treat mild-moderate heart failure and the intravenous administration of catecholamines and phosphodiesterase inhibitors in patients with acute and/or refractory heart failure. It is not, however, exactly known whether chronic enhancement of cardiac contractility indeed has harmful effects, besides increased risk of arrhythmia and mortality. We investigated the potential chronic benefit of positive inotropic modification to treat progressive cardiomyopathy and associated heart failure using a genetic complementation strategy of muscle lim-protein and phospholamban (PLN) double mutagenesis in the mouse and found clear evidence of positive effects. Subsequent somatic modification of PLN function via gene transfer with recombinant adeno-associated virus vectors in small animal models of dilated cardiomyopathy further supported the chronic benefit of enhanced cardiac function achieved in an beta-adrenergic stimulus-independent manner. This study examines current small animal models of dilated cardiomyopathy and recent multiple attempts to use these models as novel gene-based inotropic therapies.

Cardiac contractility modulation with the impulse dynamics signal: studies in dogs with chronic heart failure.

The intravenous use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure is limited by pro-arrhythmic and positive chronotropic effects. Chronic use of these agents, while eliciting an improvement in the quality of life of patients with advanced heart failure, has been abandoned because of marked increase in mortality when compared to placebo. Nevertheless, patients with advanced heart failure can benefit from long-term positive inotropic support if the therapy can be delivered 'on demand' and in a manner that is both safe and effective. In this review, we will examine the use of a novel, non-stimulatory electrical signal that can acutely modulate left ventricular (LV) contractility in dogs with chronic heart failure in such a way as to elicit a positive inotropic support. Cardiac contractility modulation (CCM) with the Impulse Dynamic(trade mark) signal was examined in dogs with chronic heart failure produced by intracoronary microembolizations. Delivery of the CCM signal from a lead placed in the great coronary vein for periods up to 10 minutes resulted in significant improvements in cardiac output, LV peak+dP/dt, LV fractional area of shortening and LV ejection fraction measured angiographically. Discontinuation of the signal resulted in a return of all functional parameters to baseline values. In cardiomyocytes isolated from dogs with chronic heart failure, application of the CCM signal resulted in improved shortening, rate of change of shortening and rate of change of relengthening suggesting that CCM application is associated with intrinsic improvement of cardiomyocyte function. The improvement in isolated cardiomyocyte function after application of the CCM signal was accompanied by an increase in the peak and integral of the Ca(2+) transient suggesting modulation of calcium cycling by CCM application. In a limited number of normal dogs, intermittent chronic delivery of the CCM signal for up to 7 days showed chronic maintenance of LV functional improvement. In conclusion, pre-clinical results to date with the Impulse Dynamics CCM signal indicate that this non-pharmacologic therapeutic modality can provide short-term positive inotropic support to the failing heart and as such, may be a useful adjunct in the treatment of advanced heart failure. Additional, long-term studies in dogs with heart failure are needed to establish the safety and efficacy of this therapeutic modality for the chronic treatment of this disease syndrome.

Energetic stimulation of the heart.

The management of patients with acute heart failure includes frequently the use of positive inotropic agents in order to increase cardiac output and hence to maintain adequate tissue perfusion. The concept of energetic stimulation of the heart was invented in order to avoid deleterious effects of conventional inotropes, i.e. catecholamines and phosphodiesterase-inhibitors, on myocardial oxygen consumption and energy reserves and to circumvent potential dangerous side effects of the drugs. Metabolic support with glucose-insulin-potassium has proven efficious of improving cardiac performance and prognosis in the setting of the ischemic and postischemic heart. The glycolytic intermediate pyruvate increases contractile performance in isolated animal and human myocardium and improves short-time hemodynamics in patients with congestive heart failure, which is discussed in detail in the present article. Energetic stimulation with pyruvate could therefore be a new promising approach to the treatment of acute heart failure, if conventional therapy fails.

Management of congestive heart failure: is the role of positive inotropic therapy fading?

Significant strides have been made in the medical therapy of chronic CHF in the past two decades. Treatment has evolved from therapy based on the older concepts of the pathophysiology of CHF to evidence-guided therapy supported by results of major landmark studies that expand the understanding of the pathophysiology. Attenuation of neurohumoral activation is now a goal of pharmacological therapy, and we know that agents that offer hemodynamic and early clinical improvement may not necessarily prolong survival-unless they also modulate these neurohormonal systems. Positive inotropic therapy (e.g., use of a digitalis glycoside) is no longer considered essential in patients with CHF in sinus rhythm. Although impressive hemodynamic benefits can be observed with the use of positive inotropic agents, long-term treatment with these drugs has not produced clinical benefits and may increase mortality. Long before the current concerns about the use of positive inotropic therapy for CHF, cardiovascular physiologists had advised that contractility does not equate with overall cardiac performance. Stimulation of myocardial contractility is a property of digoxin therapy. However, cardiac function is governed by four determinants: preload, afterload, rhythm, and contractility. All four require control. Treatment aimed at reducing preload and afterload and improving arrhythmias can achieve cardiac compensation by reducing cardiac work without the need for digoxin therapy or other inotropic drugs.

Section Review: Cardiovascular &amp; Renal: Calcium sensitisers and heart failure

To date, the use of positive inotropic agents for the treatment of heart failure has not been a success. Not only have these drugs had little documentable beneficial effect on survival, but in some instances, most notably with the phosphodiesterase inhibitors, they have-caused an unacceptable increase in early mortality due to arrhythmias [1]. This has led to a body of opinion in some quarters that positive inotropic therapy for heart failure is a doomed approach and that all efforts should be concentrated on preventing or reversing atheroma, enhancing blood flow to the myocardium and dealing with the effects of secondary compensatory mechanisms. Although everyone agrees that prevention is better than cure, it seems inevitable that there will always be substantial numbers of patients with heart failure of various degrees of severity. Thus, it is important to be very sure of the facts before abandoning any hope of pharmacological contractile support for these patients. This article briefly reviews current ...

Pharmacologic Management of Heart Failure: Positive Inotropic Agents

The use of positive inotropic agents in the acute and chronic treatment of heart failure is associated with a variety of hemodynamic effects. The beneficial effects of these agents, however, are not without associated adverse effects. An increase in cardiac output is achieved through diverse pharmacologic mechanisms of action depending on the specific inotropic agent. Digitalis glycosides, beta-adrenergic agonists, and phosphodiesterase inhibitors are described.

The Value of Positive Inotropy in Acute and Chronic Heart Failure

The different pathophysiological causes of acute and chronic heart failure prohibit a simple therapeutic approach with only one type of drug. Recent investigations have shown that the judicious use of positive inotropic agents, diuretics, and vasodilators in addition to dietary and exercise therapy can relieve the symptoms of heart failure and improve the quality of life as well as the prognosis. Apparently, the major breakthrough of modern treatment has not been the use of new or old positive inotropic drugs but rather the careful use of preload and afterload reducing agents. The proper place for beta-blocker therapy in chronic systolic or diastolic heart failure has not been established yet.