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      A randomised controlled trial of early insulin therapy in very low birth weight infants, "NIRTURE" (neonatal insulin replacement therapy in Europe)

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          Abstract

          Background

          Studies in adult intensive care have highlighted the importance of insulin and improved glucose control on survival, with 32% reduction in mortality, 22% reduction in intensive care stay and halving of the incidence of bacteraemia. Very low birth weight infants requiring intensive care also have relative insulin deficiency often leading to hyperglycaemia during the first week of life. The physiological influences on insulin secretion and sensitivity, and the potential importance of glucose control at this time are not well established. However there is increasing evidence that the early postnatal period is critical for pancreatic development. At this time a complex set of signals appears to influence pancreatic development and β cell survival. This has implications both in terms of acute glucose control but also relative insulin deficiency is likely to play a role in poor postnatal growth, which has been associated with later motor and cognitive impairment, and fewer β cells are linked to risk of type 2 diabetes later in life.

          Methods

          A multi-centre, randomised controlled trial of early insulin replacement in very low birth weight babies (VLBW, birth weight < 1500 g). 500 infants will be recruited from 10 centres in the UK and Europe. Babies will be randomised to receive a continuous insulin infusion (0.05 units/kg/h) or to receive standard neonatal care from the first day of life and for the next 7 days. If blood glucose (BG) levels fall infants will receive 20% dextrose titrated to maintain normoglycaemia (4–8 mmol/l). If BG is consistently above 10 mmol/l babies will receive standard treatment with additional insulin infusion. The primary end point will be mortality on or before expected date of delivery, secondary end points will be markers of morbidity and include episodes of sepsis, severity of retinopathy, chronic lung disease and growth.

          Trial Registration

          Current Controlled Trials ISRCTN78428828. EUDRACT Number 2004-002170-34

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          Most cited references47

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          Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period.

          The follow-up records of 605 infants with birth weights of less than 1,500 g, with data available for 2 years after birth, were examined for evidence of abnormal pulmonary signs or symptoms. A total of 119 infants were identified and the neonatal oxygen requirements of these infants were compared with those of 486 infants who had normal pulmonary function. A requirement for oxygen at 28 days of life had a positive predictive value for abnormal pulmonary findings at the time of follow-up of only 38%, whereas 31% of those with normal pulmonary findings at the time of follow-up were still receiving oxygen at this age. The need for oxygen at 28 days was a good predictor of abnormal findings in infants of greater than or equal to 30 weeks' gestational age at birth but became increasingly less useful as gestational age decreased. It was found that, irrespective of gestational age at birth, the requirement for additional oxygen at 36 weeks' corrected postnatal gestational age was a better predictor of abnormal outcome, increasing the positive predictive value to 63%. The prediction of a normal outcome remained 90% for infants not receiving oxygen at this corrected gestational age.
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            Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control.

            Maintenance of normoglycemia with insulin reduces mortality and morbidity of critically ill patients. Here we report the factors determining insulin requirements and the impact of insulin dose vs. blood glucose control on the observed outcome benefits. A prospective, randomized, controlled trial. A 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital. A total of 1,548 patients were randomly assigned to either strict normalization of blood glucose (80-110 mg/dL) with insulin infusion or the conventional approach, in which insulin is only given to maintain blood glucose levels at 180-200 mg/dL. It was feasible and safe to achieve and maintain blood glucose levels at 20 IU/hr). Between day 7 and 12, insulin requirements decreased by 40% on stable caloric intake. Brief, clinically harmless hypoglycemia occurred in 5.2% of intensive insulin-treated patients on median day 6 (2-14) vs. 0.8% of conventionally treated patients on day 11 (2-10). The outcome benefits of intensive insulin therapy were equally present regardless of whether patients received enteral feeding. Multivariate logistic regression analysis indicated that the lowered blood glucose level rather than the insulin dose was related to reduced mortality (p <.0001), critical illness polyneuropathy (p <.0001), bacteremia (p =.02), and inflammation (p =.0006) but not to prevention of acute renal failure, for which the insulin dose was an independent determinant (p =.03). As compared with normoglycemia, an intermediate blood glucose level (110-150 mg/dL) was associated with worse outcome. Normoglycemia was safely reached within 24 hrs and maintained during intensive care by using insulin titration guidelines. Metabolic control, as reflected by normoglycemia, rather than the infused insulin dose, was related to the beneficial effects of intensive insulin therapy.
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              Stress-induced hyperglycemia.

              Stress hyperglycemia is common and likely to be associated with at least some of the same complications as hyperglycemia in true diabetes mellitus, such as poor wound healing and a higher infection rate. The predominant cause is the intense counterregulatory hormone and cytokine responses of critical illness, often compounded by excessive dextrose administration, usually as TPN. Although randomized data suggesting benefit of controlling hyperglycemia in hospitalized patients are paltry, prospective controlled trials are feasible and should be initiated. In the interim, the practice at the authors' institution is to use insulin to lower plasma glucose concentrations to a safe range of 150 mg/dL to 200 mg/dL in all patients.
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                Author and article information

                Journal
                BMC Pediatr
                BMC Pediatrics
                BioMed Central (London )
                1471-2431
                2007
                10 August 2007
                : 7
                : 29
                Affiliations
                [1 ]Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital NHS Trust, Hills Road, Cambridge, CB2 2QQ, UK
                [2 ]Neonatal Unit, Rosie Hospital, Hills Road, Cambridge, CB2 2QQ, UK
                [3 ]Neonatal Unit, Kindergeneeskunde, UZ, Herestraat 49, B3000, Leuven, Belgium
                [4 ]Centre for Applied Medical Statistics, Department of Public Health and Primary Care, University of Cambridge, UK
                [5 ]Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4SA, UK
                [6 ]Department of Paediatrics, Luton and Dunstable Hospital, Lewsey Road, Luton, LU4 0DZ, UK
                [7 ]Neonatal Unit, Leeds General Infirmary, Great George Street, Leeds, LS1 3EX, UK
                [8 ]Neonatal Unit, VU University Centre, Amsterdam, The Netherlands
                [9 ]Neonatal Unit, Hospital Universitari, Passeig Sant Joan de Deu, number 2, 08950 Esplugues-Barcelona, Spain
                Article
                1471-2431-7-29
                10.1186/1471-2431-7-29
                1994677
                17692117
                d8327cf9-e50f-470a-abe9-304e57650c53
                Copyright © 2007 Beardsall et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 19 December 2006
                : 10 August 2007
                Categories
                Study Protocol

                Pediatrics
                Pediatrics

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