Experience of severe hypoglycaemia may influence both patient's and physician's subsequent treatment policy of insulin-dependent diabetes mellitus

Daily insulin doses and HbA1_c were studied 0–3 months before and 2–6, 7–11, and 12–16 months after 48 consecutive episodes of severe hypoglycaemia (coma and/or convulsion) in children and adolescents with insulin-dependent diabetes mellitus. After 69% of the attacks, either physicians or patients or both decreased daily insulin doses (for the whole group, mean ± SD: 0–3 months before the episode 0.93 ± 0.20 U/kg vs 2–6 months after 0.84 ± 0.20 U/kg, P < 0.001), which may have worsened the subsequent glycaemic control as evidenced by a significant increase in HbA1_c (8.3 ± 1.5% vs 9.1 ± 1.8%, P<0.001, respectively). Physicians decreased the insulin dose even in 14 of the 33 patients with a preventable cause for their hypoglycaemia other than erroneous excess of insulin. Conclusion Experience of severe hypoglycaemia may worsen the subsequent glycaemic control. This might in part be due to an excessive lowering of daily insulin doses by both physicians as well as patients and their families. Hypoglycaemia management must include intensive education about prevention without compromising diabetes control. Received: 30 September 1997 / Accepted in revised form: 13 February 1998     

Changes in attention with hypo- and hyperglycaemia in children with insulin dependent diabetes mellitus

We compared the results of a computerized attention test (TOVA) in 38 children with insulin dependent diabetes mellitus in relation to various spontaneously occurring blood glucose levels. Testing was performed at the following blood glucose levels: <3.3 mmol/l (hypoglycaemia), 3.3–8.3 mmol/l (normoglycaemia) and >8.3 mmol/l (hyperglycaemia) . The attention (sum of errors and response time) varied significantly with the blood glucose level (P=0.002). The highest number of errors of omission and the longest response time was observed during the test run with hypoglycaemia. Age, sex, age at manifestation of the disease, metabolic control and the results of the intelligence test had no significant influence on these results. We found that attention in children with diabetes was significantly reduced compared to TOVA norms especially during mild hypoglycaemia (P<0.001). Irrespective of the blood glucose levels, reaction time and the variability of the reaction time differed significantly between TOVA norms and diabetic children (P<0.01). Conclusion In children with diabetes mellitus a significant reduction in attention was found at mild hypoglycaemia but as well at low normal blood glucose levels. Attention deficits due to transient lowering of blood glucose may therefore occur in diabetic children even before they are aware of hypoglycaemic symptoms. Received: 24 November 1997 / Accepted: 2 March 1998     

Hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia

Two cases of hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia in unrelated infants of 7 days and 4 months of age are reported. Blood ammonia levels were 100–300 μmol/l (normal values<40 μmol/l). The hyperammonaemia was asymptomatic and not associated with any of the abnormalities of amino acids or organic acids observed in urea cycle enzyme defects. Orotic aciduria was normal. The hyperammonaemia was not influenced by the levels of blood glucose nor by subtotal pancreatectomy. On admission blood glucose was ca. 1.2 mmol/l (21.6 mg/dl) corresponding to blood insulin levels of 35 and 22 mU/l respectively in both infants. Continuous intravenous glucose perfusion was necessary to prevent hypoglycaemia. Furthermore 2-oxoglutaric acid in urine was increased in the second infant to 3.15 mg/mg creatinine (normal 0.41 +/−0.12). This may point to mutations in the glutamate dehydrogenase gene. Conclusion 2-Oxoglutaric aciduria may be an important clue to the diagnose in this syndrome. Received: 6 January 1998 / Accepted: 25 November 1998     

Frequency and correlates of severe hypoglycaemia in children and adolescents with diabetes mellitus

Frequency and correlates of severe hypoglycaemia have been retrospectively analysed in a cohort of diabetic children and adolescents with median (range) age 14.5 (3.2–25.5) years followed from the onset of the disease by the same diabetic clinic. During the years 1992–1994, 53 of the 187 patients reported 74 hypoglycaemic episodes: the average frequency of hypoglycaemia during the 3 years surveyed was 14.9 episodes/100 patients per year. Frequency of hypoglycaemia decreased significantly with age (χ² = 24.1; P < 0.0001) and was independent of duration of diabetes. Glycosylated haemoglobin and insulin dose were similar in patients with and without hypoglycaemia, matched for age and duration of diabetes. One out of two hypoglycaemic episodes occurred during sleep and no explanation was available for 50% of episodes. Conclusion In this study severe hypoglycaemia was more frequent in young children than in adolescents and was independent of metabolic control and insulin dose. Received: 25 May 1996 / Accepted: 3 February 1997     

A Japanese family with autosomal dominant growth hormone deficiency

We report a 1-year-old Japanese boy and his father with isolated growth hormone deficiency II. In both cases, a G → A transition of the first base of the donor splice site of intron 3 of the growth hormone-1 gene was detected. All unaffected family members were homozygous normal. Conclusion This is the fourth reported case of autosomal isolated growth hormone deficiency II with a G → A transition. The CG dinucleotide at the exon 3-intron 3 junction of the growth hormone-1 gene appears to be a hot spot for point mutations. Received: 1 July 1998 / Accepted in revised form: 16 December 1998     

Metabolic stroke in isolated 3-methylcrotonyl-CoA carboxylase deficiency

A mildly retarded infant with failure to thrive developed hypoglycaemia, focal seizures, respiratory failure and hemiparesis during a febrile episode at the age of 16 months. A brain scan was initially normal and showed hemilateral focal edema and gliosis at later stages. 3-Methylcrotonyl-CoA carboxylase deficiency was suggested by elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, and confirmed by enzyme assays. The patient was treated with protein restriction and carnitine and remained stable during the following 5 years. Hemiparesis and some developmental delay persisted. Conclusion In acute focal brain disease, metabolic disorders must be considered. 3-Methylcrotonyl-CoA carboxylase deficiency adds to the list of possible causes of “metabolic stroke”. Received: 24 March 1998 / Accepted in revised form: 29 December 1998     

Amlodipine once-daily in systemic hypertension

The calcium channel blocker nifedipine is widely used in children with systemic hypertension; however, because of the short duration of action, three to four daily doses of the standard preparation are required. Amlodipine once-daily, a calcium channel blocker structurally related to nifedipine with an excellent bioavailability and a long elimination half-time, has been shown to reduce blood pressure in adults. No information is available on the use of amlodipine in childhood. The effects of amlodipine once-daily (5 to 10 mg) were therefore assessed in 28 paediatric patients with hypertension. Amlodipine was withdrawn in five patients who experienced oedema and flushing. In the remaining 23 patients blood pressure was significantly reduced 3 weeks after amlodipine (on average by 7/5 mm Hg) and further decreased at 12 weeks (by 21/12 mm Hg). Heart rate and body weight were unchanged. In eight patients concomitantly treated with cyclosporine, the blood level of this agent was stable throughout the study, thus not requiring any dose adjustment. Conclusion The study illustrates the antihypertensive properties of amlodipine once-daily in paediatric hypertension. Amlodipine appears particularly indicated in patients concomitantly treated with cyclosporine. Received: 17 December 1997 / Accepted: 14 March 1998     

Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria

Primary persistent hyperinsulinaemic hypoglycaemia of infancy is rare. Diazoxide treatment remains the mainstay of medical therapy in long-term management. We reviewed 77 cases of primary persistent hyperinsulinism in neonates and infants who were treated with diazoxide and studied criteria predictive of therapeutic efficacy. The only criterion identified was age at manifestation. All but 1 of the 31 neonatal cases were unresponsive to diazoxide. Responsiveness increased with age: 12 of 39 early-infantile cases, and all seven late-infantile cases were diazoxide-responsive. In responders, a diazoxide dose of 10–15 mg/kg per day was always effective, suggesting an “all or none” response. Diazoxide-resistant hyperinsulinism is characterized by its severity with higher plasma insulin levels. The analysis of 46 surgically treated patients showed that the efficacy of diazoxide is not related to the aetiology of the pancreatic lesions. In six cases, after many years of management, diazoxide treatment was stopped without recurrence of hypoglycaemia. Conclusion Diazoxide is an efficient treatment in the long-term management of most persistent hyperinsulinaemic hypoglycaemia of infancy revealed in infants and children but is usually ineffective in neonatal forms. Drug efficacy does not correlate with anatomical lesions. Medical treatment can sometimes be stopped after many years of management without recurrence of disease manifestations. Received: 29 April 1997 / Accepted: 9 February 1998     

Good growth despite very low levels of insulin-like growth factors

A 12.5-year-old girl presented with short stature. Insulin-like growth factor 1(IGF-I) and insulin- like growth factor binding protein (IGFBP-3) were below the 0.1 percentile. Growth hormone provocation tests disclosed normal responses to l-arginine and insulin-induced hypoglycaemia. A huge benign mesenteric cyst was discovered by abdominal ultrasound and completely removed. Subsequently, the girl showed a marked catch-up growth; however, IGF-I and IGFBP-3 remained below the 0.1 percentile. Conclusion These observations imply that growth may take place even with very low levels of insulin-like growth factors. The interpretation of low IGF-I and IGFBP-3 levels in short children still requires good clinical judgement and basic knowledge of their biological action. Received: 24 September 1997 / Accepted in revised form: 16 March 1998     

The effect of early inhaled budesonide on pulmonary inflammation in infants with respiratory distress syndrome

The aim of this pilot study was to determine the effect of early inhaled budesonide on clinical and inflammatory parameters in preterm infants ventilated for respiratory distress syndrome. Conclusion Neither the inflammatory process associated with respiratory distress syndrome nor the progression to bronchopulmonary dysplasia appeared to be altered by treatment with inhaled budesonide. Received: 28 August 1998 / Accepted: 8 February 1999     

Lack of effectiveness of dexamethasone in neonatal bacterial meningitis

A clinical trial was conducted to determine whether dexamethasone as adjunctive therapy alters the outcome of bacterial meningitis in neonates. Fifty-two full-term neonates with bacterial meningitis were enrolled in a prospective study. Infants were alternately assigned to receive either dexamethasone or not. Twenty-seven received dexamethasone in addition to standard antibiotic treatment and 25 received antibiotics alone. Dexamethasone therapy was started 10–15 min before the first dose of antibiotics in a dose of 0.15 mg/kg per 6 h for 4 days. Baseline characteristics, clinical and laboratory features in the two groups were virtually similar. Both groups showed a similar clinical response and similar frequency of mortality and sequelae. Six (22%) babies in the treatment group died compared to 7 (28%) in the control group (P = 0.87). At follow up examinations up to the age of 2 years, 6 (30%) of dexamethasone recipients and 7 (39%) of the control group had mild or moderate/severe neurological sequelae. Audiological sequelae were seen in two neonates in the dexamethasone group compared to one in the control group. Conclusion Adjunctive dexamethasone therapy does not improve the outcome of neonatal bacterial meningitis. Received: 22 December 1997 / Accepted: 14 March 1998     

Efficacy and safety of acarbose in patients with cystic fibrosis and impaired glucose tolerance

Impaired glucose tolerance (IGT) is an increasingly frequent complication of cystic fibrosis (CF). In CF patients, a fast postprandial rise in plasma glucose is typically followed by a delayed but prolonged insulin response. Patients may develop symptoms of both hyper- and hypoglycaemia. The α-glucosidase inhibitor, acarbose, delays the hydrolysis and subsequent absorption of ingested carbohydrates. The aim of this study was to investigate the efficacy of acarbose in CF patients with IGT. During a 2-week inpatient period for treatment of Pseudomonas infection, 12 CF patients with IGT were studied in a double-blinded, randomized crossover trial. Each patient received acarbose (50 mg t.i.d.) for 5 days and placebo for 5 days (days 3–8 and days 10–14, respectively). Glucose, insulin and C-peptide responses to a standardized nutritional load were measured at baseline and at the end of each study period (Days 2, 8 and 14). Treatment with acarbose was associated with significant reductions in the mean value, mean peak values and the area under the curve of plasma glucose, insulin and C-peptide, compared to respective baseline values and placebo. Gastro-intestinal disturbances were recorded in 67% of patients during therapy with acarbose. Conclusion Acarbose has a positive therapeutic effect on glucose tolerance in cystic fibrosis patients, as shown by attenuation of postprandial plasma glucose increase and a significant decrease in insulin secretion response. However, acarbose treatment was associated with adverse gastro-intestinal effects that may prevent patients from accepting long-term therapy. Received: 1 December 1997 / Accepted in revised form: 15 September 1998     

A mild variant of Desbuquois dysplasia

On the basis of three newly observed cases (a pair of siblings and a sporadic case) and one previously reported case, we describe the clinical and radiological phenotype of a skeletal dysplasia resembling Desbuquois dysplasia. The skeletal alterations in the present disorder, including generalized osteopenia, mild modification of the vertebral endplates, epiphyseal flattening of the long bones, broad proximal femora with a spur-like projection of the lesser trochanters (a monkey wrench appearance of the proximal femora), and advanced carpal skeletal age, are almost identical to those of Desbuquois dysplasia. However, postnatal growth failure and minor spondylo-articular problems in the present disorder contrast with the conspicuous prenatal growth failure and severe spondylo-articular deformities of Desbuquois dysplasia. Short stature in the present disorder does not reach the degree of Desbuquois dysplasia. Molecular investigation of one patient excluded abnormalities of the diastrophic dysplasia sulphate transporter gene. Conclusion The combination of skeletal alterations identical to those of Desbuquois dysplasia with milder short stature and spondylo-articular problems in the present patients suggests the nosological proposal of “a mild variant of Desbuquois dysplasia”. Received: 22 June 1998 / Accepted: 1 November 1998     

Persistent hyperinsulinaemic hypoglycaemia of infancy: therapy, clinical outcome and mutational analysis

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is an autosomal recessive disorder characterized by irregular insulin secretion leading to hypoglycaemia. Recently, mutations in the sulphonylurea receptor (SUR) have been described in association with PHHI. We studied clinical symptoms, therapy, long-term outcome and mutational analysis in 14 patients with PHHI. In 8 patients subtotal pancreatectomy was performed whereas 6 responded to conservative treatment with diazoxide. Psychomotor retardation was found in 6 patients, most of them after a delayed diagnosis. A G-to-A point mutation in one allele of the SUR gene was detected by loss of a MspI restriction site in only one patient. Conclusion Early diagnosis and therapy in PHHI is essential to prevent brain damage. In one patient mutational analysis suggested compound heterozygosity for a known and an as yet unidentified mutation in the SUR gene. Received: 20 November 1996 / Accepted: 14 April 1997     

Comparison of sucrose and human milk on pain response in newborns

The aim of this study was to compare the analgesic effect of 2 ml 25% sucrose and human milk in a group of healthy term newborns. Healthy infants (n = 102) were randomly allocated to receive one of three solutions (sucrose, human milk, sterile water) 2 min prior to taking a heel prick blood sample. The median values of crying time, recovery time and percentage change in heart rate at 1, 2 and 3 min were recorded in response to the heel prick. Median crying times were 36, 52, and 62 s in the sucrose, placebo and human milk groups, respectively (P = 0.0009). In the sucrose group, there was a significant reduction in crying time compared to human milk and placebo groups. Similarly, the median recovery time in the sucrose group (72 s) was shorter than that in the human milk (112 s) and placebo groups (124 s) (P = 0.004). The percentage change in heart rate at 1, 2 and 3 min was also significantly lower in the sucrose group (P = 0.008, P = 0.01, P = 0.002 at 1, 2, and 3 min respectively). Conclusion The orosensorial antinociceptive effect of human milk is not as effective as an analgesic as a 25% sucrose solution. Received: 26 September 1997 and in revised form: 4 March 1998 / Accepted: 13 March 1998     

Effects of a low-calorie diet on resting metabolic rate and serum tri-iodothyronine levels in obese children

The purpose of the study was to examine the effects of weight loss on resting metabolic rate (RMR) and on serum T3 levels in obese children and to investigate whether RMR changes are related to T3 changes. Sixty-four healthy, overweight, children (age: 12.1 ± 1.1 years, body mass index 29.3 ± 4.3 kg/m²) were studied during a 6-week weight reduction programme. RMR (by indirect calorimetry) total T3, total T4, TSH and fat-free mass (FFM) (by anthropometry) were measured at baseline and after 6 weeks of dietary treatment. Weight loss resulted in a 10.1% decline in RMR (P < 0.01) and a 23.4% decrease in serum T3 levels (P < 0.001). RMR was correlated with FFM before (r = 0.78, P < 0.001) and after weight loss (r = 0.76, P < 0.001). The changes in RMR were positively correlated with the changes in FFM (r = 0.48, P < 0.05) but also with the changes in serum T3 levels (r = 0.47, P < 0.05). The initial T3 levels predicted the subsequent fall in T3 that occurred after 6 weeks of dietary treatment (r = −0.60, P < 0.001). Conclusions A significant decrease in serum T3 concentrations and resting metabolic rate occurred as a result of a 6-week weight reduction programme in an obese child population. The decline in T3 levels combined with fat-free mass loss could be responsible for the reduction in resting metabolic rate. Received: 30 June 1998 / Accepted in revised form: 22 October 1998     

Carbohydrate-deficient glycoprotein syndrome in a newborn with an unbalanced chromosomal translocation

Carbohydrate-deficient glycoprotein syndromes may occur as a primary result of distinct genetic disruption of the enzymes involved in processing the carbohydrate moeities of glycoproteins. They may also occur due to a number of secondary defects in glycosylation. Conclusion A female infant with an unbalanced chromosomal translocation [46,XX,der(21)t(17;21) (p13.1;q22.11)mat.ish der(21)t(17;21) (D17S375 × 3, D21S65-)] and with biochemical and clinical features of a carbohydrate deficient glycoprotein syndrome is reported. This chromosomal disruption is another secondary cause of the disorder. Received: 10 September 1998 / Accepted in revised form: 1 November 1998     

Dry lung syndrome: complete airway collapse mimicking pulmonary hypoplasia?

We observed a premature baby born after severe oligohydramnios who could not be ventilated efficiently even with very high pressures immediately after birth, but who, after cessation of resuscitation attempts, recovered spontaneous sufficient breathing during the following hour. After this experience we searched our case records for other newborns with dry lung syndrome using the following definition: (1) premature birth after prolonged leakage of amniotic fluid, (2) very high ventilatory requirement after birth, (3) dramatic improvement during the first 24 to 36 h and (4) respiratory distress syndrome and infection excluded. Among 93 prematures with rupture of membranes for 4 days or more we found 3, including the index case, matching this definition. Conclusion Dry lung syndrome appears to be a distinct clinical entity that is possibly underrecognised but recognisable and that merits further study. Its pathogenesis may imply complete collapse of small airways to a degree that capillary forces impede distension by ordinary ventilatory pressures. Received: 18 December 1997 and in revised form: 9 March 1998 / Accepted: 13 March 1998     

Nephrocalcinosis in full-term infants receiving furosemide treatment for congestive heart failure: a study of the incidence and 2-year follow up

In order to study the incidence and course of nephrocalcinosis in full-term infants with congestive heart failure receiving long-term furosemide treatment, 36 such infants (median age 2.9 months, range 1.2–8.0) and 36 full-term control infants not receiving any diuretics (median age 3.4 months, range 1.1–8.4) were studied by renal ultrasonography and random urine calcium variables. The infants with nephrocalcinosis were followed at 3–6 month intervals up to 2 years of age, or until ultrasonic resolution. Nephrocalcinosis was found in 5 out of the 36 (14%) treated infants, but in none of the controls (P = 0.03). The dose of furosemide was higher in the infants with nephrocalcinosis than in those without (1.9 ± 0.6 vs. 1.3 ± 0.4 mg/kg per day; P = 0.01). The urinary calcium concentration was higher in the infants receiving furosemide than in& controls and a similar trend was observed in the urinary calcium/creatinine ratio, but& these variables did not differ between the study infants with and without nephrocalcinosis. Ultrasonic resolution of nephrocalcinosis was observed in 3 of the 5& infants at 12 months, but in the other 2 the condition still persisted at 24 months. Conclusions Long-term furosemide treatment in full-term infants with congestive heart failure entails a considerable risk of developing nephrocalcinosis. Renal ultrasonography is warranted in these patients within a few months after initiation of the treatment and in the case of nephrocalcinosis alteration of the diuretic regimen is to be considered. Received: 8 September 1998 / Accepted in revised form: 12 January 1999     

Inhaled salbutamol and beclomethasone for preventing broncho-pulmonary dysplasia: a randomised double-blind study

Early inflammatory lesions and bronchial hyperresponsiveness are characteristics of the respiratory distress in premature neonates and are susceptible to aggravation by assisted ventilation. We hypothesized that treatment with inhaled salbutamol and beclomethasone might be of clinical value in the prevention of bronchopulmonary dysplasia (BPD) in ventilator-dependent premature neonates. The study was double-blinded and placebo controlled. We studied 173 infants of less than 31 weeks of gestational age, who needed ventilatory support at the 10th postnatal day. They were randomised to four groups and received either placebo + placebo, placebo + salbutamol, placebo + beclomethasone or beclomethasone + salbutomol, respectively for 28 days. The major criteria for efficacy were: diagnosis of BPD (with score of severity), mortality, duration of ventilatory support and oxygen therapy. The trial groups were similar with respect to age at entry (9.8–10.1 days), gestational age (27.6–27.8 weeks), birth weight and oxygen dependence. We did not observe any significant effect of treatment on survival, diagnosis and severity of BPD, duration of ventilatory support or oxygen therapy. For instance, the odds-ratio (95% confidence interval) for severe or moderate BPD were 1.04 (0.52–2.06) for inhaled beclomethasone and 1.54 (0.78–3.05) for inhaled salbutamol. Conclusion This randomised prospective trial does not support the use of treatment with inhaled beclomethasone, salbutamol or their combination in the prevention of BPD in premature ventilated neonates. Received: 20 November 1997 / Accepted: 2 March 1998