Flecainide administration in children: dosage, drug levels, and clinical effect.

Therapeutic drug monitoring of flecainide in children using plasma concentration measurements is undertaken by some clinicians. There is very little published evidence surrounding factors which influence plasma flecainide concentration, particularly in paediatric populations. We undertook a retrospective study of 45 children receiving flecainide to identify factors that influence its plasma concentration. Patients receiving a dose of 6 mg/kg/day had a higher mean plasma flecainide concentration than those receiving lower doses. Younger age and lighter weight were also associated with higher plasma flecainide concentrations. Children aged younger than 1 year receiving flecainide three times a day had a higher mean plasma flecainide concentration than older children who received flecainide twice a day. All supratherapeutic levels occurred in children aged less than 1 year who were receiving flecainide three times a day. Supratherapeutic levels were more common in those receiving 6 mg/kg/day while subtherapeutic levels were more common in those receiving 2 mg/kg/day. A supratherapeutic level did not correlate with adverse effects or clinical toxicity. Our results would suggest the need for a change of practice from prescribing flecainide at a frequency of three times a day in children aged younger than 1 year to twice a day in line with other ages.

Longitudinal evaluation of myocardial function in preterm infants with respiratory distress syndrome.

AIM: Preterm births and respiratory distress syndrome (RDS) are associated with pulmonary vascular disease and altered myocardial function. We serially assessed up to 1 year of age the effects of RDS on global and regional myocardial function of preterm infants, compared to preterm and term controls using conventional echocardiography parameters, tissue Doppler velocities and deformation analysis. METHODS AND RESULTS: A total of 120 infants (30 preterm [PT] with RDS, 30 PT controls without RDS, and 60 term controls) underwent conventional and tissue Doppler echocardiography within 72 hours of birth, at corrected term age for the preterm infants, at 1 month corrected, and at 1 year corrected age. At birth, compared to preterm and term controls, the PT-RDS group had decreased right ventricular (RV) long-axis function, systolic velocity, peak systolic strain, shorter pulmonary arterial acceleration time (PAAT), and lower ratio of PAAT to RV ejection time (PAAT:RVET). Preterm infants had left ventricular (LV) diastolic dysfunction at birth (lower early diastolic myocardial velocity, mitral E velocity, and mitral E:A ratio), and reduced long-axis systolic velocities and shortening. Differences between groups disappeared by 1 month corrected age, except PAAT:RVET which remained lower in the PT-RDS group. At 1 year, RV function was normal in PT-RDS apart from systolic strain rate, and LV function was normal apart from lower stroke volume and shortening, relative to body weight. CONCLUSION: PT-RDS had lower left and right ventricular systolic and diastolic function at birth which improved over time, suggesting postnatal maturation of cardiac function and resolution of lung disease.

COVID-19 in congenital heart disease (COaCHeD) study.

BACKGROUND: COVID-19 has caused significant worldwide morbidity and mortality. Congenital heart disease (CHD) is likely to increase vulnerability and understanding the predictors of adverse outcomes is key to optimising care. OBJECTIVE: Ascertain the impact of COVID-19 on people with CHD and define risk factors for adverse outcomes. METHODS: Multicentre UK study undertaken 1 March 2020-30 June 2021 during the COVID-19 pandemic. Data were collected on CHD diagnoses, clinical presentation and outcomes. Multivariable logistic regression with multiple imputation was performed to explore predictors of death and hospitalisation. RESULTS: There were 405 reported cases (127 paediatric/278 adult). In children (age <16 years), there were 5 (3.9%) deaths. Adjusted ORs (AORs) for hospitalisation in children were significantly lower with each ascending year of age (OR 0.85, 95% CI 0.75 to 0.96 (p<0.01)). In adults, there were 24 (8.6%) deaths (19 with comorbidities) and 74 (26.6%) hospital admissions. AORs for death in adults were significantly increased with each year of age (OR 1.05, 95% CI 1.01 to 1.10 (p<0.01)) and with pulmonary arterial hypertension (PAH; OR 5.99, 95% CI 1.34 to 26.91 (p=0.02)). AORs for hospitalisation in adults were significantly higher with each additional year of age (OR 1.03, 95% CI 1.00 to 1.05 (p=0.04)), additional comorbidities (OR 3.23, 95% CI 1.31 to 7.97 (p=0.01)) and genetic disease (OR 2.87, 95% CI 1.04 to 7.94 (p=0.04)). CONCLUSIONS: Children were at low risk of death and hospitalisation secondary to COVID-19 even with severe CHD, but hospital admission rates were higher in younger children, independent of comorbidity. In adults, higher likelihood of death was associated with increasing age and PAH, and of hospitalisation with age, comorbidities and genetic disease. An individualised approach, based on age and comorbidities, should be taken to COVID-19 management in patients with CHD.

Effects of atenolol, perindopril and verapamil on haemodynamic and vascular function in Marfan syndrome - a randomised, double-blind, crossover trial.

BACKGROUND: Aortic dilatation is the main therapeutic target in patients with Marfan syndrome. Standard treatment with a ß-blocker may not lower central pulse pressure - the major objective - because it does not do so in hypertension, unlike angiotensin-converting enzyme inhibitors and calcium-channel blockers. We therefore performed a prospective, randomised, double-blind, crossover trial to compare the effects of these three agents on large artery function and central aortic pressure in patients with Marfan syndrome. METHODS AND RESULTS: Eighteen patients had applanation tonometry, pulse wave analysis and echocardiography, before and after atenolol 75 mg, perindopril 4 mg and verapamil 240 mg, each given for 4 weeks, in a random order, with 2 weeks between medications. Fourteen patients completed the study. Within-drug comparisons demonstrated that perindopril (-10·3 mmHg, P = 0·002), verapamil (-9·2 mmHg, P = 0·003) and atenolol (-7·1 mmHg, P = 0·01) all reduced central systolic pressure and brachial pressure; central changes were least, and peripheral changes greatest with atenolol but between-drug comparisons (analysis of covariance) were not significant. There was a trend for augmentation to be reduced by perindopril (-6·3%, P = 0·05), verapamil (-5·5%, P = 0·07) and atenolol (-3·2%, P = 0·09). Only atenolol reduced heart rate (by 16%) and delayed expansion in the arch and abdominal aorta (by 8% and 11%) (P < 0·001, P < 0·01 and P < 0·05, respectively, for between-drug comparisons). CONCLUSIONS: Perindopril, verapamil and atenolol all reduced peripheral and central systolic pressure. As atenolol slowed heart rate and delayed aortic wave travel, ß-blockade may have a continuing role in the treatment of patients with Marfan syndrome.

Relationship of aortic pulse wave velocity and baroreceptor reflex sensitivity to blood pressure control in patients with repaired coarctation of the aorta.

BACKGROUND: Increased aortic stiffness and reduced baroreceptor reflex sensitivity have been described independently after coarctation of the aorta (CoA) repair. This study sought to determine the relationship between these variables and blood pressure control in adolescents after early CoA repair. METHODS: Spontaneous baroreceptor reflex sensitivity (sBRS) and aortic pulse wave velocity (PWV) were measured in 29 adolescents after CoA repair and compared with 20 age-matched controls. Patients treated for hypertension or having residual aortic narrowing were excluded. Ambulatory blood pressure (ABP), heart rate variability, and cardiac output were also recorded. After ABP measurement, CoA subjects were classified as normotensive or hypertensive. RESULTS: Nine patients (31%) were hypertensive according to standard definitions, and this subgroup had higher aortic PWV than the normotensive subgroup (P = .004). There was a significant positive correlation between ABP and PWV seen in the whole CoA group (r(2) = 0.5, P < .01). The normotensive subgroup had increased sBRS compared with controls (P = .02). This difference was not seen between the hypertensive subgroup and controls. There was a significant inverse relationship between sBRS and aortic PWV in the whole CoA group (r(2) = 0.25, P = .01). The normotensive subgroup had a significant reduction in stroke index compared with controls (P = .02), which was not seen in the hypertensive subgroup (P = .96). CONCLUSIONS: Adolescents with hypertension after CoA repair have increased aortic PWV and a relative reduction in sBRS compared with normotensive CoA patients. Thus, failure of the baroreceptor reflex to compensate for increasing arterial stiffness may herald the onset of hypertension in these patients.

Underrecognition of elevated blood pressure readings in children after early repair of coarctation of the aorta.

Hypertension after repair of coarctation of the aorta (CoA) is the outcome variable most closely associated with adverse long-term events such as stroke and myocardial infarction. This study sought to evaluate the outpatient management of casual blood pressure (BP) measurements in young children after early repair of CoA. A retrospective analysis was performed of clinical findings, echocardiographic data, casual BP recordings, and subsequent BP management of 114 children with CoA repair aged 1-13 years during 338 outpatient visits managed at two congenital cardiac centers. Children with associated significant congenital heart disease or corrective surgery after the age of 6 months were excluded from the study. Blood pressure was documented at 233 clinic visits (69%), and systolic BP (SBP) was above 95th percentile for age and sex in 45 instances (19%). This represented an elevated SBP recording for 31 children (27%), with two or more successive elevated recordings for 11 children (10%). Of 12 subjects receiving antihypertensive medication, three had inadequate BP control. Blood pressure is not documented at approximately 30% of outpatient visits of children with repaired CoA. When elevated BP is documented, in all cases no recorded action was taken. This may have significant implications for cardiovascular outcomes in this cohort of patients.

Reproducibility of myocardial velocity and deformation imaging in term and preterm infants.

AIMS: Myocardial velocity imaging has been validated in adults for assessment of ventricular function and indirect indices of pulmonary arterial pressure. To establish whether it could also be used in infants, we investigated the reproducibility of myocardial velocities and deformation indices in term and preterm neonates. METHODS AND RESULTS: Myocardial velocity loops acquired from 16 infants were analysed by four observers for inter-observer variability, and re-analysed after 6 months by one observer for intra-observer variability. For myocardial velocities, the coefficients of variation (CVs) for the left ventricle (LV) were 10-11 (intra-observer) and 14-20% (inter-observer) and for the right ventricle (RV) 15-19 and 18-24%, respectively. Reproducibility for annular displacements was <13% (intra-observer) and <18% (inter-observer). CVs for LV strain were 14-17 (intra-observer) and 36-43% (inter-observer) and for RV 19-24 and 25-37%. CVs for isovolumic acceleration were in general >40%. In comparison, the CVs for blood pool indices were 3-15%. CONCLUSION: Intra-observer reproducibility for myocardial velocity and deformation indices in neonates is adequate for these parameters to be used in clinical research. Inter-observer reproducibility is sub-optimal suggesting that these measurements should be used in clinical practice with caution. Myocardial acceleration, a marker of contractile function, was poorly reproducible.

Sildenafil in the management of the failing Fontan circulation.

BACKGROUND: Sildenafil is increasingly being used in the management of pulmonary arterial hypertension in the newborn. Its role in patients with congenital cardiac disease is less well defined and as yet has only been reported sporadically. AIM: Present our experience with sildenafil treatment in patients with a failing Fontan circulation. PATIENTS AND METHODS: Retrospective review of 13 symptomatic patients after Fontan palliation who received treatment with sildenafil between January, 2006 and July, 2008. RESULTS: Three patients suffered from protein-losing enteropathy, four patients presented with bronchial casts, two had severe cyanosis after fenestrated Fontan procedure, two had prolonged chylous effusions, one had a previous failure of Fontan and take-down, and one patient had arrhythmias and end-stage cardiac failure requiring conversion to an extra-cardiac Fontan. Sildenafil was used in the dosage of 1-2 milligrams per kilogram 3-4 times per day. Protein-losing enteropathy and alpha-1-antitrypsin levels improved in all three patients on sildenafil treatment. One of these patients had a concomitant catheter creation of a fenestration, as did two patients presenting with bronchial casts and both patients with persistent chylous effusions. All four patients with bronchial casts and two patients with cyanosis improved significantly on sildenafil treatment. Chylous effusions decreased after sildenafil and stent enlargement of a fenestration. There were no significant side effects requiring sildenafil withdrawal over a treatment period ranging from 2 months to 2 years. CONCLUSIONS: Sildenafil can be used safely and effectively in the treatment of patients with a failing Fontan circulation.

Maternal and fetal outcomes in pregnancies complicated by Marfan syndrome.

OBJECTIVES: Information to guide counselling and management for pregnancy in women with Marfan syndrome (MFS) is limited. We therefore conducted a UK multicentre study. METHODS: Retrospective observational study of women with MFS delivering between January 1998 and March 2018 in 12 UK centres reporting data on maternal and neonatal outcomes. RESULTS: In total, there were 258 pregnancies in 151 women with MFS (19 women had prior aortic root replacements), including 226 pregnancies ≥24 weeks (two sets of twins), 20 miscarriages and 12 pregnancy terminations. Excluding miscarriages and terminations, there were 221 live births in 139 women. Only 50% of women received preconception counselling. There were no deaths, but five women experienced aortic dissection (1.9%; one type A and four type B-one had a type B dissection at 12 weeks and subsequent termination of pregnancy). Five women required cardiac surgery postpartum. No predictors for aortic dissection could be identified. The babies of the 131 (65.8%) women taking beta-blockers were on average 316 g lighter (p<0.001). Caesarean section rates were high (50%), particularly in women with dilated aortic roots. In 55 women, echocardiographic aortic imaging was available prepregnancy and postpregnancy; there was a small but significant average increase in AoR size of 0.84 mm (Median follow-up 2.3 months) CONCLUSION: There were no maternal deaths, and the aortic dissection rate was 1.9% (mainly type B). There with no identifiable factors associated with aortic dissection in our cohort. Preconception counselling rates were low and need improvement. Aortic size measurements increased marginally following pregnancy.

Echocardiographic Screening for Pulmonary Hypertension in Congenital Heart Disease: JACC Review Topic of the Week.

Echocardiography is the mainstay in screening for pulmonary hypertension (PH). International guidelines suggest echocardiographic parameters for suspecting PH, but these may not apply to many adults with congenital heart disease (ACHD). PH is relatively common in ACHD patients and can significantly affect their exercise capacity, quality of life, and prognosis. Identification of patients who have developed PH and who may benefit from further investigations (including cardiac catheterization) and treatment is thus extremely important. A systematic review and survey of experts from the United Kingdom and Ireland were performed to assess current knowledge and practice on echocardiographic screening for PH in ACHD. This paper presents the findings of the review and expert statements on the optimal approaches when using echocardiography to assess ACHD patients for PH, with particular focus on major subgroups: patients with right ventricular outflow tract obstruction, patients with systemic right ventricles, patients with unrepaired univentricular circulation, and patients with tetralogy of Fallot with pulmonary atresia.

Effectiveness of pulse-oximetry in addition to routine neonatal examination in detection of congenital heart disease in asymptomatic newborns.

OBJECTIVE: To assess the feasibility and effectiveness of pulse-oximetry as a screening tool in the detection of critical congenital heart disease (CCHD) in newborns. METHODS: Post-natal babies born between 01/01/2007-31/12/2009 were eligible. Post-ductal pulse-oximetry was performed using Nellcor® NPB 40 pulse oximeter with reusable OXI-A/N saturation probe. Saturations ≥95% were deemed normal. If saturations were <95%, an echocardiogram was done. The regional paediatric cardiology database and death records identified babies later diagnosed with CCHD. RESULTS: 6329/9613 eligible babies were studied and pulse-oximetry was performed at a mean age of 28 hours (range 6-72 hours). Fourteen babies had saturations <95%. CCHD was diagnosed in 7/14 babies; 4/7 had no clinical signs. Of the remaining 7 babies, 3 had non-critical but significant CHD and 4 had an undiagnosed respiratory illness or sepsis. All babies with low saturations had identifiable pathologies. One baby with normal saturations was later diagnosed with transposition of the great arteries. The sensitivity and specificity of identifying an unwell baby was 93.3% and 100% respectively; the sensitivity and specificity of identifying CCHD was 87.5% and 99.8% respectively. Clinical examination alone would have missed 4/7 (57%) of these. CONCLUSION: Pulse-oximetry is safe, acceptable, non-invasive and effective. Our study supports the routine use of pulse oximetry as part of the newborn check.

Cardiovascular function in children who had chronic lung disease of prematurity.

OBJECTIVES: Although increased pulmonary arterial pressure is common in infancy in preterm infants who develop chronic lung disease of prematurity (CLD), it is unknown if the increase persists into childhood. We, therefore, assessed if 8-12-year-old children with documented CLD in infancy had evidence of right ventricular dysfunction or pulmonary arterial hypertension at rest or in response to acute hypoxia when compared to preterm and term-born controls. METHODS: We studied 90 children: 60 born at ≤32 weeks of gestation (28 with CLD and 32 preterm controls), and 30 term-born controls. All had echocardiography including myocardial velocity imaging, at rest and while breathing 15% oxygen and 12% oxygen for 20 min each. RESULTS: Baseline oxygen saturation, heart rate, blood pressure and echocardiographic markers of left and right ventricular function were similar in all three groups. While breathing 12% oxygen, the oxygen saturation decreased to 81.9% in the CLD group compared to 85.1% (p<0.05) and 84.7% (p<0.01) in the preterm and term controls, respectively. In response to hypoxia, all three groups showed increases in velocity of tricuspid regurgitation, end-diastolic velocity of pulmonary regurgitation, and right ventricular relaxation time; and decreases in pulmonary arterial acceleration time and the ratio of right ventricular acceleration time to ejection time. However, there were no differences between groups. CONCLUSIONS: Childhood survivors of CLD have comparable left and right ventricular function at 8-12 years of age to preterm and term-born children, and no evidence of increased pulmonary arterial pressure even after hypoxic exposure.

Surgical approach for aortic coarctation influences arterial compliance and blood pressure control.

BACKGROUND: Increased arterial stiffness is linked to hypertension in adults after surgical repair for coarctation of the aorta. We evaluated the influence of surgical approaches, namely, subclavian flap repair (SFR) and end-to-end anastomosis (EEA), on arterial stiffness, blood pressure, cardiac output, and cardiac baroreceptor function in a cohort of young children after coarctation repair to determine if the surgical approach influenced longer term blood pressure control. METHODS: We measured pulse wave velocity in 21 children with a mean age of 5 years, after early (less than 6 months) coarctation repair (SFR, n = 11; EEA, n = 10), and compared these with 18 matched controls. Blood pressure was recorded on three occasions from the right arm. Cardiac output was recorded using a transthoracic bioimpedence technique. We measured spontaneous baroreceptor reflex sensitivity to evaluate whether increased arterial stiffness was associated with reduced aortic baroreflex sensitivity. RESULTS: Right arm systolic blood pressure (108.3 + or - 3.5 mm Hg SFR versus 97.8 + or - 2.9 mm Hg EEA, p = 0.03) and pulse wave velocity (6.0 + or - 0.2 ms(-1) SFR versus 5.2 + or - 0.2 ms(-1) EEA, p = 0.02) were significantly greater in the SFR compared with EEA group. Blood pressure and pulse wave velocity were also higher in the SFR group compared with controls. These differences were not demonstrated when comparing the EEA group with controls. There was no difference in stroke volume, spontaneous baroreceptor reflex sensitivity, or heart rate or blood pressure variability between the groups. CONCLUSIONS: Young children undergoing SFR have higher blood pressure and stiffer upper limb arteries compared with matched children undergoing EEA. Our data suggest that better longer-term cardiovascular outcome is to be expected with the EEA surgical approach.

Aortic aneurysm formation five decades after tetralogy of Fallot repair.

Surgical repair of tetralogy of Fallot is recognized as one of the most successful palliative cardiac surgical procedures. We report a patient in whom cystic medial necrosis developed 50 years after tetralogy of Fallot repair that caused a pathologic ascending aortic aneurysm requiring operative repair. Thus, long-term clinical follow-up along with echocardiography, when indicated, is mandatory in patients undergoing tetralogy of Fallot repair.

Cardiac tumours in children.

Cardiac tumours are benign or malignant neoplasms arising primarily in the inner lining, muscle layer, or the surrounding pericardium of the heart. They can be primary or metastatic. Primary cardiac tumours are rare in paediatric practice with a prevalence of 0.0017 to 0.28 in autopsy series. In contrast, the incidence of cardiac tumours during foetal life has been reported to be approximately 0.14%. The vast majority of primary cardiac tumours in children are benign, whilst approximately 10% are malignant. Secondary malignant tumours are 10-20 times more prevalent than primary malignant tumours. Rhabdomyoma is the most common cardiac tumour during foetal life and childhood. It accounts for more than 60% of all primary cardiac tumours. The frequency and type of cardiac tumours in adults differ from those in children with 75% being benign and 25% being malignant. Myxomas are the most common primary tumours in adults constituting 40% of benign tumours. Sarcomas make up 75% of malignant cardiac masses. Echocardiography, Computing Tomography (CT) and Magnetic Resonance Imaging (MRI) of the heart are the main non-invasive diagnostic tools. Cardiac catheterisation is seldom necessary. Tumour biopsy with histological assessment remains the gold standard for confirmation of the diagnosis. Surgical resection of primary cardiac tumours should be considered to relieve symptoms and mechanical obstruction to blood flow. The outcome of surgical resection in symptomatic, non-myxomatous benign cardiac tumours is favourable. Patients with primary cardiac malignancies may benefit from palliative surgery but this approach should not be recommended for patients with metastatic cardiac tumours. Surgery, chemotherapy and radiotherapy may prolong survival. The prognosis for malignant primary cardiac tumours is generally extremely poor.