Brain mass estimation by head circumference and body mass methods in neonatal glycaemic modelling and control

Introduction: Hyperglycaemia is a common complication of stress and prematurity in extremely low-birth-weight infants. Model-based insulin therapy protocols have the ability to safely improve glycaemic control for this group. Estimating non-insulin-mediated brain glucose uptake by the central nervous system in these models is typically done using population-based body weight models, which may not be ideal. Method: A head circumference-based model that separately treats small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) infants is compared to a body weight model in a retrospective analysis of 48 patients with a median birth weight of 750g and median gestational age of 25 weeks. Estimated brain mass, model-based insulin sensitivity (SI) profiles, and projected glycaemic control outcomes are investigated. SGA infants (5) are also analyzed as a separate cohort. Results: Across the entire cohort, estimated brain mass deviated by a median 10% between models, with a per-patient median difference in SI of 3.5%. For the SGA group, brain mass deviation was 42%, and per-patient SI deviation 13.7%. In virtual trials, 87-93% of recommended insulin rates were equal or slightly reduced (δ<0.16mU/h) under the head circumference method, while glycaemic control outcomes showed little change. Conclusion: The results suggest that body weight methods are not as accurate as head circumference methods. Head circumference-based estimates may offer improved modelling accuracy and a small reduction in insulin administration, particularly for SGA infants. © 2014 Elsevier Ireland Ltd

Associations between neonatal hypoglycaemia and brain volumes, cortical thickness and white matter microstructure in mid-childhood: An MRI study

Neonatal hypoglycaemia is a common metabolic disorder that may cause brain damage, most visible in parietooccipital regions on MRI in the acute phase. However, the long term effects of neonatal hypoglycaemia on the brain are not well understood. We investigated the association between neonatal hypoglycaemia and brain volumes, cortical thickness and white matter microstructure at 9–10 years. Children born at risk of neonatal hypoglycaemia at ≥ 36 weeks’ gestation who took part in a prospective cohort study underwent brain MRI at 9–10 years. Neonatal hypoglycaemia was defined as at least one hypoglycaemic episode (at least one consecutive blood glucose concentration < 2.6 mmol/L) or interstitial episode (at least 10 min of interstitial glucose concentrations < 2.6 mmol/L). Brain volumes and cortical thickness were computed using Freesurfer. White matter microstructure was assessed using tract-based spatial statistics. Children who had (n = 75) and had not (n = 26) experienced neonatal hypoglycaemia had similar combined parietal and occipital lobe volumes and no differences in white matter microstructure at nine years of age. However, those who had experienced neonatal hypoglycaemia had smaller caudate volumes (mean difference: − 557 mm3 , 95% confidence interval (CI), − 933 to − 182, p = 0.004) and smaller thalamus (− 0.03%, 95%CI, − 0.06 to 0.00; p = 0.05) and subcortical grey matter (− 0.10%, 95%CI − 0.20 to 0.00, p = 0.05) volumes as percentage of total brain volume, and thinner occipital lobe cortex (− 0.05 mm, 95%CI − 0.10 to 0.00, p = 0.05) than those who had not. The finding of smaller caudate volumes after neonatal hypoglycaemia was consistent across analyses of pre-specified severity groups, clinically detected hypoglycaemic episodes, and severity and frequency of hypoglycaemic events. Neonatal hypoglycaemia is associated with smaller deep grey matter brain regions and thinner occipital lobe cortex but not altered white matter microstructure in mid-childhood

Probiotics, prematurity and neurodevelopment: Follow-up of a randomised trial

Objective: To determine the impact of one probiotics combination on the neurodevelopment of very preterm children at 2&ndash;5 years corrected gestational age (CA). Design: Follow-up study of survivors of a double-blinded, placebo-controlled, randomised trial of probiotic effects on late-onset sepsis in very preterm infants that found reduced necrotising enterocolitis. Setting: 10 tertiary perinatal centres in Australia and New Zealand. Patients: 1099 very preterm infants born &lt;32 weeks&rsquo; gestation and weighing &lt;1500 g. Intervention: Probiotics (Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis) or placebo administered from birth until discharge home or term CA, whichever came sooner. Main outcome measures: Major neurodevelopmental impairment comprised any of moderate/severe cerebral palsy (Gross Motor Function Classification System score 2&ndash;5), motor impairment (Bayley-III Motor Composite Scale &lt;&ndash;2SD or Movement Assessment Battery for Children &lt;15th centile if ≫42 months&rsquo; CA), cognitive impairment (Bayley-III Composite Cognitive or Language Scales &lt;&ndash;2SD or Wechsler Preschool and Primary Scale of Intelligence Full Scale Intelligence Quotient &lt;&ndash;2SD if ≫42 months&rsquo; CA), blindness or deafness. Results: Outcome data were available for 735 (67%) participants, with 71 deaths and 664/1028 survivors assessed at a mean age of 30 months. Survival free of major neurodevelopmental impairment was comparable between groups (probiotics 281 (75.3%) vs placebo 271 (74.9%); relative risk 1.01 (95% CI 0.93 to 1.09)). Rates of deafness were lower in probiotic-treated children (0.6% vs 3.4%). Conclusion: Administration of the probiotics combination Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis to very preterm babies from soon after birth until discharge home or term CA did not adversely affect neurodevelopment or behaviour in early childhood

Short and long term outcome of neonatal hyperglycemia in very preterm infants: a retrospective follow-up study

<p>Abstract</p> <p>Background</p> <p>Hyperglycemia in premature infants is associated with increased morbidity and mortality, but data on long-term outcome are limited. We investigated the effects of neonatal hyperglycemia (blood glucose ≥ 10 mmol/l, treated with insulin for ≥ 12 hours) on growth and neurobehavioral outcome at 2 years of age.</p> <p>Methods</p> <p>Retrospective follow-up study at 2 years of age among 859 infants ≤32 weeks of gestation admitted to a tertiary neonatal center between January 2002 and December 2006. Thirty-three survivors treated with insulin for hyperglycemia and 63 matched controls without hyperglycemia were evaluated at a corrected age of 2 years. Outcome measures consisted of growth (weight, length, and head circumference) and neurological and behavioural development.</p> <p>Results</p> <p>66/859 (8%) infants ≤ 32 weeks of gestation developed hyperglycemia. Mortality during admission was 27/66 (41%) in the hyperglycemia group versus 62/793 (8%) in those without hyperglycemia (p < 0.001). Mortality was higher in infants with hyperglycemia with a birth weight ≤1,000 gram (p = 0.005) and/or gestational age of 24-28 weeks (p = 0.009) than in control infants without hyperglycemia. Sepsis was more prominent in infants with hyperglycemia and a birth weight of >1,000 gram (p = 0.002) and/or gestational age of 29-32 weeks (p = 0.009) than in control infants without hyperglycemia. Growth at 2 years of age was similar, but neurological and behavioural development was more frequently abnormal among those with neonatal hyperglycemia (p = 0.036 and 0.021 respectively).</p> <p>Conclusions</p> <p>Mortality was higher in very preterm infants with hyperglycemia treated with insulin during the neonatal period. At 2 years of age survivors showed normal growth, but a higher incidence of neurological and behavioural problems. Better strategies to manage hyperglycemia may improve outcome of very preterm infants.</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Continuous glucose monitoring in neonates: a review.

Continuous glucose monitoring (CGM) is well established in the management of diabetes mellitus, but its role in neonatal glycaemic control is less clear. CGM has provided important insights about neonatal glucose metabolism, and there is increasing interest in its clinical use, particularly in preterm neonates and in those in whom glucose control is difficult. Neonatal glucose instability, including hypoglycaemia and hyperglycaemia, has been associated with poorer neurodevelopment, and CGM offers the possibility of adjusting treatment in real time to account for individual metabolic requirements while reducing the number of blood tests required, potentially improving long-term outcomes. However, current devices are optimised for use at relatively high glucose concentrations, and several technical issues need to be resolved before real-time CGM can be recommended for routine neonatal care. These include: 1) limited point accuracy, especially at low or rapidly changing glucose concentrations; 2) calibration methods that are designed for higher glucose concentrations of children and adults, and not for neonates; 3) sensor drift, which is under-recognised; and 4) the need for dynamic and integrated metrics that can be related to long-term neurodevelopmental outcomes. CGM remains an important tool for retrospective investigation of neonatal glycaemia and the effect of different treatments on glucose metabolism. However, at present CGM should be limited to research studies, and should only be introduced into routine clinical care once benefit is demonstrated in randomised trials