Early nasal continuous positive airway pressure treatment reduces the need for intubation in very low birth weight infants

Nasal continuous positive airway pressure (CPAP) applied shortly after birth is said to be an effective treatment of respiratory distress in very low birth weight infants (VLBW). We tested the hypothesis that the use of early nasal CPAP (applied as soon as signs of respiratory distress occurred, usually within 15 min after birth) reduces the need for intubation, the duration of intermittent mandatory ventilation and the incidence of bronchopulmonary dysplasia. All liveborn VLBW infants (birth weight < 1500 g) admitted to our tertiary neonatal intensive care unit in 1990 (historical controls) and in 1993 (early nasal CPAP group) entered the study. The intubation rate was significantly lower after introduction of nasal CPAP (30% vs 53%, P = 0.016). Median duration of intubation was 4.5 days (interquartile range 3–7 days) before versus 6.0 days (2.8–9 days) after nasal CPAP was introduced (P = 0.73). The incidence of bronchopulmonary dysplasia was not reduced significantly (32% vs 30%, P = 0.94). Survival until discharge was 89.5% before versus 92.9% after introduction of nasal CPAP (P = 0.54). Conclusion Early nasal CPAP is an effective treatment of respiratory distress in VLBW infants, significantly reducing the need for intubation and intermittent mandatory ventilation, without worsening other stan dard measures of neonatal outcome. We found no significant decrease in the incidence of bronchopulmo nary dysplasia. Received: 5 February 1996 and in revised form: 12 September 1996 / Accepted: 23 October 1996     

The influence of growth hormone monotherapy and growth hormone in combination with oxandrolone or testosterone on thyroxid hormone parameters and thyrxine binding globulin in patients with Ullrich- Turner syndrome

 Administration of human growth hormone (GH) has yielded conflicting results concerning its role on thyroid function in patients with Ullrich-Turner syndrome. Therefore, we investigated the course of thyroid hormone parameters and thyroxin binding globulin in relation to GH therapy, IGF-I and additional oxandrolone-(Ox) or testosterone (T) treatment in 20 patients with Ullrich-Turner syndrome. During the 1st year the patients received only GH. There was no change in T4, fT4, and TSH levels, T3 increased significantly (P <  0.01) after 6 and 12 months, resulting in a higher T3/T4 ratio. TBG (P < 0.05) and IGF-I (P < 0.01) increased after 6 months and remained elevated at 12 months. A significant positive correlation was found between the change of T4 and TBG after 6 months (r = 0.47, P < 0.05) and after 12 months (r = 0.69, P < 0.005). Thirteen patients were further investigated after addition of an anabolic compound; 7 received Ox (0.0625 mg/kg/day po) and 6 low dose T (5 mg i.m. every 14 days). Chronological age was comparable in these groups (10.7 ±  2.7 vs 10.7  ± 3.6 years). After 6 months of combination therapy with Ox, T4, T3 and TSH decreased. As T4 and T3 showed a parallel decrease the T3/T4 ratio remained elevated. TBG declined after 6 and 12 months (P < 0.05), while IGF-I showed a further increment (P < 0.05). There was no correlation between the changes in T4 and IGF-I, TSH and TBG, respectively. In the T-treated group only IGF-I increased (P < 0.05) to the same extent as in the Ox-treated patients, whereas the thyroid parameters did not change. Conclusion The observed changes in thyroid hormone and TBG levels in the Ox group were not mediated by GH or IGF-I. The Ox-induced TBG decrease might be linked to altered pancreatic functions regulating carbo-hydrate metabolism. Received: 22 April 1996 / Accepted: 1 August 1996     

The effect of obesity, age, puberty and gender on resting metabolic rate in children and adolescents

During puberty fat-free mass (FFM) and fat mass (FM) change quickly and these changes are influenced by sex and obesity. Since it is not completely known how these changes affect resting metabolic rate (RMR), the aim of the present study was to investigate the effect of body composition, age, sex and pubertal development of postabsorptive RMR in 9.5- to 16.5-year-old obese and non-obese children. Postabsorptive RMR was measured in a sample of 371 pre- and postpubertal children comprising 193 males (116 non-obese and 77 obese) and 178 females (119 non-obese and 59 obese). RMR was assessed by indirect calorimetry using a ventilated hood system for 45 min after an overnight fast. Body composition (FFM and FM) was estimated from skinfold measurements. The mean (± SD) RMR was significantly (P < 0.001) lower in non-obese (males: 5600 ± 972 kJ/24h; females: 5112 ± 632 kJ/24h) than in obese (males: 7223 ± 1220 kJ/24h; females: 6665 ± 1106 kJ/24h) children. This difference became non-significant when RMR was adjusted for body composition (FFM + FM). However, the difference between the genders still remained significant (control male: 6118 ± 507, control female: 5652 ± 507, P < 0.001; obese male: 6256 ± 507, obese female: 5818 ± 507 kJ/24h, P < 0.001). The main determinant of RMR was FFM. In the whole cohort, FFM explained 79.8% of the variation in RMR, followed by age, gender and FM adding further 3.8%, 1.1% and 0.8% to the predictability of RMR, respectively. No significant contribution for study group (obese, non-obese), pubertal stage, or fat distribution was found in the regression for RMR. The adjusted value of RMR (for FFM and FM) slightly, but significantly (P < 0.01) decreased between the age of 10–16 years, demonstrating the important effect of age on RMR. Conclusions The resting metabolic rate of obese and control children is not different when adjusted for body composition. The main determinant of RMR is the fat-free mass, however, age, gender and fat mass are also significant factors. Pubertal development and fat distribution do not influence RMR independently from the changes in body composition. Received: 4 March 1996 / Accepted: 21 August 1996     

Surfactant proteins and stable microbubbles in tracheal aspirates of infants with respiratory distress syndrome: relation to the degree of respiratory failure and response to exogenous surfactant

 Surfactant proteins (SP-A and SP-BC), albumin (ALB), and stable microbubble (SM) count were measured in tracheal aspirates from infants with respiratory distress syndrome (RDS) receiving single-dose Surfactant-TA (surfactant group, n = 32) or no surfactant (control group, n = 12), and those without RDS (non-RDS group, n = 8) to determine biochemical and biophysical status of surfactant in the course of RDS after surfactant replacement. Surfactant therapy resulted in immediate and sustained elevations of SP-BC/ALB and SM count with a rapid fall in ventilatory index to levels measured in the non-RDS group, whereas these indices improved slowly in the control group. The SP-A/ALB was initially low in both RDS groups and increased to levels measured in the non-RDS group by age 48 h. Multiple regression analysis showed that SP-BC/ALB, postnatal age, SM count, SM count/SP-A plus SP-BC, and surfactant therapy were independently associated with the severity of RDS as assessed by ventilatory index (r = 0.75, P < 0.0001; number of samples = 256). Infants with a relapse response to surfactant (n = 9) had levels of SP-A/ALB and SP-BC/ALB similar to those measured in the sustained group (n = 23), but had significantly lower SM count and SM count/SP-A plus SP-BC between 24 and 96 h of age. Conclusion Surfactant therapy normalizes the sur factant and respiratory status of infants with RDS. Surfactant dysfunction rather than depletion may explain the relapse response seen in some surfactant recipients. Received: 23 October 1995 / Accepted: 20 May 1996     

Corticosteroid treatment of erythema multiforme major (Stevens-Johnson syndrome) in children

 The effectiveness of systemic corticosteroids in erythema multiforme major (EMM) is controversial. We therefore evaluated the efficacy of corticosteroids in the treatment of EMM in a prospective study of 16 children with EMM admitted to our department within 3 days from the onset of rash. Ten patients (group A) received bolus infusions of methylprednisolone (4 mg/kg/day) while six had only supportive treatment (group B). The early use of corticosteroids compared to supportive treatment resulted in: (1) significant reduction of the period of fever (4.0 ± 1.9 vs 9.5 ± 4.2 days P = 0.01); (2) reduction of the period of acute eruption (7.0 ± 3.3 versus 9.8 ± 3.0 days P = 0.08); and (3) milder signs of prostration. Complications were minimal in both groups. Conclusion The early and short course of corticosteroids favourably influences the course of erythema multiforme major in children. Received: 29 March 1996 / Accepted: 30 July 1996     

Ureaplasma urealyticum colonization and bronchopulmonary dysplasia: a comparative prospective multicentre study

To determine the role of tracheal colonization at birth with Ureaplasma urealyticum and other pathogenic bacteria with regard to the development of bronchopulmonary dysplasia (BPD), 97 premature infants with very low birth weight (<1500 g) were followed prospectively over 30 days in a multicentre study. Of those infants, 35 were colonized with Ureaplasma urealyticum (group Ia), 22 with other pathogenic bacteria (group Ib) and 40 infants with sterile tracheal aspirates served as controls (group II). Colonization with Ureaplasma urealyticum or with pathogenic bacteria independently increased the risk of developing BPD as compared to the controls (OR 2.55; 95% CI [1.11, 5.87]). Among Ureaplasma urealyticum and bacterial colonized infants, duration of mechanical ventilation and oxygen requirement were significantly longer than among controls (P < 0.05); during the interval of 11 to 35 days of life, every additional day of ventilation significantly increased the risk of BPD (OR 1.22; CI [1.12, 1.32]). The rate of oxygen supplementation, which was similar in both groups during the first 2 weeks of life, was significantly higher among the colonized infants at day 21 (0.38 ± 0.18 and 0.39 ± 0.16 vs 0.31 ± 0.13, P < 0.05) and at day 28 (0.38 ± 0.21 and 0.34 ± 0.15 vs 0.28 ± 0.12, P < 0.05). For infants still ventilated at age of 28 days, Ureaplasma urealyticum and bacterial colonization were associated with a significant higher risk for BPD than for uncolonized controls (OR 5.53; [1.27, 24.02]. Association of Ureaplasma urealyticum and of bacterial colonization and BPD was not weakened after adjustments were made in a multivariate analysis for other significant risk factors. Conclusion Ureaplasma urealyticum colonization is as an important risk factor in the development of bronchopulmonary dysplasia as bacterial colonization even after treatment with surfactant. Received: 23 January 1997 and in revised form: 30 December 1997 / Accepted: 5 January 1998     

Respiratory control in children with Prader-Willi syndrome

  Physiological parameters of infants and children with Prader-Willi syndrome were examined in order to clarify whether there were indicators of disturbed respiratory control mechanisms in the pre-obesity stage of the syndrome. From January 1993 to March 1995 in eight patients with Prader-Willi syndrome (five boys, three girls, aged 6 weeks – 12.5 years),␣polysomnography was performed and compared with 28 children matched for gestational age, sex, birth weight and age at sleep study. The recordings included thoracic and abdominal breathing movements, nasal airflow, tcPO₂, tcPCO₂, oxygen saturation, EEG, EOG and ECG. Respiratory responses to hypercapnia during quiet sleep were obtained from five Prader-Willi patients and ten peers. The Prader-Willi group showed an increased number of apnoeas per hour of sleep, a decreased nadir of oxygen saturation, increased maximum of the instantaneous heart rate and decreased respiratory responses to hypercapnia during quiet sleep. Conclusion These findings indicate a primary dis‐turbance of central respiratory control in patients with Prader-Willi syndrome which may be worsened by the development of obesity. Received: 26 January 1996 / Accepted: 21 July 1996     

Fatty acid composition of human milk during the 1st month after term and preterm delivery

The fatty acid composition of human breast milk was determined longitudinally after term and preterm delivery by high resolution gas liquid chromatography. Milk samples were obtained at days 5, 10, 20 and 30 after term (n = 38) or preterm (n = 19) delivery. The saturated fatty acids C10:0 and C12:0 and the polyunsaturates linoleic acid (C18:2ω-6) and α-linolenic acid (C18:3ω-3) increased significantly from day 5 to day 10, whereas arachidonic acid (C20:4ω-6), total ω-6 long-chain polyunsaturates (LCP), docosahexaenoic acid (C22:6ω3) and total ω-3 LCP decreased significantly. Term and preterm milk did not differ in percentage content of linoleic acid, α-linolenic acid and LCP at any time point. Preterm milk contained significantly more medium and intermediate chain fatty acids (C10:0, C12:0 and C14:0) than term milk on days 5 (12.28 vs 9.78%; P > 0.05), 10 (16.25 vs 12.62%; P > 0.05) and 20 (17.29 vs 13.47%; P > 0.005). Conclusion The milk of mothers of preterm infants is not better suited to meet the high LCP requirements of their infants during the first weeks after birth. The slightly higher proportion of medium and intermediate chain fatty acids in preterm milk during the 1st month after birth might be advantageous for the fat and calcium absorption of preterm infants. Received: 22 February 1996 / Accepted: 1 August 1996     

The effect of blood transfusion on oxygenation in premature ventilated neonates

The effect of blood transfusion to maintain a preset packed cell volume (PCV) level in preterm ventilated infants has been investigated. Fifty infants, median gestational age 26 (range 23–33) weeks and postnatal age 4 (1–29) days, transfused a median of 15 ml/kg of blood in response to a PCV ≤ 40% were retrospectively identified and their medical records reviewed to determine the change in PCV and haemoglobin resulting from the transfusions. In addition, their mean airway pressure (MAP) was noted and, as an index of oxygenation, their oxygenation index (OI), alveolar/arterial oxygen gradient (AaDO₂) and arterial/alveolar (a/A) ratio calculated 12 h, 6 h and immediately prior to the transfusion and immediately post, 12, 18 and 24 h after the transfusion. The transfusion improved the PCV and haemoglobin (P < 0.0001). No significant changes in MAP or level of oxygenation were experienced in the 12 h prior to the transfusion. Post transfusion, despite no significant change in MAP, the AaDO₂ OI and a/A ratios compared to immediately prior to the transfusion were significantly better at 12, 18 and 24 h. Conclusion It is useful to transfuse ventilated preterm infants to maintain their PCV above a preset level. Received: 8 March 1996 / Accepted: 1 July 1996     

Effect of elective antibiotic therapy on resting energy expenditure and inflammation in cystic fibrosis

Cystic fibrosis (CF) patients often present with malnutrition which may partly be due to increased resting energy expenditure (REE) secondary to inflammation. Both REE and tumour necrosis factor-alpha (TNF-α), as other markers of inflammation, are elevated during respiratory exacerbations and decrease after antibiotic treatment. However, the effect of antibiotic therapy on REE and inflammation in patients without respiratory exacerbation is not known. The aim of our study was to determine the effect of such an elective antibiotic therapy on REE, TNF-α, and other serum markers of inflammation. Twelve CF patients 5F/7M, age 15.9 ± 6.1 years, weight for height ratio 89 ± 8% without clinically obvious exacerbation and treated by intravenous antibiotics were studied. Both before (D0) and after (D14) treatment, pulmonary function tests were performed. REE was measured by indirect calorimetry and blood taken to measure inflammation parameters. Body weight increased by 1.1 kg from D0 to D14 (P < 0.001), composed of 0.3 kg fat mass and 0.8 kg fat-free mass (FFM). The forced expiratory volume at 1 s increased from 43 ± 15% of predicted at D0 to 51 ± 15% of predicted at D14 (P < 0.01). Mean REE was 41.1 ± 7.6 kcal/kg FFM per day at D0 and did not change significantly at D14 (40.6 ± 8.5 kcal/kg FFM per day). Serum markers of inflammation decreased from D0 to D14: C-reactive protein 17 ± 17 mg/l to 4 ± 7 mg/l (P < 0.05), elastase 62 ± 29 μg/l to 45 ± 18 μg/l (P < 0.02), orosomucoid acid 1.25 ± 0.11 g/l to 0.80 ± 0.15 g/l (P < 0.001), and TNF-α 37 ± 14 pg/ml to 29 ± 6 pg/ml (P = 0.05). Individual values showed a correlation between changes in REE and in TNF-α (P < 0.02). Conclusion The contribution of inflammation to energy expenditure is possible but appears to be minimal in cystic fibrosis patients treated by antibiotics on a regular basis in the absence of clinically obvious exacerbation. Received: 6 August 1998 and in revised form: 23 November 1998 / Accepted: 23 November 1998     

Effect of blood transfusion on apnoea, bradycardia and hypoxaemia in preterm infants

We studied the effect of blood transfusion on the frequency of apnoea, bradycardia and hypoxaemia in 21 spontaneously breathing preterm infants with a median gestational age at birth of 28 (range 23–31) weeks. Age at time of study was 22 days (3–84), weight 925 g (640–2120). The patients exhibited frequent episodes of bradycardia and/or hypoxaemia and were anaemic (median haemoglobin level 109 (82–120) g/l). One infant received two transfusions and was thus studied twice. Four-hour recordings of pulse oximeter saturation (SpO₂), pulse waveforms, transcutaneous oxygen pressure, electrocardiogram, breathing movements and nasal airflow were performed immediately before and after transfusion, and again after a further interval of 12 h. Recordings were analysed for isolated and periodic apnoeas (> 4 s), bradycardias (heart rate < 2/3 of baseline), and episodic desaturation (SpO₂≤ 80%). There were no significant changes in the frequency, severity and/or duration of apnoea, bradycardia or desaturation following transfusion. The average SpO₂ nadir reached during each desaturation, however, increased by 3% following transfusion (P < 0.05), and there was a trend towards shorter desaturations. Conclusion The occurrence of frequent episodes of apnoea, bradycardia and/or hypoxaemia does not, on its own, justify a blood transfusion in moderately anaemic preterm infants. Received: 25 July 1996 / Accepted: 24 September 1996     

Dilated cardiomyopathy and thrombo-embolism

 The purpose of this study was to investigate the incidence, outcome and prevention of thrombo-embolism in children with dilated cardiomyopathy. From 130 patients with dilated cardiomyopathy, 17 (14%) showed evidence of thrombo-embolism. Seven had initial cardiac thrombus, 7 exhibited initial embolus and in 3 thrombo-embolism was only diagnosed at autopsy. All 17 patients showed seriously impaired systolic function of the left ventricle with fractional shortening (FS) of 10 ± 3%, range 5%–17%, as compared to those without thrombo-embolism with FS of 17% ± 6%, range 5%–26% (P <; 0.0001). Seven patients were treated with oral anticoagulants once thrombo-embolism had been diagnosed; one of them experienced a further embolic event as opposed to three out of four patients not treated with anticoagulants. Conclusion All children with dilated cardiomyopathy and fractional shortening below 20% should be treated with prophylactic anticoagulative agents Received: 12 May 1996 / Accepted: 29 July 1996     

Final height and puberty in 40 patients after antileukaemic treatment during childhood

Endocrine dysfunction and damage of the epiphysial growth plates have been reported as late effects of antileukaemic treatment during childhood. It is a common opinion that cranial irradiation (CI) is the most important factor for blunted growth. Accordingly, recent therapeutic strategies in acute lymphoblastic leukaemia (ALL) avoid cranial irradiation. Here we analysed longitudinal data on growth and puberty of 54 children in first complete remission, who were treated with 18 Gy CI or not submitted to radiotherapy. Two chemotherapeutic protocols were compared which were similar during the induction period but differed in the intensity of maintenance therapy. In cranial irradiated patients both in males and females the pubertal growth spurt started at a mean age of 1.2 years (SD: 0.93 years) earlier than controls. Age at diagnosis and age at pubertal growth spurt were significantly correlated (r = 0.35, P = 0.017). Similarly, menarche occurred at a mean age (n = 22) of 12.1 years and was correlated with the age at start of therapy in girls who were treated with 18 Gy CI (r = 0.61, P = 0.01). Adult height was reached spontaneously in 30 patients treated during prepubertal age and in 10 treated shortly before or during puberty. In all prepubertal patients treated for 2–3 years with intensive maintenance therapy blunted growth resulted in a significant loss of −1.85 H-SDS (median, P = 0.0051) compared to height at diagnosis. However, if continuation treatment used only methotrexate and 6-mercaptopurine (i.e. BFM protocol) final height equalled projected adult height, despite 18 Gy CI. Conclusions (1) multiagent chemotherapy is of major impact for growth and puberty; (2) 18 Gy cranial irradiation is below the critical dosage responsible for blunted growth; (3) loss in potential growth might be prevented by current CT strategies; (4) onset of puberty depends on age when antileukaemic therapy is applied. Received: 22 April 1996 / Accepted: 24 September 1996     

Plasma lipid and apolipoprotein concentrations in full term infants fed formula supplemented with long-chain polyunsaturated fatty acids and cholesterol

Recent data indicate that supplementation of infant formula with ω-3 and ω-6 long-chain polyunsaturated fatty acids might offer developmental benefits for full term infants. We investigated biochemical consequences of feeding formula supplemented with egg lipids to provide long-chain polyunsaturated fatty acids and compared triglyceride, cholesterol, lipoprotein cholesterol (HDL₂-cholesterol, HDL₃-cholesterol, non-HDL-cholesterol) and apolipoprotein A-I, A-II and B concentrations in full term infants fed either conventional formula (n = 10) or a formula supplemented with ω-3 and ω-6 long-chain polyunsaturated fatty acids and cholesterol in amounts similar to those found in mature human milk (n = 12). At the age of 5 days, cholesterol, non-HDL-cholesterol and triglyceride concentrations were significantly higher in infants fed supplemented than in those receiving conventional formula. At the age of 30 days, triglyceride concentrations were significantly higher with supplemented than with conventional formula. Thereafter throughout the study, no significant differences were seen between the two groups. Conclusion Full term infants fed formula supplemented with ω-3 and ω-6 long-chain polyunsaturated fatty acids and cholesterol showed significantly higher plasma cholesterol and triglyceride concentrations than infants receiving conventional formula on day 5 and on days 5 and 30, respectively. Thereafter no appreciable effect of diet on plasma phospholipid, triglyceride, cholesterol, lipoprotein cholesterol and apolipoprotein concentrations were seen. Received: 13 March 1996 / Accepted: 21 October 1996     

A comparison of intratracheal and intravenous administration of gentamicin during liquid ventilation

Pulmonary absorption of aminoglycosides is poor with intravenous administration, but may be enhanced by direct intratracheal administration of these drugs using perfluorochemical liquid ventilation (LV). To test this hypothesis, gentamicin sulfate was administered to two groups of newborn lambs during LV. Serum and lung tissue levels of gentamicin were compared after either pulmonary intratracheal (IT) or intravenous (IV) routes of administration. Serial serum levels of gentamicin were obtained every 15 min for the 1st h, every 30 min for the 2nd h, and then hourly until sacrifice (maximum 6 h). At sacrifice, representative samples of each lung lobe were homogenized and analyzed for tissue gentamicin content. At 1 h, serum gentamicin levels were similar in both groups: IT administration levels were 3.7 ± 0.55 SE μg/ml and IV levels were 3.5 ± 0.85 SE μg/ml. The peak serum gentamicin level of 4.8 ± 0.8 SE μg/ml for the pulmonary administration group occurred 1.5 h after administration. Lung tissue levels of gentamicin for IT administration (4.04 ± 0.62 SE μg/g) were significantly greater than for IV administration (1.75 ± 0.33 SE μg/g; P < 0.05). There were no significant differences in interlobar gentamicin distribution for either mode of administration. Conclusion Perfluorochemical can be used as a vehicle for intratracheal delivery of antimicrobials. This route provides equivalent serum levels at 1 h, higher lung tissue levels, and uniform interlobar distribution relative to intravenous administration of gentamicin. We speculate that pulmonary administered gentamicin during LV may provide an effective alternative treatment modality in the management of severe neonatal pneumonia. Received: 12 April 1996 and in revised form: 24 July 1996 / Accepted 28 July 1996     

Neonatal morbidity and mortality associated with maternal haemolysis elevated liver enzymes and low platelets syndrome

To compare the impact of maternal haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, uncomplicated hypertension in pregnancy (HIP), and no hypertension (controls) on neonatal morbidity and mortality, 108 infants were matched with respect to gestational age, date of birth, and gender. The HELLP group infants had more grade 3 and 4 respiratory distress syndromes (36%) than the HIP group (19%) or controls (11%). Cardiovascular instability (arterial hypotension, volume resuscitation) was significantly more common in HELLP neonates (20% and 31%) than in HIP infants (9% and 6%) or controls (3% and 9%). Both, HELLP and HIP infants showed a higher incidence of growth retardation than the controls. After 32 weeks of gestation the incidence of severe neonatal morbidity was not different. Conclusion Before 32 weeks of gestation both respir-atory and cardiovascular morbidity and intra-uterine growth retardation associated with HIP is further aggravated by a maternal HELLP syndrome. Received: 31 May 1996 / Received in revised form and accepted: 3 October 1996     

Magnetic resonance images of 91 children with different causes of short stature: pituitary size reflects growth hormone secretion

In order to validate an association between pituitary size and severity of growth hormone deficiency (GHD) we evaluated the magnetic resonance images (MRI) of 107 children with different causes of short stature. Ninety-one MRIs were evaluable (64 male, 27 female; age: 9.1 ± 3.9 years). The levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3), and tests of GH stimulation and spontaneous secretion, led to the following sub-groups: severe isolated GHD (SIGHD) (GH < 7 ng/ml) (n = 21); partial, isolated GHD (GH 7–10 ng/ml) (n = 22); multiple pituitary hormone deficiency (MPHD) (n = 13); neurosecretory dysfunction (n = 10); non-classifiable diagnosis (NC) (n = 13); idiopathic short stature (n = 9); and intra-uterine growth retardation (n = 3). Pituitary height (PHT) was measured and hypoplasia was assumed when PHT was <−2 SDS. An ectopic posterior pituitary with missing stalk and a hypoplastic anterior pituitary was present in 12 (57%) SIGHD cases, 12 (92%) MPHD cases and 1 patient from the NC group. An isolated hypoplastic anterior pituitary was observed in 15%−33% of the other groups. PHT (mm; mean, SD) in MPHD (1.7 ± 0.5) was lower than in SIGHD (2.7 ± 1.0, P < 0.05), with PHT of both groups being lower than in all the other groups (3.8 ± 0.9, P < 0.0001). PHT SDS correlates with IGF-I SDS (r = 0.48, P < 0.0001), IGFBP-3 SDS (r = 0.46, P < 0.0001) and the highest peaks in tests of GH stimulation and GH spontaneous secretion (r = 0.36, P < 0.0001). In contrast to all the other groups, no correlation with age was observed in MPHD and SIGHD. Breech delivery was recorded in up to 26% of patients in all seven groups. Surprisingly, only 1 out of 23 patients with an ectopic posterior pituitary was born by breech delivery, suggesting that ectopia of the posterior lobe is not necessarily related to breech delivery. Conclusion PHT is significantly correlated with GH secretion in several types of short stature. Patients with␣ectopic posterior pituitary, missing stalk and hypoplastic␣anterior pituitary either suffer from SIGHD or MPHD, and this anatomical defect is not necessarily related to breech delivery. Received: 1 December 1996 and in revised form: 8 February 1997 / Accepted: 18 February 1997     

Technical considerations for inhaled nitric oxide therapy: time response to nitric oxide dosing changes and formation of nitrogen dioxide

The aim of the present study was to analyse the time response to nitric oxide (NO) dosing changes as well as the formation of nitrogen dioxide (NO₂) with different ventilation systems, respirator settings and application sites during NO inhalation. The inspired NO and NO₂ concentrations were continuously measured using chemiluminiscence within a dummy ventilatory system equipped with two different respirator systems (Siemens Servo 900c and Bear BP 2001). NO was either introduced into the afferent limb of the ventilatory circuit close to the endotracheal tube (site A) or into the so-called low pressure port of the Servo 900c respirator, far away from the endotracheal tube (site B). In addition, the decay of the inspired NO concentration after cessation of the NO gas flow was studied. This decay was considerably prolonged when NO was introduced at site B (time constants: τ = 7.19 min versus τ = 0.29 min). Within the concentration range studied (0–25 ppm NO) a linear correlation between the NO and NO₂ concentration was found. At site A and an inspired oxygen concentration of > 0.95 NO₂ formation amounts to 1.14% ± 0.11% of the NO concentration. Using this value one can calculate the NO₂ formation for a given NO dose. For example, when 40 ppm NO are applied, a concentration of 0.45 ppm NO₂ can be expected, which is well below the relevant toxic concentrations. However, when NO was introduced at site B, NO₂ formation was significantly increased to 1.61% ± 0.16%. Passage of the ventilated gas through soda lime led only to a slight and insignificant reduction in NO₂ concentration. The continuous flow respirator BP 2001 showed a significantly lower NO₂ concentration when compared to the non-continuous flow respirator Servo 900c (0.64 ± 0.11% vs.1.14 ± 0.11%). Conclusion The application of NO close to the endotracheal tube is associated with a much faster response of the actual inspired NO concentration to dosing changes and shows the lowest NO₂ formation. In order to avoid toxic NO₂ concentrations, an upper limit of 40 ppm NO is recommended for continuous NO inhalation. Received: 21 May 1996 / Accepted: 16 September 1996     

High incidence of angiotensin I converting enzyme genotype II in Kawasaki disease patients with coronary aneurysm

A 287 base pair insertion/deletion polymorphism in intron 16 of the angiotensin I converting enzyme (ACE) gene was examined by polymerase chain reaction in 36 Kawasaki disease patients (16 without coronary aneurysm, 20 with coronary aneurysm). A polymorphism in the ACE gene was characterized by three genotypes: two D alleles (genotype DD), two I alleles (genotype II), and heterozygous allele (genotype DI). Genotype II was found in 65% of the patients with aneurysm and 12.5% of those without aneurysm (P < 0.01, odds ratio 13.0, 95% confidence intervals). Conclusion Patients with Kawasaki disease and coronary aneurysm more often than expected had the genotype II suggesting that reactions induced by the type of ACE polymorphism predispose to coronary aneurysm formation. Received: 15 March 1996 / Accepted: 10 August 1996     

Paediatric thrombo-embolism: the influence of non-genetic factors and the role of activated protein C resistance and protein C deficiency

 In many children, the pathogenesis of thrombo-embolism remains unexplained. This study examines the role of non-genetic risk factors in 37 children with venous or arterial thrombosis. Included were 17 patients with portal vein thrombosis following umbilical vein catheterisation, 6 with portal vein thrombosis and an uneventful neonatal period, 4 with deep vein␣thrombosis, 4 with renal vein thrombosis after kidney transplantation, 1 haemodialysis patient with thromboses of arteriovenous shunts, and 5 with arterial thromboses at various sites. In 25 of these 37 patients (68%) exogenic risk factors and particularly vascular manipulations (24/37) were related to the thrombotic event. Resistance to activated protein C was identified in 5 patients and protein C deficiency in 2 (7/37; 19%). This prevalence was significantly higher than that of the control group (14/243; 5.8%; χ², P < 0.008). Conclusion Our data show that non-genetic and particular iatrogenic risk factors can often be identified in children with thrombosis, but activated protein C resistance and protein C deficiency are significant genetic risk factors in this age group. Received: 23 April 1996 / Accepted: 1 August 1996