Title: Real Time Continuous Glucose Monitoring in Neonatal Intensive Care
Funder: Department of Health (England)

Abstract: Both hyperglycaemia and hypoglycaemia are common problems in babies born preterm are difficult to manage and have been linked with poor clinical outcomes(1). Detection of abnormal glucose levels is dependent on infrequent invasive blood sampling and therefore there are prolonged periods when glucose levels are unknown. Interventions to control glucose levels subsequently rely on crude sliding scales with adjustments only made every few hours which results in wide fluctuations in glucose levels and significant periods of both hyperglycaemia and hypoglycaemia. In contrast many physiological variables such as heart rate and oxygen saturations are monitored continuously allowing for more subtle alterations in treatment which can produce better targeting to physiological parameters. New developments for patients with diabetes mellitus include continuous glucose monitoring which provides detailed information about glucose levels 24 hours a day. Continuous glucose monitors are devices which comprise a subcutaneous sensor which converts interstitial glucose to an electrical signal which is transmitted to a monitor for a read out. Recent important developments include the development of real time read outs a 50% reduction in sensor size prolonged life and increasing accuracy at clinically significant thresholds(3). These real time continuous glucose monitors (rCGM) have not been used before in preterm infants. They would provide the opportunity to more accurately detect both hyperglycaemia and hypoglycaemia as well as to better titrate treatment to ensure glucose levels remain within preset clinical targets. This has the potential to impact on both short term care and long term health.Hypothesis: Real time continuous glucose monitoring could improve the detection and management of hyperglycaemia and hypoglycaemia in neonatal intensive care. Aims: 1. To carry out a feasibility study to evaluate the use of rCGM in NICU. 2. To undertake a multicentre randomised controlled trial of the efficacy and safety of rCGM in NICU. 3. To evaluate the potential role of combining rCGM with computer algorithms in closed loop management of glucose control in NICU. This project involves a single centre feasibility study of rCGM followed by a multicentre randomized controlled trial of rCGM and a pilot study of ‘closed loop’ computer assisted management of glucose control. Feasibility Study: Evaluation of rCGM in a single centre. Preterm infants at risk of hyperglycaemia and hypoglycaemia will have rCGM inserted to support glucose monitoring during the first week of life. This provides the opportunity to gain experience of the device in the clinical setting. We would recruit a total of 20 babies over 6 months. Objectives to determine i. safety and accuracy ii.user acceptabiity iii. optimal use of alarms iv.impact on clinical care. This will inform the development and design of a clinical decision support system for management of glucose control that will then be tested as part of a randomised controlled trial. Randomized Controlled Trial: A multicentre randomised controlled trial (unblinded) will be undertaken in preterm infants at risk of hyperglycaemia and hypoglycaemia. The objectives are to assess the ability of rCGM compared to standard clinical practice to: i. optimise glucose control (efficacy) ii.detect hypoglycaemia and hyperglycaemia (safety) iii. assess clinical user acceptability iv. potential cost of introduction in clinical practice. A web based randomisation program will be used to divide babies equally between 2 study arms Babies with rCGM (intervention) will have glucose control supported by the novel paper based clinical decision support system (developed from the feasibility study). Control babies (receiving standard clinical care) will have glucose control assessed using blinded CGM. Based on previously collected blinded CGM data which demonstrated significant periods of both hyperglycaemia and hypoglycaemia and in which only 66% of babies spent >80% of the time in the target range 2.6-10mmol/l a cohort of 200 babies would allow us to show an increase in the number of babies with reasonable control (ie >80% of time within the range 2.6-10mmol/l) from 66% to 83% (with 80% power at the 5% level). Similarly based on this data with 52% of babies spending >10% of their time >10mmol/s we would need 200 babies to have 90% power at the 5% level to show a reduction from 52% to 30% of babies spending >10% of their time >10mmol/l. Development of closed loop technology: Data obtained from previous blinded CGM data collection and as part of the feasibity and RCT will be used to inform the development of a computer based algorithm to combine with rCGM to further individualize glucose control in babies who have become hyperglycamic. This will be tested as part of a single centre pilot study (n=10). The use of rCGM could improve both detection and acute management of glucose control reducing the need for invasive blood sampling and increasing the time glucose levels were within a target glucose range. Based on paediatric intensive care data improved glucose control could reduce length of neonatal intensive care stay which is a costly and a limited resource(2). In addition any impact on long term neurological outcomes of preterm infants is critical as this has significant costs to society in terms of health social care and education. Validation of the use of rCGM at low glucose levels also has the potential to impact on other infants at risk of hypoglycaemia in the newborn particularly the increasingly common problem of hypoglycaemia following pregnancies complicated by diabetes. KB undertook the first pilot studies of CGM leading to their use in the NIRTURE Trial DBD is accepted as an international expert on glucose metabolism and is the Lead Paediatrician for the Cambridge Clinical Trials Unit. RH is a world leader in the development of control algorithms and close loop technology for the management of glucose control. The application is supported by the Cambridge Clinical Trials Unit. The neonatal unit in Cambridge is experienced in undertaking clinical studies and as Network lead for the East of England is well placed to cascade any developments in clinical practice to other units. Together these individuals and environment provide a uniquely experienced team.1. Bottino M et al. Cochrane Database Syst Rev 2009(1):CD007453 2. Vlasselaers D et al. Lancet 2009;373(9663):54


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE