Astrid E. Lammers

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.

Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients

AIMS previous studies have established an association between exercise intolerance and increased morbidity and mortality in congenital heart disease patients. We aimed to clarify if exercise intolerance is associated with poor outcome in Fontan patients and to identify risk factors for mortality, transplantation, and cardiac-related hospitalization. METHODS AND RESULTS a total of 321 Fontan patients (57% male, mean age 20.9 ± 8.6 years) who underwent cardiopulmonary exercise testing (CPET) at four major European centres between 1997 and 2008 were included. During a median follow-up of 21 months, 22 patients died and 6 patients underwent cardiac transplantation (8.7%), resulting in an estimated 5-year transplant-free survival of 86%. Parameters of CPET were strongly related to increased risk of hospitalization, but-with the exception of heart rate reserve-unrelated to risk of death or transplantation. In contrast, patients with clinically relevant arrhythmia had a 6.0-fold increased risk of death or transplantation (P < 0.001). Furthermore, patients with atriopulmonary/-ventricular Fontan had a 3.7-fold increased risk of death or transplantation compared with total cavopulmonary connection patients (P= 0.009). The combination of clinically relevant arrhythmia, atriopulmonary/-ventricular Fontan, and signs of symptomatic or decompensated heart failure was associated with a particularly poor outcome (3-year mortality 25%). CONCLUSION on short-term follow-up, most parameters of CPET are associated with increased risk of hospitalization but not death or transplantation in contemporary Fontan patients. Only decreased heart rate reserve and a history of clinically relevant arrhythmia, atriopulmonary/-ventricular Fontan, and/or heart failure requiring diuretic therapy are associated with poor prognosis, potentially identifying patients requiring medical and/or surgical attention.

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.

Ventilatory Efficiency and Aerobic Capacity Predict Event-Free Survival in Adults With Atrial Repair for Complete Transposition of the Great Arteries

OBJECTIVES The goal of this study was to assess the prognostic value of the cardiopulmonary exercise test (CPET) in patients who received a Mustard and Senning (M/S) operation. BACKGROUND Patients who received an M/S operation have increased long-term risk of cardiovascular morbidity and mortality. Limited information is available on how to stratify risk in this population. METHODS Between 1996 and 2007, 274 adults (age 26.3 +/- 8.9 years, range 16 to 50 years) who had received a Mustard (n = 144) or Senning (n = 130) operation in infancy were studied with CPET. During a follow-up of 3.9 +/- 2.3 years (range 0.2 to 10.8 years), 12 patients died at an age of 36 +/- 14 years, and 46 patients required a cardiac-related emergency (<24 h from the onset of symptom/condition) hospital admission at an age of 30 +/- 11 years. RESULTS At multivariate Cox analysis, the slope of ventilation per unit of carbon dioxide output (VE/VCO(2) slope) (hazard ratio: 1.088, p < 0.0001) and percentage of predicted peak oxygen uptake (Vo(2)%) (hazard ratio: 0.979, p = 0.0136) were the strongest predictors of death/cardiac-related emergency hospital admission among demographic, clinical, and exercise variables. A VE/VCO(2) slope > or =35.4 (hazard ratio: 10.7, 95% confidence interval [CI]: 7.8 to 24.6), and a peak Vo(2)% < or =52.3% (hazard ratio: 3.4, 95% CI: 2.5 to 8.2) were associated with an increased 4-year risk of death/cardiac-related emergency hospital admission. Patients who had both a VE/VCO(2) slope > or =35.4 and a peak Vo(2)% < or =52.3% of predicted value were at highest risk (4-year event rate: 78.8%). CONCLUSIONS CPET provides important prognostic information in adults with M/S operation. Subjects with enhanced ventilatory response to exercise or those with poor exercise capacity have a substantially higher 4-year risk of death/cardiac-related emergency hospital admission.

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.

B-type natriuretic peptide concentrations in contemporary Eisenmenger syndrome patients: predictive value and response to disease targeting therapy

Objective To assess the relationship between elevated levels of B-type natriuretic peptide (BNP) and outcome in patients with Eisenmenger syndrome. Design Retrospective study. Setting Tertiary centre for adult congenital heart disease. Patients All patients with Eisenmenger syndrome (n=181, age 36.9±12.1 years, 31% with Down syndrome) in whom BNP concentrations were measured as part of routine clinical care were included. Main outcome measures The study end point was all cause mortality. Results During a median follow-up period of 3.3 years, 20 patients (7 with Down syndrome) died. Higher BNP concentrations were predictive of all cause mortality on univariate analysis in patients with or without Down syndrome. On multivariable Cox proportional hazard analysis, BNP predicted survival independently of renal function, Down syndrome, or 6 min walk test distance (p=0.004). Temporal increases in BNP concentration were also found to predict mortality. Treatment with disease targeting therapies was associated with a significant reduction in BNP concentrations. Conclusions BNP concentrations predict outcome in contemporary Eisenmenger patients. Increases in BNP concentrations over time are also of prognostic significance. In addition, disease targeting therapies may help to reduce BNP concentrations in this population, while treatment-naïve patients have static or rising BNP concentrations.

Prognostic value of B-type natriuretic peptide in children with pulmonary hypertension

BACKGROUND We aimed to assess whether levels of B-type natriuretic peptide (BNP)--an established marker of ventricular dysfunction--relate to functional status and outcome in children with idiopathic and associated pulmonary hypertension (PH). METHODS AND RESULTS BNP was measured in 50 children with PHT aged 8.4 +/- 5.1 years, all receiving PH specific therapies. Twenty-seven patients were diagnosed with idiopathic PH (IPAH), while 23 patients had associated PH [congenital heart disease (n = 17), lung disease (n = 4), other (n = 2)]. Functional status, six-minute walk test, echocardiographic and haemodynamic data were assessed. Mean BNP value was 143.5 +/- 236.2 pg/ml (range <5-1250). BNP correlated with Functional Class II, III, and IV (50.8 +/- 61.3, 196.9 +/- 291.2 and 280.0 +/- 276.5 respectively; p = 0.01), with echocardiographic assessment of right ventricular function (p < 0.01), hypertrophy (p < 0.01) and dilatation (p < 0.01). In IPAH BNP correlated with pulmonary arterial pressure and, on inhaled nitric oxide also with vascular resistance. During a mean follow-up of 14.0 +/- 7.5 months seven patients died, five underwent transplantation and two were listed for transplantation. Using ROC analysis, a BNP value >130 pg/ml predicted death or need for transplantation (p < 0.04). However, six children who died or were transplanted had a BNP value lower than this. CONCLUSION BNP correlated positively with functional status in children with pulmonary hypertension, but had limited sensitivity (57%) for predicting death or need for transplantation.

Functional Classification of Pulmonary Hypertension in Children: Report from the PVRI Pediatric Taskforce, Panama 2011:

The members of the Pediatric Task Force of the Pulmonary Vascular Research Institute (PVRI) were aware of the need to develop a functional classification of pulmonary hypertension in children. The proposed classification follows the same pattern and uses the same criteria as the Dana Point pulmonary hypertension specific classification for adults. Modifications were necessary for children, since age, physical growth and maturation influences the way in which the functional effects of a disease are expressed. It is essential to encapsulate a childs clinical status, to make it possible to review progress with time as he/she grows up, as consistently and as objectively as possible. Particularly in younger children we sought to include objective indicators such as thriving, need for supplemental feeds and the record of school or nursery attendance. This helps monitor the clinical course of events and response to treatment over the years. It also facilitates the development of treatment algorithms for children. We present a consensus paper on a functional classification system for children with pulmonary hypertension, discussed at the Annual Meeting of the PVRI in Panama City, February 2011.

Comparison of 6-min walk test distance and cardiopulmonary exercise test performance in children with pulmonary hypertension

Objective To assess the relationship between 6-min walk test (6MWT) distance and variables of cardiopulmonary exercise testing (CPET) in children with pulmonary arterial hypertension (PAH). Design Retrospective study. Setting Tertiary hospital. Patients Children with PAH. Interventions CPETs and 6MWTs. Main outcome measures Correlations between variables of CPET and 6MWT distance. Results 41 exercise studies were included: 15 in children with idiopathic PAH (mean age 13.0±3.0 years; 9 female), 18 in children with PAH associated with congenital heart disease (age 14.8±2.8 years; 7 female) and 8 in children with Eisenmenger syndrome (age 11.8±2.9 years; 4 female). All underwent a CPET and 6MWT. Peak oxygen consumption (pVO2) and 6MWT distance were reduced to 31.5±12.2% and 47.7±16.7% of the predicted value, respectively (p<0.0001 for both). pVO2 and oxygen consumption at anaerobic threshold showed correlation with 6MWT distance (r=0.49; p=0.001 and r=0.40, p=0.01, respectively), while an inverse correlation was found between measures of ventilatory efficiency (eg, VE/VCO2) at anaerobic threshold and 6MWT distance (r=−0.43; p=0.005). There was a significant linear relationship between pVO2 and 6MWT up to a distance of 300 m, with the 6MWT distance accounting for 71% of the variation in pVO2 but there was hardly any association when the 6MWT distance was >300 m. Conclusions The 6MWT reflects maximal exercise capacity in patients with a 6MWT distance below 300 m. A CPET should therefore be considered as a complimentary test in children with an exercise tolerance above this threshold. These findings may have implications for assessing response to drug therapy and for consideration as an end point in future PAH trials.

Value of Tissue Doppler Echocardiography in Children with Pulmonary Hypertension

BACKGROUND The impact of pulmonary hypertension (PHT) on right ventricular and left ventricular (LV) function in children with PHT is unknown, and echocardiographic data combining conventional and Doppler tissue imaging (DTI) on PHT in children are sparse. METHODS Forty-one children (18 male; mean age, 7.9 ± 5.6 years) with PHT and structurally normal hearts (27 with idiopathic PHT, 14 with associated PHT) and 44 age-matched healthy controls were assessed using conventional echocardiography and DTI. RESULTS Children with PHT had enlarged tricuspid valve diameters, right atrial areas, pulmonary artery dimensions, and LV eccentricity indices. In addition, pulmonary acceleration time and tricuspid annular plane systolic excursion were significantly reduced in patients compared with controls. DTI revealed that children with PHT had significantly lower systolic (S) and early diastolic (E) velocities at the tricuspid and septal levels. Despite preserved LV ejection fractions, left lateral free wall systolic velocities were significantly reduced in patients with PHT. Significantly reduced LV rapid filling velocities (E) suggested an underloaded left ventricle or LV diastolic dysfunction in children with PHT compared with controls. Pulmonary acceleration time and tricuspid annular plane systolic excursion correlated best with DTI systolic tricuspid and septal velocities. CONCLUSIONS Despite not being evident on conventional two-dimensional echocardiography, LV systolic performance appears to be impaired in children with PHT. Quantitative DTI assessment of ventricular function and ventricular-ventricular interactions in this setting might provide further insights into the mechanisms leading to end-stage PHT and may guide clinicians to optimize antifailure treatment.