Carl V. Leier

Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness

CONTEXT Pulmonary artery catheters (PACs) have been used to guide therapy in multiple settings, but recent studies have raised concerns that PACs may lead to increased mortality in hospitalized patients. OBJECTIVE To determine whether PAC use is safe and improves clinical outcomes in patients hospitalized with severe symptomatic and recurrent heart failure. DESIGN, SETTING, AND PARTICIPANTS The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) was a randomized controlled trial of 433 patients at 26 sites conducted from January 18, 2000, to November 17, 2003. Patients were assigned to receive therapy guided by clinical assessment and a PAC or clinical assessment alone. The target in both groups was resolution of clinical congestion, with additional PAC targets of a pulmonary capillary wedge pressure of 15 mm Hg and a right atrial pressure of 8 mm Hg. Medications were not specified, but inotrope use was explicitly discouraged. MAIN OUTCOME MEASURES The primary end point was days alive out of the hospital during the first 6 months, with secondary end points of exercise, quality of life, biochemical, and echocardiographic changes. RESULTS Severity of illness was reflected by the following values: average left ventricular ejection fraction, 19%; systolic blood pressure, 106 mm Hg; sodium level, 137 mEq/L; urea nitrogen, 35 mg/dL (12.40 mmol/L); and creatinine, 1.5 mg/dL (132.6 micromol/L). Therapy in both groups led to substantial reduction in symptoms, jugular venous pressure, and edema. Use of the PAC did not significantly affect the primary end point of days alive and out of the hospital during the first 6 months (133 days vs 135 days; hazard ratio [HR], 1.00 [95% confidence interval {CI}, 0.82-1.21]; P = .99), mortality (43 patients [10%] vs 38 patients [9%]; odds ratio [OR], 1.26 [95% CI, 0.78-2.03]; P = .35), or the number of days hospitalized (8.7 vs 8.3; HR, 1.04 [95% CI, 0.86-1.27]; P = .67). In-hospital adverse events were more common among patients in the PAC group (47 [21.9%] vs 25 [11.5%]; P = .04). There were no deaths related to PAC use, and no difference for in-hospital plus 30-day mortality (10 [4.7%] vs 11 [5.0%]; OR, 0.97 [95% CI, 0.38-2.22]; P = .97). Exercise and quality of life end points improved in both groups with a trend toward greater improvement with the PAC, which reached significance for the time trade-off at all time points after randomization. CONCLUSIONS Therapy to reduce volume overload during hospitalization for heart failure led to marked improvement in signs and symptoms of elevated filling pressures with or without the PAC. Addition of the PAC to careful clinical assessment increased anticipated adverse events, but did not affect overall mortality and hospitalization. Future trials should test noninvasive assessments with specific treatment strategies that could be used to better tailor therapy for both survival time and survival quality as valued by patients.

Factors influencing the one-year mortality of dilated cardiomyopathy

This study was designed to determine prognostic risk indicators of nonischemic dilated cardiomyopathy (DC). Sixty-nine patients were studied. Each patient underwent physical examination (including a history), electrocardiography, echocardiography, cardiac catheterization, 24-hour monitoring and endomyocardial biopsy. The mortality rate at 1 year was 35% (24 deaths). Univariate analysis revealed that the most powerful predictor of prognosis was the left intraventricular conduction delay (p = 0.003). The pulmonary capillary wedge pressure was also predictive of mortality (p = 0.005). Other significant factors, in order of importance, were ventricular arrhythmias (p = 0.007), mean right atrial pressure (p = 0.008), angiographic ejection fraction (p = 0.03), atrial fibrillation or flutter (p = 0.01) and the presence of an S3 gallop (p = 0.05). Factors such as duration of symptoms, presence of mitral regurgitation, end-diastolic diameter, myocardial cell size and percent fibrosis in the biopsy and treatment with vasodilators, antiarrhythmic and anticoagulant drugs were not significant predictors. Multivariate analysis was used to determine which combination of factors could most accurately predict survival and death. The most important factors were left conduction delay, ventricular arrhythmias and mean right atrial pressure. An equation was derived that can be applied to the prognosis of patients with DC. Thus, the clinical assessment of patients with DC can accurately predict the probability of surviving or dying in 1 year.

Acute Hemodynamic and Clinical Effects of Levosimendan in Patients With Severe Heart Failure

BackgroundWe determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure. Methods and ResultsOne hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21±1%) who had a pulmonary capillary wedge pressure ≥15 mm Hg and a cardiac index ≤2.5 L · min−1 · m−2 were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1 to intravenous infusion of levosimendan or placebo. Drug infusions were uptitrated over 4 hours from an initial infusion rate of 0.1 &mgr;g · kg−1 · min−1 to a maximum rate of 0.4 &mgr;g · kg−1 · min−1 and maintained at the maximal tolerated infusion rate for an additional 2 hours. Levosimendan caused dose-dependent increases in stroke volume and cardiac index beginning with the lowest infusion rate and achieving maximal increases in stroke volume and cardiac index of 28% and 39%, respectively. Heart rate increased modestly (8%) at the maximal infusion rate and was not increased at the 2 lowest infusion rates. Levosimendan caused dose-dependent decreases in pulmonary capillary wedge, right atrial, pulmonary arterial, and mean arterial pressures. Levosimendan appeared to improve dyspnea and fatigue, as assessed by the patient and physician, and was not associated with a significant increase in adverse events. ConclusionsLevosimendan caused rapid dose-dependent improvement in hemodynamic function in patients with decompensated heart failure. These hemodynamic effects appeared to be accompanied by symptom improvement and were not associated with a significant increase in the number of adverse events. Levosimendan may be of value in the short-term management of patients with decompensated heart failure.

Comparative systemic and regional hemodynamic effects of dopamine and dobutamine in patients with cardiomyopathic heart failure.

SUMMARY Thirteen patients with severe cardiac failure underwent a single crossover study of dopamine and dobutamine in order to compare the systemic and regional hemodynamic effects of the two drugs. The dose-response data demonstrated that dobutamine (2.5-10 μg/kg/min) progressively and predictably increases cardiac output by increasing stroke volume, while simultaneously decreasing systemic and pulmonary vascular resistance and pulmonary capillary wedge pressure. There was no change in heart rate or premature ventricular contractions (PVCs)/min at this dose range. Dopamine (2-8 μg/kg/min) increased the stroke volume and cardiac output at 4, g/kg/min. Dopamine at > 4, Ag/kg/min provided little additional increase in cardiac output and increased the pulmonary wedge pressure and the number of PVCs/min. At > 6 Ag/kg/min, dopamine increased heart rate. During the 24-hour maintenance-dose infusion of each drug (dopamine 3.7-4, dobutamine 7.3-7.7 μg/kg/min), only dobutamine maintained a significant increase of stroke volume, cardiac output, urine flow, urine sodium concentration, creatinine clearance and peripheral blood flow. Renal and hepatic blood flow were not significantly altered by the maintenance dose of either drug. Systemic and regional hemodynamic data suggest that dobutamine has many advantages over dopamine when infused in patients with cardiac failure.

Remodeling and reparation of the cardiovascular system

Growth or altered metabolism of nonmyocyte cells (cardiac fibroblasts, vascular smooth muscle and endothelial cells) alters myocardial and vascular structure (remodeling) and function. However, the precise roles of circulating and locally generated factors such as angiotensin II, aldosterone and endothelin that regulate growth and metabolism of nonmyocyte cells have yet to be fully elucidated. Trials of pharmacologic therapy aimed at preventing structural remodeling and repairing altered myocardial structure to or toward normal in the setting of hypertension, heart failure and diabetes are reviewed. It is proposed that these are therapeutic goals that may reduce cardiovascular morbidity and mortality. Although this hypothesis remains unproved the primary goal of therapy should be to preserve or restore tissue structure and function.

Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Lack of benefit compared with placebo. Enoximone Multicenter Trial Group.

A multicenter double-blind, randomized, placebo-controlled trial of oral enoximone, a phosphodiesterase inhibitor, was conducted in 102 outpatients (50 receiving enoximone and 52 receiving placebo) with moderate to moderately severe congestive heart failure. All were on a long-term regimen of digoxin and diuretics without vasodilators and converting enzyme inhibitors. Symptom score was obtained, and exercise testing was performed monthly for 4 months. There were no differences between groups in symptoms or exercise duration at the end of 4 months. A subgroup undergoing analysis of oxygen consumption with measurement of anaerobic threshold during exercise showed an increase (p less than 0.05) in anaerobic threshold at 1 month with enoximone. (2.7 +/- 0.8 ml O2/kg/min) compared with placebo (-0.8 +/- 1.2 ml O2/kg/min). This improvement was not sustained at 4 months (0.5 +/- 1.7 ml O2/kg/min with enoximone and 0.2 +/- 1.5 ml O2/kg/min with placebo). The dropout rate was significantly higher (p less than 0.02) with enoximone (46%) than with placebo (25%). Adverse effects other than death were slightly, but not significantly, higher with enoximone (32%) than with placebo (22%). During therapy, five deaths occurred in the enoximone group, and none occurred in the placebo group (p less than 0.05). Two deaths were sudden, two were from progressive congestive heart failure, and one was from acute myocardial infarction. With intention-to-treat analysis and inclusion of patients who were removed from therapy because of lack of study drug effect, 10 deaths occurred in the enoximone group, and three occurred in the placebo group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

IMPROVED EXERCISE CAPACITY AND DIFFERING ARTERIAL AND VENOUS TOLERANCE DURING CHRONIC ISOSORBIDE DINITRATE THERAPY FOR CONGESTIVE HEART FAILURE

We studied 30 patients with moderate-to-severe congestive heart failure in a double-blind, randomized, placebo-controlled trial to determine the acute and long-term effects of isosorbide dinitrate on clinical status and on resting and exercise hemodynamics. Seventeen patients received placebo and 13 isosorbide dinitrate. First-dose isosorbide dinitrate (40 mg orally) decreased resting and exercise pulmonary capillary wedge pressure, pulmonic and systemic arterial pressures and pulmonic and systemic vascular resistances without augmenting exercise capacity. Compared with placebo, chronic therapy with isosorbide dinitrate (40 mg orally every 6 hours for 12 weeks) significantly improved clinical status and exercise capacity. Resting and exercise systemic blood pressure and systemic vascular resistance returned to baseline values during chronic isosorbide dinitrate therapy, but pulmonary capillary wedge pressure, pulmonary artery pressure and pulmonary vascular resistance remained improved. In patients with congestive heart failure, 12 weeks of oral isosorbide dinitrate therapy improves resting and exercise hemodynamics, exercise capacity, and clinical status; tolerance develops to the systemic arterial vascular effects without attenuation of the venous and pulmonary vascular effects.

Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure

OBJECTIVES The objective of this investigation was to evaluate the changes in parasympathetic tone associated with long-term angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure. BACKGROUND Angiotensin-converting enzyme inhibitors provide hemodynamic and symptomatic benefit and are associated with improved survival in patients with congestive heart failure. Angiotensin II, whose production is ultimately inhibited by these agents, exerts significant regulatory influence on a variety of target organs including the central and peripheral nervous systems. Accordingly, it would be anticipated that angiotensin-converting enzyme inhibitors would significantly alter the autonomic imbalance characteristic of patients with congestive heart failure and that this influence over neural mechanisms of cardiovascular control may significantly contribute to the hemodynamic benefit and improved survival associated with angiotensin-converting enzyme inhibitor therapy. METHODS In the current investigation, changes in autonomic tone associated with long-term administration of an angiotensin-converting enzyme inhibitor were measured using spectral analysis of heart rate variability in 13 patients with congestive heart failure who were enrolled in a double-blind randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor zofenopril. Both placebo and treatment groups were balanced at baseline study in terms of functional class, ventricular performance and autonomic tone. RESULTS After 12 weeks of therapy with placebo, there was no change in total heart rate variability, parasympathetically governed high frequency heart rate variability or sympathetically influenced low frequency heart rate variability. In contrast, therapy with zofenopril was associated with a 50% increase in total heart rate variability (p = 0.09) and a significant (p = 0.03) twofold increase in high frequency heart rate variability, indicating a significant augmentation of parasympathetic tone. CONCLUSIONS These results demonstrate that long-term treatment of patients having congestive heart failure with an angiotensin-converting enzyme inhibitor is associated with a restoration of autonomic balance, which derives in part from a sustained augmentation of parasympathetic tone. Such augmentation of vagal tone is known to be protective against malignant ventricular arrhythmias in patients with ischemic heart disease and therefore may have similar benefit in the setting of ventricular failure, thus contributing to the improved survival associated with angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure.

The cardiovascular effects of the continuous infusion of dobutamine in patients with severe cardiac failure.

Twenty-five patients with left ventricular failure and low cardiac output received a 72 hour infusion of dobutamine (10-15 Mg/kg/min) in order to determine the cardiovascular properties of this new inotropic agent. Left ventricular contractile performance improved significantly during the infusion as measured by systolic time intervals and echocardiographic parameters. Mean PEP/LVET decreased from 0.76 ± 0.03 to 0.58 ± 0.03 (P < 0.05). The percent change in internal dimension of the left ventricle from diastole to systole increased from 9.5 ± I to 16.8 ± 1 (P < 0.05) and Vcf increased from 0.47 ± 0.05 to 0.80 ± 0.06 circ/sec (P < 0.05). Mean cardiac output (nine patients) rose from 1.97 ± 0.15 to 3.33 ± 0.50 L/min/m2 while mean pulmonary capillary wedge pressure fell from 28 ± 3 to 18 ± 2 mm Hg during the infusion period (both P < 0.05). These changes in cardiac function occurred without significant changes in heart rate, ventricular irritability, or blood pressure. Urine flow and urine sodium concentration increased during the infusion period. The improvement of cardiac function without the simultaneous development or exacerbation of undesirable effects (tachycardia, premature ventricular contractions, increased pulmonary or systemic resistance, tachyphylaxis, etc.) makes dobutamine a highly desirable inotropic agent.

Tolerance to dobutamine after a 72 hour continuous infusion

Abstract In this study we investigated the hemodynamic effects of dobutamine during short-term (2 hour) and long-term (four day) infusions. The heart rate, blood pressure, cardiac output, pulmonary capillary wedge pressure and systolic time intervals were determined at baseline and then at 30 minute intervals up to 120 minutes after the commencement of intravenous dobutamine therapy in nine patients. The same parameters were measured in 14 patients at 2, 24, 48, 72 and 96 hours. The percent change of the hemodynamic measurements over baseline was evaluated relative to the plasma dobutamine level. There was no attenuation of hemodynamic effect in the first 2 hours of dobutamine therapy. Tolerance did develop during the long-term infusion and this was statistically significant at 72 and 96 hours in measurements of the cardiac output, systolic time intervals and heart rate. The hemodynamic response at 72 hours was 66 percent of that noted at 2 hours; the hemodynamic response at 96 hours was 57 percent of that at 2 hours. This study demonstrated that significant hemodynamic tolerance to dobutamine develops after three days of continuous infusion. We suggest that the most appropriate manner of dealing with this attenuation of effect is simply to increase the dose until the desired hemodynamic effect is attained.