[Primary pulmonary hypertension in children]. / Primaer pulmonal hypertensjon hos barn.

Primary pulmonary hypertension is a clinical syndrome with severe pulmonary hypertension where other causal diseases are excluded. The condition is progressive, fatal and disappointingly resistant to therapy. In this article we present three children with the disease. Two of the patients died shortly after diagnosis, one of them during heart catheterization. The third patient showed good response to treatment with calcium channel blockers, diuretics and nightly supplementary oxygen. Quality of life and hemodynamics improved during the first six months of treatment, and remained virtually unchanged for another two years. Her condition then deteriorated rapidly, and she died three years after diagnosis. According to the literature and our experience, investigations with non-invasive methods such as oxygen saturation measurement, echocardiography, and a simple exercise test provide sufficient information to start therapy and monitor therapeutic response. Some patients show vasodilatory response to treatment with drugs, and might benefit from therapy with calcium channel blockers.

Cardiac function and morphology studied by two-dimensional Doppler echocardiography in unsedated newborn pigs.

The newborn pig is currently the most used species in animal neonatal research. Valid non-invasive monitoring is important in particular for long-term survival of unsedated animals. In the unsedated newborn pig (n = 35, median age 24 h, range 7-48 h) we standardized two-dimensional Doppler echocardiography and determined the normal ranges for cardiac function. Probe positioning had to be adjusted to the V-shaped thorax and the mid-line position of the heart. Six out of the sixteen animals < 20 h had a patent ductus arteriosus compared with one of the twenty animals > 20 h old. One atrial septal defect (5 mm) and one small ventricular septal defect were diagnosed. The average heart size was 0.7-0.9% of body weight which is similar to human infants of the same size. The mean aortic diameter was 6.0 +/- 0.5 mm (mean +/- S.D.) and cardiac output was 0.38 +/- 0.08 l min-1; both correlate with body weight (r = 0.80 and 0.73, respectively). Tricuspid regurgitation velocity was 3.0 +/- 0.4 m s-1 (mean +/- S.D.), giving an estimated pressure gradient across the tricuspid valve of 37 +/- 9.7 mmHg. The aortic diameter and the heart weight per kg body weight are comparable to those reported for preterm neonates. The cardiac output and velocities across the four valves are more comparable with term neonates.

Effect of low and moderate doses of recombinant human erythropoietin on the haematological response in premature infants on a high protein and iron intake.

UNLABELLED: There is no consensus regarding protein intake and the doses of recombinant human erythropoietin (r-HuEpo) and iron in the treatment of anaemia of prematurity (AOP). This open, randomized study has compared the effectiveness of 50 IU r-HuEpo/kg with that of 100 IU/kg, both given subcutaneously thrice weekly. In addition, two different protein supplements have been compared; lyophilized human milk protein and a commercial cow's milk product. Total protein intake was 3 g/kg per day. Daily iron dose was 18-36 mg. "Healthy" preterm infants (n = 32, birth weight: 800-1400 g, gestational age < or = 31 weeks) were studied from age 3 to 8 weeks. The two protein regimens yielded no differences in body growth, reticulocyte count or Hb concentration. In both r-HuEpo dose groups increased number of reticulocytes followed start of treatment; higher levels were, however, found in the group receiving 100 IU/kg. Mean Hb concentration plateaued at 12 g/dl for infants receiving 100 IU/kg, at 11 g/dl in the 50 IU/kg group. Even though serum levels of ferritin and transferrin saturation indicated no iron deficiency, soluble transferrin receptor increased in both groups, more rapidly and to higher levels in the 100 IU/kg group. In addition, the number of infants having more than 8% hypochromic red cells increased in both groups. CONCLUSIONS: Commercial cow's milk protein added to human milk was as good as human milk protein supplementation in supporting growth and erythropoiesis. Fifty IU/kg r-HuEpo thrice weekly during AOP stimulated erythropoiesis significantly, but less so than 100 IU/kg. Even when using high oral doses of iron to preterms receiving r-HuEpo, our data suggested a certain degree of iron deficient erythropoiesis.

Erythropoietin (Epo), protein and iron supplementation and the prevention of anaemia of prematurity: effects on serum immunoreactive Epo, growth and protein and iron metabolism.

The effect of recombinant human (r-Hu) erythropoietin (Epo) (300 IU/Kg per week for 4 weeks) was studied in healthy preterm infants (n = 14) fed human milk with additional milk protein and high doses of iron. The controls (n = 15) were in themselves a study group and were used to follow the natural course of anaemia of prematurity on such nutrition. Serum immunoreactive Epo (SiEpo) increased significantly 24 h after r-HuEpo injections (range 36 to > 128 mU/ml) and remained at these levels throughout the treatment period. r-HuEpo in such moderate doses kept haemoglobin above 11 g/dl. Bodyweight gain, protein and iron parameters indicated adequacy of dietary protein and iron. In controls, siEpo increased during the first weeks after nutritional supplementation, with a concommitant rise in reticulocyte count. At age 3 weeks, despite low siEpo levels, reticulocyte counts indicated active erythropoiesis. Following further moderate increases in siEpo, the reticulocyte count increased to high levels (7%). The reticulocyte response suggests that erythropoiesis in preterm infants is less dependent upon Epo levels than in adults.

Effects of recombinant human erythropoietin on fetal and adult hemoglobin in preterm infants.

In the present study we assess the effect of recombinant human erythropoietin (r-HuEpo) upon levels of fetal Hb (HbF) and adult Hb (HbA) in preterm infants. Twenty-eight "healthy," appropriate for gestational age infants with birth weights 900-1400 g entered the study at 3 wk of age. Fourteen infants were randomized to receive r-HuEpo, and 14 infants served as controls. Four controls and six r-HuEpo treated infants had been transfused before study start, whereas four control infants were transfused in the course of the study. The untransfused infants showed a high HbF/Hb ratio during the study with only a weak tendency to decline toward the expected time of delivery. The total Hb mass increased (p < 0.05) more in the r-HuEpo-treated infants than in the untreated, whereas the rise in HbF mass was similar in the two groups. After each transfusion, the HbF/Hb ratio reverted gradually to the ratio expected at the infant's postconceptional age. There was no difference in the production rate of HbF between r-HuEpo-treated infants and controls. The present data indicate that the HbF/HbA ratio in preterm infants is subject to the same programmed mechanisms which govern intrauterine erythropoiesis until term and that exogenous r-HuEpo does not influence this pattern significantly.

Endogenous norepinephrine stimulates both alpha 1- and beta-adrenoceptors in myocardium from children with congenital heart defects.

Atrial tissue removed from the cannulation site prior to cardioplegia (n = 15), and ventricular tissue therapeutically excised from the outflow tract of the right ventricle, (RVOT) (n = 2) were examined with respect to adrenoceptor mediated inotropic effect in children with congenital heart defects (CHD). We used sequential reversal by adrenoceptor antagonists of the tyramine enhanced response to endogenous norepinephrine to quantify the role of the beta- and the alpha 1-adrenoceptors, respectively, in the intropic response. Atrial myocardium had an alpha 1-adrenoceptor mediated component of 14% (median) (range 0-44%) and a beta-adrenoceptor mediated component of 86% (median) (range 56-100%). The patients with the highest alpha 1-adrenoceptor mediated inotropic components, had right ventricular pressure loads in the systemic range. In one specimen from RVOT, the ventricular alpha 1-adrenoceptor component was estimated to be 22% of the total inotropic response, compared to 26% in the corresponding right atrium. In a ventricular specimen from another patient, we could not demonstrate any alpha 1-adrenoceptor mediated inotropic component in contrast to 13% in the right atrium. This patient, however, had infusion of the alpha-adrenoceptor antagonist phentolamine after the excision of atrial tissue, but before the excision of muscular tissue from RVOT. In myocardium of children with CHD we found evidence that endogenous norepinephrine stimulated alpha 1-adrenoceptors in addition to beta-adrenoceptors. The relative contributions from the two adrenoceptors to the inotropic response varied considerably, and may be related to the pressure load of the right ventricle. These observations may be relevant with respect both to pathophysiology and to choice of drug therapy.

Congestive heart failure caused by vitamin D deficiency?

We describe a child, 3.5 months old, with severe vitamin D deficiency, profound hypocalcaemia, hyperphosphataemia, dilated left ventricle, severely reduced myocardial contractility and congestive heart failure. She also had depressed thyroid function with subnormal thyroxine and non-detectable serum thyrotropin (TSH) levels. The child promptly responded to calcium infusions, conventional anticongestive therapy and calcitriol. She is now 3 years old and received no medication. Myocardial function is normal but she has motor delay. We believe that her transitory congestive heart failure was caused by severe vitamin D deficiency with profound hypocalcaemia.

Functional characterization of an ex vivo preparation of atrial myocardium from children with congenital heart defects: sensitivity to tyramine and adrenoceptor antagonists.

Small pieces of atrial tissue removed from the cannulation site before cardioplegia were used to develop a method for studying adrenergic regulation of the myocardial contractile force in children operated on for congenital heart defects (CHD). We measured the development of the isometric force of contraction dT/dtmax (T'max). Reduction in basal contractility induced by the beta-adrenoceptor antagonist timolol indicated that the myocardium was about half-maximally stimulated by endogenous norepinephrine (NE), probably released from nerve endings by the electrical stimulation. The inotropic effect of endogenous NE could be further increased by tyramine (EC50 approximately 5 microM). A maximal concentration of tyramine increased T'max by a median of 62.5% above the basal level. Sequential blockade of the beta- and alpha 1-adrenoceptors after tyramine stimulation by timolol and prazosin, respectively, indicated that a near-maximal response to combined adrenoceptor stimulation by endogenous NE was mediated by both beta-adrenoceptors (median 77%) and alpha 1-adrenoceptors (median 23%). The basal level of endogenous NE may conceal inotropic effects by exogenous alpha-agonists added to this type of preparation. This preparation is suitable for studying adrenergic regulation by reversing the effects of endogenous NE.

Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity.

The effectiveness of recombinant human erythropoietin (r-HuEpo) in raising haemoglobin concentrations in very low birthweight infants was examined in a randomised multicentre study. Twenty nine 'healthy' appropriate for gestational age infants with birth weights 900-1400 g entered the study at 3 weeks of age. All infants received breast milk supplemented with 9 g/l human breast milk protein from 3 to 8 weeks of age. Eighteen mg iron was given daily from week 3 and was doubled if serum iron concentration fell below 16.0 mumol/l. Fourteen infants were randomised to receive 100 U/kg r-HuEpo subcutaneously three times a week from week 3 to week 7; 15 infants served as controls. After one week reticulocyte and haemoglobin concentrations were significantly higher in the r-HuEpo treated group and the haemoglobin values remained significantly higher throughout r-HuEpo treatment and at the concentrations observed in full term infants. No adverse effects were associated with the treatment. In stable very low birthweight infants with optimal iron and protein intakes, moderate dose r-HuEpo can produce significant gains in red cell production that may be clinically useful.

[Normal hemoglobin levels in children with cyanotic heart disease. Is it iron deficiency anemia?]. / "Normal" hemoglobinverdi hos barn med cyanotisk hjertefeil. Er det jernmangelanemi?

Decreased arterial oxygen saturation in cyanotic congenital heart disease causes a compensatory rise in haemoglobin and haematocrit levels. There is an inverse correlation between arterial oxygen saturation and haemoglobin/haematocrit. This holds true as long as the erythropoiesis is not restricted by other factors. The haematological values and arterial oxygen saturations of three children with cyanotic congenital heart disease are presented. They illustrate how iron deficiency causes discrepant values for arterial oxygen saturation and haemoglobin/haematocrit and that "normal" haemoglobin/haematocrit levels in such children may constitute anaemia. Measurements of MCV, MCH and serum ferritin reveal the existence of iron deficiency anaemia. Low grade iron medication is recommended for children with cyanotic congenital heart disease.

Possible X linked congenital mitochondrial cardiomyopathy in three families.

Familial cases of childhood congestive cardiomyopathy with X linked recessive inheritance and abnormalities of heart muscle mitochondria have been previously reported. We report here three families with possible X linked congestive cardiomyopathy and specific mitochondrial abnormalities. The heart disorder presented as endocardial fibroelastosis with neonatal death in two brothers in one family, and as heart failure and death in infancy in two brothers in the other two families. In one family a maternal uncle may also have been affected. Pyodermia and neutropenia was reported in one of the boys. Electron microscopy of heart muscle after necropsy showed increased numbers of mitochondria and abnormal mitochondrial crystal condensations and paracrystalline inclusions in all sibships. Barth's syndrome has been mapped to Xq28 and includes cardiomyopathy, skeletal muscle myopathy, neutropenia, and mitochondrial abnormalities similar to those found in the three families reported here. Since the clinical picture differed in the three families, they may represent more than one entity.

[Water intoxication with hyponatremia and cramps in the newborn period]. / Vannintoksikasjon med hyponatremi og kramper i nyfødtperioden.

Acute water intoxication with hyponatraemic convulsions has been described several times in children less than two years old. We describe a two-day-old boy who developed hyponatraemia with convulsions because of water intoxication during his stay in the maternity ward. It was a hot day, and the baby was observed to sweat abundantly. The mother therefore breast fed him at frequent intervals and in addition offered him plain water, which he drank eagerly, approximately 350 ml in the course of a few hours. He then developed convulsions with bilateral clonic flexion movements of the arms, and serum sodium concentration was 113 mmol/l (114 on repeat). He was treated with diazepam and phenobarbitone and 20 mmol NaCl as slow infusion, and serum Na was 135 mmol/l after 20 hours. During treatment he passed large amounts of dilute urine and lost 110 g of weight. No abnormal loss of salt was found, and follow-up for six months has been uneventful. Neonates are at risk of developing hyponatraemia and convulsions when offered large amounts of electrolyte poor solutions, especially during hot weather.

Paediatric use of flecainide in supraventricular tachycardia: clinical efficacy and pharmacokinetics.

Twenty three children with recurrent supraventricular tachycardia were treated with flecainide. Twenty one of these received intravenous treatment during an attack (2 mg/kg over 10 minutes). The tachycardia was terminated in 17. After an intravenous bolus of flecainide, blood samples were drawn at regular intervals for analysis of flecainide concentration over 48 hours. Pharmacokinetic variables were calculated--median terminal half life 7.5 hours, median volume of distribution 6.2 l/kg, and median plasma clearance 7.2 ml/min/kg. There was a significant correlation between half life and age. Twenty of the children received long term treatment with an oral preparation of flecainide to prevent further attacks. Twelve had no further attacks and 16 were considered to have good control. Two children suffered potentially serious arrhythmogenic effects soon after the start of oral treatment and flecainide had to be stopped. During oral treatment regular blood samples were drawn and plasma concentrations were analysed to assess the therapeutic range. This did not differ substantially from that proposed in adults (400-800 micrograms/l). Eight children were electively withdrawn from oral flecainide to see whether they really needed it. Blood samples for measurement of flecainide concentration were drawn after their last oral dose. Pharmacokinetic variables were calculated: time to maximum concentration 2 hours, median terminal half life 7.9 hours. For the combined data from patients receiving intravenous and oral treatment there was a significant correlation between elimination half life and age. An intravenous dose of 2 mg/kg over at least 10 minutes and an initial oral dose of 6 mg/kg/day in three divided doses is recommended. Treatment should be started in hospital so that children in whom the drug may be arrhythmogenic can be identified and plasma concentrations measured to identify patients in whom lack of efficacy is caused by underdosage.

Correlation of plasma erythropoiesis stimulating factor(s) and immunoreactive erythropoietin levels during rapid growth in the mouse.

During the early neonatal period of rapid growth in the mouse, increased plasma levels of erythropoiesis stimulating factor(s) (ESF) have been found when measured by an in-vitro bioassay technique. It is unclear whether these increased ESF levels represent increased levels of circulating erythropoietin (Ep) alone or Ep in combination with other less-defined erythropoietic stimulatory factors. To examine this issue, plasma from neonatal mice of varying post-natal ages and from normoxic and hypoxic adult mice was studied. We found that plasma Ep levels measured by radioimmunoassay (RIA) correlated significantly with in-vitro bioassayed ESF levels (r = 0.84, P less than 0.0001, n = 21). Although an in-vivo bioassay for plasma Ep proved too insensitive for rigorous correlation with data from the RIA and in-vitro bioassay, the in-vivo data were in qualitative agreement with the other two, more sensitive, assays. In all three assays the highest plasma levels were observed in the 20-day-old mice and in adult mice which had been subjected to hypobaric hypoxia for 8 h. Based on the strong agreement of the results obtained with the RIA and the in-vitro bioassay in both neonatal and adult mouse plasma, we conclude that the high plasma ESF levels of 20-day-old mice measured with the in-vitro bioassay are largely immunochemically identifiable Ep. However, the data also suggest the presence of non-Ep factors in neonatal plasma which stimulate the in-vitro bioassay.

Serum immunoreactive erythropoietin in healthy normal children.

To provide reference data for normal children, serum immunoreactive erythropoietin (siEp) was estimated by radioimmunoassay in samples from 130 healthy children, 57 girls and 73 boys, with ages between 1 month and 16 years. In 128 of the children the (geometric) mean siEp was 15.8 miu/ml (iu: international units) with 95% range (the range within which 95% of the observations are predicted to fall) 9.1-27.6 miu/ml. There was no relation between siEp and the variables haemoglobin (Hb), PCV, age and sex. There were two outliers, both girls, aged 9.5 and 9.8 years, in whom siEp was greater than 256 miu/ml. In both, Hb and PCV were normal and we are unable to account for these atypical findings. Estimates of siEp in the 128 children were not significantly different from those in 22 healthy adults investigated simultaneously (mean 16.2 miu/ml, with 95% range 11.2-23.3 miu/ml).

Is oxygen supply the only regulator of erythropoietin levels? Serum immunoreactive erythropoietin during the first 4 months of life in term infants with different levels of arterial oxygenation.

Serum immunoreactive erythropoietin (siEp) levels were measured in 35 full-term infants aged 0-13 weeks, 31 of whom had congenital heart disease. The infants displayed a wide range in arterial oxygen tension (PaO2) and oxygen saturation (SaO2). During the first days of life siEp varied widely with a range from less than 3 to more than 10,000 mIU/ml. The wide variation is consistent with findings in cord blood at term. The siEp levels did not correlate significantly with haemoglobin, haematocrit, PaO2, SaO2, or arterial oxygen content in the total sample, nor when the cohort was split up into different age groups. Cyanotic infants aged 2-13 weeks had significantly higher siEp concentrations than normal adults (p less than 0.001) and than children with cyanotic congenital heart disease, aged 4 months-10 years (p less than 0.001). The raised siEp levels in cyanotic children aged 2-13 weeks found in this study and the normal levels found in their older counterparts (4 months-10 years) (reported elsewhere) are consistent with the pattern observed in man and animals exposed to prolonged hypobaric hypoxia, in which after an initial rise in erythropoietin concentrations the levels fall to normal while increased erythropoiesis is sustained.

Serum immunoreactive erythropoietin in children with cyanotic and acyanotic congenital heart disease.

Serum immunoreactive erythropoietin (siEp) was measured in 27 cyanotic and 21 acyanotic children with congenital heart disease, age 4 months to 10 years. The geometric mean value was 9 mIU/mL for each group with 95% range from 3 to 26 mIU/mL and 4 to 22 mIU/mL for the cyanotic and acyanotic subjects, respectively. The levels are similar to those found in normal adults using the same assay system. Three cyanotic subjects showed increased siEp values. One was anemic relative to his hypoxemia, and the other two showed signs of increasing hypoxia. There was a significant negative correlation between siEp and arterial oxygen content. However, siEp did not correlate significantly with hemoglobin, hematocrit, PaO2, or SaO2. Despite normal siEp levels, the cyanotic children showed compensatory erythropoiesis with significantly elevated hemoglobin and hematocrit levels, which did correlate inversely with PaO2 and SaO2. Arterial oxygen content was also significantly higher in the cyanotic subjects (p less than 0.02). The cyanotic children seemed to display the same pattern as observed in man and animals exposed to prolonged hypobaric hypoxia, where after an initial rise in erythropoietin values the levels fall to normal, while increased erythropoiesis is sustained.

Effects of a hemoregulatory peptide (HP5b) on erythroid and myelopoietic colony formation in vitro.

A hemoregulatory peptide (HP5b) associated with mature human granulocytes has been investigated for inhibitory effects on murine hemopoietic stem cells in vitro. Both highly purified peptide from natural sources and a synthetic analog peptide have been investigated in parallel. Strong inhibitory effects were found on myelopoietic colony formation in the dose range 10(-13)-10(-5) mol/l. On exceeding this dose, the inhibitory effect disappeared. Moderate to slight inhibitory effects on erythroid colony formation (BFU-E and CFU-E) from adult animals were only seen in 1,000 X the optimal doses for myelopoiesis. No effect was found on CFU-E from fetal liver. The peptide thus has a selective effect on myelopoiesis in a certain dose range. A regulatory mechanism for the peptide on hemopoiesis is proposed.