Thomas Danne

Oscillometric twenty-four-hour ambulatory blood pressure values in healthy children and adolescents: A multicenter trial including 1141 subjects

Ambulatory blood pressure (ABP) monitoring is increasingly used to evaluate the blood pressure of children and adolescents. The upper normal ABP values in the pediatric age group are still unknown, because reference values based on a sufficiently high number of healthy children have not yet been published. In this multicenter trial, we pooled ABP records of 1141 healthy children and adolescents with a body height between 115 and 185 cm. The study was carried out by seven centers according to a common protocol. The 50th percentile for 24-hour systolic ABP increased moderately with height, from 103 to 113 mm Hg in girls and from 105 to 120 mm Hg in boys. The 50th percentile for diastolic 24-hour means was 66 +/- 1 mm Hg, irrespective of height or gender. Diastolic daytime means were 73 +/- 1 mm Hg, which is remarkably high compared with reference values for casual blood pressure. The mean nocturnal systolic and diastolic ABP (midnight to 6 AM) was 13% +/- 6% and 23% +/- 9% lower compared with the daytime means (8 AM to 8 PM), respectively. This multicenter study provides well-based limits of normal ABP in mid-European children.

Nocturnal Glucose Control with an Artificial Pancreas at a Diabetes Camp

BACKGROUND Recent studies have shown that an artificial-pancreas system can improve glucose control and reduce nocturnal hypoglycemia. However, it is not known whether such results can be replicated in settings outside the hospital. METHODS In this multicenter, multinational, randomized, crossover trial, we assessed the short-term safety and efficacy of an artificial pancreas system for control of nocturnal glucose levels in patients (10 to 18 years of age) with type 1 diabetes at a diabetes camp. In two consecutive overnight sessions, we randomly assigned 56 patients to receive treatment with an artificial pancreas on the first night and a sensor-augmented insulin pump (control) on the second night or to the reverse order of therapies on the first and second nights. Thus, all the patients received each treatment in a randomly assigned order. The primary end points were the number of hypoglycemic events (defined as a sensor glucose value of <63 mg per deciliter [3.5 mmol per liter] for at least 10 consecutive minutes), the time spent with glucose levels below 60 mg per deciliter (3.3 mmol per liter), and the mean overnight glucose level for individual patients. RESULTS On nights when the artificial pancreas was used, versus nights when the sensor-augmented insulin pump was used, there were significantly fewer episodes of nighttime glucose levels below 63 mg per deciliter (7 vs. 22) and significantly shorter periods when glucose levels were below 60 mg per deciliter (P=0.003 and P=0.02, respectively, after adjustment for multiplicity). Median values for the individual mean overnight glucose levels were 126.4 mg per deciliter (interquartile range, 115.7 to 139.1 [7.0 mmol per liter; interquartile range, 6.4 to 7.7]) with the artificial pancreas and 140.4 mg per deciliter (interquartile range, 105.7 to 167.4 [7.8 mmol per liter; interquartile range, 5.9 to 9.3]) with the sensor-augmented pump. No serious adverse events were reported. CONCLUSIONS Patients at a diabetes camp who were treated with an artificial-pancreas system had less nocturnal hypoglycemia and tighter glucose control than when they were treated with a sensor-augmented insulin pump. (Funded by Sanofi and others; ClinicalTrials.gov number, NCT01238406.).

Use of insulin pump therapy in the pediatric age-group: consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes

Young patients with diabetes, their families, and their diabetes care providers continue to be faced with the challenge of striving to maintain blood glucose levels in the near-normal range. High blood glucose levels with elevated A1C levels are associated with long-term microvascular and macrovascular complications. Recurrent episodes of hypoglycemia, especially at young ages, may cause short- and long-term adverse effects on cognitive function and lead to hypoglycemia unawareness and may be associated with significant emotional morbidity for the child and parents. Fear of hypoglycemia, especially during the night, may compromise quality of life (QOL) for the family and jeopardize efforts to achieve optimal metabolic control. Over the past decade, continuous subcutaneous insulin infusion (CSII) has gained increasing popularity among patients with diabetes. CSII is the most physiologic method of insulin delivery currently available. It is able to closely simulate the normal pattern of insulin secretion, namely continuous 24-h adjustable “basal” delivery of insulin upon which are superimposed prandial “boluses.” In addition, CSII offers the possibility of more flexibility and more precise insulin delivery than multiple daily injection (MDI). However, there is still debate among diabetes care practitioners around the world as to whether CSII has advantages over MDI in terms of reduction in A1C levels, occurrence of severe hypoglycemic events, episodes of diabetic ketoacidosis (DKA), and frequency of hospitalizations in young patients. Furthermore, no clear criteria have been established to help the physician choose the “appropriate” patient for CSII therapy. To address these issues, the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), and the International Society for Pediatric and Adolescent Diabetes (ISPAD) convened a panel of expert physicians for a consensus conference endorsed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). For each major topic area, …

Insulin management and metabolic control of Type 1 diabetes mellitus in childhood and adolescence in 18 countries

Insulin regimens and metabolic control in children and adolescents with Type 1 diabetes mellitus were evaluated in a cross‐sectional, non‐population‐based investigation, involving 22 paediatric departments, from 18 countries in Europe, Japan, and North America. Blood samples and information were collected from 2873 children from March to August 1995. HbA1c was determined once and analysed centrally (normal range 4.4–6.3 %, mean 5.4 %). Year of birth, sex, duration of diabetes, height, body weight, number of daily insulin injections, types and doses of insulin were recorded. Average HbA1c in children under 11 years was 8.3 ± 1.3 % (mean ± SD) compared with 8.9 ± 1.8 % in those aged 12–18 years. The average insulin dose per kg body weight was almost constant (0.65 U kg−124 h−1) in children aged 2–9 years for both sexes, but there was a sharp increase during the pubertal years, particularly in girls. The increase in BMI of children with diabetes was much faster during adolescence compared to healthy children, especially in females. Sixty per cent of the children (n = 1707) used two daily insulin injections while 37 % (n = 1071) used three or more. Of those on two or three injections daily, 37 % used pre‐mixed insulins, either alone or in combination with short‐ and intermediate‐acting insulin. Pre‐adolescent children on pre‐mixed insulin showed similar HbA1c levels to those on a combination of short‐ and long‐acting insulins, whereas in adolescents significantly better HbA1c values were achieved with individual combinations. Very young children were treated with a higher proportion of long‐acting insulin. Among adolescent boys, lower HbA1c was related to use of more short‐acting insulin. This association was not found in girls. We conclude that numerous insulin injection regimens are currently used in paediatric diabetes centres around the world, with an increasing tendency towards intensive diabetes management, particularly in older adolescents. Nevertheless, the goal of near normoglycaemia is achieved in only a few.

Continuing Stability of Center Differences in Pediatric Diabetes Care: do advances in diabetes treatment improve outcome? The Hvidoere Study Group on Childhood Diabetes

OBJECTIVE—To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on metabolic outcome, hypoglycemia, and ketoacidosis. RESEARCH DESIGN AND METHODS—This was an observational cross-sectional international study in 21 centers, with clinical data obtained from all participants and A1C levels assayed in one central laboratory. All individuals with diabetes aged 11–18 years (49.4% female), with duration of diabetes of at least 1 year, were invited to participate. Fourteen of the centers participated in previous Hvidoere Studies, allowing direct comparison of glycemic control across centers between 1998 and 2005. RESULTS—Mean A1C was 8.2 ± 1.4%, with substantial variation between centers (mean A1C range 7.4–9.2%; P < 0.001). There were no significant differences between centers in rates of severe hypoglycemia or diabetic ketoacidosis. Language difficulties had a significant negative impact on metabolic outcome (A1C 8.5 ± 2.0% vs. 8.2 ± 1.4% for those with language difficulties vs. those without, respectively; P < 0.05). After adjustement for significant confounders of age, sex, duration of diabetes, insulin regimen, insulin dose, BMI, and language difficulties, the center differences persisted, and the effect size for center was not reduced. Relative center ranking since 1998 has remained stable, with no significant change in A1C. CONCLUSIONS—Despite many changes in diabetes management, major differences in metabolic outcome between 21 international pediatric diabetes centers persist. Different application between centers in the implementation of insulin treatment appears to be of more importance and needs further exploration.

Consensus Statement on the Use of Insulin Pump Therapy in the Pediatric Age-Group

Young patients with diabetes, their families, and their diabetes care providers continue to be faced with the challenge of striving to maintain blood glucose levels in the near-normal range. High blood glucose levels with elevated A1C levels are associated with long-term microvascular and macrovascular complications. Recurrent episodes of hypoglycemia, especially at young ages, may cause short- and long-term adverse effects on cognitive function and lead to hypoglycemia unawareness and may be associated with significant emotional morbidity for the child and parents. Fear of hypoglycemia, especially during the night, may compromise quality of life (QOL) for the family and jeopardize efforts to achieve optimal metabolic control. Over the past decade, continuous subcutaneous insulin infusion (CSII) has gained increasing popularity among patients with diabetes. CSII is the most physiologic method of insulin delivery currently available. It is able to closely simulate the normal pattern of insulin secretion, namely continuous 24-h adjustable “basal” delivery of insulin upon which are superimposed prandial “boluses.” In addition, CSII offers the possibility of more flexibility and more precise insulin delivery than multiple daily injection (MDI). However, there is still debate among diabetes care practitioners around the world as to whether CSII has advantages over MDI in terms of reduction in A1C levels, occurrence of severe hypoglycemic events, episodes of diabetic ketoacidosis (DKA), and frequency of hospitalizations in young patients. Furthermore, no clear criteria have been established to help the physician choose the “appropriate” patient for CSII therapy. To address these issues, the European Society for Pediatric Endocrinology (ESPE), the Lawson Wilkins Pediatric Endocrine Society (LWPES), and the International Society for Pediatric and Adolescent Diabetes (ISPAD) convened a panel of expert physicians for a consensus conference endorsed by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). For each major topic area, …

Insulin injection regimens and metabolic control in an international survey of adolescents with type 1 diabetes over 3 years: Results from the Hvidore study group

Abstract. The optimal insulin regimen for paediatric patients with type 1 diabetes remains controversial. Therefore this multicentre study was performed in adolescents over a 3-year period to assess metabolic control, severe hypoglycaemia, and weight gain in relation to insulin injection regimens. Out of 2873 children and adolescents in an international survey in 1995, 872 adolescents (433 boys, 439 girls, mean age in 1995 11.3±2.2 years) were restudied in 1998, relating insulin regimens to HbA1c measured in a central laboratory. In addition, the daily dose of insulin, changes in body mass index (BMI), and events of severe hypoglycaemia were evaluated. Over 3 years, the use of multiple injection regimens increased from 42% to 71%: 251 patients remained on twice daily insulin, 365 remained on multiple injections and 256 shifted from twice daily insulin to multiple injections. In all three subgroups an increase in insulin dose, a deterioration of metabolic control, and an increase in BMI were observed. Metabolic control deteriorated less than expected over 3 years during adolescence (HbA1c 1995: 8.7±1.6%; 1998 observed: 8.9±1.6%, HbA1c expected for 1998: 9.0%). BMI increased more than expected, the increase was greatest in patients switching from twice daily to multiple injections, and higher in females compared to males. Conclusion: in this international study, metabolic control was unsatisfactory in many adolescents with type 1 diabetes irrespective of the insulin regimen. No improvement in metabolic control was observed in this cross-sectional survey, over 3 years in any of the subgroups. Even the group switching from twice to multiple injections did not improve blood glucose control and the increase in body mass index was most pronounced in this group. Conclusive evidence, however, should be based on prospectively planned, randomised therapeutic trials in paediatric patients.

Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes

Aims  To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries.

Prevention of Hypoglycemia by Using Low Glucose Suspend Function in Sensor-Augmented Pump Therapy

BACKGROUND Severe hypoglycemic episodes are a barrier for achieving optimal glycemic control. Sensor-augmented pump (SAP) therapy with insulin in combination with a novel mechanism of automatic insulin shutoff (low glucose suspend [LGS]) can be used to prevent and reduce hypoglycemia. In a prospective study, we investigated the effect of the LGS algorithm on the frequency of hypoglycemia in children and adolescents with type 1 diabetes under real-life conditions. METHODS Twenty-one patients with type 1 diabetes (10.8±3.8 years old, duration of diabetes 5.9±3.0 years, pump therapy for 3.7±1.7 years, glycated hemoglobin level 7.8±1.1%) from three pediatric centers used the Paradigm(®) Veo(™) system (Medtronic Minimed, Northridge, CA) during two subseqent time periods: SAP without LGS for 2 weeks and then SAP with LGS enabled for 6 weeks. The primary objective was to assess the frequency of hypoglycemic episodes when using the LGS feature with an insulin delivery shutoff of a maximum of 2 h at a sensor glucose level below 70 mg/dL (3.9 mmol/L). RESULTS In total, 1,298 LGS alerts occurred (853 shorter than 5 min). Forty-two percent of LGS activations (>5 min) lasted less than 30 min, whereas 24% had a duration of 2 h. The number of hypoglycemic excursions (average/day) was reduced during SAP+LGS (<70 mg/L, 1.27±0.75 vs. 0.95±0.49, P=0.010; ≤40 mg/dL, 0.28±0.18 vs. 0.13±0.14, P=0.005) as was the time spent in hypoglycemia (average minutes/day, 101±68 vs. 58±33, P=0.002) without significant difference in the mean glucose level (145±23 vs. 148±19 mg/dL). No episodes of severe hyperglycemia or diabetic ketoacidosis were observed following LGS activation. CONCLUSIONS The present investigation provides evidence that SAP with LGS reduces the frequency of hypoglycemia without compromising safety.

New definition for the partial remission period in children and adolescents with type 1 diabetes

OBJECTIVE To find a simple definition of partial remission in type 1 diabetes that reflects both residual β-cell function and efficacy of insulin treatment. RESEARCH DESIGN AND METHODS A total of 275 patients aged <16 years were followed from onset of type 1 diabetes. After 1, 6, and 12 months, stimulated C-peptide during a challenge was used as a measure of residual β-cell function. RESULTS By multiple regression analysis, a negative association between stimulated C-peptide and A1C (regression coefficient −0.21, P < 0.001) and insulin dose (−0.94, P < 0.001) was shown. These results suggested the definition of an insulin dose–adjusted A1C (IDAA1C) as A1C (percent) + [4 × insulin dose (units per kilogram per 24 h)]. A calculated IDAA1C ≤9 corresponding to a predicted stimulated C-peptide >300 pmol/l was used to define partial remission. The IDAA1C ≤9 had a significantly higher agreement (P < 0.001) with residual β-cell function than use of a definition of A1C ≤7.5%. Between 6 and 12 months after diagnosis, for IDAA1C ≤9 only 1 patient entered partial remission and 61 patients ended partial remission, for A1C ≤7.5% 15 patients entered partial remission and 53 ended, for a definition of insulin dose ≤0.5 units · kg−1 · 24 h−1 5 patients entered partial remission and 66 ended, and for stimulated C-peptide (>300 pmol/l) 9 patients entered partial remission and 49 ended. IDAA1C at 6 months has good predictive power for stimulated C-peptide concentrations after both 6 and 12 months. CONCLUSIONS A new definition of partial remission is proposed, including both glycemic control and insulin dose. It reflects residual β-cell function and has better stability compared with the conventional definitions.