Alison A. Hislop

Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001–2006

Objective: A retrospective study of the UK Pulmonary Hypertension Service for Children for the first 5-year period of its existence. Design and patients: 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. Results: 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. Conclusion: New pulmonary hypertension-specific medicines have improved survival in children as in adults. Outcome in this series compares favourably with international outcome data.

The 6-minute walk test: normal values for children of 4–11 years of age

Objective: The 6-minute walk test (6MWT) is an established measure of exercise capacity in adults and children with chronic cardiac or respiratory disease. Despite its widespread use, there are no normal values for healthy children under 12 years of age. We aimed to provide normal values for children between 4 and 11 years. Methods: Healthy children were recruited prospectively from two UK primary schools and also children visiting Great Ormond Street Hospital. 328 children (54% male) aged 4 to 11 years were included in the study. Main outcome measures were the distance walked in 6 minutes, and oxygen saturation and heart rate during the 6 minutes and during a 3-minute recovery period. Results: Mean oxygen saturation at baseline and during the 6MWT was 97–99%. Heart rate increased from 102±19 bpm at baseline to a maximum of 136±12 bpm. Overall, the mean distance walked in 6 minutes was 470±59 m. Distance walked correlated with age (r = 0.64, p<0.0001), weight (r = 0.51, p<0.0001) and height (r = 0.65, p<0.0001) with no significant difference between boys and girls. The distance walked increased significantly year on year from 4 to 7 years (4 years 383±41 m; 5 years 420±39 m, 6 years 463±40 m; 7 years 488±35 m; p<0.05 between each); further modest increases were observed beyond 7 years of age. Conclusions: Performing a 6MWT is feasible and practical in young children. This study provides data on normal children against which the performance of sick children and the response to therapeutic intervention can be judged.

Pulmonary arterial development during childhood: branching pattern and structure

In lungs from 18 children aged between birth and 11 years the development of the branching pattern and structure of the pulmonary arteries, particularly the intralobular and intra-acinar, has been quantitatively analysed after injection with a radio-opaque medium. Up to 18 months of age as new alveolar ducts appear conventional arterial branches develop within the acinus: supernumerary arteries increase in number up to 8 years as new alveoli form. Both types increase in size with age. After birth there is an immediate drop in wall thickness of the vessels below 200 μm diameter while the larger vessels take up to 4 months to fall to adult thickness, suggesting two types of response—one dilatation, the other a growth rate change of the muscle cells. During childhood muscle cell formation in the intra-acinar arteries lags behind increase in artery size so that during childhood few muscular arteries are found within the acinus. The functional significance of these changes is discussed.

Response to bosentan in children with pulmonary hypertension

Objective: To describe an early experience of treating 40 children with the dual endothelin receptor antagonist bosentan, which is known to be safe and effective in adults with pulmonary hypertension (PH). Design: In this retrospective, observational study the UK Service for Pulmonary Hypertension for children treated 40 children with bosentan, 20 with idiopathic pulmonary arterial hypertension (IPAH) (mean age 8.03 years, range 1.2–17) and 20 with PH associated with other conditions (congenital heart disease, parenchymal lung or connective tissue disease, or HIV). Their mean age was 8.3 years (range 0.6–16 years). Patients: 39 patients were in World Health Organization (WHO) class III and IV, and all had shown recent deterioration. In IPAH the mean pulmonary vascular resistance (PVR) was 21.7 units⋅m2 (range 5.6–42.8). In secondary PH the mean PVR was 18 units⋅m2 (range 4.9–49). No child had a positive response to vasodilator testing with nitric oxide. Interventions: Bosentan was given as first line treatment to 25. Nine were given intravenous epoprostenol. Children were treated for a mean of 12.7 months (range 2–24 months). Main outcome measures: Response to treatment was judged by WHO functional class, six minute walk test, weight, ECG and echocardiographic findings, and need to add additional treatment. Results: Bosentan was well tolerated. In the IPAH group 19 (95%) stabilised with bosentan treatment but 12 (60%) patients needed combined treatment with epoprostenol. In secondary PH, WHO class, six minute walk test, and weight gain improved significantly. Conclusion: Bosentan helped stabilise children with IPAH but intravenous epoprostenol was also needed by 60%. Children with secondary PH improved.

Early lung development: Lifelong effect on respiratory health and disease

Interest in the contribution of changes in lung development during early life to subsequent respiratory morbidity is increasing. Most evidence of an association between adverse intrauterine factors and structural effects on the developing lung is from animal studies. Such evidence has been augmented by epidemiological studies showing associations between insults to the developing lung during prenatal and early postnatal life and adult respiratory morbidity or reduced lung function, and by physiological studies that have elucidated mechanisms underlying these associations. The true effect of early insults on subsequent respiratory morbidity can be understood only if the many prenatal and postnatal factors that can affect lung development are taken into account. Adverse factors affecting lung development during fetal life and early childhood reduce the attainment of maximum lung function and accelerate lung function decline in adulthood, initiating or worsening morbidity in susceptible individuals. In this Review, we focus on factors that adversely affect lung development in utero and during the first 5 years after birth, thereby predisposing individuals to reduced lung function and increased respiratory morbidity throughout life. We focus particularly on asthma and COPD.

Developmental changes in endothelium‐dependent pulmonary vasodilatation in pigs

1 We compared in vitro endothelium‐dependent vasorelaxant responses to acetylcholine (ACh) and the endothelium‐independent vasodilator response to sodium nitroprusside (SNP) in prostaglandin F2α (PGF2α)‐precontracted muscular pulmonary arteries (PA) from pigs aged 5 min to 2 h (neonatal), 3–10 days, 3–8 weeks and adults. 2 In the pulmonary artery (PA) rings from neonatal animals, the vasodilator response to ACh was negligible. However, responses to ACh were present in all PA rings from older animals, being greatest at 3–10 days and then decreasing with age (P < 0.001, ANOVA). ACh (30 μm) induced a 1 ± 1%, 92 ± 9%, 62 ± 5% and 51 ± 6% reduction of the PGF2α‐generated tension in neonatal, 3–10 days, 3–8 weeks and adult groups, respectively. 3 The relaxant response to SNP was present in the PA rings from all age groups and increased with age (P < 0.001, ANOVA). SNP (1 μm)‐induced relaxation was 55 ± 9%, 73 ± 7%, 97 ± 5% and 93 ± 6% in neonatal, 3–10 days, 3–8 week and adult groups, respectively. 4 Removal of the vascular endothelium abolished the relaxant response to ACh but had no effect on the response to SNP in any groups. 5 NG‐monomethyl‐l‐arginine (30 μm), a nitric oxide synthesis inhibitor, inhibited the response to ACh but not to SNP. The lipoxygenase inhibitor, nordihydroguaiaretic acid, had no significant effect on responses to ACh or SNP in any group. 6 These findings suggest that the nitric oxide pathway may not play a part in dilating the pig pulmonary arteries at birth, but may be important during the transitional period of establishing a stable post‐natal pulmonary circulation. The increase in response to SNP with age parallels the increase in smooth muscle cell myofilaments to which it may be related.

Role of atrial septostomy in the treatment of children with pulmonary arterial hypertension

Objectives: To assess in retrospect the safety and effectiveness of atrial septostomy in children with severe pulmonary arterial hypertension without an intracardiac communication. Methods: 20 patients were reviewed retrospectively, 19 with idiopathic pulmonary arterial hypertension. The mean age at septostomy was 8.4 years (range 3 months to 17 years). Graded balloon septostomy alone was carried out in eight patients, a blade septostomy was done in two, a blade septostomy plus graded balloon septostomy was done in three, and a fenestrated device was inserted in seven. Results: There were no fatalities. Four children suffered complications during the procedure. None had further syncope and all improved symptomatically with a significant (p < 0.01) decrease in World Health Organization functional class (mean shift −0.6) and a significant improvement in the semiquantitative echocardiographic assessment of right ventricular function (p < 0.03). The mean oxygen saturation decreased by 7.8 percentage points. The atrial communication closed in two children, necessitating a repeat procedure. After a mean follow up of 2.1 years (range one month to 6.7 years), 18 of 20 children are still alive. Conclusion: Atrial septostomy improved symptoms and quality of life in a group of children deteriorating with severe pulmonary arterial hypertension. This procedure is to be recommended for severely symptomatic children, before they become critically ill. Fenestrated devices may help ensure indefinite patency of the atrial communication.

Development of the acinus in the human lung

Hislop, Alison, and Reid, Lynne (1974).Thorax, 29, 90-94. Development of the acinus in the human lung. Development and remodelling of the acinus (those structures distal to the terminal bronchiolus) occurs during fetal life and childhood. Multiplication of the acinar air spaces and the structural changes they undergo have been described and represented schematically by summarizing previous studies, particularly those of the last two decades. Most acinar airways are present before birth. Future respiratory bronchioli are represented by the 19th intrauterine week; alveolar ducts are present as saccules by the 28th week. Alveolar sacs and alveoli, as properly described, do not appear until after birth: alveoli increase in number, particularly in the first seven or so years of life, and in size with thoracic growth.

Postnatal growth and function of the pre-acinar airways

The postnatal growth of the pre-acinar or conducting airways of the lung was examined by measuring the dimensions of selected axial pathways in lungs at different stages of development. The material included both formalin-fixed specimens and bronchograms. A method of comparing the relative sizes of each part of the pathways was developed which allowed for differences between the number of branches or generations measured in each specimen. The results indicate that the pre-acinar airways of the infant may be regarded as a miniature version of those in the adult and that this relationship persists during postnatal growth. Each individual branch grows in a symmetrical fashion both in length and in diameter and bears a constant relation to the whole. The physiological function of the conducting airways during growth was investigated using published data on the breathing pattern of infants. Particular attention was given to the conditions of airflow, to the warming and humidification of inhaled air, and to the filtration of airborne dust.

Epoprostenol treatment in children with severe pulmonary hypertension

Introduction: Severe, sustained pulmonary arterial hypertension leads to a progressive reduction in exercise capacity, right heart failure and death. Use of intravenous epoprostenol has improved survival in adults, but data are limited in children. Patients and methods: This study included all 39 children treated with continuous intravenous epoprostenol since November 1997 at Great Ormond Street Hospital for Children (London, UK). Patients were aged 4 months to 17 years (median 5.4 years) at the onset of therapy. The male:female ratio was 1:1.3. 25 patients had idiopathic pulmonary arterial hypertension and 14 had pulmonary arterial hypertension associated with congenital heart disease, connective tissue disease, chronic lung disease or HIV. All were in WHO functional class III and IV. Mean pulmonary arterial pressure (SD) was 59 (17) mmHg and mean pulmonary vascular resistance was 23.3 (11.6) units×m2. Patients were assessed regularly (2–3 monthly intervals) by physical examination, electrocardiography, transthoracic echocardiography and a 6-min walk test, when practicable. Results: The mean duration of follow-up was 27 (21) months. 7 patients died and 8 underwent transplantation. Cumulative survival at 1, 2 and 3 years was 94, 90 and 84%. The 6-min walking distance improved by a mean of 77 m (p<0.003). WHO functional class improved during the first year (p<0.001) and improvement was maintained for up to 3 years. Weight improved significantly from a baseline z score of −1.55 (1.74) to −1.16 (1.8) (p<0.03). 28 children had additional oral specific therapy. Hickman line changes were 0.33/patient year. Conclusions: Epoprostenol therapy improved survival, WHO functional class, exercise tolerance and ability to thrive in children with severe pulmonary arterial hypertension. Epoprostenol represents an effective and feasible therapy even in young children.