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Three Part Question

In [hyperglycaemic very low birth weight (VLBW) neonates on parenteral nutrition] does [addition of insulin therapy without glucose restriction] improve [glycaemic control and weight gain]?

Clinical Scenario

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?

Search Strategy

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.

Search Outcome

6 relevant studies were identified. See table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Meetze et al 1998 USA	Extremely low birth weight infants (ELBW) were enrolled on day 2 of life (n = 56). Intravenous glucose increased incrementally to a maximum of 12 mg/kg/min. Infants who developed hyperglycaemia were randomly assigned to receive insulin infusion (n = 12) or glucose reduction (n = 11). Infants whose blood sugars remained normal served as controls (n = 33). Hyperglycaemia was defined as single blood sugar >13.3 mmol/l or repeated blood sugars >8.8 mmol/l for at least 4 h	Randomised controlled trial (1b)	Glycaemic control	Euglycaemia (target blood sugar levels not documented) Insulin group: 14/14 infants Glucose reduction group: 9/11infants Hypoglycaemia episodes (blood glucose <3.3 mmol/l): none in either group	Small sample size. Randomisation procedure not explained. Analysis not based on intention to treat (2 infants from glucose reduction group assigned to insulin group). It is not clear why infants in the insulin group had lower intake of calories, protein, and fat than normal controls. Enteral intake was not controlled by the study protocol. Net weight gain between groups not compared.
			Days to reach 60 kcal/kg/day (non protein energey)	Insulin group: 5.5±0.6 days Glucose reduction group: 8.6±1.3 days Control group: 4.1±0.2 days (mean ± SEM) (p<0.01)
Collins J W et al 1991 USA	ELBW infants (n = 24) with hyperglycaemia were randomly assigned to receive insulin along with total parenteral nutrition (n = 12) or standard care (control; n = 12) with an aim to achieve 120 kcal/kg/day Glucose intolerance in the control infants was managed by reducing intravenous glucose administration to maintain serum glucose values <9.9 mmol/l without glucosuria Hyperglycaemia was defined as blood glucose >9.9 mmol/l with glycosuria	Randomised Controlled trial (1b)	Weight gain	Insulin group: 20.1±12.1 Control group: 7.8±5.1 g/kg/day (mean ± SD) (p<0.01)	Small sample size. Glucose delivery rates used are higher than usual in clinical practice. The incidence of sepsis was significantly greater in control infants (p<0.05)
			Calorie intake (non protein energy)	Insulin group: 124.7±18 Control group: 86.0 ± 6 kcal/kg/day (mean ± SD) (p<0.01)
			Glycaemic control	Euglycaemia (target blood sugar between 3.9 and 7.7 mmol/l): achieved in both groups Hypoglycaemia episodes (blood glucose <2.2 mmol/l): 4/1848 (0.2%) measurements
Binder ND et al 1989 USA	ELBW infants (n = 76) with hyperglycaemia were retrospectively reviewed, n = 34 received insulin whereas n = 42 did not Hyperglycaemia was defined as blood glucose associated with 0.5% glycosuria	Case series (level 4)	Days to regain birth weight	Insulin group: 12±6 days Non insulin group: 13±6 days (mean ± SD) (p = 0.34)	Retrospective case note review. Insulin group had a significantly lower birth weight and gestational age. Despite lower mean birth weight in the insulin group their discharge weight was higher than the control group.
			Days to achieve 100 kcal/kg/day	Insulin group: 15±8 days Non-insulin group: 17±11 days (mean ± SD) (p = 0.21)
			Glycaemic control	Hypoglycaemia (blood glucose <2.2 mmol/l) 26/7368 (0.5%) measurements
Heron P et al 1988 New Zealand	Infants <1250 g (n = 15) with hyperglycaemia were commenced on insulin infusion	Case Series (level 4)	Calorie intake	Increased post insulin infusion from 60.8±25.1 to 79.9±24.5 kcal/kg/day (mean ± SD) (p<0.001)	Small numbers, uncontrolled study. The upper limit of blood sugar chosen for hypoglycaemia is lower than the standard of 2.2 mmol/l
			Glycaemic control	Hypoglycaemia (blood glucose <2 mmol/l): 28/998 (2.8%) measurements
Ostertag SG et al 1986 USA	VLBW infants with hyperglycaemia (n = 10) were commenced on insulin	Case series (level 4)	Calorie intake	Post-insulin infusion calorie intake increased from 49.5±32 to 70.4±21 kcal/kg/day (mean ± SEM) (p<0.01)	Small numbers, uncontrolled study. The upper limit of blood sugar chosen for hypoglycaemia is lower than the standard of 2.2 mmol/l
			Weight gain	–23±39 increased to +13±34 g/day (mean ± SEM) (p<0.01)
			Glycaemic control	Hypoglycaemia (blood glucose 1.4 mmol/l): none
Vaucher YE et al 1982 USA	VLBW infants with hyperglycaemia (n = 10) were commenced on insulin	Case series (level 4)	Calorie intake	Post-insulin infusion calorie intake increased from 29 to 56 kcal/kg/day	Small numbers, uncontrolled study. The upper limit of blood sugar chosen for hypoglycaemia is lower than the standard of 2.2 mmol/l
			Weight gain	Net weight gain 8/10 infants
			Glycaemic control	Hypoglycaemia (blood glucose <1.4 mmol/l): <1% of all glucose estimations

Comment(s)

Hyperglycaemia occurs commonly in preterm neonates admitted to intensive care, with a reported incidence of 40–80% among VLBW (1000–1500 g) neonates (Pildes, Dweck, Louik). Hyperglycaemia usually develops when premature infants are given parenteral alimentation in amounts necessary to meet requirements for adequate growth (Pildes, Dweck). It can lead to osmotic diuresis with resultant dehydration and electrolyte imbalance (Wilkins). The subsequent hyperosmolar state has been associated with an increased risk of intraventricular haemorrhage (Finberg). The standard approaches to the management of hyperglycaemia in the neonate involve the use of continuous insulin infusion, glucose restriction, or both( Simeon). 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 (Heird). Glucose restriction may cause caloric deprivation and lead to suboptimal postnatal growth, and in VLBW infants may retard head circumference with consequent neurodevelopmental problems (Gibson, Powls). 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 (McCowen, Gore, Latham, Guvener). 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 (Van den Berghe 2001, Van den Berghe 2003). A similar study (Collins) 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 (Malmberg). 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 (Economides). 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 (Lindblad). Administration of intravenous fat emulsion has been shown to increase plasma glucose concentration by 24% over baseline values (Vileisis). An additive effect has been noted when glucose and amino acids were added to the intravenous fat emulsion (Savich). In contrast the establishment of oral feeds and the coupling of food related nutrient and hormonal signals increase the release of insulin (Aynsley-Green 1997, Aynsley-Green 1982, Lilien). 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 ß-cell mass (Garofano 1997, Garafano 1998) which may have long term implications. Insulin replacement during this catabolic neonatal period may potentially limit proteolysis (Pointdexter), and improve anabolism and weight gain. Furthermore, improved glycaemic control may help reduce the risk of sepsis and intraventricular haemorrhage. Two controlled studies (Meetze, Collins) compared insulin therapy to reduction in glucose intake. The study by Meetze and colleagues 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 colleagues 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. 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). All uncontrolled studies except that of Binder and colleagues reported improved glycaemic control, and increased caloric intake and weight gain on insulin therapy. However, all studies except Meetze and colleagues and Ostertag and colleagues 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.

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)

References

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