Long-term efficacy of bosentan in treatment of pulmonary arterial hypertension in children.

The aim of the present study was to evaluate a 5-yr experience of bosentan in children with pulmonary arterial hypertension (PAH). A retrospective, observational study was made of children in the UK Pulmonary Hypertension Service for Children (Great Ormond Street Hospital for Children, London, UK) who were given bosentan as monotherapy or in combination, from February 2002 to May 2008 and followed up for ≥ 6 months. Detailed studies were made of 101 children with idiopathic PAH (IPAH) (n = 42) and PAH associated with congenital heart disease (n = 59). Before treatment, World Health Organization (WHO) functional class, 6-min walk distance (6MWD), height, weight and haemodynamic data were determined. Evaluations were analysed after 6 months and annually to a maximum of 5 yrs. Median duration of treatment was 31.5 months. Initial improvement in WHO functional class and 6MWD was maintained for up to 3 yrs. Height and weight increased but the z-scores did not improve. After 3 yrs, bosentan was continued as monotherapy in only 21% of children with IPAH, but in 69% of repaired cases and 56% of those with Eisenmenger syndrome. The Kaplan-Meier survival estimates for the 101 patients were 96, 89, 83 and 60% at 1, 2, 3 and 5 yrs, respectively. A treatment regime that includes bosentan is safe and appears to be effective in slowing disease progression in children with PAH.

Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension).

BACKGROUND: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. METHODS AND RESULTS: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 12 mmHg and pulmonary vascular resistance index [PVRI] of >3 WU × m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p=0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU × m(2,) 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p<0.001). CONCLUSION: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional class.

L-arginine and substance P reverse the pulmonary endothelial dysfunction caused by congenital heart surgery.

BACKGROUND: The increase in pulmonary vascular resistance (PVR) seen in children after cardiopulmonary bypass has been attributed to transient pulmonary endothelial dysfunction (PED). We therefore examined PED in children with congenital heart disease by assessing the L-arginine-nitric oxide (NO) pathway in terms of substrate supplementation (L-arginine [L-Arg]), stimulation of endogenous NO release (substance P [Sub-P]), and end-product provision (inhaled NO) before and after open heart surgery. METHODS AND RESULTS: Ten patients (aged 0.62+/-0.27 years) with pulmonary hypertension undergoing cardiac catheterization who had not had surgery and 10 patients (aged 0.65+/-0.73 years) who had recently undergone cardiopulmonary bypass were examined. All were sedated and paralyzed and received positive-pressure ventilation. Blood samples and pressure measurements were taken from catheters in the pulmonary artery and the pulmonary vein or left atrium. Respiratory mass spectrometry was used to measure oxygen uptake, and cardiac output was determined by the direct Fick method. PVR was calculated during steady state at ventilation with room air, during FIO(2) of 0.65, then during additional intravenous infusion of L-Arg (15 mg. kg(-1). min(-1)) and Sub-P (1 pmol. kg(-1). min(-1)), and finally during inhalation of NO (20 ppm). In preoperative patients, the lack of an additional significant change of PVR with L-Arg, Sub-P, and inhaled NO suggests little preexisting PED. Postoperative PVR was higher, with an additional pulmonary endothelial contribution that was restorable with L-Arg and Sub-P. CONCLUSIONS: Postoperatively, the rise in PVR suggested PED, which was restorable by L-Arg and Sub-P, with no additional effect of inhaled NO. These results may indicate important new treatment strategies for these patients.

Severe airflow limitation after the unifocalization procedure: clinical and morphological correlates.

BACKGROUND: While unifocalization techniques have improved the treatment options in patients with pulmonary atresia, ventricular septal defect (PA-VSD), and major aortopulmonary collaterals (MAPCAs), severe airflow limitation contributes to significant early postoperative morbidity and mortality. Although this has been attributed to bronchospasm, characteristically it is refractory to bronchodilators, suggesting that other mechanisms may play a role. METHODS AND RESULTS: The clinical course and preoperative angiograms of patients who underwent unifocalization were reviewed. Patients who developed airflow limitation early after surgery underwent fiberoptic bronchoscopy. In addition, the anatomy of the MAPCAs was examined in 14 heart-lung blocks from patients with PA-VSD. Twenty-two procedures were performed in 16 children. Three developed marked airflow limitation early after surgery, necessitating prolonged high-pressure ventilation. Bronchoscopy demonstrated tracheobronchial epithelial necrosis in 2 and signs of tracheobronchial ischemia in the third. Two were successfully extubated after 15 and 16 days, but the third died after 57 days of ventilatory support. Review of the preoperative angiograms demonstrated an extensive peribronchial arterial supply arising from a MAPCA in 1 of the patients who developed severe airway necrosis after unifocalization. This was also obvious in a second patient, but the MAPCA was not included in the unifocalization. In 7 autopsy specimens, MAPCAs contributed to a peribronchial or peritracheal vascular network. Dissection of the distribution of these branches in 2 specimens revealed extensive intrapulmonary peribronchial anastomoses. CONCLUSIONS: Airflow limitation early after unifocalization is related to airway ischemia resulting from interruption of the tracheobronchial blood supply during mobilization of MAPCAs.

Right ventricular function in patients treated with inhaled nitric oxide after cardiac surgery for congenital heart disease in newborns and children.

Measurement of right ventricular (RV) function is essential for complete assessment of the effects of inhaled nitric oxide in the postoperative cardiac patient; nitric oxide therapy can result in a decrease in pulmonary vascular resistance and improved echocardiographic RV ejection fraction without necessarily inducing a significant change in pulmonary artery pressure.

Pulmonary vascular resistance after cardiopulmonary bypass in infants: effect on postoperative recovery.

OBJECTIVE: We sought to define the contemporary clinical effect of increased pulmonary vascular resistance in infants after congenital heart operations with cardiopulmonary bypass. METHODS: Fifteen infants (median age, 0.31 years; median weight, 5.1 kg) underwent cardiac operations involving cardiopulmonary bypass (range, 49-147 minutes). Pulmonary vascular resistance was measured in the immediate postoperative period in the intensive care unit by means of the direct Fick principle, with respiratory mass spectrometry to measure oxygen consumption. The effect of ventilation with an inspired oxygen fraction of 0.65, with additional infusion of L -arginine, substance P, and inhaled nitric oxide, was assessed and subsequently correlated with the length of mechanical ventilation from the end of cardiopulmonary bypass to successful extubation. RESULTS: Overall, pulmonary vascular resistance at baseline (11.7 +/- 5.6 WU. m(2)) could be reduced to a minimum of 6.1 +/- 3.5 WU. m(2). The ventilatory time was 0.86 to 14.9 days (median, 1.75 days) and correlated directly with the lowest pulmonary vascular resistance value achieved during the pulmonary vascular resistance study (r (2) = 0.64, P <.01). The patient subgroup with mechanical ventilation of greater than 2 days had significantly higher pulmonary vascular resistance at all stages of the study protocol, and in this group there was a correlation of cardiopulmonary bypass time and ventilatory support time (r (2) = 0.48, P <.05). CONCLUSION: Increased pulmonary vascular resistance, either directly or as a surrogate of the systemic inflammatory response after cardiopulmonary bypass, continues to have a significant effect on postoperative recovery of infants after cardiac operations.

Oxygen consumption after cardiopulmonary bypass surgery in children: determinants and implications.

OBJECTIVE: We sought to assess oxygen consumption and its determinants in children shortly after undergoing cardiopulmonary bypass operations. METHODS: Twenty children, aged 2 months to 15 years (median, 3.75 years), undergoing hypothermic cardiopulmonary bypass operations were studied during the first 4 hours after arrival in the intensive care unit. Central and peripheral temperatures were monitored. Oxygen consumption was continuously measured by using respiratory mass spectrometry. Oxygen delivery was calculated from oxygen consumption and arterial and mixed venous oxygen contents, which were sampled every 30 minutes. Oxygen extraction was derived by the ratio of oxygen consumption and oxygen delivery. Arterial blood lactate levels were measured every 30 minutes. RESULTS: There was a correlation between oxygen consumption and age in patients older than 3 months (r = -0.76). Mean oxygen consumption increased by 14.7% during the study. The increase in oxygen consumption was correlated with the increase in central temperature (r = 0.73). Nine patients had an arterial lactate level above 2 mmol/L on arrival. There were no significant differences in oxygen consumption, oxygen delivery, and oxygen extraction between the group with lactate levels between 2 and 3 mmol/L and the groups with normal lactate levels both on arrival and at 2 hours. One patient with a peak lactate level of 6.8 mmol/L had initially low oxygen delivery (241.3 mL. min(-1). m(-2)). CONCLUSIONS: During the early hours after a pediatric cardiac operation, the increase in oxygen consumption is mainly attributed to the increase in central temperature. Oxygen consumption is negatively related to age. Mild lactatemia is common and does not appear to reflect oxygen delivery or oxygen consumption or a more complicated recovery.

Negative pressure ventilation as haemodynamic rescue following surgery for congenital heart disease.

A low cardiac output state is an important cause of morbidity and mortality following repair of tetralogy of Fallot (ToF). This is often refractory to conventional measures. The cardiac output of these patients is highly dependent on diastolic pulmonary arterial flow which is enhanced during spontaneous respiration, but much reduced by intermittent positive pressure ventilation (IPPV). We report the successful use of negative pressure ventilation (NPV) as haemodynamic therapy in three children with a low output secondary to restrictive right ventricular (RV) physiology following ToF repair. NPV produced a significant haemodynamic improvement, with increases in cardiac output of greater than 100 % in two of the children. By augmenting pulmonary blood flow, and hence cardiac output, NPV has a role as adjunctive haemodynamic therapy in patients with a low output secondary to diastolic RV dysfunction, in whom early extubation is not possible.

Acute ventilatory restriction in children after weaning off inhaled nitric oxide: relation to rebound pulmonary hypertension.

OBJECTIVE: To assess the interaction between pulmonary hemodynamics and respiratory mechanics during acute pulmonary hypertension. PATIENTS: Ventilated and paralysed children treated with inhaled nitric oxide because of post-operative pulmonary hypertension. INTERVENTIONS: Weaning of inhaled nitric oxide. MEASUREMENTS: Air flow and airway pressure, calculation of dynamic respiratory system compliance and respiratory system resistance for each breath by multiple linear regression. RESULTS: In four patients, increases in pulmonary arterial pressure from 26.1 to 56.7 mm Hg (p<0.001) during weaning off nitric oxide were associated with decreases in tidal volume (from 9.7-->8.2 ml/kg, p<0.01) and reductions in dynamic respiratory system compliance (from 0.52-->0.34 cm H20/ml/kg, p<0.001), while respiratory system resistance was unchanged. CONCLUSIONS: Impaired ventilation during acute pulmonary hypertension is predominantly related to a reduction in respiratory system compliance.

Issues related to the management and therapy of paediatric pulmonary hypertension.

An increasing number of medical services dedicated to the diagnosis, treatment and follow-up of pulmonary hypertension (PH) in children are being established. This has, in turn, increased the need to adapt current guidelines for the treatment of PH to be more relevant to paediatric patients with PH. This article will summarise the data obtained so far from paediatric registries, national cohorts and clinical trials and discuss the best approach for developing a treatment algorithm designed for children with different types of PH. The many unanswered questions, challenges and issues relating to the PH in the paediatric population will also be discussed.

Childhood idiopathic pulmonary arterial hypertension: a national cohort study.

OBJECTIVE: To clarify the clinical characteristics and epidemiology of idiopathic pulmonary arterial hypertension (IPAH) in childhood, a rare condition with a bad prognosis, poorly documented in children. Also, to describe the long-term outcome. DESIGN: A retrospective study of 7 years' experience. SETTING: UK Service for Pulmonary Hypertension in Children based at a tertiary referral centre. PATIENTS: 64 children. INTERVENTIONS: Patients were initially treated with prostanoids (n=15), bosentan (n=23), sildenafil (n=9), combination therapy (n=11) or calcium channel antagonists (n=6). MAIN OUTCOME MEASURES: WHO functional class, distance walked in 6 minutes, escalation of therapy, survival, transplant-free survival. RESULTS: Incidence of IPAH was 0.48 cases per million children per year and the prevalence was 2.1 cases per million. 31% presented with syncope. Oedema was rare. During the first year of follow-up WHO functional class and 6-minute walk distance improved significantly. Survival at 1, 3 and 5 years was 89%, 84% and 75%, respectively; while transplant-free survival was 89% 76% and 57%, respectively. Factors predicting worse survival were WHO functional class (HR 2.4, p=0.04) and poor height and weight z-score (p<0.05 for both) at presentation. CONCLUSIONS: We showed, for the first time, that the incidence of IPAH is lower in children than adults and that the clinical features can be different. Most children present with clinical evidence of advanced disease and clinical status at presentation is predictive of outcome. This 7-year experience confirms the significant improvement in survival over historical controls.

[Pulmonary hypertension and pulmonary circulation in congenital heart disease]. / Pulmonale Hypertonie und pulmonale Zirkulation bei angeborenen Herzfehlern.

Congenital cardiac malformations are often associated with pulmonary hypertension and structural changes of both, the larger and smaller vessels of the pulmonary circulation. Approximately 5 to 10 % of adults with congenital heart disease, surgically treated or untreated, develop pulmonary arterial hypertension of variable severity from mild to severe (Eisenmenger reaction). Until recently, medical treatment options for the affected patients were very limited. Meanwhile, the advent of new pulmonary vasoactive and antiproliferative substances (including endothelin receptor antagonists, phosphodiesterase-5-inhibitors, prostanoids) offer the option to correct abnormalities in pulmonary endothelial function and to improve the outcome of affected patients. Even patients with severe congenital cardiac malformations and Fontan-type circulation or patients with pulmonary atresia and aorto-pulmonary collaterals may benefit from these new treatment strategies. In any case, the complexity of congenital cardiac malformations when associated with abnormalities in the pulmonary circulation and/or pulmonary arterial hypertension, requires medical care and follow-up in specialized centers for (adult) congenital heart disease.

Immediate clinical and haemodynamic benefits of restoration of pulmonary valvar competence in patients with pulmonary hypertension.

OBJECTIVE: To analyse the potential benefit of restoration of pulmonary valvar competence in patients with severe pulmonary regurgitation (PR) and pulmonary hypertension (PH) associated with congenital heart disease. DESIGN: Retrospective study. SETTING: Tertiary paediatric and adult congenital heart cardiac centre. INTERVENTIONS: Percutaneous pulmonary valve implantation (PPVI). PATIENTS: All patients who underwent PPVI for treatment of PR in the presence of PH (mean PAP >25 mm Hg). RESULTS: Seven patients with severe PH as a result of congenital heart disease and severe PR underwent PPVI. The valve implantation procedure was feasible and uncomplicated in all seven cases, successfully abolishing PR. There was a significant increase in diastolic (15.4 (7.3) to 34.0 (8.5) mm Hg; p = 0.007) and mean (29.7 (8.1) to 41.3 (12.9) mm Hg; p = 0.034) pulmonary artery pressures, and an improvement in NYHA functional class (from median IV to median III; p<0.008). Peripheral oxygen saturations rose from 85.9% (11.0%) to 91.7% (8.3%) (p = 0.036). Right ventricular (RV) volumes decreased (from 157.0 (44.7) to 140.3 (53.3) ml/m(2)), while effective RV stroke volume increased (from 23.4 (9.3) to 41.0 (11.6) ml/m(2)). During a median follow-up of 20.3 months (range 1.3-47.5), valvar competence was well maintained despite near systemic pulmonary pressures. None of the valved stents were explanted during follow-up. CONCLUSION: Trans-catheter treatment of PR in patients with PH is well tolerated and leads to clinical and haemodynamic improvement, most probably caused by a combination of increased pulmonary perfusion pressures and RV efficiency.

[Pharmacological treatment of pulmonary hypertension in patients with congenital heart disease]. / Medikamentöse Therapie des Lungenhochdrucks bei Patienten mit angeborenen Herzfehlern.

The development of drugs for lowering pressures in pulmonary arterial hypertension (PHT) has provided possible therapeutic application in patients with pulmonary hypertension associated with congenital heart disease (CHD). Prostanoids, both nonselective and selective endothelin-receptor antagonists and phosphodiesterase-V inhibitors have been used for this purpose. The efficacy of these drugs - from different classes of bioactivity - in this context have been shown in several studies. However, the long-term effects of drug treatment on prognosis and course of PHT have not yet been adequately investigated. The current status of drug treatment of PHT in patients with CHD is reviewed in this article.

[Pulmonary hypertension in congenital heart disease]. / Pulmonalarterielle Hypertonie bei angeborenen Herzfehlern.

The prevalence of pulmonary arterial hypertension (PAH) in congenital heart anomalies is rising, because an increasing proportion of these patients now reach adulthood. However, morbidity and mortality rates in these patients are modified by the existing cardiac anomaly and thus differ from idiopathic pulmonary hypertension (IPAH). There are, in addition to Eisenmenger's syndrome, special forms such as local PAH or hemodynamically relevant increased pulmonary vascular resistance associated with a dysfunctional or absent right ventricle. In all these forms of PAH it is the therapeutic aim to achieve pulmonary vascular dilatation to reduce symptoms of right ventricular stress and to increase pulmonary blood flow and raise systemic oxygen supply. Just as in IPAH, intravenous, inhaled or oral medications--prostanoids, endothelin-receptor inhibitors, phosphodiesterase-5 inhibitors--are being used with increasing success.

First experience with an oral combination therapy using bosentan and sildenafil for pulmonary arterial hypertension.

BACKGROUND: 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. MATERIALS AND METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Magnetic resonance imaging guided catheterisation for assessment of pulmonary vascular resistance: in vivo validation and clinical application in patients with pulmonary hypertension.

OBJECTIVES: To validate in vivo a magnetic resonance imaging (MRI) method for measurement of pulmonary vascular resistance (PVR) and subsequently to apply this technique to patients with pulmonary hypertension (PHT). METHODS AND RESULTS: PVR was assessed from velocity encoded cine MRI derived pulmonary artery (PA) flow volumes and simultaneously determined invasive PA pressures. For pressure measurements flow directed catheters were guided under magnetic resonance fluoroscopy at 1.5 T into the PA. In preliminary validation studies (eight swine) PVR was determined with the thermodilution technique and compared with PVR obtained by MRI (0.9 (0.5) v 1.1 (0.3) Wood units.m2, p = 0.7). Bland-Altman test showed agreement between both methods. Inter-examination variability was high for thermodilution (6.2 (2.2)%) but low for MRI measurements (2.1 (0.3)%). After validation, the MRI method was applied in 10 patients with PHT and five controls. In patients with PHT PVR was measured at baseline and during inhalation of nitric oxide. Compared with the control group, PVR was significantly increased in the PHT group (1.2 (0.8) v 13.1 (5.6) Wood units.m2, p < 0.001) but decreased significantly to 10.3 (4.6) Wood units.m2 during inhalation of nitric oxide (p < 0.05). Inter-examination variability of MRI derived PVR measurements was 2.6 (0.6)%. In all experiments (in vivo and clinical) flow directed catheters were guided successfully into the PA under MRI control. CONCLUSIONS: Guidance of flow directed catheters into the PA is feasible under MRI control. PVR can be determined with high measurement precision with the proposed MRI technique, which is a promising tool to assess PVR in the clinical setting.

Initial experience with bosentan (Tracleer) as treatment for pulmonary arterial hypertension (PAH) due to congenital heart disease in infants and young children.

INTRODUCTION: Bosentan, a dual endothelin-receptor antagonist, has been shown to be an effective treatment option in patients with the idiopathic form of pulmonary arterial hypertension (PAH). We used bosentan as compassionate treatment in infants and young children with congenital heart disease (CHD) who had a) PAH preoperatively representing a contraindication to corrective surgery or b) persisting PAH after corrective surgery causing right heart failure and reduced exercise tolerance. METHODS: Seven children with PAH due to CHD (median age 3.8 years; range 1.5 to 6.4 years) received 3 mg/kg/d bosentan (Tracleer) orally. Clinical, echocardiographic and hemodynamic parameters were measured and laboratory tests performed before treatment and during steady state while on treatment. Routine liver function parameters were monitored monthly. RESULTS: Mean bosentan treatment time was 8.6+/-5 months. During bosentan therapy there were no significant adverse events. The clinical status remained stable or improved in all patients: NYHA class decreased from 2.6+/-0.6 to 1.7+/-0.6 (p<0.05). This was associated with a mean reduction of the right ventricular systolic pressure (RVSP) from 96+/-11 mmHg to 71+/-26 mmHg (p<0.05). CONCLUSIONS: Treatment with bosentan in infants and young children with PAH due to congenital heart disease was tolerated without significant side effects and resulted in stabilization of clinical status. A significant reduction in right ventricular systolic pressure (RVSP) could be demonstrated. These results suggest that the dose regimen used is appropriate and safe for the treatment of infants and children with PAH, resulting in a reduction of pathologically increased pulmonary vascular resistance.