Transition to adult diabetes care in Germany-High risk for acute complications and declining metabolic control during the transition phase.

OBJECTIVE: There is evidence that transition from pediatric to adult health care is frequently associated with deterioration of health in youths with type 1 diabetes (T1D). The aim of this study was to compare metabolic control, acute complications and microvascular complications in adolescents and young adults before and after transfer to an adult treatment center with respect to the time between first visit in the adult center and last visit in pediatric treatment. METHODS: All data were collected during routine care and retrieved from the German/Austrian DPV database. We analyzed data as of March 2017. RESULTS: We found 1283 young adults with available data of the last pediatric treatment year and the first year after transition to adult care. HbA1c increased significantly from 8.95% (74 mmol/mol) before to 9.20% (77 mmol/mol) in the first year after transition. Frequency of DKA with hospitalization (0.10-0.191 per annum, P < .0001) and severe hypoglycemia (0.23-0.46 per annum, P = .013) doubled during transition. Microvascular complications increased dramatically depending on the time between first visit in adult treatment and last visit in pediatric care. We could not find a significant correlation of this rise of microvascular complications to the duration of transition (short or long). CONCLUSION: This phase of life bears a high risk for detrimental outcome in young adults with T1D. Structured transition programs with case management are therefore needed to improve the transition process and outcomes.

Blood pressure regulation determined by ambulatory blood pressure profiles in children and adolescents with type 1 diabetes mellitus: Impact on diabetic complications.

BACKGROUND: The combination of high blood pressure and hyperglycemia contributes to the development of diabetic complications. Ambulatory monitoring of blood pressure (ABPM) is seen as standard to assess blood pressure (BP) regulation. OBJECTIVE: We evaluated 24-hour BP regulation in 3529 children with type 1 diabetes, representing 5.6% of the patients <20 years of age documented in the DPV registry, and studied the influence of BP parameters including pulse pressure (PP) and blood pressure variability (BPV) on microalbuminuria (MA) and diabetic retinopathy (DR). RESULTS: BP was increased in this selected cohort of children with diabetes compared to healthy German controls (standard deviation score (SDS) day: systolic BP (SBP) +0.06, mean arterial pressure (MAP) +0.08, PP +0.3; night: SBP +0.6, diastolic BP +0.6, MAP +0.8), while daytime diastolic BP (SDS -0.2) and dipping of SBP and MAP were reduced (SBP -1.1 SDS, MAP 12.4% vs 19.4%), PP showed reverse dipping (-0.7 SDS). Children with microvascular complications had by +0.1 to +0.75 SDS higher BP parameters, except of nocturnal PP in MA and diurnal and nocturnal PP in DR. Reverse dipping of PP was more pronounced in the children with MA (-5.1% vs -0.8%) and DR (-2.6% vs -1.0%). BP alteration was stronger in girls and increased with age. CONCLUSION: There is an early and close link between 24-hour blood pressure regulation and the development of diabetic complications not only for systolic, diastolic, and mean arterial BP but also for the derived BP parameter PP and BPV in our selected patients.

Introducing excess body weight in childhood and adolescence and comparison with body mass index and waist-to-height ratio.

BACKGROUND: Weight status in children and adolescents is commonly defined using age- and gender-corrected standard deviation scores for body mass index (BMI-SDS, also called z-scores). Values are not reliable for the extremely obese however. Moreover, paediatricians and parents may have difficulties understanding z-scores, and while percentiles are easier to gauge, the very obese have values above the 99th percentile, making distinction difficult. The notion of excess body weight (EBW) is increasingly applied in adult patients, mainly in the context of bariatric surgery. However, a clear definition is not available to date for the paediatric population. METHODS: A simple definition of EBW for children and adolescents is introduced, with median weight as a function of height, age and gender (characterized by an asterisk): EBW (%) = 100x(weight-median weight*)/median weight*. EBW is compared with BMI-SDS and waist-to-height ratio (WHtR). Using two data sources (APV registry and German Health Interview and Examination Survey for Children and Adolescents (KiGGS)) including more than 14,000 children, the relationships between these anthropometric and various metabolic parameters are analysed for a group of overweight/obese children who have sought obesity therapy (APV), for the general paediatric population and for the subset of overweight/obese children from the general population (KiGGS). RESULTS: The three anthropometric parameters are strongly correlated, with the linear correlation coefficients exceeding 0.8 in the general population and 0.75 in those seeking obesity therapy. Moreover, their relationship to metabolic parameters is quite similar regarding correlations and area under the curve from receiver operating characteristic analyses. CONCLUSIONS: EBW has similar predictive value for metabolic or cardiovascular comorbidities compared with BMI and WHtR. As it is reliable at the extreme end of the obesity spectrum, easily communicable and simple to use in daily practice, it would make a very useful addition to existing tools for working with obese children and adolescents. Its usefulness in assessing weight change needs to be studied however.

Medium-chain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening.

BACKGROUND: Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common disorder of mitochondrial fatty acid ß-oxidation and a target disease of newborn screening in many countries. CASE PRESENTATION: We report on two siblings with mild MCAD deficiency associated with a novel splice site mutation in the ACADM gene. The younger sibling was detected by newborn screening, while the older sister was missed, but diagnosed later on by genetic family testing. Both children were found to be compound heterozygous for the common c.985A > G (p.K329E) mutation and a novel splice site mutation, c.600-18G > A, in the ACADM gene. To determine the biological consequence of the c.600-18G > A mutation putative missplicing was investigated at RNA level in granulocytes and monocytes of one of the patients. The splice site mutation was shown to lead to partial missplicing of the ACADM pre-mRNA. Of three detected transcripts two result in truncated, non-functional MCAD proteins as reflected by the reduced octanoyl-CoA oxidation rate in both patients. In one patient a decrease of the octanoyl-CoA oxidation rate was found during a febrile infection indicating that missplicing may be temperature-sensitive. CONCLUSIONS: Our data indicate that the c.600-18G > A variant activates a cryptic splice site, which competes with the natural splice site. Due to only partial missplicing sufficient functional MCAD protein remains to result in mild MCADD that may be missed by newborn screening.

Long-term Surveillance of Children with Congenital Hypothyroidism: Data from the German Registry for Congenital Hypothyroidism (AQUAPE "Hypo Dok").

BACKGROUND: The German study group for quality assurance in pediatric endocrinology and the University of Ulm have established a software ("Hypo Dok") for the documentation of longitudinal data of patients with congenital primary hypothyroidism (CH). Aim of this study was to analyse the long-term follow-up of patients with CH and to compare treatment with current guidelines. METHODS/PATIENTS: Anonymised data of 1,080 patients from 46 centres were statistically analysed. RESULTS: Newborn screening result was available at a mean age of 7.3 days. Confirmation of the diagnosis was established at 8.4 days and therapy was started at 11 days. The average screening TSH was 180.0 mIU/L. During the first 3 months mean levothyroxine (LT4) dose was 10.7 µg/kg/day or 186.0 µg/m²/day. Weight-, BMI- and height-SDS did not differ significantly from the normal population. Only 25% of the patients (n=262) underwent formal EQ/IQ-testing. Their average IQ was 98.8 ± 13.2 points. DISCUSSION: In Germany screening, confirmation and start of treatment of CH are within the recommended time frame of 14 days. Initial LT4-doses are adequate. The auxological longterm outcome of young CH patients is normal. The implementation of standardized IQ testing has to be improved in routine patient care. CONCLUSION: Longitudinal data of patients with CH was analysed and compared to current guidelines. Confirmation and start of treatment are according to the recommendations. However standardised IQ testing requires improvement.

[Evidence-based procedures for the treatment of diseases associated with childhood obesity]. / Evidenzbasierung von Maßnahmen zur Behandlung der Folgeerkrankungen kindlicher Adipositas.

Childhood obesity is associated with cardiovascular events in adulthood. Multidisciplinary conventional obesity treatment programmes may reduce the body mass index standard deviation score at any age. However, over the years they lose their effectiveness especially during childhood. Only one study dealing with adult type 2 diabetic patients could show persistent weight reduction over the period of 4 years. Therefore, these conventional programmes may have short-term but no long-term influence on cardiovascular events. Bariatric surgery in childhood is exclusively performed in cases of morbid obesity. In adults, experience with regard to persistent weight loss has existed for over 20 years now and has reached good therapeutic results in type 2 diabetes. However, randomized and controlled long-term studies as to cardiovascular events and death do not exist. The Swedish Obese Subjects (SOS) study showed a significant decrease of cardiovascular events and death in the bariatric surgery study group compared to the conventional therapy group, but the groups were not randomized. The surgery group was younger and healthier compared to the conservatively treated group. The late start of therapy probably also had an unfavourable influence on cardiovascular events.

Propionic acidemia: neonatal versus selective metabolic screening.

BACKGROUND: Whereas propionic acidemia (PA) is a target disease of newborn screening (NBS) in many countries, it is not in others. Data on the benefit of NBS for PA are sparse. STUDY DESIGN: Twenty PA patients diagnosed through NBS were compared to 35 patients diagnosed by selective metabolic screening (SMS) prompted by clinical findings, family history, or routine laboratory test results. Clinical and biochemical data of patients from 16 metabolic centers in Germany, Austria, and Switzerland were evaluated retrospectively. Additionally, assessment of the intelligent quotient (IQ) was performed. In a second step, the number of PA patients who have died within the past 20 years was estimated based on information provided by the participating metabolic centers. RESULTS: Patients diagnosed through NBS had neither a milder clinical course regarding the number of metabolic crises nor a better neurological outcome. Among NBS patients, 63% were already symptomatic at the time of diagnosis, and <10% of all patients remained asymptomatic. Among all PA patients, 76% were found to be at least mildly mentally retarded, with an IQ <69. IQ was negatively correlated with the number of metabolic decompensations, but not simply with the patients' age. Physical development was also impaired in the majority of patients. Mortality rates tended to be lower in NBS patients compared with patients diagnosed by SMS. CONCLUSION: Early diagnosis of PA through NBS seems to be associated with a lower mortality rate. However, no significant benefit could be shown for surviving patients with regard to their clinical course, including the number of metabolic crises, physical and neurocognitive development, and long-term complications.

Mutation analysis in 54 propionic acidemia patients.

Deficiency of propionyl CoA carboxylase (PCC), a dodecamer of alpha and beta subunits, causes inherited propionic acidemia. We have studied, at the molecular level, PCC in 54 patients from 48 families comprised of 96 independent alleles. These patients of various ethnic backgrounds came from research centers and hospitals in Germany, Austria and Switzerland. The thorough clinical characterization of these patients was described in the accompanying paper (Grünert et al. 2012). In all 54 patients, many of whom originated from consanguineous families, the entire PCCB gene was examined by genomic DNA sequencing and in 39 individuals the PCCA gene was also studied. In three patients we found mutations in both PCC genes. In addition, in many patients RT-PCR analysis of lymphoblast RNA, lymphoblast enzyme assays, and expression of new mutations in E.coli were carried out. Eight new and eight previously detected mutations were identified in the PCCA gene while 15 new and 13 previously detected mutations were found in the PCCB gene. One missense mutation, p.V288I in the PCCB gene, when expressed in E.coli, yielded 134% of control activity and was consequently classified as a polymorphism in the coding region. Numerous new intronic polymorphisms in both PCC genes were identified. This study adds a considerable amount of new molecular data to the studies of this disease.

Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop.

Published data on treatment of fatty acid oxidation defects are scarce. Treatment recommendations have been developed on the basis of observations in 75 patients with long-chain fatty acid oxidation defects from 18 metabolic centres in Central Europe. Recommendations are based on expert practice and are suggested to be the basis for further multicentre prospective studies and the development of approved treatment guidelines. Considering that disease complications and prognosis differ between different disorders of long-chain fatty acid oxidation and also depend on the severity of the underlying enzyme deficiency, treatment recommendations have to be disease-specific and depend on individual disease severity. Disorders of the mitochondrial trifunctional protein are associated with the most severe clinical picture and require a strict fat-reduced and fat-modified (medium-chain triglyceride-supplemented) diet. Many patients still suffer acute life-threatening events or long-term neuropathic symptoms despite adequate treatment, and newborn screening has not significantly changed the prognosis for these severe phenotypes. Very long-chain acyl-CoA dehydrogenase deficiency recognized in neonatal screening, in contrast, frequently has a less severe disease course and dietary restrictions in many patients may be loosened. On the basis of the collected data, recommendations are given with regard to the fat and carbohydrate content of the diet, the maximal length of fasting periods and the use of l-carnitine in long-chain fatty acid oxidation defects.

Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop.

At present, long-chain fatty acid oxidation (FAO) defects are diagnosed in a number of countries by newborn screening using tandem mass spectrometry. In the majority of cases, affected newborns are asymptomatic at time of diagnosis and acute clinical presentations can be avoided by early preventive measures. Because evidence-based studies on management of long-chain FAO defects are lacking, we carried out a retrospective analysis of 75 patients from 18 metabolic centres in Germany, Switzerland, Austria and the Netherlands with special regard to treatment and disease outcome. Dietary treatment is effective in many patients and can prevent acute metabolic derangements and prevent or reverse severe long-term complications such as cardiomyopathy. However, 38% of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency had intermittent muscle weakness and pain despite adhering to therapy. Seventy-six per cent of patients with disorders of the mitochondrial trifunctional protein (TFP)-complex including long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, had long-term myopathic symptoms. Of these, 21% had irreversible peripheral neuropathy and 43% had retinopathy. The main principle of treatment was a fat-reduced and fat-modified diet. Fat restriction differed among patients with different enzyme defects and was strictest in disorders of the TFP-complex. Patients with a medium-chain fat-based diet received supplementation of essential long-chain fatty acids. l-Carnitine was supplemented in about half of the patients, but in none of the patients with VLCAD deficiency identified by newborn screening. In summary, in this cohort the treatment regimen was adapted to the severity of the underlying enzyme defect and thus differed among the group of long-chain FAO defects.

Moebius sequence: behaviour problems of preschool children and parental stress.

This study investigates behaviour problems of preschool children with Moebius sequence, and their primary caregivers' stress. To this end, parents of all preschool children with Moebius sequence known to the German Moebius foundation were anonymously asked to fill out questionnaires, e.g. the Child Behavior Checklist [CBCL] 1.5-5. The primary caregivers of 13/22 children (seven males, six females; mean age: 3;10 [2;1-5;11] years) sent back filled-out questionnaires. Two children were rated as clinical on the CBCL-1.5-5. Boys had significantly higher scores on the scales aggressive behavior and total problems than girls. Compared to the general population, but not to other parents of mentally and / or physically handicapped children, the primary caregivers experienced higher levels of stress. In conclusion, preschool children with Moebius sequence do not show essentially increased rates of clinical behaviour problems. Nevertheless, their primary caregivers experience increased stress and need early and adequate support.

Overweight and Obesity Based on Four Reference Systems in 18,382 Paediatric Patients with Type 1 Diabetes from Germany and Austria.

AIM: To evaluate the prevalence of overweight and obesity in paediatric type 1 diabetes (T1D) subjects, based on four commonly used reference populations. METHODS: Using WHO, IOTF, AGA (German pediatric obesity), and KiGGS (German Health Interview and Examination Survey for Children and Adolescents) reference populations, prevalence of overweight (≥90th percentile) and obesity (≥97th percentile) and time trend between 2000 (n = 9,461) and 2013 (n = 18,382) were determined in 2-18-year-old T1D patients documented in the German/Austrian DPV database. RESULTS: In 2000, the overweight prevalence was the highest according to IOTF (22.3%), followed by WHO (20.8%), AGA (15.5%), and KiGGS (9.4%). The respective rates in 2013 were IOTF (24.8%), WHO (22.9%), AGA (18.2%), and KiGGS (11.7%). Obesity prevalence in 2000 was the highest according to WHO (7.9%), followed by AGA (4.5%), IOTF (3.1%), and KiGGS (1.8%). In 2013, the respective rates were WHO (9.6%), AGA (6.2%), IOTF (4.5%), and KiGGS (2.6%). Overall, the prevalence of overweight and obesity increased from 2000 to 2006 (p < 0.001) but showed stabilization thereafter in girls and overweight in boys. CONCLUSION: Overweight and obesity prevalence in T1D subjects differs significantly if it is assessed by four separate reference populations. More detailed assessment of each child is required to determine obesity-related risks.

Mutations of the TSH receptor as cause of congenital hyperthyroidism.

4 patients of two families with congenital persistent hyperthyroidism without detectable autoantibodies are reported. The members of the first family affected by hyperthyroidism, i.e. the mother and her two children, showed a germline mutation, a transition of GCC to GTC in the genomic DNA of the TSH receptor, leading to an exchange of alanine by valine at the position 623. The mother was thyroidectomized at two times because of recurrent nodular goiter. The third child of a healthy second family showed a transition of AGC to AAC leading to an exchange of serine by asparagine at the position 505 of the TSH receptor. The mutation of family 1, as a somatic point mutation leading to autonomous thyroid adenoma, has originally been demonstrated to constitutively activate TSH independent cAMP accumulation. The functional tests of the TSH receptor gen mutation, detected in family 2, are ongoing, but an exchange of serine by arginine at the same position has been shown to lead to constitutively active cAMP accumulation. The cases of congenital hyperthyroidism in the first family lead to a reduction of the birth weight and head circumference and to a neonatal but not fetal tachycardia. Bone age of both children was accelerated by one year. In contrast to that, congenital hyperthyroidism of the second family lead to more marked signs of intrauterine hyperthyroidism. The mother observed marked symptoms of fetal and neonatal hyperthyroidism. The bone age at a chronological age of 6 months was 4-6 years and the neonate showed a mild exophthalmus. We conclude, that congenital hyperthyroidism due to constitutively activating TSH receptor mutations has to be considered, if hyperthyroidism is not transient but persistent, and the parameters of autoimmunity are absent. Constitutively active TSH receptor germline mutations lead to different degrees of congenital hyperthyroidism. In contrast to patients with Graves' disease, more aggressive means of treatment like total thyroidectomy and/or radiation seem to be recommendable in cases with severe hyperthyroidism to control the disease.

Plasma catecholamines after endotracheal administration of adrenaline during postnatal resuscitation.

To analyse the degradation of adrenaline after cardiopulmonary resuscitation of preterm neonates, free and sulphoconjugated adrenaline, noradrenaline, and dopamine were determined in 31 preterm neonates by a radioenzymatic method. Nine of the neonates received a high dose (250 micrograms/kg) of endotracheally administered adrenaline (1:1000); three of them had more than one dose of adrenaline. With the exception of sulphoconjugated dopamine, the free and sulphoconjugated catecholamine concentrations in preterm infants treated with adrenaline initially exceeded those in the untreated group. The concentrations decreased to the same range about two hours after birth. Free and sulphoconjugated adrenaline concentrations remained significantly increased in the adrenaline treated group, however, indicating a plateau effect. The correlation between free adrenaline and noradrenaline concentrations with their respective sulphoconjugated concentrations was highly significant. It is concluded that free catecholamines are rapidly degraded by sulphoconjugation in preterm neonates.

Impact of overweight on effectiveness of treatment with human growth hormone in growth hormone deficient children: analysis of German KIGS data.

BACKGROUND: We hypothesized that overweight children with growth hormone deficiency (GHD) demonstrate a lower response to growth hormone (GH) as a result of a misclassification since obesity is associated with lower GH peaks in stimulation tests. METHODS: Anthropometric data, response, and responsiveness to GH in the first year of treatment were compared in 1.712 prepubertal children with GHD from the German KIGS database according to BMI (underweight=group A, normal weight=group B, overweight=group C) (median age: group A, B, C: 7.3, 7.28, and 8.4 years). RESULTS: Maximum GH levels to tests (median: group A, B, C: 5.8, 5.8, and 4.0 µg/ml) were significantly lower in group C. IGF-I SDS levels were not different between the groups. Growth velocity in the first year of GH treatment was significantly lower in the underweight cohort (median: group A, B, C: 8.2, 8.8, and 9.0 cm/yr), while the gain in height was not different between groups. The difference between observed and predicted growth velocity expressed as Studentized residuals was not significantly different between groups. Separating the 164 overweight children into obese children (BMI>97th centile; n=71) and moderate overweight children (BMI>90th to 97th centile, n=93) demonstrated no significant difference in any parameter. CONCLUSIONS: Overweight prepubertal children with idiopathic GHD demonstrated similar levels of responsiveness to GH treatment compared to normal weight children. Furthermore, the IGF-I levels were low in overweight children. Therefore, a misclassification of GHD in overweight prepubertal children within the KIGS database seems unlikely. The first year growth prediction models can be applied to overweight and obese GHD children.

First description of three patients with multifocal lymphangiomatosis and protein-losing enteropathy following palliation of complex congenital heart disease with total cavo-pulmonary connection.

The objective was to identify abdominal lymphatic malformations in pediatric patients with protein-losing enteropathy after palliation of complex congenital heart disease with total cavo-pulmonary connection (TCPC). In 2006, we performed complete hemodynamic and laboratory workup and thoracic and abdominal MRT screens in three patients who newly presented with symptoms of protein-losing enteropathy. All three patients, aged 3, 5, and 7 years, showed excellent TCPC hemodynamics with central venous pressures of 10-13 mm Hg. None of the patients had right-to-left overflow. All three patients showed extensive thoracic and mesenterial lymphangiomatosis. One patient died after 18 months of therapy, which included long-term parenteral nutrition, somatostatin, subcutaneous heparin injections, and frequent albumin and immunoglobulin substitution. The other two patients are in stable condition. Lymphangiomatosis might play an unknown role in the pathogenesis of protein-losing enteropathy after TCPC. It remains unclear whether lymphangiomatosis is a primary congenital disease related to the cardiac disease or if it is triggered by repeated surgery or venous congestion. The presence of lymphangiomatosis should be given diagnostic and therapeutic consideration in TCPC patients in the future.

22q11.2 deletion syndrome: behaviour problems of infants and parental stress.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2 DS) can be associated with a variety of somatic symptoms, developmental delays and psychiatric disorders. At present, there is little information on early behaviour problems, and nothing is known about parental stress and possible relations between these factors. Therefore, the aim of this study was to investigate behaviour problems of infants with 22q11.2 DS, and their primary caregivers' stress. METHODS: Parents of infants with 22q11.2 DS known to the German 22q11.2 deletion syndrome foundation were anonymously asked to fill out several questionnaires, e.g. the Child Behavior Checklist (CBCL) 1.5-5. RESULTS: The primary caregivers of 22/30 children [12 boys and 10 girls aged 1 year 8 months to 3 years 11 months (mean age: 2 years 9 months)] sent back filled-out questionnaires. Seventeen out of 21 children showed motor, and 15/21 language delay. Five out of 21 children were rated as clinical on at least one CBCL 1.5-5 scale. The patients' age was correlated with anxiety problems, and girls had significantly more sleep problems than boys. Compared with the general population, the primary caregivers did not experience higher levels of strain, and compared with parents of mentally and/or physically handicapped children, their parental stress was significantly lower. Parental stress and strain were correlated to a variety of child behaviour problems, e.g. externalizing and anxious/depressed behaviour. CONCLUSIONS: Longitudinal studies are required to show whether behaviour problems and parental stress worsen when 22q11.2 DS patients grow older.

[Bilateral pheochromocytoma. Is there stimulation of an extra-adrenal adrenaline liberation after bilateral adrenalectomy?]. / Beidseitiges Phäochromozytom. Gibt es eine stimulierbare extraadrenale Adrenalinfreisetzung nach beidseitiger Adrenalektomie?

BACKGROUND: In order to determine plasma and urine epinephrine levels after bilateral adrenalectomy, we examined a 16 year old young man with bilateral pheochromocytoma. Bilateral removal of the adrenals was performed because of a left sided pheochromocytoma relapse. An extra-adrenal pheochromocytoma could be excluded by scintigraphy. Macroscopically all adrenal tissue was removed during surgery. METHODS: A modified radioenzymatic determination of the free catecholamines epinephrine, norepinephrine and dopamine was used according to Peuler and Johnson. Sulfoconjugated catecholamines were measured after addition of 60 microU arylsulfatase type VI. Urine catecholamine levels were determined fluorometrically. RESULTS: The elevated plasma andurine norepinephrine levels before surgery returned to normal after surgery. In contrast, plasma epinephrine levels returned to subnormal values thereafter but increases 5-fold at the end of anesthesia suggesting an extra-adrenal source of epinephrine. Urine epinephrine levels remained in the lower normal range. An insulin induced hypoglycemia was performed resulting in adrenergic symptoms of hypoglycemia and a subnormal increase of epinephrine. CONCLUSIONS: We conclude, that epinephrine mediated physiological regulations occur inspite of bilateral adrenalectomy probably by a regulated extra-adrenal source of epinephrine. The kidney could be the site of extra-adrenal epinephrine production.

[Free and sulfoconjugated plasma catecholamines in premature infants and mature newborn infants after birth]. / Freie und sulfatkonjugierte Plasma-Katecholamine bei Frühgeborenen und reifen Neugeborenen nach der Geburt.

Sulfate conjugation represents a major pathway for the inactivation of free catecholamines. We investigated the ability of newborns to protect the body against an overflow of free catecholamines by sulfoconjugation. No difference of free catecholamines in the umbilical artery was found in preterm and term newborns. Furthermore, preterm and term newborns were able to form sulfoconjugated catecholamines. In term newborns, but not in preterm newborns, there was a significant relationship between free catecholamines and their respective sulfoconjugated forms (p less than 0.001). In comparison to term infants sulfoconjugated dopamine and norepinephrine were significantly decreased in preterm newborns, although the placental extraction rates of these catecholamines were markedly lower in preterm infants. This favors the conclusion, that synthesis rather than increased degradation may be responsible for the low levels of sulfoconjugated catecholamines in preterm infants. Thus, preterm newborns might be less able to inactivate free catecholamines by sulfoconjugation. The clinical importance of these results concerning treatment of preterm newborns with dopamine and noradrenaline has yet to be established.

Free epinephrine, norepinephrine and dopamine in saliva and plasma of healthy adults.

To investigate whether salivary catecholamine levels reflect short term changes of sympathoadrenal activity, we simultaneously measured plasma and saliva epinephrine, norepinephrine and dopamine concentrations at rest, during bicycle ergometry and during epinephrine infusion in 12 healthy adults, using a radioenzymatic method. Whereas all plasma catecholamines significantly increased during bicycle ergometry and epinephrine infusion, no changes were observed in the salivary catecholamine concentrations and the salivary catecholamine flow rate after stimulation by rhythmic chewing. Moreover, salivary catecholamine concentrations were related neither to heart rate nor to blood pressure. Obviously, free catecholamines are rapidly inactivated by enzymatic degradation, neuronal reuptake or extraneuronal uptake in tissues before they diffuse through the tight junctions into the saliva. Therefore, stimulated saliva catecholamine levels do not reflect short term changes in the activity of the sympathoadrenal nervous system.