sildenafil-citrate and Heart-Defects--Congenital

Sildenafil was first prescribed for angina pectoris and then for erectile dysfunction from its effects on vascular smooth muscle relaxation and vasodilatation. Recently, sildenafil has been proposed for congenital heart diseases induced pulmonary hypertension, which constitutes a huge burden on children's health and can attribute to fatal complications due to presence of unoxygenated blood in the systemic circulation. Therefore, our meta-analysis aims to further investigate the safety and efficacy of sildenafil on children population.. We searched the following electronic databases: PubMed, Cochrane CENTRAL, WOS, Embase, and Scopus from inception to April 20th, 2022. Randomized controlled trials that assess the efficacy of using sildenafil in comparison to a placebo or any other vasodilator drug were eligible for inclusion. The inverse variance method was used to pool study effect estimates using the random effect model. Effect sizes are provided in the form of mean difference (MD) with 95% confidence intervals (CI).. Our study included 14 studies with (n = 849 children) with a mean age of 7.9 months old. Sildenafil showed a statistically significant decrease over placebo in mean and systolic pulmonary artery pressure (PAP) with MD -7.42 (95%CI [-13.13, -1.71], P = 0.01) and -8.02 (95%CI [-11.16, -4.88], P < 0.0001), respectively. Sildenafil revealed a decrease in mean aortic pressure and pulmonary artery/aortic pressure ratio over placebo with MD -0.34 (95%CI [-2.42, 1.73], P = 0.75) and MD -0.10 (95%CI [-0.11, -0.09], P < 0.00001), respectively. Regarding post corrective operations parameters, sildenafil had a statistically significant lower mechanical ventilation time, intensive care unit stay, and hospital stay over placebo with MD -19.43 (95%CI [-31.04, -7.81], s = 0.001), MD -34.85 (95%CI [-50.84, -18.87], P < 0.00001), and MD -41.87 (95%CI [-79.41, -4.33], P = 0.03), respectively. Nevertheless, no difference in mortality rates between sildenafil and placebo with OR 0.25 (95%CI 0.05, 1.30], P = 0.10) or tadalafil with OR 1 (95%CI 0.06, 17.12], P = 1).. Sildenafil is a well-tolerated treatment in congenital heart diseases induced pulmonary hypertension, as it has proven its efficacy not only in lowering both PAP mean and systolic but also in reducing the ventilation time, intensive care unit and hospital stay with no difference observed regarding mortality rates.

Topics: Child; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Randomized Controlled Trials as Topic; Sildenafil Citrate; Vasodilator Agents

The Fontan procedure is currently the mainstay therapy for single functional ventricles. However, with prolonged follow-up duration, various complications have been observed that seriously influence the quality of life of patients.. The aim of this meta-analysis is to compare the effectiveness of pharmacologic agents in improving exercise capacity in patients with Fontan circulation.. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement and has been registered in the International Prospective Register for Systematic Reviews database with registration no. 282352. Quality assessments of the included studies were assessed using the Strengthening Reporting of Observational Studies in Epidemiology (STROBE) statement.. Twelve studies met the predetermined inclusion criteria and were included in this metaanalysis. This meta-analysis found that treatment with bosentan significantly improved New York Heart Association Functional Class (NYHA FC) in Fontan patients (standard mean difference - 0.59, 95% CI -0.94 - -0.25; P=0.0008; I. This meta-analysis shows that people with Fontan circulation may benefit from using bosentan as it decreases postexercise heart rate and improves NYHA FC and 6-minute walking test results. Therefore, indirectly improving exercise capacity. Nonetheless, considerable work is required to strengthen our knowledge in improving the exercise capacity of Fontan patients.

Topics: Bosentan; Exercise Test; Exercise Tolerance; Fontan Procedure; Heart Defects, Congenital; Humans; Quality of Life; Sildenafil Citrate; Sulfonamides; Treatment Outcome

Protein-losing enteropathy (PLE) is a chronic condition involving multiple organ systems that may develop any time following Fontan completion. The pathogenesis of PLE is complex and multifactorial. Chronic venous hypertension, low cardiac output, and abnormal lymphatics may all play a role in the pathogenesis of PLE. Common signs and symptoms include chronic diarrhea, abdominal pain, and ascites. Diagnosis is based on the presence of signs and symptoms in addition to hypoalbuminemia and elevated stool alpha 1 antitrypsin. Early identification and a comprehensive approach to evaluation and treatment are important, as they may affect survival. The initial evaluation should include cardiac catheterization for hemodynamic assessment. Although an evidence base for treatment is lacking, various medical, interventional, and surgical approaches have been described with variable degrees of success. Commonly used therapies include nutritional support, diuretics, subcutaneous unfractionated heparin, budesonide, and sildenafil. Limited data exist for Fontan conversion or takedown. Assessment for heart transplantation should be considered. PLE mortality is high-approximately 50%-but may be mitigated by aggressive investigation and management. The evolving understanding of the role of lymphatics in the pathophysiology of PLE and the emerging role of interventional lymphatic procedures may further improve outcomes in this patient population.

Topics: Abdominal Pain; Academic Medical Centers; Ascites; Budesonide; Chronic Disease; Combined Modality Therapy; Diagnosis, Differential; Diarrhea; Diuretics; Female; Fontan Procedure; Heart Defects, Congenital; Heparin; Humans; Male; Prognosis; Protein-Losing Enteropathies; Rare Diseases; Risk Assessment; Sildenafil Citrate; Treatment Outcome

In recent years, there has been a rise in the number patients with CHD surviving into adulthood. Many have complications related to their CHD or its treatments, outside the heart, including ocular abnormalities. The objective of this review is to highlight the ocular abnormalities that occur in adults with CHD, either from their condition or related to the common drugs prescribed to manage it. In particular, we reviewed the effects of cyanosis, coarctation of the aorta, endocarditis, and the side effects of Sildenafil and Amiodarone. A change in the retinal vasculature is a common observation with cyanosis or coarctation of the aorta. Occlusion of the retinal vessels may also be observed in cyanotic patients, as well as those with infectious endocarditis. Sildenafil has established ocular side effects; here they are explored in the context of therapy for pulmonary hypertension. Similarly, Amiodarone has established ocular risks, which are summarised. The high prevalence of ocular consequences in adult CHD patients reinforces the need for knowledge of the risks involved and for frequent ophthalmological screening where appropriate.

Topics: Adult; Amiodarone; Aortic Coarctation; Cyanosis; Endocarditis; Eye Diseases; Heart Defects, Congenital; Humans; Retinal Vessels; Sildenafil Citrate

Sildenafil is a pulmonary artery hypertension (PH)-targeted drug that finds an increased indiscriminate use in children with PH secondary to congenital heart disease (CHD).We performed a meta-analysis to evaluate the effects of sildenafil on pediatric patients with PH secondary to CHD during perioperative period.PubMed, EMBASE, the Cochrane Library, and the Google Scholar were searched up to May 2016 for randomized controlled trials (RCTs) assessing the perioperative treatment of sildenafil in pediatric patients with PH secondary to CHD. Major clinical outcomes were mortality before discharge, length of ICU stay, and length of hospitalization. The outcomes were analyzed as continuous and dichotomized variables by using fixed or random effect model, and we computed the pooled RR and MD with 95% confidence interval.Five RCTs involving 238 pediatric patients with PH experienced CHD operation were included. Sildenafil was used in all trials. We observed no differences in mortality before discharge (RR 0.35; 95% CI 0.06-2.10; χ

Topics: Adolescent; Child; Child, Preschool; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Length of Stay; Perioperative Care; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Treatment Outcome

The Fontan circulation is the optimal treatment for patients with univentricular hearts. These patients are at high risk of circulatory failure. There is no consensus on the optimal drug treatment for the prevention of failure of the Fontan circulation. The aim of this systematic review was to provide an overview of evidence for drug therapy used in the prevention of Fontan circulatory failure.. We searched the Embase database for articles that reported drug therapy in Fontan patients. Studies published between 1997 and 2014 were included if efficacy or safety of medication was assessed, drug therapy aimed to prevent or treat failure of the Fontan circulation, and if the full text was available. Case reports were excluded.. A total of nine studies were included with a total of 267 Fontan patients; four studies evaluated the medication sildenafil, one iloprost, three bosentan, and one enalapril. Among all, two sildenafil studies reported improvement in exercise capacity, one in exercise haemodynamics, and one in ventricular performance. In the largest study of bosentan, an increase in exercise capacity was found. Enalapril did not result in improvements.. The studies analysed in this review suggest that bosentan, sildenafil, and iloprost may improve exercise capacity at the short term. Given the limitations of the studies, more, larger, placebo-controlled studies with longer follow-up periods are needed to better understand which drug therapies are effective in the prevention of failure of the Fontan circulation.

Topics: Bosentan; Endothelin Receptor Antagonists; Exercise Test; Exercise Tolerance; Fontan Procedure; Heart Defects, Congenital; Hemodynamics; Humans; Iloprost; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Vasodilator Agents

The Fontan operation is the final step of palliation for patients with a functionally single ventricle. Since its introduction in the 1970s, the Fontan surgery has become part of a successful surgical strategy that has improved single ventricle mortality. In recent years, we have become more aware of the limitations and long-term consequences of the Fontan physiology. Pulmonary vascular resistance plays an important role in total cavopulmonary circulation, and has been identified as a potential therapeutic target to mitigate Fontan sequelae. In this review, we will discuss the results of different pulmonary vasodilator trials and the use of pulmonary vasodilators as a treatment strategy for Fontan patients.

Topics: Bosentan; Cardiac Output; Endothelin Receptor Antagonists; Fontan Procedure; Heart Defects, Congenital; Heart Failure; Humans; Phenylpropionates; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Pulmonary Circulation; Pyridazines; Sildenafil Citrate; Sulfonamides; Vascular Resistance; Vasodilator Agents

Despite advancements in surgical techniques over the past 20 years, Fontan patients have decreased exercise capacity as a consequence of an inherent inability to adequately increase cardiac output during exercise. They are also affected by several complications that are associated with considerable morbidity and mortality. As the systemic and pulmonary circulations are placed in series without a subpulmonary ventricle propelling blood through the pulmonary vasculature, the systemic venous pressure and the respiratory mechanics are the only forces driving pulmonary blood flow. In Fontan circulation, pulmonary vascular resistance is the single most important factor involved in the limitation of cardiac output and treatments able to decrease pulmonary vascular resistance might conversely improve cardiac output and exercise capacity. In this article we discuss the initial experience with the use of sildenafil in Fontan patients and we discuss the possible mechanisms through which sildenafil might positively act in Fontan circulation.

Topics: Cardiac Output; Collateral Circulation; Coronary Circulation; Exercise Tolerance; Fontan Procedure; Heart Defects, Congenital; Humans; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Time Factors; Vascular Resistance

Plastic bronchitis is the occlusion of the major bronchial airways by a firm, gelatinous mucoid cast. It is a rare condition, which while classically described in asthma and sickle cell disease has greater mortality in patients with congenital heart disease. The management of this disease is obscure given the lack of clinical data regarding treatment therapies.. We describe a case of an 11-year-old female status after Fontan surgery who presented with respiratory distress secondary to atelectasis of the right lung.. A bronchoscopy was performed demonstrating an obstructing bronchial cast with successful extraction. The plastic bronchitis continued to recur and she was placed on multiple inhaled mucolytics as well as inhaled tissue plasminogen activator with temporary resolution. Further evaluation of the etiology of her casts revealed that she had elevated pulmonary arterial pressures. Repeated bronchoscopic removal of the casts was utilized as well as continuation of the aggressive airway clearance. Ultimately fenestration of her Fontan was performed along with treatment of pulmonary vasodilators sildenafil and bosentan. Although there was improvement of the cast formation, her airway clearance could only be weaned to four times a day therapy with which she was discharged home after a 3-month hospitalization. She continues to remain on this therapy and has not required hospitalization since the initial incident over 1 year ago.. Plastic bronchitis in a patient with Fontan physiology presents a treatment dilemma that may require comprehensive therapy in severe cases such as described.

Topics: Antihypertensive Agents; Bosentan; Bronchitis; Bronchoscopy; Child; Combined Modality Therapy; Drug Therapy, Combination; Expectorants; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Tissue Plasminogen Activator; Treatment Outcome; Vasodilator Agents

Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD), with most cases occurring in patients with congenital cardiac shunts. In patients with an uncorrected left-to-right shunt, increased pulmonary pressure leads to vascular remodelling and dysfunction, resulting in a progressive rise in pulmonary vascular resistance and increased pressures in the right heart. Eventually, reversal of the shunt may arise, with the development of Eisenmenger's syndrome, the most advanced form of PAH-CHD. The prevalence of PAH-CHD has fallen in developed countries over recent years and the number of patients surviving into adulthood has increased markedly. Today, the majority of PAH-CHD patients seen in clinical practice are adults, and many of these individuals have complex disease or received a late diagnosis of their defect. While there have been advances in the management and therapy in recent years, PAH-CHD is a heterogeneous condition and some subgroups, such as those with Down's syndrome, present particular challenges. This article gives an overview of the demographics, pathophysiology and treatment of PAH-CHD and focuses on individuals with Down's syndrome as an important and challenging patient group.

Topics: Antihypertensive Agents; Bosentan; Clinical Trials as Topic; Comorbidity; Down Syndrome; Eisenmenger Complex; Endothelium, Vascular; Epoprostenol; Health Behavior; Heart Defects, Congenital; Heart Transplantation; Humans; Hypertension, Pulmonary; Lung Transplantation; Oxygen Inhalation Therapy; Phosphodiesterase 5 Inhibitors; Piperazines; Practice Guidelines as Topic; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Thrombosis

The Fontan procedure is the final common pathway in the surgical palliation of many single ventricle heart defects. Mortality has improved but morbidity remains significant. Pleural effusions continue to present challenges after this operation and account for increased length of stay and increased time with draining tube thoracostomies. This review examines recent publications addressing this problem.. Four papers in 2008-2009 addressed effusions after the Fontan procedure. Off-pump Fontan procedures did not decrease time until chest tube removal. Pulmonary vascular compliance, derived from an electrical circuit model, predicted chest tube indwelling time. A retrospective study identified mean pulmonary artery pressure as a risk factor for effusions lasting more than 14 days after the Fontan procedure. One prospective, randomized trial evaluated the effects of lisinopril on pleural effusions after the Fontan procedure. There was no difference in the length of pleural drainage between the two groups.. Pleural effusions after the Fontan procedure continue to be a challenge. The cause is likely multifactorial and could explain why the literature has no clear message. One randomized, prospective trial suggests that fenestration reduces effusions. Many other reviews report no benefit to fenestration. Sildenafil after the Fontan procedure should be studied in a randomized, prospective fashion.

Topics: Antihypertensive Agents; Chest Tubes; Drainage; Fontan Procedure; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Lisinopril; Piperazines; Pleural Effusion; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil is a phosphodiesterase 5 inhibitor widely used for the treatment of pulmonary hypertension in children. Despite limited available safety and efficacy evidence, use of sildenafil continues to increase. To date, sildenafil use for pediatric pulmonary hypertension has been characterized for 193 children through 16 studies and 28 case series and reports. The primary efficacy data suggest that sildenafil is beneficial for facilitating the weaning of inhaled nitric oxide in children after cardiac surgery. Compiled safety data suggest that sildenafil is well tolerated among children with idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with congenital heart disease. This review summarizes the available data describing the use, safety, and efficacy of sildenafil for children with pulmonary hypertension.

Topics: Child; Clinical Trials as Topic; Drug Interactions; Drug Therapy, Combination; Economics, Pharmaceutical; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient's physical capacity.. We analyzed circulating (plasma) markers of endothelial and platelet activation/dysfunction (enzyme-linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty-one patients were enrolled (age 10-54 years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6 months (sildenafil [n = 16], 20 mg t.i.d.; tadalafil [n = 15], single daily dose of 40 mg). Measurements were performed at baseline, and 90 and 180 days.. Compared to controls, patients had elevated baseline β-thromboglobulin (β-TG, P = .002), P-selectin (P = .027), tissue-type plasminogen activator (t-PA, P = .009), and von Willebrand factor antigen (VWF:Ag, P = .010). Thrombomodulin was importantly reduced (TM, P < .001), while soluble CD40 Ligand was not changed (P = .320). Tadalafil administration was associated with improvement of β-TG (P = .004), t-PA (P = .003) and TM (P = .046) levels, while P-selectin was improved by sildenafil treatment only (P = .034). VWF:Ag improved transiently in the sildenafil group (P = .019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6-minute test, P < .05), hematocrit and hemoglobin level (P < .05), and health-related quality of life (physical and mental components, P < .05).. In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators.

Topics: Adolescent; Adult; Cardiac Catheterization; Child; Dose-Response Relationship, Drug; Echocardiography; Female; Follow-Up Studies; Heart Defects, Congenital; Heart Ventricles; Humans; Hypertension, Pulmonary; Magnetic Resonance Imaging, Cine; Male; Microcirculation; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Circulation; Pulmonary Wedge Pressure; Retrospective Studies; Sildenafil Citrate; Tadalafil; Treatment Outcome; Young Adult

Young children with CHD and large systemic-to-pulmonary shunts eventually develop pulmonary hypertension. At present, phosphodiesterase type-5 inhibitors such as sildenafil have been used to control pulmonary pressure before and after cardiac surgery. Recently, tadalafil has been utilised in older children with similar efficacy, but it has been used to a lesser extent in young infants. From April, 2015 to June, 2016, 42 patients aged 3-24 months with a large septal defect and pulmonary arterial hypertension were randomly divided into two equal groups: one group received oral sildenafil (1-3 mg/kg/day every 8 hours), whereas the other group received oral tadalafil (1 mg/kg once a day) from 7-10 days before surgery to 3-4 weeks after surgery. During the first 48 hours after surgery, pulmonary artery-to-aortic pressure ratio and recorded systolic pulmonary artery pressures were not significantly different between the two groups (p>0.05); moreover, there were no differences in paediatric ICU length of stay, mechanical ventilation time, clinical findings of low cardiac output state, and echocardiographic data between the two groups (p>0.05). Most of the patients had no side effects, and only five patients had a minor with no significant difference in both groups (p=0.371). Tadalafil can be considered as an effective oral therapy for preoperative and postoperative pulmonary hypertension in young infants. It can be administered at a once-daily dose with an appropriate efficacy and safety profile as sildenafil, and therefore it can be considered as an alternative to sildenafil in young children.

Topics: Cardiac Surgical Procedures; Child, Preschool; Echocardiography; Female; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Humans; Hypertension, Pulmonary; Infant; Iran; Length of Stay; Male; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Sildenafil Citrate; Tadalafil; Treatment Outcome

Aims Sildenafil is frequently prescribed to children with single ventricle heart defects. These children have unique hepatic physiology with elevated hepatic pressures, which may alter drug pharmacokinetics. We sought to determine the impact of hepatic pressure on sildenafil pharmacokinetics in children with single ventricle heart defects.. A population pharmacokinetic model was developed using data from 20 single ventricle children receiving single-dose intravenous sildenafil during cardiac catheterisation. Non-linear mixed effect modelling was used for model development, and covariate effects were evaluated based on estimated precision and clinical significance.. The analysis included a median (range) of 4 (2-5) pharmacokinetic samples per child. The final structural model was a two-compartment model for sildenafil with a one-compartment model for des-methyl-sildenafil (active metabolite), with assumed 100% sildenafil to des-methyl-sildenafil conversion. Sildenafil clearance was unaffected by hepatic pressure (clearance=0.62 L/hour/kg); however, clearance of des-methyl-sildenafil (1.94×(hepatic pressure/9)(-1.33) L/hour/kg) was predicted to decrease ~7-fold as hepatic pressure increased from 4 to 18 mmHg. Predicted drug exposure was increased by ~1.5-fold in subjects with hepatic pressures ⩾10 versus <10 mmHg (median area under the curve=533 versus 792 µg*h/L). Discussion Elevated hepatic pressure delays clearance of the sildenafil metabolite - des-methyl-sildenafil - and increases drug exposure. We speculate that this results from impaired biliary clearance. Hepatic pressure should be considered when prescribing sildenafil to children. These data demonstrate the importance of pharmacokinetic assessments in patients with unique cardiovascular physiology that may affect drug metabolism.

Topics: Cardiac Catheterization; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Heart Defects, Congenital; Heart Ventricles; Humans; Infant; Injections, Intravenous; Liver; Male; Models, Theoretical; Phosphodiesterase 5 Inhibitors; Pressure; Sildenafil Citrate; Treatment Outcome

Sildenafil has strong cardiac preconditioning properties in animal studies and has a safe side-effect profile in children. Therefore, we evaluated the application of Sildenafil preconditioning to reduce myocardial ischaemia/reperfusion injury in children undergoing surgical ventricular septal defect (VSD) closure.. This is a randomized, double-blind study. Children (1-17 years) undergoing VSD closure were randomized into three groups: placebo (Control group), preconditioning with 0.06 mg/kg (Sild-L group) and 0.6 mg/kg Sildenafil (Sild-H group).. troponin release. CK-MB, Troponin I, inflammatory response (IL-6 and TNF-α), bypass and ventilation weaning times, inotropy score and echocardiographic function were assessed. Data expressed as median (range), and a value of P < 0.05 was considered significant.. Thirty-nine patients were studied (13/group). Aortic cross-clamp time was similar [27 (18-85) and 27 (12-39) min] in the Control and Sild-L groups, respectively, but significantly longer [39 (20-96) min] in the Sild-H group when compared with the Control group. Area under the curve of CK-MB release was 1105 (620-1855) h ng/ml in the Control group, 1672 (564-2767) h ng/ml in the Sild-L group and was significantly higher in the Sild-H group [1695 (1252-3377) h ng/ml] when compared with the Control group. There were no significant differences in inflammatory response markers, cardiopulmonary bypass and ventilation weaning times, inotropy scores and echocardiographic function between the groups.. In this small study, Sildenafil failed to reduce myocardial injury in children undergoing cardiac surgery, nor does it alter cardiac function, inotropic needs or postoperative course. A subclinical increase in cardiac enzyme release after Sildenafil preconditioning cannot be excluded.. CTRI/2014/03/004468.

Topics: Adolescent; Blood Pressure; Cardiac Surgical Procedures; Child; Child, Preschool; Female; Heart; Heart Defects, Congenital; Humans; Infant; Ischemic Preconditioning, Myocardial; Male; Sildenafil Citrate

High pulmonary vascular resistance (PVR) may be a risk factor for early and late mortality in both Glen shunt and Fontan operation patients. Furthermore, PVR may increase long after the Fontan operation. Whether pulmonary vasodilators such as phosphodiesterase 5 inhibitors can decrease PVR in patients with single ventricular physiology remains undetermined.. This was a prospective, multicenter study. Patients with single ventricular physiology who have a PVR index higher than 2.5 Wood units·㎡ (WU) were enrolled. Cardiac catheterization was performed before and after administration of sildenafil in all patients. After the Fontan operation, a six minute walk test (6MWT) was also performed. A total of 42 patients were enrolled. PVR was significantly decreased in each stage of single ventricular physiology after sildenafil administration: from 4.3±1.5WU to 2.1±0.6WU (p<0.01) in patients before a Glenn shunt, from 3.2±0.5WU to 1.6±0.6WU (p<0.001) in patients after a Glenn shunt, and from 3.9±1.7WU to 2.3±0.8WU (p<0.001) in patients after Fontan. In patients after Fontan, the 6MWT increased from 416±74m to 485±72m (p<0.01), and NYHA functional class improved significantly (p<0.05) after sildenafil administration. No major side effects were observed in any patients.. Sildenafil reduced PVR in patients with single ventricle physiology. Sildenafil increased exercise capacity and improved NYHA functional class in patients after a Fontan operation. This implies that pulmonary vasodilation is a potential therapeutic target in selected patients with elevated PVR with single ventricle physiology. Long-term clinical significance warrants further study.

Topics: Adolescent; Child, Preschool; Female; Fontan Procedure; Heart Defects, Congenital; Heart Ventricles; Hemodynamics; Humans; Hypertension, Pulmonary; Infant, Newborn; Japan; Male; Outcome and Process Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Sildenafil Citrate; Vascular Resistance; Vasodilator Agents

Determine sildenafil exposure and hemodynamic effect in children after Fontan single-ventricle surgery.. Prospective dose-escalation trial.. Single-center pediatric catheterization laboratory.. Nine children post Fontan single-ventricle surgical palliation and undergoing elective cardiac catheterization: median (range) age and weight, 5.2 years (2.5-9.4 yr) and 16.3 kg (9.5-28.1 kg). Five children (55%) were boys, and six of nine (67%) had a systemic right ventricle.. Catheterization and echocardiography performed before and immediately after single-dose IV sildenafil (0.25, 0.35, or 0.45 mg/kg over 20 min).. Peak sildenafil and desmethyl sildenafil concentration, change in hemodynamic variables measured by cardiac catheterization and echocardiography. Maximum sildenafil concentrations ranged from 124 to 646 ng/mL and were above the in vitro threshold needed for 77% phosphodiesterase type-5 inhibition in eight of nine children and 90% inhibition in seven of seven children with doses more than or equal to 0.35 mg/kg. Sildenafil improved stroke volume (+22%, p = 0.05) and cardiac output (+10%, p = 0.01) with no significant change in heart rate in eight of nine children. Sildenafil also lowered systemic (-16%, p = 0.01) and pulmonary vascular resistance index in all nine children (median baseline pulmonary vascular resistance index 2.4 [range, 1.3-3.7]; decreased to 1.9 [0.8-2.7] Wood Units × m; p = 0.01) with no dose-response effect. Pulmonary arterial pressures decreased (-10%, p = 0.02) and pulmonary blood flow increased (9%, p = 0.02). There was no change in myocardial performance index and no adverse events.. After Fontan surgery, sildenafil infusion acutely improves cardiopulmonary hemodynamics, increasing cardiac index. For the range of doses studied, exposure was within the acute safety range reported in adult subjects.

Topics: Arterial Pressure; Cardiac Catheterization; Child; Child, Preschool; Echocardiography; Female; Fontan Procedure; Heart Defects, Congenital; Heart Rate; Hemodynamics; Humans; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Postoperative Care; Prospective Studies; Pulmonary Artery; Purines; Sildenafil Citrate; Stroke Volume; Sulfones; Vascular Resistance

A single dose of sildenafil improves exercise capacity in Fontan patients. However, a recent study failed to show a long-term effect of sildenafil. This study evaluated whether there are factors that might predict sildenafil effects.. We studied 36 patients (16-42 years, 14 female) with univentricular heart after various modifications of the Fontan surgery (13 APC, 16 AVC, 7 TCPC). They performed two cardiopulmonary exercise tests, with at least 120 min rest and a single dose of 50 mg sildenafil in between.. After sildenafil administration, patients improved their peak oxygen uptake from 64.5 to 67.3 % predicted (p = 0.0003) without change in ventilatory efficiency ([Formula: see text] slope), oxygen saturation (SpO2) at rest or at peak exercise, respiratory exchange ratio. In addition, resting systolic blood pressure was slightly reduced after sildenafil administration. There was a moderate negative correlation of this improvement to baseline peak oxygen uptake (r = -0.395; p = 0.017). The change in peak oxygen uptake could not be correlated to time of surgery, type of surgery, NT-pro-BNP, or to other clinical data. Nevertheless, all four patients with NT-pro-BNP levels higher than 1,000 pg/ml had the most prominent improvements in exercise capacity.. Fontan patients have an improved exercise capacity after a single dose of sildenafil. Patients with worse baseline peak oxygen uptake profit more.

Topics: Adolescent; Adult; Blood Pressure; Exercise Test; Exercise Tolerance; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Male; Natriuretic Peptide, Brain; Oxygen Consumption; Peptide Fragments; Piperazines; Purines; Sildenafil Citrate; Sulfonamides; Vasodilator Agents; Young Adult

The objective of this study was describe the impact of sildenafil on echocardiographic measures of myocardial performance in children and young adults with a functional single-ventricle physiology late after Fontan surgery. A double-blind, placebo-controlled, crossover trial was conducted in children and young adults after the Fontan operation at a single pediatric center. Subjects were randomized to receive placebo or sildenafil (20 mg tid) for 6 weeks. After a 6-week washout period, subjects were crossed for an additional 6 weeks. Each subject underwent an echocardiogram at the start and finish of each phase. A total of 27 subjects completed study testing at a mean age of 14.9 years and a mean time from Fontan surgery of 11.3 years. After sildenafil, subjects demonstrated improvement in their myocardial performance index (MPI; -0.051; 95% CI -0.095, -0.0077; p 0.02) and in the product of the velocity time integral (VTI) of the dominant outflow tract and the heart rate (HR; 110 cm × bpm; 95% CI 7.5, 220; p = 0.04). Measures of diastolic performance, including inflow velocities, myocardial velocities, and the ratio of blood pool velocity to myocardial velocity during passive inflow, did not change. In this cohort, there were significant improvements in both the MPI and the product of the VTI × HR after 6 weeks of treatment with sildenafil. These findings suggest that sildenafil may be a useful therapy to improve or maintain ventricular performance in select patients after the Fontan operation.

Topics: Administration, Oral; Adolescent; Biomarkers; Child; Cross-Over Studies; Double-Blind Method; Echocardiography; Female; Fontan Procedure; Heart Defects, Congenital; Hemodynamics; Humans; Linear Models; Male; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Placebos; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

To evaluate the efficacy and safety of intravenous sildenafil for immediate postoperative pulmonary hypertension (PH) in pediatric patients undergoing congenital heart surgery.. A double-blind, multicenter, placebo-controlled, dose-ranging, parallel-group trial was conducted. Patients were randomized to one of three doses of intravenous sildenafil, or placebo, for a minimum of 24 h.. The study was heavily underpowered. Whereas enrollment of 228 patients (57 per treatment arm) was required to achieve the sample size estimate to detect difference between arms, the sponsor terminated the study after 15 months owing to slow patient accrual. Seventeen patients (median age 5 months) experiencing postoperative PH were randomized and treated, five with placebo and four each with low-, medium-, and high-dose sildenafil. In the first 24 h, 40% of placebo and 17% of sildenafil patients required additional therapy (p = 0.330). Median time to extubation (3 versus 8 days, p = 0.023) and intensive care unit stay (6 versus 15 days, p = 0.008) were shorter for sildenafil patients. Mean ± standard deviation systolic pulmonary artery pressure was reduced with sildenafil (46 ± 11 to 35 ± 6 mmHg, p = 0.027 versus placebo). No adverse events or systemic hypotension were attributed to sildenafil.. Intravenous sildenafil reduced pulmonary artery pressure and shortened time to extubation and intensive care unit stay in children with postoperative PH.

Topics: Adolescent; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Infusions, Intravenous; Male; Piperazines; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Topics: Child; Eisenmenger Complex; Female; Follow-Up Studies; Heart Defects, Congenital; Humans; Hypoxia; Infant; Male; Oxygen; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones

Children and young adults with single-ventricle physiology have abnormal exercise capacity after the Fontan operation. A medication capable of decreasing pulmonary vascular resistance should allow improved cardiac filling and improved exercise capacity.. This study was a double-blind, placebo-controlled, crossover trial conducted in children and young adults after Fontan. Subjects were randomized to receive placebo or sildenafil (20 mg three times daily) for 6 weeks. After a 6-week washout, subjects crossed over for an additional 6 weeks. Each subject underwent an exercise stress test at the start and finish of each phase. After taking sildenafil, subjects had a significantly decreased respiratory rate and decreased minute ventilation at peak exercise. At the anaerobic threshold, subjects had significantly decreased ventilatory equivalents of carbon dioxide. There was no change in oxygen consumption during peak exercise, although there was a suggestion of improved oxygen consumption at the anaerobic threshold. Improvement at the anaerobic threshold was limited to the subgroup with single left or mixed ventricular morphology and to the subgroup with baseline serum brain natriuretic peptide levels ≥100 pg/mL.. In this cohort, sildenafil significantly improved ventilatory efficiency during peak and submaximal exercise. There was also a suggestion of improved oxygen consumption at the anaerobic threshold in 2 subgroups. These findings suggest that sildenafil may be an important agent for improving exercise performance in children and young adults with single-ventricle physiology after the Fontan operation. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00507819.

Topics: Administration, Oral; Adolescent; Adult; Child; Cross-Over Studies; Double-Blind Method; Exercise; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Male; Natriuretic Peptide, Brain; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Young Adult

The difference in underlying pathophysiology in different congenital heart disease (CHD) may have an influence on clinical outcome. It remains unclear whether the effect of sildenafil on pulmonary arterial hypertension (PAH) varies in different types of CHD.. The potential effect of sildenafil on pulmonary arterial hypertension related to CHD may be associated with shunt location.. In this 12-week, prospective, open label, multicenter trial, 55 patients with CHD were divided into the 3 groups: atrial septal defects group (ASD, n = 15), ventricular septal defects group (VSD, n = 24), and patent ductus arteriosus group (PDA, n = 16). Exercise capacity, hemodynamic parameters, and arterial oxygen saturation were assessed at baseline and after sildenafil therapy (25 mg, 3 times daily).. Six-minute walk distance significantly increased from 377.2 ± 68.7 m to 436.0 ± 70.4 m in patients with ASD, from 371.2 ± 66.0 m to 413.7 ± 83.1 m in VSD, and from 384.3 ± 90.2 m to 440.9 ± 71.8 m in PDA (P<0.01, respectively). Moreover, sildenafil also improved the pulmonary vascular resistance and pulmonary blood flow index in the 3 groups, whereas no significant changes in systemic vascular resistance and systemic arterial pressure were observed. However, arterial oxygen saturation was significantly improved in the ASD group only. The incidence of adverse events was similar among the 3 groups.. Sildenafil therapy seems to be effective and safe for PAH secondary to ASD, VSD, and PDA, although some clinical and hemodynamic parameters were changed in a different manner among the 3 groups.

Topics: Adolescent; Adult; Antihypertensive Agents; Chi-Square Distribution; China; Ductus Arteriosus, Patent; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Heart Septal Defects, Atrial; Heart Septal Defects, Ventricular; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Oxygen; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents; Young Adult

Sildenafil is a strong pulmonary vasodilator that increases the intracellular cyclic guanosine monophosphate concentration through inhibition of phosphodiesterase-5. We assessed the benefit of oral sildenafil for persistent pulmonary hypertension early after congenital cardiac surgery in paediatric patients.. Sildenafil was administered at a starting dose of 0.5 mg kg(-1) following admission to the intensive care unit. With careful monitoring of haemodynamics, the dose was increased stepwise by 0.5 mg kg(-1) every 4-6 h up to a maximum of 2 mg kg(-1). After successful weaning from a ventilator and from other vasodilators, sildenafil was gradually discontinued over the next 5-7 days.. A retrospective review of medical records showed an age distribution of <1 month (n=26), > or = 1-<6 months (n=36), > or = 6-<12 months (n=19), 1-3 years (n=8), 4-9 years (n=9) and >10 years (n=2) at the time of surgery. The surgeries were performed for ventricular septal defect closure (n=17), arterial switch (n=30), truncus arteriosus repair (n=10), complete atrioventricular septal defect repair (n=12), total anomalous venous drainage repair (n=9), and other open-heart surgery (n=22). The aforementioned concomitant inhaled nitrous oxide treatment was performed in 66 patients. Pulmonary arterial pressure decreased in 28, was unchanged in five and elevated in one patient out of the total of 34 cases for which data from continuous pressure monitoring were available. Bosentan was added in three cases with persistent symptoms due to pulmonary hypertension despite sildenafil treatment. After sildenafil administration, modest oxygen desaturation occurred in seven cases, but no 'rebound' pulmonary hypertension occurred. There were no significant adverse events during sildenafil treatment.. Our results suggest that oral sildenafil is a safe and effective alternate for persistent pulmonary hypertension following congenital heart surgery in children.

Topics: Administration, Oral; Age Distribution; Child; Child, Preschool; Drug Administration Schedule; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Oxygen Consumption; Phosphodiesterase 5 Inhibitors; Piperazines; Postoperative Care; Postoperative Complications; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

It has been demonstrated that sildenafil is effective in patients with pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH in adults with congenital heart disease (CHD) has been less investigated.. In this prospective, open-label, uncontrolled and multicenter study, 60 patients with PAH related to CHD received oral sildenafil (75 mg/day) for 12 weeks. The enrolled patients underwent six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of the 12 weeks. The primary end point was the changes in exercise capacity assessed by SMWT; the secondary end point included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening (defined as death, transplantation, and rehospitalization for PAH). Drug safety and tolerability were also examined.. Oral sidenafil significantly increased SMWT distances (422.94 ± 76.95 m vs. 371.99 ± 78.73 m, P < 0.0001). There was also remarkable improvement in Borg dyspnea score (2.1 ± 1.32 vs. 2.57 ± 1.42, P = 0.0307). Moreover, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also discovered (mean pulmonary artery pressure, P = 0.0002; cardiac index, P < 0.0001; pulmonary vascular resistance, P < 0.0001). Side effects in this study were mild and consistent with reported studies. None of the enrolled patients experienced significant clinical worsening.. This study confirmed and extended previous studies. It suggested that oral sildenafil was safe and effective for the treatment of adult patients with CHD-related PAH.

Topics: Administration, Oral; Adolescent; Adult; Antihypertensive Agents; Blood Pressure; Cardiac Catheterization; China; Drug Administration Schedule; Dyspnea; Exercise Test; Exercise Tolerance; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Young Adult

It is shown that phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil can modulate pulmonary arterial hypertension (PAH) via increasing the level of guanosine-3,5-cyclic monophosphate (cGMP) and decreases pulmonary artery pressure (PAP). In this study we determined the effectiveness of sildenafil and compared its efficacy with inhaled nasal oxygen (O2) during cardiac catheterization in patients with congenital heart diseases (CHD) and PAH, as a test of feasibility for surgical repair of the patients. We studied 15 patients, 9 male and 6 female, with a mean age of 8.3 years. Hemodynamic measurements were made at baseline, after O2 administration for 20 min (5 L/min by mask), and then 45 min after administration of a single dose of sildenafil (0.5 mg/kg orally or via nasogastric tube). Mean PAP at baseline was 72.2 +/- 12.54 mm Hg and was reduced by sildenafil to 52.5 +/- 9.6 and by O2 to 61.3 +/- 10.39. Both sildenafil and O2 decreased PAP effectively (p = 0.08 and p = 0.04, respectively). Pulmonary vascular resistance (PVR) was calculated for 12 patients, with a baseline level of 9.08 +/- 1.09 mm Hg . L(-1) . min, which was significantly decreased by O2, to 3.74 +/- 0.43, and by sildenafil, to 5.93 +/- 0.75 (p = 0.005 and p = 0.05, respectively). Sildenafil, as a single oral dose, can effectively reduce PAP and PVR. This novel PDE5 inhibitor can be used for assessment of feasibility of operation for patients with CHD and PAH when inhaled NO is not available.

Topics: Administration, Oral; Adolescent; Cardiac Catheterization; Child; Child, Preschool; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Male; Oxygen Inhalation Therapy; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones

This study investigates the role of oral sildenafil in decreasing pulmonary pressure after congenital heart surgery. Between September 2002 and September 2004, among a group of postoperative children with large septal defects, moderate to severe pulmonary hypertension [pulmonary artery (PA) to aortic (Ao) pressure ratio of 0.76 +/- 0.17] and systemic desaturation (Ao Sat = 0.89 +/- 0.11), oral sildenafil (0.3 mg x kg(-1), every 3 hours) was administered for a period of 24-48 hours (sildenafil group). These patients were compared to a group of 22 children with similar pathologies who did not receive sildenafil (control group). Postoperative PA pressure (28.61 +/- 7.80 vs 39.40 +/- 10.80 mm Hg) and PA/Ao pressure (0.28 +/- 0.08 vs 0.41 +/- 0.11) were significantly lower in the sildenafil group ( p = 0.001 and 0.001 respectively). Pulmonary hypertensive crisis was detected in 4 patients in the control group, but none in the sildenafil group ( p = 0.02). There was no significant rise in PA pressure following discontinuation of the drug (26.30 +/- 6.66 vs 28.49 +/- 10.93 mm Hg, p = 0.366). No significant complications were noticed regarding sildenafil use. Low doses of oral sildenafil appear to be effective and safe to control postoperative PA pressure in children. Absence of rebound pulmonary hypertension, availability, and low cost of the drug are considered as its major advantages.

Topics: Administration, Oral; Adolescent; Antihypertensive Agents; Cardiac Surgical Procedures; Child; Child, Preschool; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Rebound pulmonary hypertension (PHT) can complicate the weaning of nitric oxide (NO), and is in part related to transient depletion of intrinsic cyclic guanosine monophosphate. Rebound is characterized by increased pulmonary arterial (PA) pressure, cardiopulmonary instability, and in some cases, the need to continue NO beyond the intended period of use. There is anecdotal evidence that sildenafil, a phosphodiesterase-5 inhibitor, may prevent recurrence of rebound.. We investigated the role of sildenafil in preventing rebound (an increase in PA pressure of 20% or greater, or failure to discontinue NO) in patients in whom previous attempts had not been made to wean from NO.. Thirty ventilated infants and children, receiving 10 ppm or greater inhaled NO, were randomized to receive 0.4 mg/kg of sildenafil, or placebo, 1 h before discontinuing NO. Twenty-nine patients completed the study.. PA pressures and blood gases were measured before the study drug, and 1 and 4 h after stopping NO.. Rebound occurred in 10 of 14 placebo patients, and 0 of 15 sildenafil patients (p < 0.001). PA pressure increased by 25% (14-67) in placebo patients, and by 1%(-9-5) in sildenafil patients (p < 0.001). Four placebo patients could not be weaned from NO due to severe cardiovascular instability, whereas all sildenafil patients were weaned (p = 0.042). Duration of ventilation after study was 98.0 (47.0-223.5) h for placebo patients and 28.2 (15.7-54.6) h for sildenafil patients (p = 0.024).. A single dose of sildenafil prevented rebound after withdrawal of NO, and reduced the duration of mechanical ventilation. Prophylaxis with sildenafil should be considered when weaning patients from inhaled NO.

Topics: Administration, Inhalation; Blood Pressure; Double-Blind Method; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Pulmonary Artery; Purines; Respiration, Artificial; Sildenafil Citrate; Sulfones; Time Factors

Sildenafil is a selective Phosphodiesterase-5 inhibitor that has been reported to be a potent pulmonary vasodilator. We evaluated the safety, efficacy and pharmacokinetics of oral Sildenafil in a case series of children with pulmonary hypertension.. Three children, 1 with primary pulmonary hypertension (patient 1) and 2 with pulmonary hypertension associated with congenital heart disease (patients 2 and 3) were enrolled. Sildenafil was started at 0.5 mg/kg 4-hourly and the dose increased to 1.0 and then to 2.0 mg/kg/dose. Patients were assessed at baseline and then monthly for a total of 6 visits.. All patients reported increased exercise capacity with improvement in New York Heart Association functional class. The distance walked during the 6-min test increased by 74% (patient 1), 75% (patient 2) and 25% (patient 3) and oxyhaemoglobin saturations increased from 79%, 97% and 80% to 93%, 100% and 93%, respectively. There were no side effects and no fall in systemic blood pressure. Sildenafil plasma levels 1 h after a 0.5, 1.0 and 2 mg/kg dose of Sildenafil were 109+/-87, 150+/-62 and 368+/-200 ng/ml, respectively. They fell to 211+/-106 ng/ml 3 h after the 2.0 mg/kg dose.. Medium term Sildenafil therapy improves oxyhaemoglobin saturations and exercise tolerance in children with pulmonary hypertension without any side effects. Mean plasma levels 1 h after doses of 0.5-2.0 mg/kg are similar to the maximum plasma concentrations reported in adults receiving doses within the therapeutic range. Sildenafil use in children appears to be safe and may be beneficial in the management of pulmonary arterial hypertension.

Topics: Administration, Oral; Adolescent; Child; Chronic Disease; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Safety; Sildenafil Citrate; Sulfones

Increased pulmonary vascular resistance (PVR) because of congenital heart disease (CHD) may be caused by a dysfunction in endogenous pulmonary endothelial nitric oxide (NO) production. In other forms of pulmonary vascular disease with increased PVR, an elevated activity of a phosphodiesterase type 5 (PDE-5), responsible for the degradation of cyclic guanidine monophosphate (cGMP), the second messenger of endothelially produced NO, has been demonstrated. This study compares the effects of inhaled NO before and after the specific inhibition of the PDE-5 by intravenous sildenafil (Viagra) in pre- and postoperative children with increased PVR because of CHD.. 12 children with congenital heart disease (age 0.2 to 15.7 years, median 2.4 years) and increased mean pulmonary arterial pressure, and 12 postoperative children (age 0.11 to 0.65 years, median 0.32 years) with increased PVR (8.3+/-1.0 Wood Units*m2) were studied during cardiac catheterization ("cath laboratory"), or within 2 hours after return from cardiac surgery ("post op"), respectively. All were sedated, tracheally intubated and paralyzed. During alveolar hyperoxygenation (FiO2=0.65), the effects of inhaled NO (20 ppm) were compared before and after the stepwise infusion of sildenafil ("cath laboratory", 1 mg/kg; post op, 0.25 mg/kg). Intravenous sildenafil more effectively reduced PVR than NO (11.5% versus 4.3% in the "cath laboratory" patient group, P<0.05, and 25.8% versus 14.6% in the post op patient group, P=0.09. The increase in cGMP in response to NO was potentiated (2- to 2.4-fold) by PDE-5 inhibition. While the vasodilating effects of sildenafil showed pulmonary selectivity, its infusion was associated with increased intrapulmonary shunting in the postoperative patients (Qs/Qt=16.5+/-4.7% to 25.5+/-18.2% P=0.04).. Intravenous sildenafil is as effective as inhaled NO as a pulmonary vasodilator in children with congenital heart disease. Although clinically insignificant in this study, increased intrapulmonary shunting with sildenafil may be disadvantageous in some patients after CHD surgery.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Inhalation; Adolescent; Blood Pressure; Cardiac Catheterization; Child; Child, Preschool; Combined Modality Therapy; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Heart Defects, Congenital; Hemodynamics; Humans; Infant; Infusions, Intravenous; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Postoperative Period; Pulmonary Artery; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Pulmonary vasodilators improve the functional capacity of some patients with pulmonary arterial hypertension. However, pulmonary vasodilators frequently fail to improve unequivocal endpoints of efficacy in patients with lower pulmonary arterial pressures who have been palliated with a Fontan procedure.. Haemodynamic measurements and the results of acute vasodilator testing in a subset of patients were reviewed to determine whether some patients acutely respond more favourably to sildenafil and might be candidates for precision care with a phosphodiesterase V inhibitor long term.. Heart catheterisation was performed in 11 patients with a Fontan procedure. Haemodynamic measurements were performed before and after treatment with intravenous sildenafil (mean 0.14, range 0.05-0.20 mg/kg). Results (mean ± standard deviation) were compared by paired and unpaired t-tests to identify statistically significant changes.. Sildenafil was acutely associated with changes in mean pulmonary arterial pressure, transpulmonary gradient, indexed blood flow, and indexed vascular resistance. Changes in mean pulmonary arterial pressure were greater for patients with a mean pulmonary arterial pressure greater than 14 mmHg compared to patients with a lower mean pulmonary arterial pressure. Changes in transpulmonary gradient were greater for patients with a transpulmonary gradient greater than 5 mmHg compared to patients with a lower transpulmonary gradient.. Sildenafil acutely decreases mean pulmonary arterial pressure and transpulmonary gradient and causes greater acute changes in patients with higher mean pulmonary arterial pressures and transpulmonary gradients. Haemodynamic measurements and vasodilator testing might help to guide precision care following Fontan palliation.

Topics: Administration, Intravenous; Adolescent; Adult; Blood Pressure; Cardiac Catheterization; Child; Child, Preschool; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Pulmonary Circulation; Retrospective Studies; Sildenafil Citrate; Utah; Vascular Resistance; Vasodilator Agents; Young Adult

In children with single ventricle physiology, increased pulmonary vascular resistance may impede surgical progression or result in failing single ventricle physiology. The use of pulmonary vasodilators has been suggested as a potential therapy. However, knowledge on indication, dosage, and effect is limited. A retrospective case notes review of all (n = 36) children with single ventricle physiology, treated with pulmonary vasodilators by the UK Pulmonary Hypertension Service for Children 2004-2017. Therapy was initiated in Stage 1 (n = 12), Glenn (n = 8), or TCPC (n = 16). Treatment indications were high mean pulmonary arterial pressure, cyanosis, reduced exercise tolerance, protein-losing enteropathy, ascites, or plastic bronchitis. Average dose of sildenafil was 2.0 mg/kg/day and bosentan was 3.3 mg/kg/day. 56% had combination therapy. Therapy was associated with a reduction of the mean pulmonary arterial pressure from 19 to 14 mmHg (n = 17, p < 0.01). Initial therapy with one or two vasodilators was associated with an increase in the mean saturation from 80 to 85%, (n = 16, p < 0.01). Adding a second vasodilator did not give significant additional effect. 5 of 12 patients progressed from Stage 1 to Glenn, Kawashima, or TCPC, and 2 of 8 from Glenn to TCPC during a mean follow-up time of 4.7 years (0-12.8). Bosentan was discontinued in 57% and sildenafil in 14% of treated patients and saturations remained stable. Pulmonary vasodilator therapy was well tolerated and associated with improvements in saturation and mean pulmonary arterial pressure in children with single ventricle physiology. It appears safe to discontinue when no clear benefit is observed.

Topics: Adolescent; Arterial Pressure; Bosentan; Child; Child, Preschool; Drug Therapy, Combination; Exercise Tolerance; Female; Heart Defects, Congenital; Heart Ventricles; Humans; Hypertension, Pulmonary; Infant; Male; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; United Kingdom; Vascular Resistance; Vasodilator Agents

To assess the demographics, treatment algorithm, and outcomes in a large cohort of children treated with sildenafil.. A retrospective cohort study of children with pulmonary hypertension (PH) treated with sildenafil at a single institution between 2004 and 2015. Baseline and follow-up data collected by chart review.. There were 269 children included in this study: 47 with idiopathic pulmonary arterial hypertension, 53 with congenital heart disease, 135 with bronchopulmonary dysplasia, 24 with congenital diaphragmatic hernia, and 7 with other causes. Sildenafil was initial monotherapy in 84.8% and add-on therapy in 15.2%. Median follow-up time was 3.1 years (2  weeks-12.4 years). On follow-up, 99 (37%) remained on sildenafil or transitioned to tadalafil, 93 (35%) stopped sildenafil for improvement in PH, 54 (20%) died, and 20 (7%) were lost to follow-up. PH was most likely to improve in those with bronchopulmonary dysplasia, allowing for the discontinuation of sildenafil in 45%. Eighteen deaths were related to PH and 36 from other systemic causes. Two patients stopped sildenafil owing to airway spasm with desaturation. Overall survival was significantly lower in World Health Organization group 3 PH (bronchopulmonary dysplasia and congenital diaphragmatic hernia) vs group 1 (idiopathic pulmonary arterial hypertension and congenital heart disease), P = .02.. In this retrospective experience in children with mainly World Health Organization groups 1 and 3 PH, low-dose sildenafil was well-tolerated, safe, and had an acceptable side effect profile. Although patients with group 3 PH have high mortality, survivors have a high likelihood of PH improving.

Topics: Adolescent; Bronchopulmonary Dysplasia; Child; Child, Preschool; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Male; Sildenafil Citrate; Tadalafil; Treatment Outcome; Vasodilator Agents

We evaluated whether the administration of sildenafil in children undergoing the TCPC operation shortened the interval from the operation to the removal of the pleural and peritoneal drains.. We retrospectively reviewed the data of 122 patients who had undergone the TCPC operation between 2004 and 2014. Patients were divided into two groups on the basis of their treatments. Sildenafil was orally administered pre-operatively in the morning of the procedure or within 24 hours after the TCPC operation to the sildenafil group (n = 48), which was compared to a control group (n = 60). Fourteen patients were excluded from the study.. The primary outcome measure was the time from the operation to the removal of the drains. The study groups had similar demographics. The median [interquartile range] time for the removal of drains (sildenafil group 11 [8-19] vs control group 11 [7-16] d, P = .532) was comparable between the groups. The median [interquartile range] fluid balance on the first post-operative day was significantly higher (P = .001) in the sildenafil group compared with controls (47 [12-103] vs 7 [-6-67] mL kg. Sildenafil administration, pre-operatively or within 24 hours after the TCPC operation, did not reduce the required time for pleural and peritoneal drains but was associated with a significantly higher positive fluid balance.

Topics: Ascitic Fluid; Child, Preschool; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Male; Outcome Assessment, Health Care; Pleural Effusion; Retrospective Studies; Sildenafil Citrate; Time Factors; Water-Electrolyte Balance

Fontan operation can be complicated by persistent chest tube output (CTO) leading to prolonged hospital length of stay (LOS). Postoperative sildenafil administration has been shown to improve clinical outcomes in selected patients after Fontan. We initiated a practice change utilizing intravenous (IV) sildenafil in early postoperative period in all patients undergoing Fontan operation with aim to decrease LOS and CTO. Nineteen patients (February 2014-May 2016) received 0.35 mg/kg sildenafil IV (three doses) followed by enteral, 1 mg/kg every eight hours until hospital discharge. Clinical outcomes were compared to 84 pre-protocol controls. Vital signs were recorded after second sildenafil dose. Demographics were similar between groups. Sildenafil group had longer median LOS [9 (7, 11) vs. 13 (8, 25) days, p = 0.016]. CTO days were longer [6 (5, 8) vs. 8 (6, 13) days, p = 0.011]. Sildenafil group had longer mechanical ventilation [6.9 (3.5, 11.1) vs. 4 (2, 7) h, p = 0.045] and longer oxygen therapy [99 (52, 225) vs. 14.5 (14, 56) h, p = 0.001]. There was a trend towards more albumin 5% resuscitation in first 24 h [17 (1, 30) vs. 21 (10, 40) ml/kg, p = 0.069]. There was no difference in inotrope score at 24 h, maximum lactate, or fluid balance. Readmission rates were similar. There was no mortality. IV sildenafil was well tolerated, and no doses were held. Routine early administration of sildenafil after Fontan operation is not associated with an improvement in any measured clinical outcome, including postoperative CTO, LOS, colloid administration, or duration of mechanical ventilation.

Topics: Chest Tubes; Child, Preschool; Female; Fluid Therapy; Fontan Procedure; Heart Defects, Congenital; Hemodynamics; Humans; Length of Stay; Male; Phosphodiesterase 5 Inhibitors; Postoperative Period; Respiration, Artificial; Retrospective Studies; Sildenafil Citrate; Treatment Outcome

To study the concentration of the asymmetrical dimethyl-L-arginine (ADMA) in patients with pulmonary arterial hypertension (PAH) commbination with congenital heart disease (CHD) and its clinical value as a biomaker for diagnosis and prognosis.
 Methods: A total of 100 patients with CHD and 25 healthy adult subjects were recruited. CHD patients were divided into three groups: normal pulmonary arterial pressure group (group A, n=25), mild-to-moderate PAH group (group B, n=25), severe PAH group (group C, n=50). Twenty patients in Group C were treated with sildenafil and followed up for 6 months. The clinical data, including echocardiographic measurements, hemodynamic parameters and ADMA levels, for all subjects were collected.
 Results: The ADMA concentrations in patients with CHD-PAH significantly increased compared with that in the CHD patients without PAH or the health controls, and the ADMA concentrations in CHD patients with severe PAH were significantly higher than that in the CHD patients with mild-to-moderate PAH; serum ADMA concentration was correlated with mean pulmonary arterial pressure (mPAP) (r=0.61, P<0.001) and pulmonary vascular resistance (PVR) (r=0.417, P<0.001) in CHD patients; when using AMDA>0.485 µmol/L as criteria for diagnosis of CHD-PAH, the specificity was 82.7% and the sensitivity was 92.0%; the pulmonary arterial pressure significantly decreased after sildenafil therapy for 6 months, same as the ADMA levels.
 Conclusion: Plasma ADMA could be used as a biomarker to identify PAH in patients with CHD and as a prognosic index to reflect the sildenafil treatment effect.. 目的：研究血浆不对称二甲基精氨酸(asymmetrical dimethyl-L-arginine，ADMA)作为先天性心脏病(congenital heart disease，CHD)相关肺动脉高压(pulmonary arterial hypertension，PAH)患者诊断、分层与随访指标的应用价值。
方法：收集湘雅二医院心血管内科2013年10月至2014年10月经超声心动图证实的CHD患者(n=100)，将其分为3组：无PAH组、轻中度PAH组、重度PAH组；重度PAH组又分为动力型亚组、艾森曼格综合征前期亚组、艾森曼格综合征亚组；同时收集健康成人作为对照组(n=25)；对20例阻力型患者使用西地那非治疗后随访6个月。采集入选病例所有临床一般情况、心脏彩色超声检查和心导管检查结果，检测血浆ADMA浓度。结果：轻中度PAH组血浆ADMA水平显著高于无PAH组及对照组(均P<0.001)；重度PAH组血浆ADMA水平显著高于无PAH组及对照组(均P<0.001)；无PAH组血浆ADMA水平与对照组无统计学差异(P=0.209)；在重度PAH组中，艾森曼格综合征亚组患者血浆ADMA水平显著高于动力型亚组(P<0.001)；ADMA水平与平均肺动脉压(mPAP)，全肺阻力(PVR)呈显著正相关(r分别为0.61，0.417，P<0.001)；血浆ADMA浓度0.485 µmol/L时诊断CHD合并重度PAH敏感度为92.0%，特异性为82.7%(P<0.001)；20例阻力型PAH患者使用西地那非治疗6个月后，肺动脉压力得到改善(P=0.001)，血浆ADMA水平显著降低(P<0.01)。结论：血浆ADMA水平可作为早期识别CHD-PAH的无创性筛查指标，在一定程度上反映西地那非治疗效果，有望成为CHD-PAH患者重要的随访指标。.

Topics: Adult; Arginine; Biomarkers; Echocardiography; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Prognosis; Sensitivity and Specificity; Sildenafil Citrate

In congenital heart disease, severity of pulmonary hypertension and operability is defined by noninvasive parameters (clinical history, physical examination, and echocardiography) and sometimes, cardiac catheterization. We investigated how circulating levels of inflammatory mediators correlate with such parameters in a young pediatric population (age, 2.0 months to 3.1 years) and the effects of preoperative pulmonary vasodilator therapy with sildenafil. Cytokines were analyzed in serum using chemiluminescence signals. In the whole patient group (n = 47), interleukin 17E, a Th2 immune response mediator increased with increasing age, considered as a parameter of disease severity (R

Topics: Child, Preschool; Cytokines; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Infant; Male; Sildenafil Citrate; Vasodilator Agents

Aim of this study was to investigate the potential effects of sildenafil on the function of endothelial cells from patients with congenital heart disease with pulmonary hypertension (CHDPH). Patients who are diagnosed as CHD with PH (n=30) or without PH (n=30), and 30 healthy persons (control) were enrolled in this study. The 30 CHDPH cases were separated into two groups, one was given aspirin while the other received aspirin and sildenafil. An ELISA assay was used to detect the biological indexes for endothelial cells. Furthermore, 24 male New Zealand white rabbits were used to construct the CHDPH model. The signal pathway-related protein expression was analyzed using RT-PCR and western blotting. Compared to that in healthy people, levels for flowmediated dilatation (FDM), NO, and adiponectin (APN) were significantly decreased while endothelin (ET-1) was significantly increased in CHD patients, while their levels were drastically changed in CHDPH patients (P<0.01). Besides, no significant differences for expression levels including FDM, APN, NO, and ET-1 was observed in CHDPH patients receiving aspirin. But the levels for FDM, APN, NO, and ET-1 were significantly changed in CHDPH patients after treatment with sildenafil for 3 months (P<0.01). The mRNA and protein levels for JNK1/2, MAPK, and NF-κB were significantly increased in CHDPH rabbits compared to the control (P<0.01), but their levels were significantly suppressed by the sildenafil application compared to the CHDPH group (P<0.01). Taken together, our study suggested that sildenafil may play a protective role on endothelial function via suppressing the JNK and NF-κB signal pathways in CHDPH patients.

Topics: Adiponectin; Animals; Aspirin; Endothelial Cells; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Healthy Volunteers; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; NF-kappa B; Nitric Oxide; Platelet Aggregation Inhibitors; Rabbits; Signal Transduction; Sildenafil Citrate; Vasodilation; Vasodilator Agents

This study aims to compare the lifetime costs and health outcomes of both first-line and sequential combination treatments with standard treatment for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) (PAH-CHD) patients.. A cost-utility analysis was performed using a Markov model based on a societal perspective. One-way and probabilistic sensitivity analyses were performed to investigate the effect of parameter uncertainty.. As first-line treatments, both beraprost (incremental cost-effectiveness ratio (ICER) = 192,752 and 201,308 Thai baht (THB) per quality-adjusted life year (QALY) gained) and sildenafil (ICER = 249,770 and 226,802 THB per QALY gained) seemed cost-effective for PAH-CHD patients aged ≤30 years in functional classes II and III, respectively, while no treatment was cost-effective for the sequential combination therapy.. Sildenafil should be included in the National Drug List of Essential Medicines as the first-line treatment for PAH-CHD, and its price per dose should be negotiated to be reduced by 43-57%.

Topics: Adult; Budgets; Cost-Benefit Analysis; Drug Costs; Drugs, Essential; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Markov Chains; Quality-Adjusted Life Years; Sildenafil Citrate; Thailand; Vasodilator Agents

This study investigated the potential value of serum high mobility group box-1 (HMGB1) level in the diagnosis, staging and treatment response of patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD).. This was a single-center prospective study in 106 CHD patients. Serum HMGB1 levels were measured by enzymelinked immunosorbent assay. HMGB1 levels were significantly increased in patients with PAH compared to patients without PAH (P<0.01) and healthy controls (P<0.001). HMGB1 levels significantly correlated with pulmonary arterial pressure (P<0.001) and pulmonary vascular resistance (PVR) (P<0.001). In patients with severe PAH, HMGB1 levels were significantly higher in patients with Eisenmenger syndrome (ES) than in patients exhibiting low PVR (P<0.001). Severe PAH and ES was identified by serum HMGB1 with a cutoff value of 13.62ng/mL (P<0.001) with a specificity of 82.8% and a sensitivity of 90%, and a cutoff value of 21.62ng/mL (P=0.001) with a specificity of 85.2% and a sensitivity of 64.3%, respectively. HMGB1 levels were significantly decreased after sildenafil therapy for 6months (P<0.01).. Our study suggests that serum HMGB1 level may be used as a biomarker to identify PAH in CHD patients, assess pulmonary vascular remodeling, and evaluate the treatment response to sildenafil.

Topics: Adult; Biomarkers; Case-Control Studies; Eisenmenger Complex; Enzyme-Linked Immunosorbent Assay; Female; Heart Defects, Congenital; HMGB1 Protein; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Sensitivity and Specificity; Severity of Illness Index; Sildenafil Citrate; Treatment Outcome; Vascular Resistance; Young Adult

Although mortality is low after the modified Fontan procedure, there is a significant percentage of patients with prolonged postoperative recovery. The objective of this study is to evaluate the usefulness of postoperative administration of oral sildenafil and inhaled nitric oxide on early postoperative outcome. A prospective interventional and comparison study with a historical cohort was conducted. Between January, 2010 and March, 2013, 16 patients received oral sildenafil during immediate modified Fontan postoperative period. Inhaled nitric oxide was also administered if the patient was kept intubated 12 hours after surgery. Early postoperative outcome was compared with a historical cohort of 32 patients on whom the modified Fontan procedure was performed between March, 2000 and December, 2009. Postoperative administration of sildenafil and nitric oxide had no influence on early postoperative outcome after the modified Fontan procedure in terms of duration of pleural effusions, mechanical ventilation time, length of stay in the ICU, and length of hospital stay.

Topics: Child; Child, Preschool; Female; Fontan Procedure; Heart Defects, Congenital; Humans; Male; Nitric Oxide; Postoperative Complications; Postoperative Period; Prospective Studies; Risk Factors; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

This study investigated the clinical value of plasma asymmetrical dimethyl-L-arginine (ADMA) level in the diagnosis, staging, and treatment response in congenital heart disease (CHD) patients with pulmonary arterial hypertension (PAH). This was a single-center prospective observational study in 80 CHD patients. Plasma ADMA levels were measured by enzyme-linked immunosorbent assay. Plasma ADMA levels were significantly increased in CHD patients with PAH compared with CHD patients without PAH (P < 0.01) and healthy controls (P < 0.001). In CHD patients with severe PAH, plasma ADMA levels were significantly higher in patients with Eisenmenger's syndrome (ES) than in patients exhibiting low pulmonary vascular resistance (P < 0.001). The plasma ADMA levels significantly correlated with pulmonary arterial pressure (P < 0.001) and pulmonary vascular resistance (P < 0.001) in patients with CHD. Severe PAH was identified by plasma ADMA with a cutoff value of 0.485 μmol/L (P < 0.001) with a specificity of 82.8 % and a sensitivity of 90 %. ES was identified by plasma ADMA with a cutoff value of 0.85 μmol/L (P < 0.05) with a specificity of 85.2 % and a sensitivity of 64.3 %. ADMA levels were significantly decreased after sildenafil therapy for 6 months compared with before therapy levels (0.91 ± 0.22 vs. 0.57 ± 0.30, P < 0.01). Our study suggests that plasma ADMA level may be used as a biomarker for identifying PAH in patients with CHD, assessing pulmonary vascular remodeling, and evaluating the treatment response of CHD patients with PAH to sildenafil.

Topics: Adult; Arginine; Biomarkers; Female; Follow-Up Studies; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Pulmonary Artery; Sildenafil Citrate; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Young Adult

Pulmonary arterial hypertension is a severe disease with a complex pathogenesis, for which combination therapy is an attractive option.This study aimed to assess the impact of sequential combination therapy on both short-term responses and long-term outcomes in a real-world setting.Patients with idiopathic/heritable pulmonary arterial hypertension, or pulmonary arterial hypertension associated with congenital heart disease or connective tissue disease and who were not meeting treatment goals on either first-line bosentan or sildenafil monotherapy, were given additional sildenafil or bosentan and assessed after 3-4 months. Double combination therapy significantly improved clinical and haemodynamic parameters, independent of aetiology or the order of drug administration. Significant improvements in functional class were observed in patients with idiopathic/heritable pulmonary arterial hypertension. The 1-, 3- and 5-year overall survival estimates were 91%, 69% and 59%, respectively. Patients with pulmonary arterial hypertension associated with connective tissue disease had significantly poorer survival rates compared to other aetiologies (p<0.003).The favourable short-term haemodynamic results and good survival rates, observed in patients receiving both bosentan and sildenafil, supports the use of sequential combination therapy in patients failing on monotherapy in a real-world setting.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Bosentan; Cause of Death; Child; Connective Tissue Diseases; Drug Therapy, Combination; Exercise Test; Familial Primary Pulmonary Hypertension; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Italy; Kaplan-Meier Estimate; Male; Middle Aged; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Survival Rate; Treatment Outcome; Vasodilator Agents; Young Adult

The objective of this study is to evaluate the safety and tolerability of the pharmacological treatment of pulmonary hypertension in pediatric patients. It is a retrospective, longitudinal, observational study on pediatric patients undergoing treatment with pulmonary targeted therapies. 63 patients were included (51% male), with a median age of 3.4 years (IQR, 3.6 months-10 years) and a median weight 13 kg (IQR, 6-30 kg). Congenital heart disease was the etiology of pulmonary hypertension in the majority of cases (n = 33) and 28 patients were in NYHA functional class III-IV. The most commonly used drug was sildenafil (n = 79, 56%), followed by bosentan (n = 27, 23%), and a combination of both (n = 14, 41%). 34 patients had adverse reactions (54%) with an incidence rate of 1.02 per patient per year. The most commonly reported reactions were gastrointestinal symptoms (22%) and spontaneous erections (22%) in males. Nine severe adverse reactions (10%) occurred, requiring eight treatment withdrawal and one hospital admission. Treatment with targeted therapies for pulmonary hypertension is safe in the pediatric population. Severe ADRs were uncommon both in monotherapy and in combination therapy. Combination therapy was associated with a higher rate of ADRs. We observed similar survival rates in children receiving sildenafil doses according to the European Medicines Agency (EMA) recommendations or higher.

Topics: Antihypertensive Agents; Bosentan; Child; Child, Preschool; Drug Therapy, Combination; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Longitudinal Studies; Male; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Patients with Fontan circulation have reduced exercise capacity. The absence of a presystemic pump may limit flow through the pulmonary circulation, restricting ventricular filling and cardiac output. We evaluated exercise hemodynamics and the effect of sildenafil on exercise hemodynamics in Fontan patients.. Ten Fontan patients (6 men, 20±4 years) underwent cardiac magnetic resonance imaging at rest and during supine bicycle exercise before and after sildenafil. Systemic ventricular volumes were obtained at rest and during low- (34±15 W), moderate- (69±29 W), and high-intensity (97±36 W) exercise using an ungated, free-breathing cardiac magnetic resonance sequence and analyzed correcting for cardiac phase and respiratory translation. Radial and pulmonary artery pressures and cGMP were measured. Before sildenafil, cardiac index increased throughout exercise (4.0±0.9, 5.9±1.1, 7.0±1.6, 7.4±1.7 L/(min·m(2)); P<0.0001) with 106±49% increase in heart rate. Stroke volume index (P=0.015) and end-diastolic volume index (P=0.001) decreased during exercise. End-systolic volume index remained unchanged (P=0.8). Total pulmonary resistance index (P=0.005) increased, whereas systemic vascular resistance index decreased during exercise (P<0.0001). Sildenafil increased cardiac index (P<0.0001) and stroke volume index (P=0.003), especially at high-intensity exercise (interaction P=0.004 and P=0.003, respectively). Systemic vascular resistance index was reduced (P<0.0001-interaction P=0.1), whereas total pulmonary resistance index was reduced at rest and reduced further during exercise (P=0.008-interaction P=0.029). cGMP remained unchanged before sildenafil (P=0.9), whereas it increased significantly after sildenafil (P=0.019).. In Fontan patients, sildenafil improved cardiac index during exercise with a decrease in total pulmonary resistance index and an increase in stroke volume index. This implies that pulmonary vasculature represents a physiological limitation, which can be attenuated by sildenafil, the clinical significance of which warrants further study.

Topics: Cardiac Catheterization; Exercise; Exercise Test; Female; Fontan Procedure; Heart Defects, Congenital; Heart Ventricles; Hemodynamics; Humans; Magnetic Resonance Imaging, Cine; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Young Adult

Pulmonary hypertension is a progressive disease of diverse origin with devastating consequences in adults as well as in children. The phosphodiesterase 5 inhibitor sildenafil successfully lowers pulmonary vascular resistance. However, because of its poor enteral absorption, resulting in ineffective plasma concentrations, responses in infants and children are often erratic.. We report the cases of two Caucasian boys, one born at term (case 1) and one aged 2.5 years (case 2), who had structural cardiac and pulmonary defects accompanied by symptomatic pulmonary hypertension. They received sildenafil enterally and sublingually and also intravenously in one of them. Plasma samples were taken at various time points to determine the plasma concentrations of sildenafil and its partially active metabolite. Sildenafil and N-desmethyl sildenafil were quantified using a validated liquid chromatography/mass spectrometry method. Oxygen partial pressure was determined from routine arterial blood gas samples.. In agreement with previous observations in adults, we found that sublingual sildenafil was more extensively absorbed in our two pediatric patients. After sublingual administration, sildenafil plasma concentrations increased by 314% to 361% compared to enteral dosing. Concurrently, the metabolic ratio increased, suggesting not only that the overall absorption was enhanced but also that first-pass metabolism was partially bypassed. In case 2, the free fraction of sildenafil was 0.9%, which is considerably less than in adults (4%), suggesting that, in case 2, higher plasma concentration would have been needed to achieve effects similar to those in adults. Sublingual sildenafil appears to be a promising alternative route of administration in children with poor enteral absorption.

Topics: Administration, Sublingual; Biological Availability; Child, Preschool; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant, Newborn; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

We report a case of posterior non-arteritic ischaemic optic neuropathy (NAION) causing bilateral visual loss in a 7-month-old female infant, after a therapeutic course with sildenafil, a phosphodiesterase type 5 inhibitors (PDE5i). The patient was affected by a complex cyanotic congenital heart defect and had undergone cavopulmonary anastomosis (Glenn operation) 3 months ago. After 2 months of recurring chylothorax, a course of oral sildenafil was administered, with the hypothesis that pulmonary vascular resistances were increased. Approximately 4 weeks later the acute onset of visual worsening and poor pupillary light reflex prompted the diagnosis of posterior NAION. Despite a rapid cessation of PDE5i and systemic treatment with corticosteroids, no visual recovery was noticed at 2-year follow-up. NAION has been associated with PDE5i therapy in adults, but to the best of our knowledge it is almost unheard of in children. We suggest close monitoring of visual function in children undergoing treatment with sildenafil.

Topics: Acute Disease; Blindness; Diagnosis, Differential; Female; Follow-Up Studies; Heart Defects, Congenital; Humans; Infant; Magnetic Resonance Imaging; Optic Neuropathy, Ischemic; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Visual Acuity

Study of pulmonary hypertension (PAH) during pregnancy has characteristics of the high risk factors for patient death and its clinical characteristics.. Death in patients with clinical data was collected from January 2006 to October 2013 in Beijing Anzhen Hospital Affiliated to Capital Medical University treated 8 cases of pregnancy complicated with PAH in hospital. According to the mechanism of PAH patients will be divided into two categories, Idiopathic pulmonary arterial hypertension (IPAH) in 4 cases, 4 cases of secondary PAH [are secondary to congenital heart disease, also known as congenital heart disease associated PAH (CHD-PAH)]. Analyze the clinical features of 8 cases of patients and pregnancy outcome.. (1) In 8 patients, 4 cases were IPAH, none of them with primary diseases, and they were complicated with severe tricuspid regurgitation. 4 cases were CHD-PAH, all with Eisenmenger's syndrome. 8 patients were not preconception counseling and regular prenatal examination. (2) The pregestational cardiac function of 8 cases was grade I-II, and it was grade III-IV on admission. The estimation pressure (sPAP) of pulmonary artery systolic by echocardiography was 101 mmHg (1 mmHg = 0.133 kPa). In 8 patients, 7 cases were in pregnancy 27 weeks and beyond for treatment since the clinical symptoms increased, 1 case of pregnant 18 weeks for treatment caused by the increased clinical symptoms. (3) In 8 patients, 1 patient with CHD- PAH secondary to patent ductus arteriosus, its sPAP was 170 mmHg, dead at 12 hours after admission; the remaining 7 cases termination with cesarean section. 4 patients with IPAH were continuous epidural anesthesia, including 1 case for the intraoperative PAH crisis and respiratory and cardiac arrest with general anesthesia, 3 cases of CHD- PAH patients in 1 case with continuous epidural anesthesia, 2 cases of general anesthesia.(4) In 8 patients, 7 cases of median death time were 3 days after delivery, including 4 cases of IPAH patients death for 2.5 days after delivery; the causes of death were PAH crisis and heart failure. Time of death in 4 cases of CHD-PAH, 1 case was dead at 12 hours after admissions, the remaining 3 cases median death time were 13 days after delivery; the death causes for 4 cases of CHD-PAH were PAH crisis and multiple organ failure. (5) In 8 patients, 1 patient with CHD-PAH secondary to patent ductus arteriosus in gestational week 31 stillbirths occur. 1 case of pregnant 19 weeks had treatment of caesarean operation, the remaining 6 cases respectively at 28-30 weeks of gestation live birth, neonatal survival. (6) Before delivery, 4 cases of IPAH and 3 cases of CHD-PAH patients treated with alprostadil, iloprost, sildenafil, reduction of pulmonary artery pressure treatment, 1 case of CHD-PAH patient was dead after 12 hours in hospital, no drug treatment.. (1) PAH in patients need for consultation prior to conception, pregnancy must conduct regular prenatal examination, symptoms occur during pregnancy, the cardiac function was significantly decreased, and no improvement of drug treatment should be early terminated the pregnancy. (2) Compared with the pregnant women with CHD- PAH, faster progress and poor prognosis in patients with IPAH disease. (3)The patients during cesarean operation or intrapartumare easy to cause PAH crisis and heart failure or multiple organ failure. Taking active measures to maintain stability of hemodynamics is the key to prevent the occurrence of death of pregnant women with PAH.

Topics: Anesthesia, General; Cesarean Section; Delivery, Obstetric; Echocardiography; Familial Primary Pulmonary Hypertension; Female; Gestational Age; Heart Defects, Congenital; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Maternal Mortality; Piperazines; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy Outcome; Pulmonary Artery; Purines; Risk Factors; Sildenafil Citrate; Sulfonamides

New evidence of increased phosphodiesterase-5 (PDE-5) in hypertrophied human myocardium suggests that sildenafil, a selective PDE-5 inhibitor, may improve muscle contraction and therefore improve ventricular function. The purpose of this study was to compare ventricular function as assessed by echocardiography in 10 surgically palliated single-ventricle patients at baseline and again after a single dose of sildenafil. The velocity time integral of the ventricular outflow tract was increased 2 h after sildenafil administration (p = 0.01), thus suggesting an improvement in cardiac output.

Topics: Administration, Oral; Child; Child, Preschool; Dose-Response Relationship, Drug; Echocardiography; Female; Follow-Up Studies; Heart Defects, Congenital; Heart Ventricles; Humans; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Ventricular Function

A 1-year-old boy who had left isomerism and corrected transposition of the great arteries (c-TGA) with moderate-sized ventricular septal defect, severe pulmonary artery hypertension (PAH), and pulmonary vascular disease with significant right-to-left shunting received a diagnosis of type 2 Abernethy malformation, which was partly responsible for disproportionate PAH in the child. The malformation was treated by plugging of the portosystemic shunt. Follow-up cardiac catheterization on sildenafil demonstrated significant left-to-right shunting (2.16:1) and a fall in pulmonary vascular resistance, making surgical correction possible. This case highlights the importance of searching for additional rare causes of PAH in patients with congenital heart diseases when the degree of pulmonary hypertension is disproportional to the defect size.

Topics: Abnormalities, Multiple; Cardiac Catheterization; Cardiac Surgical Procedures; Disease Progression; Familial Primary Pulmonary Hypertension; Heart Defects, Congenital; Heterotaxy Syndrome; Humans; Hypertension, Pulmonary; Infant; Male; Piperazines; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Topics: Child; Child, Preschool; Fontan Procedure; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Wedge Pressure; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Good status of pulmonary perfusion is essential for a successful outcome after the Fontan procedure. Increased pulmonary pressure and vascular resistance, small size of the pulmonary arteries, and significant branch stenoses reflect some of the main problems causing failing Fontan circulation. Here we report a child who underwent a staged Fontan procedure with subsequent subtotal loss of the left-sided pulmonary perfusion, although branch stenosis was successfully treated by stent implantation. Oral sildenafil caused restoration of the capillary vascular bed, improved left-sided lung perfusion, and resulted in significant clinical benefit.

Topics: Capillaries; Child, Preschool; Fontan Procedure; Heart Defects, Congenital; Humans; Lung; Male; Microcirculation; Piperazines; Pulmonary Circulation; Pulsatile Flow; Purines; Sildenafil Citrate; Sulfones; Vascular Diseases; Vasodilator Agents

An additional source of pulmonary blood flow in a patient with bidirectional Glenn procedure (BGD) may cause elevation of mean pulmonary artery pressure (MPAP), precluding safe completion of the Fontan operation. We present a case of single ventricle physiology after pulmonary artery banding (PAB) and Glenn procedure. At the age of six years, cardiac catheterisation revealed in the patient elevated MPAP (22 mm Hg). The PAB was closed through the right internal jugular vein with an Amplatzer Atrial Septal Occluder. After the procedure, MPAP remained at a similar level. Sildenafil oral therapy was applied for six months. Subsequent heart catheterisation confirmed complete closure of PAB and decrease of MPAP to 10 mm Hg. The abovementioned complex treatment of elevated MPAP pressure in a child after Glenn therapy allowed safe completion of the Fontan operation.

Topics: Cardiac Catheterization; Child; Fontan Procedure; Heart Atria; Heart Defects, Congenital; Humans; Male; Piperazines; Pulmonary Artery; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension associated with pediatric congenital heart defects is a major cause of postoperative morbidity and death. Sildenafil has been combined with inhaled nitric oxide to treat pulmonary hypertension. We retrospectively studied the pre- and postoperative effects of oral sildenafil as monotherapy in children with pulmonary hypertension who underwent surgery to correct congenital cardiac defects. From September 2005 through November 2009, 38 children with moderate-to-severe pulmonary arterial hypertension (pulmonary arterial/aortic pressure ratio, >0.7) underwent cardiac surgery at our institution. Fifteen patients were given sildenafil (0.35 mg/kg, every 4 hr) orally or through nasogastric tubes 1 week before and 1 week after surgery. Twenty-three patients of comparable medical status were given sildenafil only upon the institution of cardiopulmonary bypass and for 1 week after surgery. Postoperatively, the 15 patients who were given preoperative sildenafil had significantly lower mean pulmonary arterial pressures (25.6 ± 3.1 vs. 30.4 ± 5.7 mmHg; P = 0.005) and pulmonary arterial/aortic pressure ratios (0.35 ± 0.05 vs. 0.42 ± 0.07; P = 0.002) than did the other 23 patients. The preoperative therapy also shortened cardiopulmonary bypass time, mechanical ventilation time, and lengths of intensive care unit and hospital stays. No sildenafil-related hypertensive crises or sequelae occurred. As monotherapy, oral sildenafil in low doses appears to control pulmonary hypertension safely and effectively in children undergoing operations to correct congenital heart defects, particularly when it is given both preoperatively and postoperatively. Further study is warranted.

Topics: Administration, Oral; Antihypertensive Agents; Blood Pressure; Cardiac Surgical Procedures; Cardiopulmonary Bypass; Child, Preschool; Drug Administration Schedule; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Intensive Care Units; Italy; Length of Stay; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Respiration, Artificial; Retrospective Studies; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Vasodilator Agents

We sought to determine the efficacy of postoperative oral sildenafil therapy (OST) in pediatric patients with congenital heart disease (CHD). A retrospective review of 45 postoperative patients with CHD who received OST was performed. Patients were categorized into three groups according to clinical indications: (1) to stabilize pulmonary vascular reactivity after biventricular repair (group 1 [n = 15]), (2) to lower pulmonary vascular resistance after bidirectional cavopulmonary shunt (group 2 [n = 12]), and (3) to improve post-Fontan hemodynamics (group 3 [n = 18]). Thirty-four patients (34 of 45 [75.6%]) had received inhaled nitric oxide (iNO) while on OST. Mean pulmonary arterial pressure (mPAP), mean systemic blood pressure (mSBP), and peripheral oxygen saturation (SpO(2)) were recorded during the first 24 hours after the initiation of OST. In group 1, the baseline mPAP/mSBP ratio (0.60 +/- 0.17) decreased significantly after the second (0.46 +/- 0.14, p = 0.004) and fourth (0.50 +/- 0.18, p = 0.025) doses of OST. In group 2, baseline SpO(2) (71.0 +/- 12.3%) increased after the fourth dose (75.1 +/- 12.3%, p = 0.04) of OST, without significant changes in mPAP. In group 3, baseline mPAP (14.8 +/- 3.3 mmHg) decreased significantly after the first (13.9 +/- 2.8 mmHg, p = 0.025) and second (13.3 +/- 1.9 mmHg, p = 0.016) doses of OST, without changes in SpO(2). In thirty-one (31 of 34 [92%]) subjects, iNO was discontinued within a median of 2 days after the initiation of OST, without rebound phenomena. There were no OST-related complications. Sildenafil citrate can be used safely in postoperative pediatric patients with CHD. Benefits from OST may be manifested differently in various clinical settings.

Topics: Administration, Inhalation; Administration, Oral; Adolescent; Blood Pressure; Child; Child, Preschool; Drug Therapy, Combination; Female; Heart Defects, Congenital; Hemodynamics; Humans; Infant; Infant, Newborn; Male; Nitric Oxide; Oxygen; Piperazines; Postoperative Complications; Pulmonary Artery; Pulmonary Wedge Pressure; Purines; Retrospective Studies; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

A retrospective study of the UK Pulmonary Hypertension Service for Children for the first 5-year period of its existence.. Records of 216 children with idiopathic pulmonary arterial hypertension (IPAH) and associated pulmonary arterial hypertension (APAH) were reviewed. Kaplan-Meier survival curves were constructed for different diagnostic groups and for different therapies.. At cardiac catheterisation only 7.4% of those with IPAH and 6% of those with APAH responded positively to vasodilator testing and so were treated with nifedipine. Others needing treatment were given continuous intravenous epoprostenol, bosentan or sildenafil singly or in combination. For IPAH survival rates were 85.6%, 79.9% and 71.9% at 1, 3 and 5 years, respectively, compared with a survival time of less than a year in historical untreated controls. A combination of intravenous epoprostenol with either bosentan or sildenafil, or both, appeared to achieve the best outcome. Six children underwent lung transplantation. In APAH survival rates were 92.3%, 83.8% and 56.9% at 1, 3 and 5 years, respectively, postoperative congenital heart disease with severe pulmonary hypertension having the worst outcome.. New pulmonary hypertension-specific medicines have improved survival in children as in adults. Outcome in this series compares favourably with international outcome data.

Topics: Adolescent; Bosentan; Case-Control Studies; Child; Child, Preschool; Epoprostenol; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Kaplan-Meier Estimate; Lung Transplantation; Male; Nifedipine; Piperazines; Purines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Sulfones; Survival Rate; United Kingdom; Vasodilator Agents

Pulmonary arterial hypertension is a rare disorder in childhood, the two most common types being idiopathic pulmonary arterial hypertension and pulmonary hypertension associated with congenital left-to-right shunt lesions, together accounting for almost 90% of cases.. The clinical presentation of idiopathic pulmonary arterial hypertension (familial and non familial) is essentially non-specific and varies with age. Pulmonary vasoreactivity testing identifies responders and non-responders. Responders are treated with calcium channel blockers and have a better prognosis. Non-responders have a very limited survival beyond diagnosis if not treated with more selective pulmonary arterial vasodilators. Prostacyclin, endothelin receptor antagonists and phosphodiesterase-5 inhibitors improve haemodynamics, functional class and exercise tolerance and delay deterioration. Patients with congenital left-to-right shunts and irreversible pulmonary arterial hypertension leading to Eisenmenger's syndrome have multiple organ disease. Despite a very pronounced exercise intolerance, their clinical course is rather stable with survival up to 40-60 years, depending on the complexity of their underlying cardiac defect. Treatment is based on general measures along with the same three types of selective pulmonary vasodilators as in idiopathic pulmonary arterial disease. Improvement in haemodynamics, functional class and exercise tolerance are comparable for both patient groups.. Pulmonary hypertension in children is idiopathic or associated with congenital heart disease in the majority of patients. Treatment with new selective pulmonary vasodilators offers haemodynamic and functional improvement.

Topics: Activin Receptors, Type II; Antigens, CD; Antihypertensive Agents; Bone Morphogenetic Protein Receptors, Type II; Bosentan; Calcium Channel Blockers; Child; Electrocardiography; Endoglin; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Incidence; Piperazines; Point Mutation; Prevalence; Purines; Receptors, Cell Surface; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

This report deals with a 28-year-old male patient, admitted with a type A aortic dissection, potentially related to the use of sildenafil. In the literature, we found only two other potentially sildenafil-related cases of aortic dissections, one type A and one type B. In our patient, a bicuspid aortic valve and an ascending aortic aneurysm were other underlying anomalies that could have led to the aortic dissection.

Topics: Adult; Aortic Aneurysm; Aortic Dissection; Aortic Valve; Aortography; Heart Defects, Congenital; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Substance-Related Disorders; Sulfones; Tomography, X-Ray Computed; Treatment Outcome; Vascular Surgical Procedures

Topics: Administration, Oral; Blood Gas Analysis; Follow-Up Studies; Heart Bypass, Right; Heart Defects, Congenital; Humans; Piperazines; Postoperative Care; Pulmonary Circulation; Pulmonary Gas Exchange; Purines; Risk Assessment; Sildenafil Citrate; Sulfones; Treatment Outcome; Vasodilator Agents

Topics: Abnormalities, Multiple; Arteriovenous Fistula; Cardiac Catheterization; Child, Preschool; Endothelium-Dependent Relaxing Factors; Female; Follow-Up Studies; Heart Bypass, Right; Heart Defects, Congenital; Humans; Hypoxia; Nitric Oxide; Piperazines; Postoperative Complications; Pulmonary Artery; Purines; Radiography; Risk Assessment; Sildenafil Citrate; Sulfones; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Sildenafil (Viagra, Pfizer) is being increasingly used to treat pulmonary hypertension in children. However, there are limited data available to suggest dosage regimens. The purpose of this study was to determine the effects of escalating doses of sildenafil on hemodynamics and gas exchange in children with pulmonary hypertension because of congenital cardiac defects.. Prospective, observational study.. Pediatric intensive care unit in a tertiary care children's hospital.. Ten children with pulmonary hypertension because of congenital cardiac defects who were in the intensive care unit and on nitric oxide after cardiac surgery.. Patients received sildenafil every 4 hours via a gastric tube in incremental doses of 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, and 2.0 mg/kg along with nitric oxide during their stay in the intensive care unit until they were extubated. Hemodynamic and arterial blood gas measurements were taken before (baseline) and 60 minutes after the administration of sildenafil.. All doses of sildenafil caused significant reduction in pulmonary artery pressure with no significant effect on systemic arterial and central venous pressures. Arterial partial pressure of oxygen was decreased after a 2.0 mg/kg dose of sildenafil but not significantly. No significant differences were found among the 4 doses.. For the treatment of pulmonary hypertension in children with congenital cardiac defects, a 0.5 mg/kg dose of sildenafil every 4 hours is therapeutically as effective as a 2.0 mg/kg dose every 4 hours. However, a large dose-ranging and pharmacokinetic study of sildenafil in children with pulmonary hypertension because of congenital cardiac defects is needed to validate the safety and efficacy of the dose-range and dosing interval suggested by this study.

Topics: Analysis of Variance; Blood Gas Analysis; Bronchodilator Agents; Cardiac Surgical Procedures; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Heart Defects, Congenital; Heart Rate; Humans; Hypertension, Pulmonary; Male; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Purines; Research Design; Sildenafil Citrate; Sulfones; Treatment Outcome; United Kingdom; Vasodilator Agents

Topics: Anti-Anxiety Agents; Attention Deficit and Disruptive Behavior Disorders; Child; Comorbidity; Diagnosis, Differential; Dose-Response Relationship, Drug; Down Syndrome; Heart Defects, Congenital; Hospitalization; Humans; Hypertension, Pulmonary; Lorazepam; Male; Oxygen Inhalation Therapy; Piperazines; Pulmonary Disease, Chronic Obstructive; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

We report a case of successful administration of oral sildenafil (ie, a phosphodiesterase-5 inhibitor) in an infant for impaired pulmonary circulation that caused early clinical deterioration after a bicavopulmonary shunt. The transpulmonary pressure gradient (ie, a clinical indicator of pulmonary circulation) was initially normalized by inhaled nitric oxide; however, an increase in transpulmonary pressure gradient and oxygen desaturation occurred after extubation and discontinuation of inhaled nitric oxide on postoperative day 1. Subsequent administration of oral sildenafil in stepwise doses resulted in normalization of transpulmonary pressure gradient and improved oxygen saturation with successful discontinuation of intravenous vasodilators. Our results suggest that oral sildenafil may be a potent adjunctive therapy for impaired postoperative pulmonary circulation after right heart bypass surgery.

Topics: Administration, Oral; Heart Bypass, Right; Heart Defects, Congenital; Humans; Infant; Male; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vascular Diseases; Vasodilator Agents

We describe successful use of enteral sildenafil following surgery for congenital heart disease in three cases. One infant after repair of ventricular septal defect and aortic coarctation had pulmonary hypertension non-responsive to nitric oxide, another infant and 3.5 year child following palliative surgery for congenital heart disease with univentricular physiology were treated with inhaled nitric oxide and had severe systemic desaturations associated with endotracheal suctioning. Therapy with sildenafil reduced pulmonary arterial pressure, prevented episodes of arterial desaturations and allowed weaning from nitric oxide (Ref. 7). Full Text (Free, PDF) www.bmj.sk

Topics: Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Infant; Phosphodiesterase Inhibitors; Piperazines; Postoperative Complications; Purines; Sildenafil Citrate; Sulfones; Vascular Resistance; Vasodilator Agents

Skeletal manifestations are the hallmark of the osteogenesis imperfecta group of disorders. Extraskeletal involvement may, however, contribute significantly to morbidity. Structural cardiovascular anomalies reported in osteogenesis imperfecta include aortic root dilatation and aortic and mitral valve dysfunction. Herein is reported the first case of involvement of the right side of the heart in osteogenesis imperfecta.

Topics: Endothelium-Dependent Relaxing Factors; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Infant, Newborn; Length of Stay; Nitric Oxide; Osteogenesis Imperfecta; Patient Discharge; Piperazines; Purines; Radiography, Thoracic; Sildenafil Citrate; Sulfones; Treatment Outcome; Tricuspid Valve; Ultrasonography; Vasodilator Agents

New oral substances such as beraprost, bosentan and sildenafil have proven effective in different forms of pulmonary arterial hypertension (PAH), both alone and in combination with standard treatment such as intravenous and inhaled prostacyclins. However, there are few reports so far on the effect of a combination of exclusively oral substances. In this paper, we present our initial findings of treatment using a combination of these oral substances in a heterogeneous group of patients with different forms of PAH.. Eleven patients with a median age of 12.9 years (5.5-54.7 years) with both idiopathic PAH and forms associated with congenital cardiac defects (PAH-CHD) with a mean pulmonary arterial pressure > 25 mmHg were enrolled in an observational, open-label, prospective, single-centre study. Either combination treatment with bosentan and sildenafil was started initially, or an existing bosentan treatment was complemented with sildenafil given as an add-on therapy. Mean doses given were 2.3 +/- 0.6 mg kg(-1) for bosentan and 2.1 +/- 0.9 mg kg(-1) for sildenafil. Clinical status, exercise capacity, and haemodynamics were assessed at baseline and at the end of the observation period after a mean follow-up time of 1.1 years (0.5-2.5 years).. No major side effects regarding liver function and blood pressure regulation were noted. One patient died of sudden death elsewhere. Most patients were in New York Heart Association (NYHA) functional class III. Clinical improvement was about one NYHA class (mean 2.8 +/- 0.4-1.6 +/- 0.8, P = 0.001), which was associated with an increase of transcutaneous oxygen saturation (89.9 +/- 9.9-92.3 +/- 7.1%; P = 0.037), maximum oxygen uptake (18.1 +/- 6.8-22.8 +/- 10.4 mL kg(-1) x min; P = 0.043), and 6-minute walking distance (351 +/- 58-451 +/- 119 m; P = 0.039). Mean pulmonary arterial pressure measured invasively decreased (62 +/- 12-46 +/- 18 mmHg; P = 0.041).. In our patient group, a combination of oral bosentan and sildenafil proved to be safe and effective. Clearly, randomized, double-blind, placebo-controlled studies are warranted to define the role and type of combination therapies in PAH.

Topics: Administration, Oral; Adolescent; Adult; Antihypertensive Agents; Bosentan; Child; Child, Preschool; Drug Therapy, Combination; Endothelin Receptor Antagonists; Exercise Test; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome