sildenafil-citrate and Cardiac-Output--Low

The field of cardiac intensive care is rapidly evolving with nearly simultaneous advances in surgical techniques and adjunctive therapies, respiratory care, intensive care technology and monitoring, pharmacologic research and development, and computing and electronics. The focus of care has now shifted toward reducing morbidity and improving "quality of life" while the survival of infants and children with congenital heart defects, including those with univentricular hearts has dramatically improved during the last three decades. Despite these advances, there remains a predictable fall in cardiac output after cardiopulmonary bypass. This article focuses on early identification and aggressive treatment of the low cardiac output syndrome peculiar to these patients. The authors also briefly review the recent advances in the treatment of pulmonary hypertension, mechanical support, and neurologic surveillance after cardiac surgery.

Topics: Cardiac Output, Low; Cardiac Surgical Procedures; Cardiotonic Agents; Child; Critical Care; Dye Dilution Technique; Heart-Assist Devices; Humans; Hypertension, Pulmonary; Iloprost; Intraoperative Care; Milrinone; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

We sought to investigate the effects of sildenafil, a phosphodiesterase-5 (PDE(5)) inhibitor, on lung function and exercise performance in chronic heart failure (CHF).. In CHF, nitric oxide-mediated regulation of lung vascular tone and alveolar-capillary membrane conductance is impaired and contributes to exercise intolerance. The potential for benefits due to increased nitric-oxide availability is unexplored.. In 16 patients with CHF and 8 normal subjects, we measured-before and 60 min after sildenafil (50 mg) or placebo-ejection fraction, pulmonary hemodynamics, carbon monoxide diffusion capacity (DLco), with its membrane (D(M)) and capillary blood volume (V(c)) subcomponents, endothelial function (brachial reactive hyperemia) at rest, peak oxygen uptake (VO(2)), increments in VO(2) versus work rate (DeltaVO(2)/DeltaWR), changes in ventilation versus CO(2) production (VE/VCO(2)) slope, and recovery VO(2) time constant (tau) on exertion.. In CHF, sildenafil did not affect cardiac index, wedge pulmonary pressure, or ejection fraction; it significantly (p < 0.01) decreased pulmonary mean artery pressure (-20.4%) and arteriolar resistance (-45.1%), VE/VCO(2) slope (-9.0%) and recovery tau (-25.8%), and increased (p < 0.01) DLco (+11.1%), D(M) (+9.9%) peak VO(2) (+19.7%), DeltaVO(2)/DeltaWR (+11.0%), and brachial reactive hyperemia (+33.3%). No variations occurred in normal subjects and after placebo. Changes in DLco were related to those in VE/VCO(2) slope (r = -0.71; p = 0.002), and changes in brachial hyperemia correlated with those in DeltaVO(2)/DeltaWR (r = 0.80; p = 0.0002).. This study shows that in CHF PDE(5) inhibition modulates pulmonary pressure and vascular tone, and improves DLco, exercise peak VO(2), aerobic (DeltaVO(2)/DeltaWR) and ventilatory (VE/VCO(2) slope) efficiencies, and oxygen debt (recovery tau). Endothelial mechanisms may underlie these effects.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cardiac Output, Low; Chronic Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Exercise; Exercise Tolerance; Female; Hemodynamics; Humans; Kinetics; Male; Middle Aged; Oxygen Consumption; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Circulation; Pulmonary Diffusing Capacity; Purines; Respiration; Sildenafil Citrate; Sulfones

To determine the acute effects of type 5 phosphodiesterase inhibition with sildenafil on flow-mediated vasodilation in the brachial artery of patients with chronic heart failure.. Impaired endothelium-dependent, flow-mediated vasodilation in patients with heart failure is partly attributable to hyporesponsiveness of cyclic guanosine monophosphate (cGMP) mediated vasorelaxation effector mechanisms in vascular smooth muscle. The effect of inhibition of cGMP degradation with sildenafil, a specific type 5 cGMP phosphodiesterase inhibitor, on flow-mediated dilation in heart failure is unknown.. Flow-mediated vasodilation after release of 1, 3 and 5 min of transient arterial occlusion was measured in the brachial artery with high resolution two-dimensional ultrasound imaging in 48 patients with chronic heart failure before and 1 h after randomized, double-blind assignment to a single oral dose of sildenafil 12.5, 25 or 50 mg or matching placebo.. In response to oral administration of a single dose of study drug, the change in flow-mediated vasodilation after release of 1, 3 and 5 min of arterial occlusion was significantly greater in patients receiving sildenafil 25 mg (3.3 +/- 1.9, 3.8 +/- 1.8 and 4.0 +/- 1.8%, respectively, p < 0.05) and patients receiving sildenafil 50 mg (3.7 +/- 1.3, 4.1 +/- 1.1, 3.9 +/- 1.3%, respectively, p < 0.05) than that of patients receiving placebo (0.7 +/- 1.1, 0.2 +/- 1.2, 0.6 +/- 0.8%, respectively).. Acute type 5 phosphodiesterase inhibition with sildenafil 25 and 50 mg increases endothelium-dependent, flow-mediated vasodilation in patients with chronic heart failure when compared with placebo.

Topics: Blood Circulation; Blood Flow Velocity; Cardiac Output, Low; Chronic Disease; Double-Blind Method; Female; Humans; Isoenzymes; Male; Middle Aged; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Reference Values; Sildenafil Citrate; Sulfones; Vasodilation

Topics: Acute Disease; Adult; Cardiac Output, Low; Catheterization; Critical Care; Electrocardiography; Female; Femoral Artery; Gastrectomy; Humans; Multiple Sclerosis; Peptic Ulcer Perforation; Piperazines; Pulmonary Embolism; Purines; Sildenafil Citrate; Sulfones; Thrombolytic Therapy; Vasodilator Agents; Vena Cava Filters

Heart failure (HF) is frequently associated with dysregulation of nitric oxide-mediated pulmonary vascular tone. Sildenafil, a type 5 phosphodiesterase inhibitor, lowers pulmonary vascular resistance in pulmonary hypertension by augmenting intracellular levels of the nitric oxide second messenger, cyclic GMP. We tested the hypothesis that a single oral dose of sildenafil (50 mg) would improve exercise capacity and exercise hemodynamics in patients with chronic systolic HF through pulmonary vasodilation.. Thirteen patients with New York Heart Association class III HF underwent assessment of right heart hemodynamics, gas exchange, and first-pass radionuclide ventriculography at rest and with cycle ergometry before and 60 minutes after administration of 50 mg of oral sildenafil. Sildenafil reduced resting pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance, and increased resting and exercise cardiac index (P<0.05 for all) without altering mean arterial pressure, heart rate, or pulmonary capillary wedge pressure. Sildenafil reduced exercise pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular resistance/systemic vascular resistance ratio, which indicates a selective pulmonary vasodilator effect with exercise. Peak VO2 increased (15+/-9%) and ventilatory response to CO2 output (VE/VCO2 slope) decreased (16+/-5%) after sildenafil treatment. Improvements in right heart hemodynamics and exercise capacity were confined to patients with secondary pulmonary hypertension (rest pulmonary arterial pressure >25 mm Hg).. The present study shows that in patients with systolic HF, type 5 phosphodiesterase inhibition with sildenafil improves peak VO2, reduces VE/VCO2 slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with HF and pulmonary hypertension.

Topics: Adult; Blood Pressure; Cardiac Output; Cardiac Output, Low; Exercise; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Piperazines; Pulmonary Gas Exchange; Purines; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Left

Topics: Cardiac Output, Low; Heart; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Management of primary pulmonary hypertension is usually difficult because the disease is uncommon and the aetiology of the disease is not well understood. The disease is potentially lethal because it can lead to failure of the right ventricle, low cardiac output, and ensuing multiple organ failure. We report the successful treatment of a case of low-output syndrome due to primary pulmonary hypertension using combined drug therapy and atrial septostomy. Latest developments in the treatment of this disease are also discussed.

Topics: Adult; Cardiac Output, Low; Female; Heart Atria; Heart Septum; Humans; Hypertension, Pulmonary; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents; Ventricular Dysfunction, Right

Recent studies implicate increased cGMP synthesis as a postreceptor contributor to reduced cardiac sympathetic responsiveness. Here we provide the first evidence that modulation of this interaction by cGMP-specific phosphodiesterase PDE5A is also diminished in failing hearts, providing a novel mechanism for blunted beta-adrenergic signaling in this disorder. In normal conscious dogs chronically instrumented for left ventricular pressure-dimension analysis, PDE5A inhibition by EMD82639 had modest basal effects but markedly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on either basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein and enzyme activity was similar among groups, the proportion of EMD82639-inhibitable activity was significantly lower in failure cells. Immunohistochemistry confirmed PDE5A expression in both the vasculature and myocytes of normal and failing hearts, but there was loss of z-band localization in failing myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate beta-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the beta-adrenergic response.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adenylyl Cyclases; Adrenergic beta-Agonists; Animals; Blood Pressure; Cardiac Output, Low; Colforsin; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Dobutamine; Dogs; Female; Heart; Hemodynamics; Immunohistochemistry; Male; Myocardial Contraction; Myocardium; Phosphodiesterase Inhibitors; Piperazines; Purines; Purinones; Pyrazoles; Receptors, Adrenergic, beta; Signal Transduction; Sildenafil Citrate; Sulfones