Safety and Glycemic Outcomes With a Tubeless Automated Insulin Delivery System in Very Young Children With Type 1 Diabetes: A Single-Arm Multicenter Clinical Trial.

OBJECTIVE: Very young children with type 1 diabetes often struggle to achieve glycemic targets, putting them at risk for long-term complications and creating an immense management burden for caregivers. We conducted the first evaluation of the Omnipod 5 Automated Insulin Delivery System in this population. RESEARCH DESIGN AND METHODS: A total of 80 children aged 2.0-5.9 years used the investigational system in a single-arm study for 13 weeks following 14 days of baseline data collection with their usual therapy. RESULTS: There were no episodes of severe hypoglycemia or diabetic ketoacidosis. By study end, HbA1c decreased by 0.55% (6.0 mmol/mol) (P < 0.0001). Time with sensor glucose levels in target range 70-180 mg/dL increased by 10.9%, or 2.6 h/day (P < 0.0001), while time with levels <70 mg/dL declined by median 0.27% (P = 0.0204). CONCLUSIONS: Use of the automated insulin delivery system was safe, and participants experienced improved glycemic measures and reduced hypoglycemia during the study phase compared with baseline.

Intensive remote monitoring versus conventional care in type 1 diabetes: A randomized controlled trial.

OBJECTIVE: While frequent contact with diabetes care providers may improve glycemic control among patients with type 1 diabetes (T1D), in-person visits are labor-intensive and costly. This study was conducted to assess the impact of an intensive remote therapy (IRT) intervention for pediatric patients with T1D. METHODS: Pediatric patients with T1D were randomized to IRT or conventional care (CC) for 6 months. Both cohorts continued routine quarterly clinic visits and uploaded device data; for the IRT cohort, data were reviewed and patients were contacted if regimen adjustments were indicated. Glycated hemoglobin (HbA1c) change from baseline was assessed at 6 and 9 months. Diabetes-related quality of life (QoL), healthcare services utilization, and hypoglycemic events were also tracked. RESULTS: Among 117 enrollees (60 IRT, 57 CC), mean (SD) 6-month %HbA1c change for IRT vs CC was -0.34 (0.85) (-3.7 mmol/mol) vs -0.05 (0.74) (-0.5 mmol/mol) overall (P = .071); -0.15 (0.67) (1.6 mmol/mol) vs -0.02 (0.66) (0.2 mmol/mol) for ages 8 to 12 (P = .541); and -0.50 (0.95) (-5.5 mmol/mol) vs -0.06 (0.80) (-0.7 mmol/mol) for ages 13 to 17 (P = .056). Diabetes-related QoL increased by 6.5 and 1.3 points for IRT and CC, respectively (P = .062). Three months after intervention cessation, %HbA1c changed minimally among treated children aged 8 to 12 but increased by 0.22 (0.89) (2.4 mmol/mol) among those aged 13 to 17. CONCLUSIONS: IRT substantially affected diabetes metrics and improved QoL among pediatric patients with T1D. Adolescents experienced a stronger treatment effect, but had difficulty in sustaining improved control after intervention cessation.

Yoga Therapy in Children with Cystic Fibrosis Decreases Immediate Anxiety and Joint Pain.

This study was designed to determine whether yoga might alleviate symptoms of pain, sleep disturbance, anxiety, and depression in children with cystic fibrosis (CF). CF is the most common genetic, life-limiting chronic disease among Caucasian populations. It primarily affects the lungs but also many other secretory organs and consequently leads to significant morbidities. Research has shown that children with CF have significantly increased depression, anxiety, and pain compared to their healthy counterparts. Subjects participated in six one-on-one sessions over a 10-week period with a certified instructor who designed each yoga practice based on a preestablished list of 30 yoga asanas. Questionnaires evaluating pain, sleep disturbance, sustained anxiety, immediate anxiety, and depression were administered. Differences between premeasures and postmeasures were evaluated using a two-sided test. Twenty subjects were assessed (12 females/8 males), median age of 11 (7-20) years. Mean immediate anxiety scores decreased (before session to after session 29 to 23.6, respectively, p < 0.001). Joint pain improved (3.25 to 3.65, p = 0.028). CFQ-R emotion subscale improved from 79.2 to 85 (p = 0.073), and the respiratory subscale improved from 66.7 to 79.2 (p = 0.076). Other results were less notable. We conclude that yoga may reduce immediate anxiety and joint pain in patients with CF.

The association between fasting hypoglycemia and methylated mercaptopurine metabolites in children with acute lymphoblastic leukemia.

BACKGROUND: Symptomatic fasting hypoglycemia has been reported as an unusual side effect in patients with acute lymphoblastic leukemia (ALL) on maintenance therapy. We evaluated the relation of the red cell 6-mercaptopurine (6-MP) metabolite 6-methyl-mercaptopurine (6MMP) with hypoglycemia. PROCEDURE: We retrospectively reviewed charts of three patients with ALL and symptomatic hypoglycemia while fasting who were noted to have high levels of 6MMP. All patients had an empiric trial of switching from evening to morning 6-MP administration, and two patients were subsequently switched to twice daily dosing. Patients also received complex carbohydrates at bedtime. RESULTS: Switching 6-MP from evening to morning administration reduced 6MMP levels yet preserved adequate levels of the active metabolite red cell 6-thioguanine nucleotide (6TGN). All patients had decreased hypoglycemic events when changed from evening to morning dosing. Two patients showed a rebound in 6MMP levels with return of hypoglycemic symptoms. Both were then switched to twice daily 6-MP dosing with one having a decrease in 6MMP and hypoglycemic symptoms. CONCLUSIONS: High levels of 6MMP are associated with symptomatic hypoglycemia which may be mitigated by switching to morning or twice daily 6-MP dose administration.

Safety and efficacy of metformin for therapy-induced hyperglycemia in children with acute lymphoblastic leukemia.

BACKGROUND: Hyperglycemia during corticosteroid and asparaginase therapy for acute lymphoblastic leukemia is a significant side effect that is usually treated with insulin. Metformin is an oral antidiabetic biguanide that may cause metabolic acidosis and liver enzyme abnormalities of possible concern in patients receiving chemotherapy. PROCEDURE: We reviewed patients with acute lymphoblastic leukemia treated with corticosteroids and asparaginase who received metformin for control of hyperglycemia. RESULTS: Seventeen patients received metformin, including 4 who received insulin before starting metformin therapy. Twelve were treated during initial induction therapy and 5 during relapse reinduction. Corticosteroids included dexamethasone in 11, prednisone in 5, and megesterol in 1. Fifteen received pegasparaginase.Patients were treated with metformin for a median of 6 days (range, 2 to 46 d). Metformin was started at a median glucose level of 286 mg/dL (range, 112 to 499 mg/mL). The glucose level was controlled with metformin alone in 12 patients without the need for insulin. Four patients received insulin before or concomitantly with metformin. In 1 patient, metformin failed to control the glucose level, and insulin was administered.No significant toxicity from metformin was seen. Two patients had an elevated anion gap and creatinine level because of extreme hyperglycemia. One patient had mild elevation in total bilirubin and 5 patients had mild elevation in serum alanine aminotransferase levels. There were no episodes of hypoglycemia. CONCLUSIONS: Metformin is safe and effective for therapy-induced hyperglycemia. Initially, insulin may be required for significant hyperglycemia or metabolic abnormalities. We are unaware of any prior studies using metformin in this population.

Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study.

The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9-16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m(2)) were enrolled in a 6-month, randomized, open-label, crossover, clinical trial consisting of two, 3-month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase-order (i.e., starting with control or drug therapy) then crossed-over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3-, and 6-months. The mean change over each 3-month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (-1.7 kg/m(2), 95% confidence interval (CI) (-3.0, -0.4), P = 0.01), body weight (-3.9 kg, 95% CI (-7.11, -0.69), P = 0.02), and fasting insulin (-7.5 mU/l, 95% CI (-13.71, -1.37), P = 0.02). Significant improvements were observed for OGTT-derived insulin sensitivity (P = 0.02) and ß-cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well-tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well-controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.

The Medtronic Minimed Gold continuous glucose monitoring system: an effective means to discover hypo- and hyperglycemia in children under 7 years of age.

BACKGROUND: The glycemic patterns of children less than 7 years with type 1 diabetes have not been well studied using continuous glucose monitoring. Our goal was to assess the incidence of hypoglycemia as well as postprandial glycemic patterns in this age group utilizing continuous glucose monitoring. METHODS: Nineteen children used the Medtronic MiniMed (Northridge, CA) CGMS System Gold on three to seven occasions over approximately 6 months. RESULTS: Nineteen children (nine girls and 10 boys; mean age 4.8 +/- 1.4 years, range 1.6-6.8 years) used the CGMS 102 times, providing 434 days of data; 79% of days were optimal based on CGMS Solutions software version 3.0. Mild hypoglycemia (glucose or=2 mg/dL/min following 50% of breakfasts. Children with hemoglobin A1c levels >or=8% had higher postprandial glucose concentrations. There was no significant advantage of continuous subcutaneous insulin infusion therapy over multiple daily injection therapy in decreasing postprandial hyperglycemia. CONCLUSIONS: CGMS tracings from young children with diabetes demonstrate frequent mild nocturnal hypoglycemia and significant postprandial hyperglycemia, with a rapid rise in glucose following the meal. The most rapid rate of rise and the most severe postprandial hyperglycemia occurred after breakfast.

Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and death in the pediatric intensive care unit.

OBJECTIVE: We evaluated retrospectively plasma glucose levels and the degree of hypoglycemia, hyperglycemia, and glucose variability in a PICU and then assessed their association with hospital length of stay and mortality rates. METHODS: Electronic medical records at the Packard Children's Hospital at Stanford University were reviewed retrospectively for all PICU admissions between March 1, 2003, and March 31, 2004. Patients with a known diagnosis of diabetes mellitus were excluded. The prevalence of hyperglycemia was defined with cutoff values of 110, 150, and 200 mg/dL. Hypoglycemia was defined as < or = 65 mg/dL. Glucose variability was assessed with a calculated glucose variability index. RESULTS: In 13 months, 1094 eligible admissions generated 18865 glucose values (median: 107 mg/dL; range: 13-1839 mg/dL). Patients in the highest maximal glucose quintile had a significantly longer median PICU length of stay, compared with those in the lowest quintile (7.5 days vs 1 day). Mortality rates increased as patients' maximal glucose levels increased, reaching 15.2% among patients with the greatest degree of hyperglycemia. Hypoglycemia was also prevalent, with 18.6% of patients (182 of 980 patients) having minimal glucose levels of < or = 65 mg/dL. There was an increased median PICU length of stay (9.5 days vs 1 day) associated with glucose values in the lowest minimal quintile, compared with those in the highest quintile. Hypoglycemia was correlated with mortality rates; 16.5% of patients with glucose levels of < or = 65 mg/dL died. Glucose variability also was associated with increased length of stay and mortality rates. In multivariate logistic regression analyses, glucose variability, taken with hyperglycemia and hypoglycemia, showed the strongest association with mortality rates. CONCLUSIONS: Hyperglycemia and hypoglycemia were prevalent in the PICU. Hypoglycemia, hyperglycemia, and, in particular, increased glucose variability were associated with increased morbidity (length of stay) and mortality rates.

Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty.

BACKGROUND: Dosing of monthly depot leuprolide (DL) in central precocious puberty (CPP) varies considerably. U.S. practitioners use 7.5-15 mg, in contrast with the international standard of 3.75 mg. Pubertal suppression using the newer 3-month DL also has been reported from Europe. To date there have been no direct comparisons of these different DL doses. OBJECTIVES: In an open 12-month protocol, we tested the efficacy of three DL doses (7.5 mg- and 3.75 mg-1 month and 11.25 mg-3 month) given sequentially to subjects treated for CPP. Primary outcome measures were stimulated gonadotropin (Gn) levels at 12-wk intervals. The null hypothesis was no difference among doses. METHODS: Both existing and new patients with CPP received our standard therapy (DL 7.5 mg every 4 wk) for a minimum of 24 wk. In subjects with DL-stimulated LH 2 IU/liter or less, the dose was changed to 3.75 mg every 4 wk and evaluated 12 wk later. Subjects who met LH criteria (<4.5 IU/liter) on 3.75 mg then received a single dose of 11.25 mg-3 month and were reevaluated 12 wk later. Serum LH/FSH and sex steroids were obtained 40 min after DL injection. RESULTS: Thirty subjects were enrolled (20 naive; 24 girls, 6 boys), and 21 were evaluated on all three DL doses. DL-stimulated LH levels (mean +/- sd) were 1.30 +/- 0.74, 1.73 +/- 0.99, and 2.13 +/- 1.41 on 7.5 mg, 3.75 mg, and 11.25 mg-3 month, respectively (7.5 vs. 3.75 mg, P = 0.019; 7.5 mg vs. 11.25 mg-3 month, P = 0.004, Wilcoxon ranked sign test). Mean FSH levels were 2.86 +/- 1.91, 3.91 +/- 1.98, and 3.96 +/- 1.34, respectively (7.5 vs. 3.75 mg, P = 0.017; 7.5 mg vs. 11.25 mg-3 month, P = 0.020). No differences were detected in mean sex steroid levels. CONCLUSIONS: Stimulated LH and FSH levels were significantly higher during therapy with both the 3.75 mg and 11.25 mg-3 month depot leuprolide doses, compared with 7.5 mg, contradicting the null hypothesis of no difference. These data suggest that low-dose 1- and 3-month DL preparations are associated with persistently greater gonadal stimulation in most CPP patients, but the LH/FSH results were not corroborated by differences in sex steroid levels. Whether various DL doses lead to long-term therapeutic differences remains to be determined.

Is growth hormone stimulation testing in children still appropriate?

The diagnosis of growth hormone deficiency (GHD) historically has relied on measurement of growth hormone (GH) concentrations following stimulation, usually with a non-physiologic provocative agent. Despite the use of more specific GH assays, the peak concentration of GH below which a child is considered GH deficient has risen. We examine the pitfalls associated with GH stimulation tests, specifically, the lack of reliability and accuracy of these tests, and their inability to predict who will benefit from GH therapy. We recommend that GH stimulation tests no longer routinely be used for the diagnosis of GHD in children.

Use of the Cygnus GlucoWatch biographer at a diabetes camp.

BACKGROUND: Detection and prevention of nocturnal hypoglycemia is a major medical concern at diabetes camps. OBJECTIVE: We conducted an open-label trial of the Cygnus GlucoWatch biographer to detect nocturnal hypoglycemia in a diabetes camp, a nonclinical environment with multiple activities. METHODS: Forty-five campers (7-17 years old) wore a biographer. The biographer was placed on the arm at 6:00 PM, with the low alarm set to 85 mg/dL (4.7 mmol/L). Overnight glucose monitoring occurred per usual camp protocol. Counselors were to check and record blood glucose values if the biographer alarmed. RESULTS: Biographers were worn for 154 nights by 45 campers. After a 3-hour warm-up period, 67% of biographers were calibrated, of which 28% were worn the entire night (12 hours). Thirty-four percent of readings were skipped because of: "data errors" (65%), sweat (20%), and temperature change (16%). Reported biographer values correlated with meter glucose values measured 11 to 20 minutes later (r = 0.90). Of 20 low-glucose alarms with corresponding meter values measured within 20 minutes, there were 10 true-positive alarms, 10 false-positive alarms, and no false-negative alarms. Campers reported sleep disruption 32% of the nights, and 74% found the biographer helpful. Campers reported they would wear the biographer 4 to 5 nights each week. CONCLUSIONS: Half of the biographer low-glucose alarms that had corresponding blood meter values were true-positive alarms, and the remaining were false-positive alarms. There was close correlation between the biographer and meter glucose values. The majority of campers found the biographer helpful and would use it at home.

Low-dose intravenous pamidronate reduces fractures in childhood osteoporosis.

Despite the proven efficacy of low-dose pamidronate in adults with osteoporosis, the efficacy of the low-dose regimen in children has not been studied. Pamidronate (1 mg/kg) was administered intravenously once every 3 months to 11 children with osteoporosis. Treatment was associated with reduced fracture rates and increased areal (BMD) and volumetric (BMAD) bone mineral density measured by dual energy X-ray absorptiometry (DXA). The mean annualized percent gain was 20.1 +/- 16.9 (4.7 to 59.1, n = 9) for spinal BMD and 15.1 +/- 18.1 (-11.0 to 40.2, n = 9) for spinal BMAD. Common adverse effects including fever, muscle aches, nausea and fatigue were self-limited and generally occurred only after the first infusion. Clinically significant hypocalcemia did not occur. Low-dose pamidronate appears promising in the treatment of childhood osteoporosis.