Early Insulin Therapy in Very-Low-Birth-Weight Infants

University of Cambridge, Cambridge, United Kingdom.
New England Journal of Medicine (Impact Factor: 55.87). 11/2008; 359(18):1873-84. DOI: 10.1056/NEJMoa0803725
Source: PubMed


Studies involving adults and children being treated in intensive care units indicate that insulin therapy and glucose control may influence survival. Hyperglycemia in very-low-birth-weight infants is also associated with morbidity and mortality. This international randomized, controlled trial aimed to determine whether early insulin replacement reduced hyperglycemia and affected outcomes in such neonates.
In this multicenter trial, we assigned 195 infants to continuous infusion of insulin at a dose of 0.05 U per kilogram of body weight per hour with 20% dextrose support and 194 to standard neonatal care on days 1 to 7. The efficacy of glucose control was assessed by continuous glucose monitoring. The primary outcome was mortality at the expected date of delivery. The study was discontinued early because of concerns about futility with regard to the primary outcome and potential harm.
As compared with infants in the control group, infants in the early-insulin group had lower mean (+/-SD) glucose levels (6.2+/-1.4 vs. 6.7+/-2.2 mmol per liter [112+/-25 vs. 121+/-40 mg per deciliter], P=0.007). Fewer infants in the early-insulin group had hyperglycemia for more than 10% of the first week of life (21% vs. 33%, P=0.008). The early-insulin group had significantly more carbohydrate infused (51+/-13 vs. 43+/-10 kcal per kilogram per day, P<0.001) and less weight loss in the first week (standard-deviation score for change in weight, -0.55+/-0.52 vs. -0.70+/-0.47; P=0.006). More infants in the early-insulin group had episodes of hypoglycemia (defined as a blood glucose level of <2.6 mmol per liter [47 mg per deciliter] for >1 hour) (29% in the early-insulin group vs. 17% in the control group, P=0.005), and the increase in hypoglycemia was significant in infants with birth weights of more than 1 kg. There were no differences in the intention-to-treat analyses for the primary outcome (mortality at the expected date of delivery) and the secondary outcome (morbidity). In the intention-to-treat analysis, mortality at 28 days was higher in the early-insulin group than in the control group (P=0.04).
Early insulin therapy offers little clinical benefit in very-low-birth-weight infants. It reduces hyperglycemia but may increase hypoglycemia (Current Controlled Trials number, ISRCTN78428828.)

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Available from: Claire Theyskens, Oct 13, 2015
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    • "The use of insulin infusions to treat hyperglycaemia and/or promote growth has shown positive outcomes including reduced proteolysis , improved glucose tolerance, increased insulin-like growth factor (IGF-I) levels, and improved caloric intake and weight gain [6] [7] [8]. However, many insulin trials were unsuccessful in safely providing glycaemic control due to increased hypoglycaemia [8] [9]. All reported insulin therapy trials used protocols that fixed insulin dosing based on weight or other factors [10], or depended on clinical judgement to determine insulin infusion rates. "
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    ABSTRACT: Hyperglycaemia is a prevalent complication in the neonatal intensive care unit (NICU) and is associated with worsened outcomes. It occurs as a result of prematurity, under developed endogenous glucose regulatory systems and clinical stress. The stochastic targeting (STAR) framework provides patient-specific, model-based glycaemic control with a clinically proven level of confidence on the outcome of treatment interventions, thus directly managing the risk of hypo- and hyper- glycaemia. However, the stochastic models that are over conservative can limit control performance. Clinical data from 61 episodes (25 retrospective and 36 from a prospective BG control study), of insulin therapy in very-low birth weight (VLBW) and extremely-low birth weight (ELBW) neonates are used to create a new stochastic model of model-based insulin sensitivity (S I). Sub-cohort models based on gestational age (GA) and birth weight (BW) are also created. Performance is assessed by the percentage of patients who have 90% of actual intra-patient variability in SI captured by the 90% confidence bands of the cohort based (inter-patient) stochastic variability model created. This assessment measures per-patient accuracy for any given cohort model. Per-patient coverage trends were very similar between prospective and retrospective cohorts, providing a measure of external validation of cohort similarity. Per patient coverage was improved though the use of BW and GA dependent stochastic models, which ensures that the stochastic models more accurately capture both inter- and intra- patient variability. Stochastic forecasting is limited by significant interpatient variability, which implies that more patient specific methods will be required to improve forecasting and glycaemic control.
    Biomedical Signal Processing and Control 07/2013; 8(4):1746-8094. DOI:10.1016/j.bspc.2013.01.006 · 1.42 Impact Factor
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    • "Hence, the few larger trials have experienced problems with persistent hypoglycaemia and poor control [8]. However, using insulin to treat hyperglycaemia has been associated with positive outcomes [7] [8] [9] [10] [11] [12] [13] [14]. In addition to maintaining patient-specificity, STAR aims to increase the consistency of treatment across a broad range of patients and attending clinicians. "
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    ABSTRACT: Hyperglycaemia is a common complication of prematurity and stress in neonatal intensive care units (NICUs). It has been linked to worsened outcomes and mortality. There is currently no universally accepted best practice glycaemic control method, with many protocols lacking patient specificity or relying heavily on ad hoc clinical judgment from clinical staff who may be caring or overseeing care for several patients at once. The result is persistent hypoglycaemia and poor control. This research presents the virtual trial design and optimisation of a stochastic targeted (STAR) approach to improve performance and reduce hypoglycaemia. Clinically validated virtual trials based on NICU patient data (N = 61 patients, 7006 h) are used to develop and optimise a STAR protocol that improves on current STAR-NICU performance and reduce hypoglycaemia. Five approaches are used to maximise the stochastic range of BG outcomes within 4.0–8.0 mmol/L, and are designed based on an overall cohort risk to provide clinically specified risk (5%) of BG above or below a clinically specified level. The best protocol placed the 5th percentile BG outcome for an intervention on 4.0 mmol/L band. The optimised protocol increased %BG in the 4.0–8.0 mmol/L band by 3.5% and the incidence of BG < 2.6 mmol/L by 1 patient (50%). Significant intra- and inter-patient variability limited possible performance gains so that they are unlikely to be clinically substantial, indicating a need for a further increase patient-specific or sub-cohort specific approaches to manage variability. This result sets the direction for future research.
    Biomedical Signal Processing and Control 03/2013; 8(2):215-221. DOI:10.1016/j.bspc.2012.08.002 · 1.42 Impact Factor
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    • "However, this approach also deprives the neonate of crucial energy required to promote growth [2]. A small number of prospective trials have used insulin infusions to treat hyperglycemia and/or promote growth [10-18]. Positive outcomes of insulin infusion have included reduced proteolysis, improved glucose tolerance, increased IGF-I levels and improved caloric intake and weight gain. "
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    ABSTRACT: Hyperglycemia often occurs in premature, very low birthweight infants (VLBW) due to immaturity of endogenous regulatory systems and the stress of their condition. Hyperglycemia in neonates has been linked to increased morbidities and mortality and occurs at increasing rates with decreasing birthweight. In this cohort, the emerging use of insulin to manage hyperglycemia has carried a significant risk of hypoglycemia. The efficacy of blood glucose control using a computer metabolic system model to determine insulin infusion rates was assessed in very-low-birth-weight infants. Initial short-term 24-hour trials were performed on 8 VLBW infants with hyperglycemia followed by long-term trials of several days performed on 22 infants. Median birthweight was 745 g and 760 g for short-term and long-term trial infants, and median gestational age at birth was 25.6 and 25.4 weeks respectively. Blood glucose control is compared to 21 retrospective patients from the same unit who received insulin infusions determined by sliding scales and clinician intuition. This study was approved by the Upper South A Regional Ethics Committee, New Zealand ( registration NCT01419873). Reduction in hyperglycemia towards the target glucose band was achieved safely in all cases during the short-term trials with no hypoglycemic episodes. Lower median blood glucose concentration was achieved during clinical implementation at 6.6 mmol/L (IQR: 5.5 - 8.2 mmol/L, 1,003 measurements), compared to 8.0 mmol/L achieved in similar infants previously (p < 0.01). No significant difference in incidence of hypoglycemia during long-term trials was observed (0.25% vs 0.25%, p = 0.51). Percentage of blood glucose within the 4.0 - 8.0 mmol/L range was increased by 41% compared to the retrospective cohort (68.4% vs 48.4%, p < 0.01). A computer model that accurately captures the dynamics of neonatal metabolism can provide safe and effective blood glucose control without increasing hypoglycemia. registration NCT01419873.
    BMC Pediatrics 08/2012; 12:117. DOI:10.1186/1471-2431-12-117 · 1.93 Impact Factor
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