Optimizing the Timing of Highest Hydrocortisone Dose in Children and Adolescents With 21-Hydroxylase Deficiency

CONTEXT: Hydrocortisone treatment of young patients with 21-hydroxylase deficiency (21OHD) is given thrice daily, but there is debate about the optimal timing of the highest hydrocortisone dose, either mimicking the physiological diurnal rhythm (morning), or optimally suppressing androgen activity (evening). OBJECTIVE: We aimed to compare 2 standard hydrocortisone timing strategies, either highest dosage in the morning or evening, with respect to hormonal status throughout the day, nocturnal blood pressure (BP), and sleep and activity scores. METHODS: This 6-week crossover study included 39 patients (aged 4-19 years) with 21OHD. Patients were treated for 3 weeks with the highest hydrocortisone dose in the morning, followed by 3 weeks with the highest dose in the evening (n = 21), or vice versa (n = 18). Androstenedione (A4) and 17-hydroxyprogesterone (17OHP) levels were quantified in saliva collected at 5 am; 7 am; 3 pm; and 11 pm during the last 2 days of each treatment period. The main outcome measure was comparison of saliva 17OHP and A4 levels between the 2 treatment strategies. RESULTS: Administration of the highest dose in the evening resulted in significantly lower 17OHP levels at 5 am, whereas the highest dose in the morning resulted in significantly lower 17OHP and A4 levels in the afternoon. The 2 treatment dose regimens were comparable with respect to averaged daily hormone levels, nocturnal BP, and activity and sleep scores. CONCLUSION: No clear benefit for either treatment schedule was established. Given the variation in individual responses, we recommend individually optimizing dose distribution and monitoring disease control at multiple time points

The PPAR-γ Pro12Ala polymorphism associates with weight gain during GH-treatment in short children born small for gestational age

Context: Short children born small for gestational age (SGA) have a lean phenotype with lower insulin sensitivity and higher blood pressure. GH treatment results in weight gain, and a decrease in blood pressure and insulin sensitivity. However, not all children respond in the same way. The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPAR-gγ) gene is inversely associated with body mass index (BMI), changes in BMI and the risk to develop type 2 diabetes mellitus. Objective: To analyze the contribution of the PPAR-γ Pro12Ala polymorphism to GH induced changes in determinants of metabolic and cardiovascular disease in short SGA children. Methods: PPAR-γ was genotyped in 238 Caucasian short SGA children (mean age 7.5 years). Height, weight, blood pressure, and serum lipids were measured before start and during 4 years of GH treatment. In addition, glucose homeostasis by homeostasis model assessment insulin resistance ratio (HOMA-IR) (n=148) and by frequently sampled i.v. glucose tolerance test (n=51), and body composition by dual energy X-ray absorptiometry (n=79) were measured. Results: At baseline, the Ala12 allele was not associated with any determinant of metabolic and cardiovascular disease. After 4 years of GH treatment, the increase in weight for height SDS and BMI SDS was significantly greater in carriers of an Ala12 allele than in noncarriers. The change in all other parameters was not associated with Pro12Ala genotype. Conclusion: The Ala12 variant of the PPAR-γ gene is associated with higher weight gain during GH treatment but not with changes in determinants of metabolic and cardiovascular diseases in Caucasian subjects born SGA

Serum insulin-like growth factor-binding protein-2 levels and metabolic and cardiovascular risk factors in young adults and children born small for gestational age

Background: IGF binding protein (IGFBP)-2 might protect against cardiovascular disease. Small for gestational age (SGA) birth could be associated with a higher risk for type 2 diabetes mellitus and cardiovascular disease in later life. No data are available on the relationship between serum IGFBP-2 levels and cardiovascular risk factors in young adults and children born SGA. Objecti

Independent effects of prematurity on metabolic and cardiovascular risk factors in short small-for-gestational-age children

Context: Both small-for-gestational-age (SGA) and preterm birth have been associated with an increased incidence of adult cardiovascular disease and diabetes mellitus type 2. However

Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data

Background: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care. Methods: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered. Findings: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09–2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75–3·10, p<0·0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1·53, 95% CI 1·14–2·04, p=0·0044). The risk of bias and variability between studies was assessed to be low. Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons