A. Heusch

Off-label drug use among hospitalised children: identifying areas with the highest need for research

Objective of the study To analyse the off-label use of drugs on a paediatric ward in Germany, and to identify domains of pharmacotherapy with the highest need for research concerning off-label use in children. Setting A prospective observational study was conducted on a paediatric ward in Duesseldorf in Germany between January and June 2006. Method Data about patients, diagnoses and prescribed drugs were collected from the prescription records and the discharge letters. Diagnoses were classified in groups by means of the International Classification of Diseases. Drugs were grouped according to the Anatomical Therapeutic Chemical Classification system. We compared the off-label prescriptions with those on the list of paediatric needs and priority list established by the European Medicines Agency (EMEA). Main outcome measure Off-label use was defined due to age, indication, route of application and dose. Results The study included 417 patients. We analysed 1,812 prescriptions representing 211 different drugs. In total, 253 patients (61%) received at least one off-label prescription. Of all analysed prescriptions, 553 (31%) were off-label. The percentage of off-label prescriptions among the five most frequently prescribed drug groups were as follows: 60% cardiovascular drugs (CV: 129/216), 42% anti-infectives (AI: 190/449), 30% drugs for respiratory system (RS: 100/335), 25% drugs for alimentary tract and metabolism (AM: 67/269) and 3% analgesics and antipyretics (AA: 8/264); with 17 drugs, the cardiovascular drugs also showed the highest number of different off-label prescribed drugs due to age: AI: 14; AM: 11; RS: 5; AA: 1. In addition, there was a nearly complete overlap between the identified off-label prescriptions in cardiovascular drugs and those listed by the EMEA to be prioritized for urgent research in Europe. ConclusionCardiovascular drugs are a domain of pharmacotherapy, with a large need for research in paediatrics. The results of our study can guide the researcher to future trials on off-label prescriptions such as cardiovascular drugs, especially due to the fact that the identified off-label prescribed drugs in this group are also mentioned by the EMEA to be prioritized for paediatric research.

Evans syndrome in a patient with chromosome 22q11.2 deletion syndrome: A case report

One patient with a chromosome 22q11.2 deletion and Evans syndrome is reported in this paper. Microdeletions of 22q11.2 are the main etiology for DiGeorge syndrome, a disorder characterized by heart defects, immune deficiencies due to aplasia or hypoplasia of the thymus, and hypocalcemia. Evans syndrome refers to a hematological autoimmune disorder with autoimmune hemolytic anemia accompanied by immune thrombocytopenia. A wide range of autoimmune disorders have been described in DiGeorge syndrome and velocardiofacial syndrome, including one prior report of autoimmune hemolytic anemia and immune thrombocytopenia. The patient reported herein strengthens the association between the 22q11.2 deletion spectrum and Evans syndrome.

Volumetric analysis of the right ventricle in children with congenital heart defects: comparison of biplane angiography and transthoracic 3-dimensional echocardiography.

BACKGROUND Three-dimensional echocardiography is a non-invasive imaging technique. The fact that it permits volumetric analyses independently of geometrical assumptions makes it a putatively useful method for the precise measurement of the volumes of the irregularly shaped right ventricles in children. The aim of this study was to assess the feasibility of this method and its agreement with angiocardiography based estimates of right ventricular volume in children with congenital heart disease. METHODS We studied 102 children with congenital heart disease. The angiocardiographic right ventricular volumetry was performed using a biplanar technique using Simpsons rule and corrected with Langes correction factors. The echo data sets were registered trans-thoracically with a rotating transmitter. Volumes were calculated after manual planimetry by adding the volumes of the individual slices. RESULTS Calculation of right ventricular volume echocardiographically was possible only in 34% of patients, mostly infants and toddlers. In comparison to angiocardiography, the measured volumes were 1.1 +/- 6.9 ml (19.5 +/- 34.1%) or 6.3 +/- 9.4 ml (42.5 +/- 33.6%) smaller during systole or diastole, respectively. The limits of agreement were -12.5 and 13.6 ml, or 12.45 and 25.15 ml during systole or diastole, respectively. When plotted to a logarithmical scale, the correlation coefficients r2 were 0.70 for systolic and 0.79 for diastolic measurements. CONCLUSION Transthoracic 3-dimensional echocardiography with a rotating transmitter is feasible for volumetry only in small children. The volumes measured were significantly smaller than the ones calculated from the angiocardiographic images. The correlation between the two methods is moderate.

Volume Measurement of the Left Ventricle in Children with Congenital Heart Defects: 3-Dimensional Echocardiography versus Angiocardiography

Background: Volume measurement of the left ventricle is currently done by 2-dimensional echocardiography or angiocardiography. However, for the calculation of volumes by these methods, geometrical assumptions must be made. For a precise ventricular volumetry, independent of mathematical assumptions, imaging techniques as the 3-dimensional echocardiography (3D-echo) are required, which permit the imaging of the real ventricular shape. The aim of the study was therefore to detect, whether 3D-echocardiography is suitable for left ventricular volumetry in children with congenital heart disease and whether the 3D-echocadiographically measured volumes correlate sufficiently well with angiocardiographically measured left ventricular volumes. Methods: 102 children with congenital heart disease were investigated. For angiocardiographic left ventricular volume measurement Simpson’s rule was used. Results were corrected with Lange’s correction factors. The 3D-echo data sets were registered with a rotating transthoracic transducer. Ventricular volumes were calculated after manual planimetry by summation of the volumes of the single slices. Results: The left ventricular volume could be calculated by 3D-echo in 83% of patients of all ages. In comparison to angiocardiography, the measured volumes were 0.6 ± 3.3 ml (0.9 ± 25.8%) or 7.1 ± 28.4 ml (7.4 ± 12.1%) smaller during systole or diastole, respectively. The correlation coefficients r2 were 0.89 for systolic and 0.93 for diastolic measurements after logarithmic transformation. Pressure or volume overload did not influence significantly the difference between the two methods. Conclusion: Transthoracic 3D-echocardiography with a rotating transmitter is feasible for volumetry of the left ventricle in most children. The volumes measured by 3D-echo were significantly smaller than those calculated from the angiocardiography by Simpson’s rule. The measurements were not influenced by the kind of load of the ventricle. The correlation between the two methods is good.

Anomalous Origin of All Coronary Arteries from the Pulmonary Trunk

The origin of both coronary arteries from the pulmonary artery is a rare cardiac malformation. We report a baby who presented with an echocardiographically diagnosed perimembranous ventricular septal defect and normal left ventricular (LV) function. Later on the boy developed failure to thrive and increasing tachypnea. At the age of 5 weeks the ECG showed that LV strain and echocardiographic LV function had worsened (FS 18%). Echocardiography and heart catheterization showed that all coronary arteries originated from the pulmonary trunk. Intraoperative inspection revealed a single ostium for the right and left coronary artery in the nonfacing sinus of the pulmonary trunk. A tube was constructed connecting the coronary artery to the ascending aorta. Coronary perfusion was sufficient and the sinus rhythm was restored. However, in the early postoperative period there was a sudden deterioration of cardiac output followed by cardiac arrest. Reanimation was not successful.

Complete AV-block in two children with immunohistological proven myocarditis

We report two children with acquired third degree AV-block caused by acute myocarditis. The diagnosis was proven by endomyocardial biopsy. Severe lymphocytic myocardial infiltration was shown using immunohistological methods. One of the children was treated with prednisone. During therapy conduction disturbance nearly disappeared and infiltration was markedly reduced in a subsequent biopsy. In the other patient the parents refused immunosuppressive treatment and a permanent pacemaker was necessary for persistent bradycardia.

Normative angiographic data relating to the dimensions of the aorta and pulmonary trunk in children and adolescents.

BACKGROUND Definition of normative data of the great arteries from neonatal to adult ages may aid in assessment of the growth of cardiovascular structures, thus guiding the timing and type of intervention in patients with congenital cardiac disease. METHODS We calculated the cross-sectional areas of the arterial roots at the basal attachment of the valvar leaflets, the sinuses, and standardized distal sites using cineangiograms of 59 normal children and adolescents with mean age of 5.4 plus or minus 4.7 years and a range from 0.1 to 16 years, the children having a mean weight of 21.2 plus or minus 15.7 kilograms, with a range from 2.2 to 68 kilograms, and mean height of 108 plus or minus 35 centimetres, with a range from 43 to 184 centimetres. Values at each site were calculated averaging end-diastolic and end-systolic measurements, and indexed to body surface area. Results are expressed as the mean plus or minus the standard deviation. RESULTS The diameter of the aortic root at the basal attachment of the leaflets was 249 plus or minus 26, the midpoint of the sinuses 379 plus or minus 59, the sinutubular junction 290 plus or minus 58, the isthmus 158 plus or minus 36, the postisthmic region 152 plus or minus 33, and the descending aorta at the level of diaphragm 130 plus or minus 18 millimetres squared per metre squared. The pulmonary root measured at the basal attachment of the leaflets was 253 plus or minus 28, the midpoint of the sinuses 352 plus or minus 58, the sinutubular junction 293 plus or minus 58, the right pulmonary artery 176 plus or minus 25, the left pulmonary artery 153 plus or minus 20, and sum of right and left pulmonary arteries 330 plus or minus 37 millimetres squared per metre squared. All indexes were consistent over a wide range for body surface areas. CONCLUSIONS Definition of normative data of the great vessels may aid in the evaluation of congenital or acquired abnormalities, serving as guidelines for intervention during medical or surgical management and follow-up.

Balloon valvoplasty in infants with tetralogy of Fallot: effects on oxygen saturation and growth of the pulmonary arteries.

Balloon valvoplasty was undertaken in 27 patients with tetralogy of Fallot for first-stage palliation. Indications were arterial saturation of oxygen < 80%, hypoxic spells and duct-dependant pulmonary perfusion. The dilation was performed following diagnostic heart catheterization. Saturations improved from 75% +/- 8.5 before valvoplasty to 85% +/- 8.4 after the procedure, and worsened little to 83% +/- 9.6 at follow-up after 3.4 months. The pulmonary valvar orifice was hypoplastic in most patients (Z = -3.3 +/- 1.2), and did not change after the procedure. The cross-sectional area of the pulmonary arteries was diminished initially, reflected by a Nakata index of 186 +/- 95 mm2/m2. After valvoplasty, we found widening of the vessels (Nakata index 225 +/- 100 mm2/m2). At follow-up no further growth of the arteries was observed (Nakata index 209 +/- 109 mm2/m2). The procedure was complicated by hypoxic spells in three patients which were controlled by intravenous propranolol, and deep venous thrombosis in four patients. Our data demonstrate that balloon valvoplasty is feasible for initial palliation in patients with tetralogy of Fallot. It does not, however, produce growth of the pulmonary arteries or of the pulmonary valve.

Acute purulent pericarditis in pneumococcal meningitis

local abscesses twice. A detailed immunological work-up revealed an isolated immunoglobulin G4 deficiency. It remains unclear whether this was reactive or preexistent. In systemic bacterial infection, e.g., sepsis or meningitis, purulent pericardial effusion may develop rapidly. The incidence of pericarditis in meningococcal disease is higher (3–19%) [1] than in invasive pneumococcal disease (none of 166 pediatric cases) [2]. Cardiac tamponade or constrictive pericarditis may result, particularly if diagnosis and treatment are delayed; therefore, radiological cardiomegaly should prompt echocardiography in order to achieve an early diagnosis. Medical treatment of purulent pericarditis consists of the use of appropriate antibiotics in combination with anti-inflammatory drugs such as short-term steroids and long-term non-steroidal antiphlogistic drugs. For acute decompression of cardiac tamponade percutaneous or open surgical drainage may be necessary. The risk of development of constrictive pericarditis appears higher in delayed drainage [3]. An alternative to surgical evacuation may be intrapericardial fibrinolysis [4, 5]. This non-surgical approach is less traumatic to the patient but may be contraindicated in septic patients with acquired clotting disorders and bleeding tendency. At present, the number of published cases is too small to deduct clear evidencebased recommendations. In summary, in a seriously ill and hypotensive patient suffering from bacterial meningitis, purulent pericarditis should be excluded.

Aortico-linksventrikulärer Tunnel: Seltene Differentialdiagnose einer kongenitalen Aorteninsuffizienz

Aortico-left ventricular tunnel (ALVT) is a rare congenital cardiac malformation that presents with cardiac failure and clinical findings of severe aortic regurgitation in early infancy. The diagnosis should be made with 2-D echocardiography by demonstrating an abnormal tunnel-like structure that connects the ascending aorta with the left ventricle. Up to 45% of the patients may have associated cardiac defects, and the development of this bizarre lesion is still unclear. In contrast to congenital aortic regurgitation, ALVT has a better prognosis. Early surgical intervention is curative, but non-operated children die because of heart failure. Therefore, knowledge of this rare cardiac malformation is mandatory if an infant presents with findings of aortic regurgitation. Der Aortico- linksventrikuläre Tunnel (ALVT) ist eine seltene angeborene kardiale Malformation, die typischerweise im frühen Säuglingsalter mit Herzinsuffizienzzeichen und dem klinischen Bild einer schweren Aortenregurgitation auffällt.    Die Diagnosestellung ist mittels 2D-Echokardiographie möglich, wobei man die tunnelförmige paravalvuläre Verbindung zwischen der aszendierenden Aorta und dem linken Ventrikel darstellen muss. Bis zu 45% der Patienten haben weitere kardiale Fehlbildungen, wobei die Ursache dieser eigentümlichen Malformation bisher nicht klar ist. Im Gegensatz zur kongenitalen Aorteninsuffizienz ist der ALVT schon frühzeitig kurativ operabel. Nicht operierte Kinder versterben jedoch bald an zunehmender Herzinsuffizienz. Die Kenntnis dieser seltenen Fehlbildung ist daher bei differentialdiagnostischen Überlegungen einer kongenitalen Aortenisuffizienz wichtig.