Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects.

Warfarin is used in paediatric populations, but dosing algorithms incorporating pharmacogenetic data have not been developed for children. Previous studies have produced estimates of the effect of polymorphisms in Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on stable warfarin dosing, but data on time in therapeutic range, initial dosing and adverse effects are limited. Participants (n=97) were recruited, and routine clinical data and salivary DNA samples were collected from all participants and analysed for CYP2C9*2, *3 and VKORC1-1639 polymorphisms.VKORC1 -1639 was associated with a greater proportion of the first 6 months' treatment time spent within the target International Normalised Ratio (INR) range, accounting for an additional 9.5% of the variance in the proportion of time. CYP2C9*2 was associated with a greater likelihood of INR values exceeding the target range during the initiation of treatment (odds ratio (OR; per additional copy) 4.18, 95% confidence interval (CI) 1.42, 12.34). CYP2C9*2 and VKORC1-1639 were associated with a lower dose requirement, and accounted for almost 12% of the variance in stable dose. VKORC1-1639 was associated with an increased likelihood of mild bleeding complications (OR (heterozygotes vs homozygotes) 4.53, 95% CI 1.59, 12.93). These data show novel associations between VKORC1-1639 and CYP2C9*2 and INR values in children taking warfarin, as well as replicating previous findings with regard to stable dose requirements. The development of pharmacogenomic dosing algorithms for children using warfarin has the potential to improve clinical care in this population.

Diagnosis and assessment of disease activity in takayasu arteritis: a childhood case illustrating the challenge.

Takayasu Arteritis (TA) is a rare, debilitating large vessel vasculitis occurring in patients of all ages, including infants, but the disease most commonly presents in the third decade. Diagnosis is often delayed and consequently TA is associated with significant morbidity and mortality. Accurate methods of monitoring disease activity or damage are lacking and currently rely on a combination of clinical features, blood inflammatory markers, and imaging modalities. In this report we describe a case of a 14-year-old boy with childhood-onset TA who, despite extensive negative investigations, did indeed have on-going active large vessel vasculitis with fatal outcome. Postmortem analysis demonstrated more extensive and active disease than originally identified. This report illustrates and discusses the limitations of current modalities for the detection and monitoring of disease activity and damage in large vessel vasculitis. Clinicians must be aware of these limitations and challenges if we are to strive for better outcomes in TA.

Retained central venous lines (CVLs) after attempted removal: an 11-year series and literature review.

BACKGROUND: Central venous lines (CVLs) are frequently used in the management of many neonatal and pediatric conditions. Failure to remove the luminal part of the line (retained CVL) is rare. Consequently, there is lack of experience and consensus in its optimal management. AIM: To document the incidence and management of retained CVLs in a tertiary pediatric surgical centre with access to interventional cardiology services. To review the literature and report efficacy/morbidity of attempted extraction of retained CVLs. METHODS: Children with retained CVLs were identified from departmental morbidity and mortality records over an 11-year period. A literature search was performed in PubMed and Scopus to identify studies reporting retained CVLs (earliest date to 1 January 2012). This was supplemented by scanning bibliographies of retrieved articles. RESULTS: The 11-year incidence of retained CVL was 0.3% (n=10; median duration in-situ 66.5 {range 47-146} months). The underlying pathology in 8 was cystic fibrosis. Antegrade transfemoral snare retrieval was successful in 6 of 7 attempts. In the remaining 3, a conservative approach was adopted following consultation with the family. None of the 4 with retained CVL developed complications (median follow-up 7.5 {range 1-53} months). The literature describes 38 pediatric index cases (including 10 from the current series). Seventeen (49%) were managed conservatively either intentionally or by default after failed endovascular removal attempt (n=4). No complications directly attributed to retained CVLs have been reported (median follow-up 40 {range 1-120} months). Reported morbidity associated with endovascular retrieval includes: procedural failure 30%, line embolization 8%, and intra-operative thrombo-embolism 8%. CONCLUSION: Literature regarding management of retained CVLs is anecdotal. Although uncommon, the complication should feature in consent for removal of CVLs. Conservative management carries long-term risks of infection, thrombosis, and even migration, albeit unquantified over a child's lifetime. Endovascular retrieval is feasible with appropriate expertise.

Idiopathic multifocal intracardiac and pulmonary thrombosis: successful treatment with rTPA.

A 21-month-old boy with respiratory symptoms for one month secondary to idiopathic multichamber intracardiac and pulmonary thrombosis is presented who was successfully treated with recombinant tissue plasminogen activator (rTPA). The etiology and risk factors of pediatric intracardiac thrombosis are discussed and the literature and all reported cases are reviewed. It is important to consider cardiopulmonary thrombosis as a differential diagnosis of respiratory distress in childhood.

Mechanical occlusion of the patent ductus arteriosus with Jackson coils.

The effectiveness and safety of a protocol for transcatheter patent ductus arteriosus (PDA) closure was assessed. Our goal is complete mechanical occlusion of the PDA in the catheterization laboratory by adding coils until it is no longer possible to cross the PDA with a guidewire. Detachable coil closure of a PDA with a narrowest diameter of 2.4 +/- 0.1 mm was attempted in 83 patients with a median age of 2.8 years (0.7 to 27.8 years) and whose median weight was 14.5 kg (6 to 61.6 kg). Coils were successfully implanted in 82 of 83 patients, and in 1 patient a large Rashkind double umbrella was used instead. Complete closure was obtained in 80 (97.6%) patients, 48 of those (59%) received more than one coil. Reintervention for residual shunting was required in only 1 patient and another patient has a trivial residual shunt. Device embolization occurred in three cases. Despite the use of multiple coils there was no evidence of significant left pulmonary artery stenosis. The fluoroscopy time increased from 14.0 +/- 2.0 minutes for a single coil to 25.3 +/- 2.9 minutes for multiple coils (p < 0.01). Attempting to obtain complete mechanical occlusion of the PDA during the implant procedure by adding extra coils reduces the need for reintervention for residual or recurrent shunting.

Comparison of the Sideris and Amplatzer septal occlusion devices.

The results of transcatheter atrial septal defect (ASD) occlusion with 2 different devices (Sideris adjustable buttoned device vs Amplatzer Septal Occluder) were compared in 2 consecutive series of patients. Comparative outcomes were assessed by whether a device was implanted or not, by complications and fluoroscopy time of implantation, and by the incidence of residual shunting on transthoracic echocardiography at follow-up. The patient and defect characteristics were similar in both groups. Twenty-eight of 33 Sideris devices and 37 of 39 Amplatzer devices were implanted. The fluoroscopy time for the Amplatzer implants was 13.4 minutes (range 8 to 41) compared with 23.7 minutes (range 11 to 60.6) for the Sideris implants (p <0.001). The complete occlusion rate for the Amplatzer device was 93% compared with 44% for the Sideris device at 1 year (p <0.001). In conclusion, the Amplatzer device produces higher occlusion rates of ASDs with shorter fluoroscopy times.

Balloon expandable stents for systemic venous pathway stenosis late after Mustard's operation.

OBJECTIVES: Description and evaluation of current experience with the use of balloon expandable stents for the relief of systemic venous pathway stenosis late after Mustard's operation. DESIGN: Retrospective observational study of technical procedures, angiographic, and haemodynamic findings. PATIENTS: Twenty long term survivors of Mustard's operation for transposition of the great arteries (TGA) with angiographic evidence of systemic venous pathway narrowing. INTERVENTION: Systemic venous pathway stenoses were stented using balloon expandable Palmaz stents. RESULTS: Twenty seven stents were deployed across 24 stenoses. Seventeen stents were placed in the inferior baffle (16 patients), with an increase in mean (range) minimum diameter from 9.6 (4.5-15.9) to 16.5 (11.9-22.2) mm (p = 0.007), and a reduction in mean pressure gradient from 3.1 (0-8) to 0.67 (0-3) mm Hg (p = 0.002). Eight stents were placed in the superior pathways of eight patients, with diameters widened from 9.1 (3.5-14.1) to 15.2 (8.7-19.2) mm (p = 0.018), and gradients reduced from 6.4 (2-11) to 0.9 (0-2) mm Hg (p = 0.02). Two badly deployed stents were safely withdrawn from their intracardiac positions and redeployed in the iliac vein. Transvenous pacemaker insertion was facilitated by prior stent insertion. CONCLUSIONS: The use of balloon expandable stents for late systemic pathway narrowing after Mustard's operation is safe and effective. The beneficial effects of stenting are likely to be more durable than those of balloon angioplasty alone, but longer term follow up is required.

Transcatheter occlusion of the patent ductus arteriosus with Cook detachable coils.

OBJECTIVE: To report initial experience with a new occlusion device for native and residual patent ductus arteriosus. DESIGN: Descriptive study of consecutive non-randomised patients undergoing a new method of patent ductus arteriosus closure with detachable coils. SETTING: Tertiary centres for paediatric cardiology. PATIENTS: 71 consecutive patients, aged 1.2-22 years, with a patent ductus arteriosus (PDA) underwent elective transcatheter closure. 45 had native PDAs (group A) with a minimum diameter of 1.0 mm-5.0 mm (median 2.0 mm). A further 26 had undergone one or more previous occlusion attempts (group B). INTERVENTIONS: A total of 133 detachable (Cook) spring coils were successfully implanted in 70 patients. The procedure was performed transvenously in 51 patients, retrograde arterially in 13, and by both routes in a further 6 patients. One 5 mm coil migrated but was successfully retrieved. MAIN OUTCOME MEASURES: In group A colour flow Doppler echocardiography showed that complete occlusion was achieved in 40/45 (89%) at 24 hours, 41/45 (91%) at 1 month, and 44/45 (98%) by 6 months post procedure. Occlusion rates in residual PDAs were 22/25 (88%) occluded at 24 hours, 23/25 (92%) at 1 month, and 24/25 (96%) at 6 months follow up. CONCLUSIONS: Transcatheter occlusion using detachable (Cook) spring coils is a safe and effective alternative to presently available devices. The delivery system allows full retrieval of the coil until a satisfactory position is obtained.

Prognosis of supravalve aortic stenosis in 81 patients in Liverpool (1960-1993).

OBJECTIVE: To determine the prognosis of supravalve aortic stenosis into early adult life and the factors affecting this prognosis. DESIGN: 81 patients with supravalve aortic stenosis were followed for a median duration of 8.3 (range 1 to 29) years. PATIENTS: 40 patients (49.4%) had Williams' syndrome, 18 (22.2%) familial supravalve aortic stenosis, 18 (22.2%) sporadic supravalve aortic stenosis, and five (6.2%) other syndromes. Nineteen patients had additional levels of left ventricular outflow tract obstruction. RESULTS: 47 patients (58%) underwent operation; 20% within a year of presentation. Multivariable analysis predicted that 88% of patients would undergo intervention within 30 years of follow up. The chance of intervention was increased by more severe aortic stenosis at presentation and the presence of multilevel obstruction in patients with sporadic supravalve aortic stenosis. Three deaths occurred before operation and 13 within a month of operation. Ten (62.5%) of the postoperative deaths were in patients with multilevel obstruction. Predicted survival 30 years after presentation was 66%. Risk factors for survival were age and severity of aortic stenosis at presentation. Multilevel obstruction did not emerge as a significant risk factor for death because of the high association with the severity of stenosis at presentation. 74% of survivors had mild or insignificant stenosis at follow up. CONCLUSIONS: Long-term survival is related to age and the severity of aortic stenosis at presentation. Most patients will require intervention, and most survivors will have mild stenosis.

Measurement of cerebral venous oxyhemoglobin saturation in children by near-infrared spectroscopy and partial jugular venous occlusion.

Changes in cerebral venous oxyhemoglobin saturation reflect changes in the balance between cerebral oxygen delivery and cerebral oxygen consumption. Invasive monitoring of cerebral venous saturation (CSVO2) has provided useful information in the management of critically ill adults at risk of cerebral hypoxia. This study describes the development and validation of a non-invasive method of measuring CSVO2 suitable for use in sick neonates using near-infrared spectroscopy (NIRS) and partial jugular venous occlusion. This technique was validated by comparison with an invasive measurement of CSVO2, co-oximetry of jugular bulb blood obtained during cardiac catheterization. Agreement between the two methods was assessed using the method of J. M. Bland and D. G. Altman. Fifteen children were studied, aged 3 mo to 14 y (median 2 y). CSVO2 by co-oximetry ranged from 36 to 80% (median 60%). The mean difference (Co-Oximeter - NIRS) was 1.5%. Limits of agreement were -12.8 to 15.9%. Three different methods of analyzing the NIRS signal were compared. The best agreement was obtained when the changes occurring during the first 5 s of partial jugular venous occlusion were studied. Greatest accuracy was seen in those subjects with least movement artifact, and we believe this technique will be reliable in sick neonates.

Twiddler's syndrome in children: an unusual cause of pacemaker failure.

Mechanical causes of pacemaker failure are well recognised. Twiddler's syndrome leading to pacemaker failure has been previously recognised in adults, but there have been no published reports of its occurring in children. Two cases leading to failure of the pacing system are reported. In the first twiddling led to fracture of the lead and in the second it led to displacement of the lead from the heart. Children may be more susceptible to twiddler's syndrome because they have thinner subcutaneous tissues, making leads more accessible, and their comprehension of the consequences may be poor.

Morphology of left ventricular outflow tract structures in patients with subaortic stenosis and a ventricular septal defect.

OBJECTIVE: To compare the incidence and prognosis of subaortic stenosis associated with a ventricular septal defect and to define the morphological basis of subaortic stenosis. DESIGN: Presentation and follow up data on 202 patients with subaortic stenosis seen at the Royal Liverpool Children's Hospital between 1 January 1960 and 31 December 1991 were reviewed. Survivors were traced to assess their current clinical state. Necropsy specimens of 291 patients with lesions associated with subaortic stenosis were also examined. RESULTS: In the clinical study; 65 (32.1%) of the 202 patients with subaortic stenosis had a ventricular septal defect (excluding an atrioventricular septal defect). 32 of these patients had a short segment (fibromuscular) subaortic stenosis. 33 had subaortic stenosis produced by deviation of muscular components of the outflow tracts. In 17 patients (51.5%) this was caused by posterior deviation or extension of structures into the left ventricular outflow tract, resulting in obstruction above the ventricular septal defect. In the other 16 patients (48.5%) there was over-riding of the aorta with concordant ventriculoarterial connections, (without compromise to right ventricular outflow) producing subaortic stenosis below the ventricular septal defect. Additional fibrous obstruction occurred in 39% of the patients with deviated structures. The age at presentation was lower (P < 0.01) in patients with deviated structures (median (range) 0.4 (0 to 9.2) months) than in those with short segment obstruction (median (range) 4.2 (0 to 84.9) months). The incidence of aortic arch obstruction was higher (P < 0.002) in patients with deviated structures than in those with short segment obstruction (38%). In the morphological study 35 pathological specimens showed obstructive muscular structures in the left ventricular outflow tract either above or below the ventricular septal defect. 16 had either posterior deviation of the outlet septum or extension of the right ventriculoinfundibular fold, or both of these together into the left ventricle. 19 had anterior deviation of the outlet septum into the right ventricle with overriding of the aorta (without compromise to right ventricular outflow). The earliest age at which additional fibrous obstruction was seen was 9 months. The aortic valve circumference was small in 18% of specimens. FOLLOW UP: The median (range) duration of follow up in survivors from the clinical study was 6.6 (1 to 25.7) years. 16 patients with deviated musculature (49%) and 16 with short segment fibromuscular stenosis (50%) underwent operation for subaortic stenosis. Patients with deviated structures were younger at operation than those with short segment stenosis (P < 0.005). Patients with posterior deviation or extension of structures into the left ventricular outflow tract underwent operation for subaortic stenosis more frequently (P < 0.05) than those with anterior deviation of the outlet septum and aortic override. The ventricular septal defect required surgical closure more frequently (P < 0.005) in patients with deviation (93.9%) than in those with short segment obstruction (21.9%). There was no significant difference in the mortality between patients with deviation (27%) and those with short segment obstruction (12%). CONCLUSIONS: 32% of patients in the clinical study with subaortic stenosis had a ventricular septal defect. Only 51% of these had obstructive and deviated muscular structures in the left ventricular outflow tract. These patients had a significantly higher incidence of aortic arch obstruction and required surgery for subaortic stenosis at a younger age than those with short segment obstruction. The ventricular septal defect also required surgical closure more frequently in those patients with deviation. The morphological study defined the two sites of obstruction. The presence or absence and type of deviation should be clearly defined in all patients with a ventricular septal defect,

Incidence and prognosis of obstruction of the left ventricular outflow tract in Liverpool (1960-91): a study of 313 patients.

OBJECTIVE: To determine the incidence of the various types of obstruction of the left ventricular outflow tract in patients born in the five health districts of Liverpool and to compare their prognosis into early adult life. DESIGN: Notes of all patients with obstruction of the left ventricular outflow tract born in the study area between 1960 and 1991 were reviewed. Patients with hypoplastic left ventricle, mitral valve atresia, and those with discordant atrioventricular or ventriculoarterial connections were excluded. Survivors were traced and assessed clinically; eight were lost to follow up. RESULTS: Obstruction of the left ventricular outflow tract occurred in 313 patients (67% male), giving an incidence of 6.1/10,000 live births. The median (range) age at presentation was 13.9 months (0-20 yr). Aortic valve stenosis occurred in 71.2%: subvalve in 13.7%, supravalve in 7.7%, and multilevel in 7.4%. The median (range) duration of follow up was 10.0 (1-29) yr. Aortic regurgitation at presentation occurred more often (p < 0.001) in patients with subvalve stenosis than in those with other types of obstruction, but there was an increased incidence (p < 0.001) at follow up in patients with valve stenosis. Ninety eight patients (31.3%) underwent operation. The reoperation rate was 27% for valve stenosis and 9% for subvalve obstruction. No patients with supravalve stenosis underwent reoperation. The median duration from first operation to aortic valve replacement (17 patients) was 12.3 years. Hazard analysis confirmed that the risk of death was higher in patients presenting at a younger age, with more severe stenosis, and those with subaortic, multilevel obstruction or a syndrome. Hazard analysis also showed that the risk of a clinical event (surgery, balloon dilatation, or endocarditis) was greater in patients who presented at a younger age, with more severe stenosis or aortic regurgitation, and in those with subvalve or multilevel obstruction. CONCLUSIONS: Aortic valve stenosis was the most common type of obstruction. Hazard analysis indicates that the age and severity of obstruction at presentation have a significant effect on survival and freedom from a clinical event. The risk of premature death in patients presenting with moderately severe valve stenosis is reasonably small, but increases considerably in those with subvalve, supravalve, and multilevel obstruction. Patients who present with mild valve stenosis have a good prognosis. The risk of sudden death is less than previous predictions. Patients with subvalve and multilevel obstruction, even when mild at presentation, are more likely to undergo intervention or develop endocarditis than those with valve or supravalve stenosis. Follow up into adult life is essential.

Congenital complete heart block and vasodepressor syncope.

An 18-year-old boy with congenital complete heart block presented with recurrent syncope following insertion of a rate-responsive dual-chamber pacemaker. Head-up tilt testing demonstrated a primary vasodepressor response with severe hypotension and reproduction of symptoms. Treatment with fludrocortisone and salt abolished symptoms, and repeat tilt testing was negative.

Fallot's tetralogy with absent pulmonary valve and anomalous origin of the left pulmonary artery.

A 1-day-old asymptomatic neonate with a to and fro precordial murmur was diagnosed by cross sectional echocardiography to have Fallot's tetralogy with absent pulmonary valve, and origin of the left pulmonary artery from the ascending aorta. Moderate stenoses at the origin of the anomalous left pulmonary artery and of the right pulmonary artery were present, allowing definitive surgical correction to be deferred.

The progression of mild congenital aortic valve stenosis from childhood into adult life.

UNLABELLED: We studied 187 patients who presented with mild congenital aortic valve stenosis or a bicuspid aortic valve without stenosis at presentation; 63% were males. Information on all clinical events was obtained, and patients were traced to assess current clinical status. RESULTS: The median age at presentation was 2 years (range, 0-15). Additional cardiac lesions occurred in 51 patients, more commonly in patients presenting under 1 year of age (P < 0.0001). The median duration of follow-up was 10 years (range, 1-28); seven patients were lost to follow-up. Thirty-two patients progressed to require intervention (28 surgical, five balloon valvuloplasty) at a median age of 10.5 years. No patient who presented with a bicuspid aortic valve required intervention. Two patients developed endocarditis. There were eight deaths; four after surgery for aortic stenosis and four due to other cardiac lesions. There were no sudden deaths. Actuarial and hazard analysis showed that progression beyond mild stenosis was closely related to duration of follow-up. CONCLUSIONS: Congenital aortic valve stenosis is most frequently mild at presentation. Progression is related to duration of follow-up. Fewer than 20% of patients are likely to still have mild stenosis after 30 years. Follow-up into adult life is essential.

Recanalisation of an occluded modified Blalock-Taussig shunt by balloon dilatation.

A four year old boy with pulmonary atresia and ventricular septal defect had an acute cyanotic episode three years after undergoing a right-sided, 6 mm diameter, modified Blalock-Taussig shunt. On admission no continuous murmur could be heard from the shunt and the typical high velocity, continuous flow profile of the shunt could not be identified by Doppler echocardiography. At catheterisation a right subclavian artery angiogram confirmed shunt occlusion. From the subclavian artery, an 0.035 inch wire was used to enter the occluded shunt and then the pulmonary artery. Balloon angioplasty of the entire length of the shunt was performed with 6 mm diameter balloon. After angioplasty the arterial oxygen saturation increased from 63% to 83%. The patient was treated with intravenous heparin followed by warfarin. Repeat catheterisation and angiography eight days later confirmed wide patency of the shunt.