Off label and unlicensed drugs use in paediatric cardiology.

OBJECTIVES: The use of drugs in an off label or unlicensed manner to treat children is a widespread phenomenon in Europe and the United States. The incidence of unlicensed and off label prescribing in paediatric cardiology practice has not been studied to date. This study was designed to assess the extent and nature of off label and unlicensed drug use in paediatric cardiology inpatients. METHODS: In a prospective study, drug prescriptions in a paediatric cardiology ward were reviewed during a 2-year period. Data were collected and analyzed by special software created for this purpose. RESULTS: The children (n = 544) studied varied in age from 4 h to 18 years. One or more off label and unlicensed prescriptions were given to 414 (76%) patients. Of the 2,130 prescriptions given during the 2-year period, more than one-half were unlicensed (11%) or off label (47%). While children aged 2-11 years received most of the unlicensed drug prescriptions (17%), neonates, who did not receive unlicensed drugs, led (64%) in the use of off label drugs. CONCLUSIONS. This study showed that the problem of off label and unlicensed drug use also exists in paediatric cardiology. The findings imply that the phenomenon of off label and unlicensed use of drugs in children can be correlated with the deficiency of paediatric drug formulations on the global market and insufficient data from clinical studies which must be performed to confirm the efficacy and safety of drugs in the paediatric population. Therefore, efforts to improve paediatric labelling are important and need the full support of all involved.

Transcatheter closure of high pulmonary artery pressure persistent ductus arteriosus with the Amplatzer muscular ventricular septal defect occluder.

BACKGROUND: The design of devices currently used for closure of persistent ductus arteriosus (PDA) with high pulmonary artery pressure is not ideal and there is a risk of embolisation into the aorta. OBJECTIVE: To investigate the use of the Amplatzer muscular ventricular septal defect occluder (AMVSDO) for treatment of PDA with high pulmonary artery pressure. PATIENTS AND DESIGN: Seven patients, aged 5-12 years, with large PDAs and systemic or near systemic pulmonary artery pressure underwent attempted transcatheter closure using the AMVSDO. The device consists of two low profile disks made of a nitinol wire mesh with a 7 mm connecting waist. Balloon occlusion of the duct was performed before closure from the venous side, and prosthesis size was chosen according to the measured diameter of the occluding balloon. A 7 French sheath was used to deliver the device. All patients underwent a complete haemodynamic and angiographic study one year after occlusion. RESULTS: The mean (SD) angiographic PDA diameter was 9.8 (1.7) mm (range 7-13 mm) and the mean AMVSDO diameter was 11.4 (1.8) mm (range 9-16 mm). Q(p)/Q(s) ranged from 1.9-2.2 (mean 2.0 (0.1)). Successful device delivery and complete closure occurred in all patients (100% occlusion rate, 95% confidence interval 59.04% to 100.00%). Mean systolic pulmonary artery pressures were as follows: before balloon occlusion, 106 (13) mm Hg; during occlusion, 61 (6) mm Hg; immediately after the procedure, 57 (5) mm Hg; and at the one year follow up catheterisation, 37 (10) mm Hg. Fluoroscopy time was 10.4 (4.3) min (range 7-18 min). No complications occurred. CONCLUSIONS: AMVSDO is an important adjunct for closure of large PDAs associated with high pulmonary artery pressure. Further studies are required to document its efficacy, safety, and long term results in a larger number of patients.

Partial left ventriculectomy in a two-year-old girl with dilated cardiomyopathy.

We report the case of a two-year-old girl with end-stage dilated cardiomyopathy who was a status I heart transplant candidate. Partial left ventriculectomy and novel mitral valve repair were performed. Early hemodynamic and functional improvements were maintained at the 18-month follow-up.

Initial clinical experience with PerDUCER device: promising new tool in the diagnosis and treatment of pericardial disease.

BACKGROUND: The idea to enter the normal pericardial sac safely was unrealistic until recently. The development of a novel instrument (PerDUCER pericardial access device) for percutaneous access to the pericardium could potentially have a significant impact, not only on patients with pericardial diseases but even more, or primarily, on diagnosis and treatment of myocardial and coronary disease and arrhythmias. HYPOTHESIS: The overall objective of the present study was to evaluate the feasibility and safety of the percutaneous pericardial access with PerDUCER in patients with pericardial disease, and to analyze our initial experience with this new technique, with particular emphasis on sequential procedural steps. METHODS: The device was studied in five patients with pericardial disease (two men, mean age 50.4 years, range 30-68, four with normal body mass index). The procedure consists of two distinct techniques: (1) access to the mediastinal space, and (2) pericardial capture, puncture, and insertion of the guidewire. Access to the mediastinal space includes the introduction of a blunt cannula, a 0.038 guidewire, a dilator-introducer sheath set, and insertion of the PerDUCER device. Key points of the PerDUCER procedure are as follows: introduction of the blunt cannula without resistance, placement of the dilator-introducer sheath at the upper third of the heart, systolic movements of the PerDUCER device, successful vacuum and capture of pericardium, puncture and introduction of the intrapericardial guidewire. RESULTS: Access to the mediastinal space was accomplished in four of five patients, as were pericardial capture and probably puncture. However, despite numerous successful captures and probably punctures of pericardium, we were not able to confirm introduction of the intrapericardial guidewire into the pericardial cavity in any of our patients (0/5). The procedure was very well tolerated in all patients (5/5). No major complications developed during the procedure, bearing in mind that the intrapericardial placement of the guidewire was not achieved. Minor complications included pain at the dilator-introducer sheath entry site (5/5) and mild transient fever (2/5). CONCLUSIONS: According to the present experience, we believe that, with minor modifications, the PerDUCER device could be successfully implemented for pericardial entry in patients with pericardial disease. Further studies are needed to evaluate the feasibility and safety of this new instrument in patients with a normal pericardium. This could open a most exciting spectrum of possible implementations of the device in the future.

Percutaneous balloon dilatation of the atrial septum: immediate and midterm results.

OBJECTIVES: To assess the effectiveness of atrial septostomy by percutaneous balloon dilatation in patients with congenital heart defects or primary pulmonary hypertension. PATIENTS AND DESIGN: Twenty three patients (15 boys, eight girls; aged 10 days to 10 years; 17 with congenital heart defects and six with primary pulmonary hypertension), all haemodynamically unstable under optimal medical treatment, underwent atrial septostomy by percutaneous balloon dilatation. INTERVENTIONS: The balloon catheter entered the left atrium through a patent foramen ovale (n = 14) or via transseptal puncture in cases with an intact atrial septum (n = 9). The size of the balloons used ranged from 13 to 18 mm. RESULTS: There were no complications. The interatrial communication (mm) increased (P < 0.05) after dilatation and remained unchanged (P = NS) during a 16.6 (13.8) month follow up (2 (1.7) v 8.8 (1.4) v 8.2 (1.1), respectively). Transatrial gradient (mm Hg) fell and arterial oxygenation (%) improved both in patients with transposition (6.3 (0.8) v 0.8 (1) (P = 0.0001) and 40.6 (4.2) v 76.5 (4.8) (P = 0.0001), respectively) and in those with mitral atresia (13.4 (1.9) v 2 (1.4) (P = 0.0001) and 77.1 (3.9) v 81.5 (4.2) (P = 0.008), respectively). There were two failures, one early and one late, both in the group of patients with mitral atresia or stenosis. A decrease in arterial oxygenation (94.8 (1.5) v 83 (2.4), P = 0.004) and an increase in left atrial pressure (6.8 (0.9) v 8.3 (1.2), P = 0.02) and cardiac index (2.3 (0.2) v 3.1 (0.2) l/min/m2, P = 0.002) was observed in patients with primary pulmonary hypertension. CONCLUSIONS: Percutaneous balloon dilatation is an effective and safe procedure for creating an adequate interatrial communication that can be used as an alternative to blade septostomy.

Myocardial catecholamines in primary heart muscle disease: fact or fancy?

The pathophysiological role of myocardial catecholamines in cardiomyopathies is still not completely understood. We there-fore assessed myocardial catecholamine concentrations (MCC) in 34 patients with hypertrophic cardiomyopathy (HCM) (76.5% males; mean age 46.7 +/- 11.6 years; left ventricular ejection fraction [LVEF] 75.3 +/- 9.8%) and in 32 patients with dilated cardiomyopathy (DCM) (87.5% males, mean age 43.1 +/- 12.5 years, LVEF 34.9 +/- 8.3%). Initial assessment included clinical work up, cardiac catheterization and endomyocardial biopsy. Myocardial norepinephrine (MNEC), epinephrine (MEC), and dopamine (MDC) concentrations in endomyocardial biopsy samples were measured using the catechol-O- methyl transferase radioenzymatic method. Significantly higher MNEC and MEC were demonstrated in HCM than in DCM patients (MNEC: 781.9 +/- 125.8 ng.g-1 fresh myocardial tissue (ft) HCM vs 262.6 +/- 68.9 ng.g-1 ft DCM, p < 0.01; and MEC: 91.6 +/- 13.9 ng.g-1 ft HCM vs 35.8 +/- 6.2 ng.g-1 ft DCM, P < 0.01). The difference in MDC did not reach statistical significance (76.1 +/- 8.3 ng.g-1 ft HCM vs 70.1 +/- 11.8 ng.g ft DCM; P > 0.05). In addition, we compared the MCC levels in 24 patients, clinically presented as dilated cardiomyopathy categorized according to the various aetiologies: 12/24 with primary DCM (75.0% males, mean age 49.6 +/- 9.5 years; LVEF 25.8 +/- 63%), 7/24 with alcohol-induced heart disease (85.7% males, mean age 46.8 +/- 7.1 years; LVEF 26.4 +/- 4.6%), and 5/24 with hypertensive heart disease (100% males, 45.1 +/- 10.6 years; LVEF 25.6 +/- 9.1%), but no significant difference was found among them (P > 0.05). There was no significant difference in tissue dopamine concentrations.

Endomyocardial biopsy: a meta-analysis of diagnostic value.

To clarify the controversy of endomyocardial biopsy (EMB) in terms of its diagnostic value, we performed a meta-analysis of EMB studies published between 1982 and 1993, including our own experience. A total of 255 articles was retrieved using both a computer search of the Medline database and a manual bibliographic search, but only 30 studies with 4,313 patients met the predefined inclusion/exclusion criteria. The diagnostic value of EMB was classified into four categories, according to the effect of EMB findings on the discharge diagnosis: aetiology uncovered, new diagnosis of heart muscle disease (HMD) revealed, clinical diagnosis confirmed, and no useful information obtained. Clarification of aetiology of HMD was reported in 28 out of 30 studies with a total of 4,195 patients and it was achieved by EMB in 17.9% of these patients (95% confidence interval (CI) was 16.8-19.1%). A new unexpected diagnosis of HMD was arrived at in 25 of 30 studies (3,947 patients) and this occurred in 19.3% of patients (95% CI = 18.1-20.6%). Confirmed clinical diagnosis of HMD by EMB was covered by 12 studies (1,231 patients) and was proven in 40.1% of patients (95% CI = 37.3-42.7%). EMB not providing any useful clinical information was mentioned in seven of 30 studies (857 patients); this happened in 5.9% of patients (95% CI = 4.5-7.4%). Therefore, these results confirmed the remarkable diagnostic value of EMB. It was equally helpful in all diagnostic categories and had considerable overall diagnostic utility.

Doppler echocardiographic analysis of the transmitral flow velocity profile in patients with ventricular septal defects.

Using continuous-wave Doppler echocardiography, we evaluated the mitral flow velocity pattern in 30 ventricular septal defect patients, 11 of whom had severe pulmonary vascular obstructive disease (Group I); 10 of whom had severe pulmonary hypertension without pulmonary vascular obstructive disease (Group II); and 9 of whom had no pulmonary hypertension and hemodynamically unimportant left-to-right shunts (Group III). In addition, 25 healthy subjects (Group IV) were studied for comparative purposes. The peak velocity of early left ventricular filling (E) was significantly lower in Group I than in all the other groups (p < 0.01). The peak velocity of late left ventricular filling (A) was significantly higher (p < 0.01) in Group I than in Group III, or than in normal individuals (Group IV) (p < 0.01). The ratio A/E was the most prominent difference between Group I patients and the other groups, with Group I having a significantly higher ratio (p < 0.01), which was 1 or greater in 9 of 11 patients. In contrast, none of the remaining ventricular septal defect patients or normal subjects had an A/E ratio of 1 or greater. Group II had increased mitral flow velocities, while Group III had normal mitral flow velocity profiles. A positive correlation between the magnitude of the left-to-right shunt and early mitral flow velocity peak (r = 0.86) and late peak (r = 0.81) was found, regardless of the degree of pulmonary hypertension. These results indicate that significant alterations of the mitral flow velocity pattern, which mimic the abnormalities associated with impaired left ventricular diastolic function (A/E ratio of 1 or greater), occur in ventricular septal defect patients who have severe pulmonary vascular obstructive disease. The transmitral velocity profiles in the ventricular septal defect patients without severe pulmonary vascular obstructive disease were similar to those of the normal patients, although the values relative to the degree of left-to-right shunting were higher in the ventricular septal defect patients.

[Cardiotoxic effect of anthracycline antibiotics]. / Kardiotoksicni efekti antraciklinskih antibiotika.

Anthracycline antibiotic (Rubidomycin and Adriamycin) are often used for treatment of acute leukemia and variety of solid tumors. The use of greater doses of these agents is mostly limited by the damage of the cardiac muscle and by heart failure. The Rubidomycin cardiac toxicity analysis of children with acute leukemia has been considered in this paper. The results were obtained by investigating 53 patients who received this drug. They were classified in subgroups in relation to the total dose administered. Acute or chronic myocardial damage appeared in 6 children. The subgroup incidence of damage is directly proportional to the total dose administered.