Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study.

BACKGROUND: In neonatal encephalopathy, the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance (MR) spectroscopy (MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after neonatal encephalopathy. METHODS: We did a prospective multicentre cohort study across eight neonatal intensive care units in the UK and USA, recruiting term and near-term neonates who received therapeutic hypothermia for neonatal encephalopathy. We excluded infants with life-threatening congenital malformations, syndromic disorders, neurometabolic diseases, or any alternative diagnoses for encephalopathy that were apparent within 6 h of birth. We obtained T1-weighted, T2-weighted, and diffusion-weighted MRI and thalamic proton MRS 4-14 days after birth. Clinical neurodevelopmental tests were done 18-24 months later. The primary outcome was the association between MR biomarkers and an adverse neurodevelopmental outcome, defined as death or moderate or severe disability, measured using a multivariable prognostic model. We used receiver operating characteristic (ROC) curves to examine the prognostic accuracy of the individual biomarkers. This trial is registered with ClinicalTrials.gov, number NCT01309711. FINDINGS: Between Jan 29, 2013, and June 25, 2016, we recruited 223 infants who all underwent MRI and MRS at a median age of 7 days (IQR 5-10), with 190 (85%) followed up for neurological examination at a median age of 23 months (20-25). Of those followed up, 31 (16%) had moderate or severe disability, including one death. Multiple logistic regression analysis could not be done because thalamic N-acetylaspartate (NAA) concentration alone accurately predicted an adverse neurodevelopmental outcome (area under the curve [AUC] of 0·99 [95% CI 0·94-1·00]; sensitivity 100% [74-100]; specificity 97% [90-100]; n=82); the models would not converge when any additional variable was examined. The AUC (95% CI) of clinical examination at 6 h (n=190) and at discharge (n=167) were 0·72 (0·65-0·78) and 0·60 (0·53-0·68), respectively, and the AUC of abnormal amplitude integrated EEG at 6 h (n=169) was 0·73 (0·65-0·79). On conventional MRI (n=190), cortical injury had an AUC of 0·67 (0·60-0·73), basal ganglia or thalamic injury had an AUC of 0·81 (0·75-0·87), and abnormal signal in the posterior limb of internal capsule (PLIC) had an AUC of 0·82 (0·76-0·87). Fractional anisotropy of PLIC (n=65) had an AUC of 0·82 (0·76-0·87). MRS metabolite peak-area ratios (n=160) of NAA-creatine (<1·29) had an AUC of 0·79 (0·72-0·85), of NAA-choline had an AUC of 0·74 (0·66-0·80), and of lactate-NAA (>0·22) had an AUC of 0·94 (0·89-0·97). INTERPRETATION: Thalamic proton MRS measures acquired soon after birth in neonatal encephalopathy had the highest accuracy to predict neurdevelopment 2 years later. These methods could be applied to increase the power of neuroprotection trials while reducing their duration. FUNDING: National Institute for Health Research UK.

Protocol of a randomised controlled trial of real-time continuous glucose monitoring in neonatal intensive care 'REACT'.

INTRODUCTION: Hyperglycaemia is common in the very preterm infant and has been associated with adverse outcomes. Preventing hyperglycaemia without increasing the risk of hypoglycaemia has proved challenging. The development of real-time continuous glucose monitors (CGM) to inform treatment decisions provides an opportunity to reduce this risk. This study aims to assess the feasibility of CGM combined with a specifically designed paper guideline to target glucose control in the preterm infant. METHODS AND ANALYSES: The Real Time Continuous Glucose Monitoring in Neonatal Intensive Care (REACT) trial is an international multicentre randomised controlled trial. 200 preterm infants ≤1200 g and ≤24 hours of age will be randomly allocated to either real-time CGM or standard care (with blinded CGM data collection). The primary outcome is time in target 2.6-10 mmol/L during the study intervention assessed using CGM. Secondary outcomes include efficacy relating to glucose control, utility including staff acceptability, safety outcomes relating to incidence and prevalence of hypoglycaemia and health economic analyses. ETHICS AND DISSEMINATION: The REACT trial has been approved by the National Health Service Health Research Authority National Research Ethics Service Committee East of England (Cambridge Central); Medical Ethics Review Committee, VU University Medical Centre, Amsterdam, The Netherlands and the Research Ethics Committee, Sant Joan de Déu Research Foundation, Barcelona, Spain. Recruitment began in July 2016 and will continue until mid-2018. The trial has been adopted by the National Institute of Health Research Clinical Research Network portfolio (ID: 18826) and is registered with anInternational Standard Randomised Control Number (ISRCTN registry ID: 12793535). Dissemination plans include presentations at scientific conferences, scientific publications and efforts at stakeholder engagement. TRIAL REGISTRATION NUMBER: ISRCTN12793535; Pre-results.

Platelets for neonatal transfusion - study 2: a randomised controlled trial to compare two different platelet count thresholds for prophylactic platelet transfusion to preterm neonates.

INTRODUCTION: Neonatal thrombocytopenia is a common and important clinical problem in preterm neonates. A trial assessing clinically relevant outcomes in relation to the different platelet count thresholds used to trigger transfusion has never been undertaken in preterm neonates with severe thrombocytopenia. OBJECTIVES: Platelets for Neonatal Transfusion - Study 2 (PlaNeT-2) aims to assess whether a higher prophylactic platelet transfusion threshold is superior to the lower thresholds in current standard practice in reducing the proportion of patients who have a major bleed or die up to study day 28. METHODS: PlaNeT-2 is a two-stage, randomised, parallel-group, superiority trial. PlaNet-2 compares clinical outcomes in preterm neonates (<34 weeks' gestation at birth) randomised to receive prophylactic platelet transfusions to maintain platelet counts at or above either 25 × 10(9)/l or 50 × 10(9)/l. The primary outcome measure is the proportion of patients who either die or experience a major bleed up to and including study day 28. A total of 660 infants will be randomised. RESULTS AND CONCLUSIONS: This trial will help define optimal platelet transfusion support for severely thrombocytopenic preterm neonates by evaluating the risks and benefits of two different prophylactic neonatal platelet transfusion thresholds.