Measurement of salivary cortisol level for the diagnosis of critical illness-related corticosteroid insufficiency in children.

OBJECTIVE: To compare serum total, serum free and salivary cortisol in critically ill children. DESIGN: Prospective observational cohort study. SETTING: Tertiary pediatric critical care unit at Ronald McDonald Children's Hospital at Loyola University Medical Center. PATIENTS: We enrolled 59 patients (4 weeks to 18 years of age) between January 2012 and May 2013. Thirty-four patients were included in the salivary to serum free cortisol correlational analysis. INTERVENTIONS: Blood and saliva samples were obtained simultaneously within 24 hours of admission between the hours of 6 AM and 12 PM. Salivary cortisol was tested by liquid chromatography/tandem mass spectrometry, serum free cortisol by liquid chromatography/tandem mass spectrometry followed by equilibrium dialysis, and serum total cortisol by liquid chromatography/tandem mass spectrometry. MEASUREMENTS AND MAIN RESULTS: Salivary and serum free cortisol values from 34 patients had a correlation coefficient (r) of 0.87 (95% CI, 0.75-0.93; p < 0.0001). The total serum and salivary cortisol values had a correlation coefficient (r) of 0.67 (95% CI, 0.42-0.81; p < 0.0001). The total serum and serum free cortisol values had a correlation coefficient (r) of 0.83 (95% CI, 0.69-0.91; p < 0.0001). CONCLUSIONS: Serum free and salivary cortisol values correlate in critically ill children. Salivary cortisol can be used as a surrogate for serum free cortisol in critically ill pediatric patients. Salivary cortisol is a cost-effective and less invasive measure of bioavailable cortisol and offers an alternate and accurate method for assessing critical illness-related corticosteroid insufficiency in children.

Hypoparathyroidism, Sensorineural Deafness, and Renal Disease Syndrome Presenting With Febrile Seizures and Hypocalcemia.

HDR syndrome is a rare genetic disorder caused by mutations in the GATA3 gene and characterized by hypoparathyroidism, sensorineural deafness, and renal disease. Here, we report case of a 9-month-old male with history of hydronephrosis and sensorineural deafness who presented with febrile seizures. He was found to have hypocalcemia and inappropriately normal parathyroid hormone. His neurologic and infectious workup were negative. Genetic testing revealed a nonsense mutation in the GATA3 gene, consistent with HDR syndrome. Hypocalcemia was responsive to calcium carbonate and calcitriol treatment. This case highlights hypocalcemia caused by hypoparathyroidism as a potential etiology of seizures. When hypoparathyroidism is detected with either hearing loss or renal disease, HDR syndrome should be considered, and other features of the syndrome should be investigated.

Improving Timeliness of Insulin Administration by Using an Insulin Dose Calculator.

OBJECTIVES: Insulin is a high-risk medication, and its dosing depends on the individualized clinical and nutritional needs of each patient. Our hospital implemented an insulin dose calculator (IDC) imbedded in the electronic medical record with the goal of decreasing average wait times in inpatient insulin ordering and administration. In this study, we evaluated whether implementation of an IDC decreased the average wait time for insulin administration for hospitalized pediatric patients. METHODS: This pre- and postintervention cohort study measured wait times between point-of-care glucose testing and insulin administration. Patients admitted to the inpatient pediatric services who were treated with subcutaneous insulin during the study period were included. Additionally, nurses completed satisfaction surveys on the insulin administration process at our hospital pre- and post-IDC implementation. Descriptive statistics, χ2, Fisher's exact test, and Student t tests were used to compare groups. Statistical process control charts were used to analyze data trends. RESULTS: The preintervention cohort included 79 insulin doses for admitted pediatric patients. The postimplementation cohort included 128 insulin doses ordered via the IDC. Post-IDC implementation, the average wait time between point-of-care glucose testing and insulin administration decreased from 37 to 25 minutes (P < .05). The statistical process control chart revealed a 5-month run below the established mean after implementation of the IDC. Before IDC implementation, 15.6% of nurses expressed satisfaction in the insulin-dosing process compared with 69.2% postimplementation (P < .05). CONCLUSIONS: Implementation of an IDC reduced the average wait time in ordering and administration of rapid-acting insulin and improved nursing satisfaction with the process.

Implementation of a Diabetes Transition of Care Program.

For adolescents with diabetes, ineffective health care transition to adult health services may result in suboptimal adherence to medical supervision, leading to poor glycemic control, increased diabetes complications, and hospitalization. Despite national recommendations, few youth receive the needed preparation to transition to adult health services. A data transition registry was created at a large Midwest urban academic medical center to identify patients 14 years and older with Type 1 diabetes. Thirty-nine patients with Type 1 diabetes were identified, and 33 were eligible to begin transition planning. Baseline Transition Readiness Assessment Questionnaires (TRAQs) were completed in 21 (64%) of the 33 identified patients, with a mean TRAQ skill score of 66.62 out of 100. There was no correlation between better TRAQ scores and hemoglobin A1c level. Participants had lower baseline TRAQ scores for appointment keeping and tracking health issues. Participants were confident managing daily activities, talking with providers, and managing medications.

Serum Thyroid-Stimulating Hormone Levels and Body Mass Index Percentiles in Children with Primary Hypothyroidism on Levothyroxine Replacement.

OBJECTIVE: To determine the association, if any, between thyroid-stimulating hormone (TSH) levels and body mass index (BMI) percentiles in children with primary hypothyroidism who are chemically euthyroid and on treatment with levothyroxine. METHODS: This retrospective cross-sectional study consisted of a review of medical records from RUSH Medical Center and Stroger Hospital, Chicago, USA of children with primary hypothyroidism who were seen in the clinic from 2008 to 2014 and who were chemically euthyroid and on treatment with levothyroxine for at least 6 months. The patients were divided into two groups based on their TSH levels (0.34-<2.5 mIU/L and ≥2.5-5.6 mIU/L). The data were analyzed by Spearman rank correlation, linear regression, cross tabulation and chi-square, Mann-Whitney U test, and Kruskal-Wallis test. RESULTS: One hundred and forty-six children were included, of which 26% were obese (BMI ≥95%), 21.9% overweight (BMI ≥85-<95%), and 52.1% of a healthy weight (BMI ≥5-<85%). There was a significant positive correlation between TSH and BMI percentiles (r=0.274, p=0.001) and a significant negative correlation between TSH and serum free T4 (r=-0.259, p=0.002). In the lower TSH group, 68.4% of the children had a healthy weight, while the percentage of obese children was 60.5% in the upper TSH group (p=0.012). CONCLUSION: In children diagnosed with primary hypothyroidism who are chemically euthyroid on treatment with levothyroxine, there is a positive association between higher TSH levels and higher BMI percentiles. However, it is difficult to establish if the higher TSH levels are a direct cause or a consequence of the obesity. Further studies are needed to establish causation beyond significant association.

Recurrent familial hypocalcemia due to germline mosaicism for an activating mutation of the calcium-sensing receptor gene.

De novo activating mutations in the calcium-sensing receptor (CASR) gene are a common cause of sporadic isolated hypoparathyroidism. Here, we describe a family in which two affected siblings were found to be heterozygous for a novel F788L mutation in the fifth transmembrane domain encoded by exon 7 of the CASR. Both parents and the third sibling were clinically unaffected and genotypically normal by direct sequencing of their leukocyte exon 7 PCR amplicons. However, the mother was revealed to be a mosaic for the mutation by sequence analysis of multiple subclones as well as denaturing HPLC of the CASR exon 7 leukocyte PCR product. A functional analysis of the mutation was performed by transiently transfecting wild-type and mutant CASRs tagged with a c-Myc epitope in human embryonic kidney (HEK293) cells. The mutant CASR was expressed at a similar level as the wild type. The F788L mutant produced a significant shift to the left relative to the wild-type CASR in the MAPK response to increasing extracellular calcium concentrations. This is the first report of mosaicism for an activating CASR mutation and suggests that care should be exercised in counseling for risks of recurrence in a situation where a de novo mutation appears likely.

Steroid profiling by tandem mass spectrometry improves the positive predictive value of newborn screening for congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is primarily caused by 21-hydroxylase deficiency and leads to an accumulation of 17-hydroxyprogesterone and reduced cortisol levels. Newborn screening for CAH is traditionally based on measuring 17-hydroxyprogesterone by different immunoassays. Despite attempts to adjust cutoff levels for birth weight, gestational age, and stress factors, the positive predictive value for CAH screening remains less than 1%. To improve this situation, we developed a method using liquid chromatography-tandem mass spectrometry to measure 17-hydroxyprogesterone, androstenedione, and cortisol simultaneously in blood spots. A total of 1222 leftover blood spots from six different screening programs using different immunoassays (fluorescent immunoassay and ELISA) were reanalyzed in a blinded fashion by liquid chromatography-tandem mass spectrometry. Thirty-one samples were from babies with CAH, 190 had yielded false-positive results by immunoassay, and the remaining 1001 samples were from babies with normal screening results. Steroid profiling allowed for an elimination of 169 (89%) of the false-positive results and for an improvement of the positive predictive value from the reported 0.5 to 4.7%. Although this method is not suitable for mass screening due to the length of the analysis (12 min), it can be used as a second-tier test of blood spots with positive results for CAH by the conventional methods. This would prevent unnecessary blood draws, medical evaluations, and stress to families.

Prevalence of risk of deficiency and inadequacy of 25-hydroxyvitamin D in US children: NHANES 2003-2006.

AIM: To assess prevalence and population estimates of increased risk of 25-hydroxyvitamin D [25(OH)D] deficiency and inadequacy in US children based on the current Institute of Medicine Committee to Review Dietary References Intakes for Vitamin D and Calcium guidelines. METHODS: The analysis was limited to a nationally representative sample of non-institutionalized US children and adolescents aged 6-18 years who participated in the National Health and Nutrition Examination Survey completed in 2003-2006 and had complete data on 25(OH)D measurements (n=2877). The 25(OH)D levels were adjusted for assay drift and prevalence, and population estimates of increased risk of 25(OH)D deficiency (<12 ng/mL), risk of inadequacy (<16 ng/mL), and adequacy (>20 ng/mL) were calculated. RESULTS: Overall, 4.61% of children and adolescents are at increased risk of deficiency (population estimate 2.5 million) and 10.3% are at risk of inadequacy (population estimate 5.5 million) based on the Institute of Medicine guidelines. CONCLUSION: Approximately 10.3% of US children aged 6-18 years (population estimate 5.5 million) have 25(OH)D levels <16 ng/mL.

Improved specificity of newborn screening for congenital adrenal hyperplasia by second-tier steroid profiling using tandem mass spectrometry.

BACKGROUND: Newborn screening for congenital adrenal hyperplasia (CAH) involves measurement of 17alpha-hydroxyprogesterone (17-OHP), usually by immunoassay. Because this testing has been characterized by high false-positive rates, we developed a steroid profiling method that uses liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure 17-OHP, androstenedione, and cortisol simultaneously in blood spots. METHODS: Whole blood was eluted from a 4.8-mm (3/16-inch) dried-blood spot by an aqueous solution containing the deuterium-labeled internal standard d(8)-17-OHP. 17-OHP, androstenedione, and cortisol were extracted into diethyl ether, which was subsequently evaporated and the residue dissolved in LC mobile phase. This extract was injected into a LC-MS/MS equipped with pneumatically assisted electrospray. The steroids were quantified in the selected-reaction monitoring mode by use of peak areas in reference to the stable-isotope-labeled internal standard. We analyzed 857 newborn blood spots, including 14 blood spots of confirmed CAH cases and 101 of false-positive cases by conventional screening. RESULTS: Intra- and interassay CVs for 17-OHP were 7.2-20% and 3.9-18%, respectively, at concentrations of 2, 30, and 50 microg/L. At a cutoff for 17-OHP of 12.5 microg/L and a cutoff of 3.75 for the sum of peak areas for 17-OHP and androstenedione divided by the peak area for cortisol, 86 of the 101 false-positive samples were within reference values by LC-MS/MS, whereas the 742 normal and 14 true-positive results obtained by conventional screening were correctly classified. CONCLUSION: Steroid profiling in blood spots can identify false-positive results obtained by conventional newborn screening for CAH.