Jürgen Grulich-Henn

Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study

BACKGROUND Serum thyroid hormone concentrations decline transiently during critical illness and after surgical procedures. We investigated prospectively the endocrine and haemodynamic effects of tri-iodothyronine treatment after cardiopulmonary bypass operations in children with congenital cardiac malformations. METHODS We did a randomised, double-blind, placebo-controlled trial, in which 40 children (median age 0.6 years; range 2 days to 10.4 years) were randomly assigned placebo (saline) or one daily infusion of tri-iodothyronine (2 microg/kg bodyweight on day 1 after surgery and 1 microg/kg bodyweight on subsequent postoperative days up to 12 days after surgery. Before and 2 h, 24 h, and 72 h after the first infusion, plasma concentrations of thyroid hormones were measured by RIA, and systolic cardiac function was evaluated by echocardiography. During the postoperative course intensive-care measures were assessed by use of the therapeutic intervention scoring system. FINDINGS In all patients, postoperative plasma concentrations of thyrotropin, thyroxine, free thyroxine, tri-iodothyronine were abnormally low and plasma concentrations of reverse tri-iodothyronine were raised. After start of treatment, tri-iodothyronine was significantly higher in patients given tri-iodothyronine than in those receiving placebo, whereas thyrotropin, thyroxine, free thyroxine, and reverse tri-iodothyronine remained similar in the two groups. At discharge, thyroid hormones of all patients were within the normal range, but thyrotropin secretion increased to plasma concentrations higher than those seen before treatment. The mean change of cardiac index was significantly higher in children given tri-iodothyronine (20.4% [SD 19.6] vs 10.0% [15.2]; p=0.004). Systolic cardiac function improved most in patients given tri-iodothyronine after longer cardiopulmonary bypass operations. Overall, patients given tri-iodothyronine had significantly lower mean treatment scores. INTERPRETATION Treatment of children with tri-iodothyronine after cardiopulmonary bypass operations raises tri-iodothyronine plasma concentrations and improves myocardial function especially in patients with low postoperative cardiac output without adverse events, and without delaying postoperative recovery of thyroid function. Furthermore, tri-iodothyronine reduces the need for postoperative intensive care.

Transient Secondary Hypothyroidism in Children after Cardiac Surgery

Thyroid hormone status was assessed in 132 children with congenital heart defects undergoing cardiac surgery (median age 3.1 y; range 2 d to 16.2 y). Plasma TSH, thyroxine (T4), free thyroxine (fT4), triiodothyronine (T3), reverse triiodothyronine (rT3), thyroglobulin (Tg), and urinary iodine excretion were measured before and every other day after cardiac surgery (d 1-21). After surgery we observed strikingly low plasma concentrations of TSH (0.4 mU/L; 0.2-1.3), T3(0.6 nmol/L; 0.3-1.2), T4 (48.9 nmol/L; 12.9-82.4), fT4 (12.9 pmol/L; 5.1-19.3), and Tg (9.4 μg/L; 1.5-20.6), whereas rT3 plasma concentrations increased (0.13 pmol/L; 0.05-0.3; n = 40). The maximal postoperative changes of TSH and rT3 preceded changes of T3, T4, fT4, and Tg. Postoperative urinary iodine excretion increased significantly (n = 109). Thyroid hormone plasma concentrations were lowest after cardiopulmonary bypass operations and in patients treated with dopamine. In patients with postoperative T3 plasma concentrations less than 0.6 nmol/L (n = 52) the period of mechanical ventilation and intensive care treatment was significantly prolonged. Furthermore, the cumulative doses of inotropic and vasoactive catecholamines and furosemide were significantly higher in this patient group. Our results demonstrate transient secondary hypothyroidism in children after cardiac surgery that may contribute to postoperative cardiac and respiratory dysfunction and may delay recovery. Possible benefits of thyroid hormone replacement therapy need to be thoroughly examined.

Novel Respiratory Syncytial Virus (RSV) Genotype ON1 Predominates in Germany during Winter Season 2012-13

Respiratory syncytial virus (RSV) is the leading cause of hospitalization especially in young children with respiratory tract infections (RTI). Patterns of circulating RSV genotypes can provide a better understanding of the molecular epidemiology of RSV infection. We retrospectively analyzed the genetic diversity of RSV infection in hospitalized children with acute RTI admitted to University Hospital Heidelberg/Germany between October 2012 and April 2013. Nasopharyngeal aspirates (NPA) were routinely obtained in 240 children younger than 2 years of age who presented with clinical symptoms of upper or lower RTI. We analyzed NPAs via PCR and sequence analysis of the second variable region of the RSV G gene coding for the attachment glycoprotein. We obtained medical records reviewing routine clinical data. RSV was detected in 134/240 children. In RSV-positive patients the most common diagnosis was bronchitis/bronchiolitis (75.4%). The mean duration of hospitalization was longer in RSV-positive compared to RSV-negative patients (3.5 vs. 5.1 days; p<0.01). RSV-A was detected in 82.1%, RSV-B in 17.9% of all samples. Phylogenetic analysis of 112 isolates revealed that the majority of RSV-A strains (65%) belonged to the novel ON1 genotype containing a 72-nucleotide duplication. However, genotype ON1 was not associated with a more severe course of illness when taking basic clinical/laboratory parameters into account. Molecular characterization of RSV confirms the co-circulation of multiple genotypes of subtype RSV-A and RSV-B. The duplication in the G gene of genotype ON1 might have an effect on the rapid spread of this emerging RSV strain.

Lymphocytic hypophysitis with central diabetes insipidus and consequent panhypopituitarism preceding a multifocal, intracranial germinoma in a prepubertal girl

Abstract We report the clinical course of a prepubertal girl with central diabetes insipidus (DI) and consequent panhypopituitarism evolving over a period of 10 years due to lymphocytic hypophysitis and subsequent germinoma. Two years after the diagnosis of central DI was established, MRI revealed a thickened pituitary stalk. Later pituitary enlargement and increasing thickening of the pituitary stalk impinging on the optic chiasm required a trans-sphenoidal biopsy which disclosed active hypophysitis with lymphocytic infiltrates and necrosis. High dose dexamethasone treatment only temporarily halted the disease process. Therefore, stereotactic radiation therapy was performed as a rescue treatment and MRI findings almost reversed. However, the subsequent MRI showed multiple intracranial lesions identified histologically as a germinoma and a standard chemotherapy and radiation was performed. Conclusion The diagnosis of diabetes insipidus in children requires long-term follow up beyond the pubertal age in order to establish the underlying cause. In contrast to lymphocytic hypophysitis in adults, lymphocytic hypophysitis in prepubertal children may represent the first sign of a host reaction to an occult germinoma.

Longitudinal Trajectories of Metabolic Control From Childhood to Young Adulthood in Type 1 Diabetes From a Large German/Austrian Registry: A Group-Based Modeling Approach

OBJECTIVE Worsening of glycemic control in type 1 diabetes during puberty is a common observation. However, HbA1c remains stable or even improves for some youths. The aim is to identify distinct patterns of glycemic control in type 1 diabetes from childhood to young adulthood. RESEARCH DESIGN AND METHODS A total of 6,433 patients with type 1 diabetes were selected from the prospective, multicenter diabetes patient registry Diabetes-Patienten-Verlaufsdokumentation (DPV) (follow-up from age 8 to 19 years, baseline diabetes duration ≥2 years, HbA1c aggregated per year of life). We used latent class growth modeling as the trajectory approach to determine distinct subgroups following a similar trajectory for HbA1c over time. RESULTS Five distinct longitudinal trajectories of HbA1c were determined, comprising group 1 = 40%, group 2 = 27%, group 3 = 15%, group 4 = 13%, and group 5 = 5% of patients. Groups 1–3 indicated stable glycemic control at different HbA1c levels. At baseline, similar HbA1c was observed in group 1 and group 4, but HbA1c deteriorated in group 4 from age 8 to 19 years. Similar patterns were present in group 3 and group 5. We observed differences in self-monitoring of blood glucose, insulin therapy, daily insulin dose, physical activity, BMI SD score, body-height SD score, and migration background across all HbA1c trajectories (all P ≤ 0.001). No sex differences were present. Comparing groups with similar initial HbA1c but different patterns, groups with higher HbA1c increase were characterized by lower frequency of self-monitoring of blood glucose and physical activity and reduced height (all P < 0.01). CONCLUSIONS Using a trajectory approach, we determined five distinct longitudinal patterns of glycemic control from childhood to early adulthood. Diabetes self-care, treatment differences, and demographics were related to different HbA1c courses.

Ligand Blot Analysis of Insulin-Like Growth Factor-Binding Proteins using Biotinylated Insulin-Like Growth Factor-I

A nonradioactive method for the detection of insulin-like growth factor-binding proteins (IGFBPs) was developed utilizing human recombinant insulin-like growth factor-I (IGF-I) biotinylated with N-hydroxysuccinimido-biotin. Human plasma samples were separated by 15% SDS polyacrylamide gel electrophoresis, and proteins were transferred to nitrocellulose by Western blotting. The nitrocellulose sheets were incubated overnight with IGF-I-biotin at 4°C. The next day streptavidin-peroxidase was added for 1 h, and IGFBPs were visualized by an enhanced chemiluminescence system. Five characteristic bands with molecular weights of 41 and 39 (IGFBP-3), 34 (IGFBP-2), 30 (IGFBP-1) and 24 kD (IGFBP-4) were detected. Binding was specific for IGFs, since unlabeled IGF-I inhibited IGF-I-biotin binding. IGFBP ligand blots with biotinylated IGF-I and 125I-IGF-I yielded comparable results. The suitability of the new assay for clinical purposes was demonstrated by several clinical examples. In summary, a rapid, reliable, nonradioactive assay for qualitative analysis of IGFBPs has been developed.

Bilateral renal venous thrombosis in a neonate associated with resistance to activated protein C

Abstract. Renal venous thrombosis (RVT) is a serious complication of neonates. In most cases the underlying cause of RVT remains unclear. Here we report a neonate with bilateral RVT and adrenal haemorrhage associated with a heterozygous mutation of the gene encoding for clotting factor V, resulting in resistance to activated protein C. Vigorous thrombolytic therapy with urokinase followed by recombinant tissue plasminogen activator dissolved the thrombus in the inferior vena cava and restored perfusion of both kidneys. However, a haemorrhagic rupture of the right kidney occurred, requiring emergency nephrectomy. Despite reperfusion of the left kidney and resumption of urine output, the patient remained dialysis dependent. Due to persistent adrenal insufficiency, long-term substitution of hydrocortisone was necessary. The patient was prophylactically treated with coumarin during the first 6 months of life and is now waiting for renal transplant at the age of 1 year.

Tracking of Metabolic Control from Childhood to Young Adulthood in Type 1 Diabetes

OBJECTIVE This prospective longitudinal survey was designed to follow patients with diabetes from disease onset in childhood over an extended period of time including puberty until young adulthood with respect to metabolic control. STUDY DESIGN An electronic diabetes patient documentation system used in diabetes centers in Austria and Germany was utilized for standardized data collection. Complete documentation of metabolic control for prepuberty (≤ 13 years), puberty (14-19 years), and adulthood (≥ 20 years) was available in 1146 patients. RESULTS Median age at diabetes manifestation was 7.2 (IQR 4.7-9.4) years; 49% were male. In the prepubertal stage, median glycated hemoglobin A1c (HbA1c) was 7.5 (IQR 6.8-8.3), during puberty 8.0 (IQR 7.3-8.9), and after puberty 7.8 (IQR 7.1-9.0). A significant intra-individual correlation was found for prepuberty to puberty HbA1c levels (R = 0.55, P < .001), puberty to adulthood (R = 0.59, P < .001), as well as prepuberty to adulthood (R = 0.30, P < .001). When patients were divided into tertiles of prepubertal HbA1c, HbA1c increased in all 3 groups over time, however, significant group differences tracked into adulthood (P < .001 at all stages). A regression model identified pre-pubertal HbA1c as a significant and relevant predictor of metabolic control in young adulthood adjusted for confounders (P < .001). CONCLUSIONS This survey provides evidence for long-term tracking of metabolic control from childhood until adulthood, suggesting an early focus on metabolic control.

Short-term, high-dose testosterone treatment fails to reduce adult height in boys with constitutional tall stature.

Abstract Height predictions based on three different methods (Bayley-Pinneau [BP], Tanner-Whitehouse Mark II [TW II], Roche-Wainer-Thissen [RWT]) were compared to adult heights in 19 males with constitutional tall stature previously treated with high-dose testosterone oenanthate for 6 months (group A) and 25 untreated tall males (group B). Their chronological ages (CA) at the initial evaluation of tall stature ranged from 12.1 to 16.6 years in group A and from 10.4 to 15.7 years in group B; at the time of assessment of adult height ages ranged from 18.0 to 26.5 years and from 18.4 to 25.1 years, respectively. Height measurements and predicted adult heights were expressed as height standard deviation scores (height SDS) for chronological age using the tables of Reinken and van Oost [14]. Height SDS in group A were 2.8 (range = 1.8–5.4) before testosterone treatment, 3.0 (range = 2.0–4.8) thereafter and finally 3.0 (range = 2.1–4.2) (P=NS) and in group B 2.7 (range = 0.5–4.3) and 2.4 (range = 1.3–3.5) (P=NS). A significant difference between adult height SDS and predicted height SDS according to BP was detected both in group A (3.0; range = 2.1–4.2 vs 3.6; range = 2.4–5.0; P≤0.004) and group B (2.4; range = 1.3–3.5 vs 3.0; range = 2.0–4.9; P≤0.0002), whereas no significant difference between adult height SDS and predicted height SDS according to TW II and RWT was found in either group. These data indicate that BP height predictions overestimated adult height in our patient group of treated and untreated males with constitutional tall stature. In contrast, the TW II and RWT methods were more accurate in predicting adult height in these patients, but also failed to demonstrate that testosterone therapy in boys with constitutional tall stature can be limited to a 6-month period in order to reduce adult height. Conclusion The widely used height prediction method of BP is inaccurate in boys with constitutional tall stature. High dose testosterone treatment fails to reduce adult height in these individuals when discontinued before complete closure of the epiphyses.

Current use of metformin in addition to insulin in pediatric patients with type 1 diabetes mellitus: an analysis based on a large diabetes registry in Germany and Austria

With increasing obesity in childhood and adolescence, weight gain, and insulin resistance become also more frequent in patients with type 1 diabetes mellitus (T1DM). Especially during puberty, insulin therapy often has to be intensified and higher insulin doses are necessary. Some studies point to a beneficial effect of metformin in addition to insulin in these patients. In order to describe current practice and possible benefits, we compared pediatric T1DM patients with insulin plus metformin (n = 525) to patients with insulin therapy only (n = 57 487) in a prospective multicenter analysis.