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- glucose restriction
- very low birth weight infants
- extremely low birth weight infants
A 1000 g neonate develops persistent hyperglycaemia, glycosuria, and osmotic diuresis on day 2 of total parenteral nutrition. The specialist registrar decides to restrict glucose content in total parenteral nutrition (TPN). However, the consultant disagrees and decides to start a continuous insulin infusion while administering full TPN to control blood glucose and achieve weight gain. Is the consultant’s decision based on sound evidence?
Structured clinical question
In hyperglycaemic very low birth weight (VLBW) neonates on parenteral nutrition [patient] does addition of insulin therapy without glucose restriction [intervention] improve glycaemic control and weight gain [outcome]?
Search strategy and outcome
Primary search: the Cochrane Library (2005, issue 2). Search term [hyperglycemia AND insulin]. Search results: 560 controlled trials in CENTRAL of which two were relevant and 19 were reviews that were not relevant.
Secondary search: Pubmed and Medline 1966–2005, Embase 1974–2005, Cinahl 1982–2005 using Dialog DataStar. Search term [hyperglycemia AND insulin]. Filter clinical queries. Limit to newborn, human and English language. Search results: Pubmed (17), Medline (19), Embase (75) and Cinahl (1) of which two were controlled trials (already retrieved by Cochrane) and four were case series.
See table 3.
Hyperglycaemia occurs commonly in preterm neonates admitted to intensive care, with a reported incidence of 40–80% among VLBW (1000–1500 g) neonates.7–9 Hyperglycaemia usually develops when premature infants are given parenteral alimentation in amounts necessary to meet requirements for adequate growth.7,8 It can lead to osmotic diuresis with resultant dehydration and electrolyte imbalance.10 The subsequent hyperosmolar state has been associated with an increased risk of intraventricular haemorrhage.11 The standard approaches to the management of hyperglycaemia in the neonate involve the use of continuous insulin infusion, glucose restriction, or both.12 It is not clear which of these strategies is more effective in the short term control of hyperglycaemia and optimising nutrition in this vulnerable population. The resting energy expenditure in premature infants is considered to be about 60 kcal/kg/day.13 Glucose restriction may cause caloric deprivation and lead to suboptimal postnatal growth, and in VLBW infants may retard head circumference with consequent neurodevelopmental problems.14,15 On the other hand continuous insulin infusion may cause hypoglycaemia and hypokalaemia. Moreover, the long term clinical significance of large doses of exogenous insulin in association with early high energy intake in the preterm neonate is unknown.
In adult post-surgical and burns injury patients, uncontrolled hyperglycaemia has been associated with increased episodes of sepsis.16–19 Recent studies involving use of insulin for rigid blood glucose control in hyperglycaemic adult intensive care patients have shown significant decrease in their mortality, intensive care stay, and incidence of sepsis.20,21 A similar study2 in neonates has also shown a reduction in the incidence of sepsis. Studies in patients with post-myocardial infarction have also suggested an improved long term outcome in patients who received insulin and had better glycaemic control.22 It is difficult to delineate the contribution of anabolic effects of insulin to these beneficial effects.
Fetal plasma insulin increases with gestation, largely determined by the glucose flux across the placenta.23 At birth the disruption of placental supply of nutrients leads to a period of catabolism, and birth weight is not usually recovered until 7–10 days of age. The blood glucose levels during this period are maintained by gluconeogenesis and glycolysis driven by counter regulatory hormones such as catecholamines, growth hormone, and cortisol, diverting glucose utilisation from muscle to brain. The very high blood sugar levels in the first few weeks of life may therefore reflect insulin resistance and/or relative insulin deficiency. The practice of early TPN may also increase the likelihood of hyperglycaemia.24 Administration of intravenous fat emulsion has been shown to increase plasma glucose concentration by 24% over baseline values.25 An additive effect has been noted when glucose and amino acids were added to the intravenous fat emulsion.26 In contrast the establishment of oral feeds and the coupling of food related nutrient and hormonal signals increase the release of insulin.27–29 However, in the VLBW infants it may not be possible to initiate oral feeding and thus induce normal insulin secretion. This leads to prolongation of the catabolic state and as a consequence birth weight may not be regained for several weeks. Fetal growth restriction in animal models has been shown to be associated with impaired pancreatic development and a reduced β-cell mass,30,31 which may have long term implications.
Insulin replacement during this catabolic neonatal period may potentially limit proteolysis,32 and improve anabolism and weight gain. Furthermore, improved glycaemic control may help reduce the risk of sepsis and intraventricular haemorrhage.
The literature search yielded six relevant trials of insulin therapy; two controlled trials, and one case series in extremely low birth weight (ELBW, <1000 g) infants, and three case series in VLBW infants (<1500 g).
Two controlled studies1,2 compared insulin therapy to reduction in glucose intake. The study by Meetze and colleagues1 showed improved glycaemic control without hypoglycaemia and significantly shorter duration to reach resting energy expenditure of 60 kcal/kg/day. It remains to be elucidated whether such short term benefits confer any long term advantages. Collins and colleagues2 showed improved glycaemic control, increased calorie intake and weight gain, and decreased incidence of sepsis in the insulin group. However, the glucose delivery rates were much higher than common practise.
All uncontrolled studies except that of Binder and colleagues3 reported improved glycaemic control, and increased caloric intake and weight gain on insulin therapy. However, all studies except Meetze and colleagues1 and Ostertag and colleagues5 reported episodes of hypoglycaemia ranging from 0.2% to 2.8% of all observations in the insulin group. The further exploration of both side effects and the population to consider use of insulin infusions is complicated by the marked variation between studies regarding the definition of hyperglycaemia and hypoglycaemia (see table 3).
CLINICAL BOTTOM LINE
Insulin therapy in the hyperglycaemic ELBW infant improves blood glucose control, caloric intake, and probably weight gain. It is not clear whether this confers any long term advantage. (Grade B)
Insulin therapy in the hyperglycaemic VLBW infant between 1000 and 1500 g is difficult to evaluate due to lack of good quality studies in this weight category. (Grade C)
Hypoglycaemia remains an important complication of insulin therapy. (Grade B)
Edited by Bob Phillips