Neonatal Hyperglycemia Paul J. Rozance and William W. Hay, Jr Neoreviews 2010;11;e632 DOI: 10.1542/neo.

11-11-e632

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/11/11/e632

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Article

endocrinology

Neonatal Hyperglycemia
Paul J. Rozance, MD,* William W. Hay, Jr, MD*

Abstract
Neonatal hyperglycemia is one of the most common metabolic abnormalities encountered in preterm and critically ill newborns. Although the denition varies, a blood glucose concentration greater than 125 mg/dL (6.9 mmol/L) or a plasma or serum glucose concentration greater than 150 mg/dL (8.3 mmol/L) often is used. Management of hyperglycemia is highly variable, probably because of the lack of evidence for improved outcomes in most neonates with any specic approach. This review focuses on the risk factors and causes for neonatal hyperglycemia, the associated consequences and pathology, and current management strategies.

Author Disclosure Drs Rozance and Hay have disclosed no nancial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/ device.

Objectives

After completing this article, readers should be able to:

1. Explain the causes of neonatal hyperglycemia and how they relate to clinical risk factors. 2. Review the potential complications of neonatal hyperglycemia. 3. Discuss the benets and risks of various treatment options for neonatal hyperglycemia, including continuous insulin infusions. 4. Highlight the reasons why the denition and treatment of neonatal hyperglycemia remains controversial.

Overview
Neonatal hyperglycemia has been dened arbitrarily as a blood glucose concentration greater than 125 mg/dL (6.9 mmol/L) or a plasma or serum glucose concentration greater than 150 mg/dL (8.3 mmol/L), regardless of gestational or postnatal age. (1) However, the dening value varies considerably among sources. For example, a survey in Australasia indicated that most neonatologists dened neonatal hyperglycemia as a plasma glucose concentration greater than 180 mg/dL (10.0 mmol/L). (2) Reasons for this value were arbitrary, but not because there are clear indications that glucose concentrations just greater than 180 mg/dL (10.0 mmol/L) have specic and serious adverse effects. Continuous glucose monitoring using a subcutaneous needle electrode shows that hyperglycemia is more common in the rst 3 to 5 days after birth, but it can be found for up to 10 days or more after birth. (3)(4) Acute hyperglycemia resolves over 2 to 3 days in most infants. Neonatal hyperglycemia is inversely related to birthweight (18 times more common in infants whose birthweights are less than 1,000 g than among those weighing 1,000 to 2,000 g) and is most common in very preterm infants. (5)(6)(7)(8)(9) Older data from Dweck and Cassady (5) showed that 86% of infants whose birthweights were less than 1,100 g had hyperglycemia (serum glucose 125 mg/dL [6.9 mmol/L]), and of these, 84% had one or more serum glucose concentrations greater than 300 mg/dL (16.7 mmol/L). Such occurrence rates are common today. Neonatal hyperglycemia is directly related to illness and all forms of stress, particularly septicemia. (1) The causes of neonatal hyperglycemia are variable and ill-dened. Generally, hyperglycemia represents a mixture of excessive glucose production by the infant, too much infused exogenous glucose, and a reduced capacity for glucose utilization. There are no demonstrable clinical signs of neonatal hyperglycemia and no changes in an infants clinical condition when glucose concentrations are acutely raised or lowered. For example, during experimental hyperglycemia, preterm infants develop glucosuria but not an os*Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Co. e632 NeoReviews Vol.11 No.11 November 2010

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motic diuresis with increased urine ow rates. (10) Therefore, hyperglycemia remains a biochemical disorder that would not be diagnosed without the measurement of glucose concentrations in the blood or plasma.

Table 1.

Risks for Hyperglycemia in Newborn Infants

Preterm birth Intrauterine growth restriction (IUGR) Increased stress hormones Increased catecholamine infusions and plasma concentrations Increased glucocorticoid concentrations (from use of antenatal steroids, postnatal glucocorticoid administration, and stress) Increased glucagon concentrations Early and high rates of intravenous (IV) lipid infusion Higher-than-needed rates of IV glucose infusion Insufcient pancreatic insulin secretion (preterm and IUGR) Absence of enteral feedings, leading to diminished incretin secretion and action, limiting their potential to promote insulin secretion

Causes of Neonatal Hyperglycemia

The principal causes of hyperglycemia in newborns are identied in Table 1. Preterm infants, particularly those who have intrauterine growth restriction (IUGR), appear to have lower capacities for insulin secretion. (11) (12)(13)(14)(15) This sets them up for hyperglycemia because nearly all receive higher intravenous infusion rates of glucose than their capacity for glucose utilization allows. Glucose infusion rates greater than 10 to 11 mg/kg per minute consistently are associated with hyperglycemia. Both preterm infants and those who experience IUGR have reduced muscle mass and, thus, less capacity for insulin to promote peripheral glucose utilization. Infants who have IUGR also can have hepatic insulin resistance, thereby allowing hepatic glucose production to persist despite high plasma glucose concentrations. (1) Preterm infants also are not fed enterally immediately after birth, reducing gastric secretion of incretins. Incretins are hormones that promote insulin secretion from the pancreas, thereby enhancing glucose metabolism after enteral feeding. One of the most common causes of hyperglycemia is increased circulating stress-reactive hormones such as epinephrine and norepinephrine. These hormones, whether induced by stress or by infusion to promote cardiac output and increase peripheral vascular resistance, inhibit both insulin secretion and action. Such effects are not limited to infants born closer to term, who have more mature sympathetic nervous systems and adrenal development; they also are common in preterm infants. In fact, these effects are well recognized in fetal life. (16)(17) Circulating concentrations of epinephrine and norepinephrine also increase during infusion of dopamine and dobutamine by as much as two- to sixfold, either by enhanced endogenous secretion, reduced clearance (saturation of binding receptors), or both. Also, stress-induced or infused cortisol (as hydrocortisone or dexamethasone) promotes protein breakdown, thereby providing amino acids that fuel gluconeogenesis. Cortisol also activates phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase and increases gluconeogenesis and hepatic glucose release. Similarly, stress-induced increases of glucagon promote glycogenolysis and activation of PEPCK, which leads to increased hepatic glucose production. Commonly, the same conditions that produce increased secretion of catechol-

amines, glucagon, and cortisol also reduce insulin secretion, doubling the propensity for hyperglycemia. Intravenous lipid infusion producing high circulating concentrations of free fatty acids (FFAs) also can produce hyperglycemia. (18)(19) FFAs limit glucose oxidation competitively by providing additional carbon substrates for oxidative metabolism. FFA metabolic products promote gluconeogenesis by increasing concentrations or activity of enzymes in the gluconeogenic pathway. Glycerol in intravenous lipid emulsions fuels gluconeogenesis directly. (20)(21)(22) Very preterm infants have relatively low energy requirements (only 40 to 50 kcal/kg per day) due to energy-sparing treatments that include the use of incubators and radiant heat, high relative humidity in their immediate environment, ventilation or continuous positive airway pressure, muscle relaxant drugs, and swaddling that reduces their already low muscle activity. (23)(24) It is not surprising, therefore, that high intravenous (IV) lipid infusion rates that contribute to increased rates of gluconeogenesis also produce hyperglycemia because energy-consuming processes are low at the same time.

Unusual Causes of Severe Hyperglycemia

Based on one of the authors (Hay) personal experience in medical-legal cases, if a neonates plasma glucose concentration exceeds 1,000 to 2,000 mg/dL (55.5 to 111.0 mmol/L) (the record high found by Dr Hay in such cases was 2,950 mg/dL [163.7 mmol/L]), the clinician should evaluate the dextrose infusate. Almost
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certainly it will be in error, possibly by mistakenly substituting D75 for the dextrose concentrations ordered. D75 is commonly used by pharmacies to produce dextrose solutions other than D5 or D10. A best practice approach is to use only pharmaceutical company stock dextrose solutions (D5, D10). Although they may also be in error, this is extremely unlikely, given industry standards for manufacturing and surveillance. If the pharmacy makes different solutions, individual institutions might consider developing policies to preempt such errors. For example, the pharmacy might measure the infusate glucose concentration before it is administered.

Possible Benets of Tight Glucose Control*

Table 3.

Reduced morbidity and mortality Improved metabolic status (improved energy expenditure) Improved cardiovascular status (cardiac output) Improved systemic and regional delivery of oxygen Improved immunity, reduced infection Better wound healing Improved nitrogen balance

*Primarily noted in adults and some older children.

Consequences of Neonatal Hyperglycemia

Concerns for potential adverse effects of neonatal hyperglycemia persist and often lead to rapid and sometimes aggressive treatment responses, even though there is little evidence that such treatments improve outcomes. Such concerns are partly based on problems rarely encountered unless hyperglycemia is acute and severe, usually with glucose concentrations greater than 400 to 500 mg/dL (22.2 to 27.8 mmol/L). These concerns include glucosuria leading to dehydration, hyperosmolar coma with cerebral and neuronal edema, seizures, and intracranial hemorrhage. Other concerns relate to a large variety of problems that are presumed to be caused by high circulating glucose concentrations themselves, although most have not been separated from the associated conditions producing or contributing to the hyperglycemia (Table 2). These problems have been identied primarily in critically ill adults in surgical or medical intensive care units or in adults who have longerstanding hyperglycemia with diabetes mellitus. Such potential adverse effects of hyperglycemia are supported by related observations of possibly improved outcomes when hyperglycemia is treated successfully (Table 3).

Pathology Associated With Neonatal Hyperglycemia

Acute neonatal hyperglycemia has the potential for producing uid disorders such as osmotic diuresis and dehydration, electrolyte imbalances such as hyponatremia and hypokalemia, and acid-base complications such as dilutional acidosis. Hyperosmolality, with osmotic shifts and risk of intracranial hemorrhage, generally has been seen only with very rapid increases of plasma glucose concentrations to excessively high values, usually more than 500 mg/dL (27.8 mmol/L). (1) Each 18 mg/dL (1.0 mmol/L) of plasma glucose concentration produces 1 mOsm/L. (5) Thus, plasma glucose concentrations of 500 mg/dL (27.8 mmol/L) provide an additional 25 mOsm/L that, when present for several hours, can produce brain cell dehydration, capillary dilation, and cerebral bleeding. Such conditions can cause acute and permanent brain injury. Even lower degrees of hyperglycemia in neonates, however, have been associated with increased mortality rates and later adverse neurodevelopmental outcomes. (25)(26)(27) However, these are simply associations and do not demonstrate a cause-andeffect relationship between hyperglycemia and adverse outcomes. Therefore, it is not clear if such moderately high glucose concentrations cause brain injury or simply are a sign of severe underlying diseases that independently and by other mechanisms cause brain damage. Longer-term hyperglycemia has the potential for inducing various metabolic adaptations that result in insulin resistance and glucose intolerance. These conditions have been observed in both fetal and neonatal animal models. In the chronically catheterized fetal sheep, marked hyperglycemia results in peripheral insulin resistance and glucose intolerance. The marked and chronic hyperglycemia has been associated with decreased concentrations of tissue glucose transporters,

Complications of Hyperglycemia or Conditions Associated With Hyperglycemia

Table 2.

Increased morbidity and mortality Impaired immunity Increased infection Poor wound healing Loss of skeletal and cardiac muscle

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which regulate basal and insulin-mediated glucose uptake and utilization rates. Presumably, reduced transporter expression could reduce glucose uptake and utilization capacity. (28) Persistent, marked hyperglycemia in the fetal sheep also gradually suppresses both basal and glucose-stimulated fetal insulin secretion, perhaps a fetal form of glucose toxicity. (29) As a result of these changes, the fetuses become progressively less responsive to insulin and demonstrate reduced glucose tolerance and insulin sensitivity. More recent studies in neonatal piglets have shown that IV glucose infusion, administered as part of parenteral nutrition, can induce the same problems of glucose intolerance and insulin resistance. (30)(31)

Insulin Treatment
Most of the controversy surrounding treatment of hyperglycemia comes from the use of insulin to treat severe neonatal hyperglycemia. Risks and benets of insulin infusion for hyperglycemia have been reviewed. (1) The primary potential benet of IV insulin infusion is its rapid lowering of plasma glucose concentrations, rst by increasing peripheral glucose utilization and second by reducing hepatic insulin production. This treatment also reduces the hyperglycemia-produced hyperosmolarity as well as hyperkalemia. Insulin also may decrease amino acid release from protein breakdown, which decreases gluconeogenic substrates. There also is the potential for promotion of protein synthesis and net protein balance. (32) When administered with amino acid infusions, improved protein balance might be a valuable side benet to the use of insulin to lower very high glucose concentrations. There is little evidence in neonates, however, that other morbidities or even mortality are affected by insulin infusions to lower very high glucose concentrations. The adult literature, particularly from studies of surgical patients and those who have other forms of severe illness, is highly charged with claims for improved outcomes from the use of insulin. Several studies even have indicated that intensive insulin therapy might lower the risk of death among surgical patients in intensive care units, although lowering blood glucose concentrations with insulin does not affect mortality in all critically ill patients. As summarized recently by Van den Berghe and associates, (33) there were important methodologic differences among the studies showing variable outcomes, including different target ranges for blood glucose concentrations in control and intervention groups, differences in the duration of hyperglycemia before the start of the intervention, the degree of success in reaching the target level while avoiding hypoglycemia, different routes for insulin administration and types of infusion pumps, different sampling sites, different accuracies of glucose meters, and different nutritional strategies and varying levels of expertise. These researchers concluded that such differences do not permit condent recommendations for a single optimal glucose concentration target in different intensive care unit settings. Respecting the primum non nocere principle, they recommended a simple overall fallback position of maintaining blood glucose concentrations as close to normal as possible without evoking unacceptably rapid and large uctuations in circulating glucose concentrations or persistent hypoglycemia or hypokalemia. There is even less information about the potential
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Treatment of Hyperglycemia
Despite the reasonably well-understood risk factors and mechanisms for how neonatal hyperglycemia develops, it remains extremely common. No clear consensus has been reached on if, when, and how to treat neonatal hyperglycemia. This is due to the previously noted reasons: acute and severe complications are rare in most cases, but associations between high glucose concentrations and poor outcomes have been suggested. (25) (26)(27) As a result, treatment options are highly variable. Little research data indicate whether one approach is better than another or makes a difference to long-term outcomes. It is possible that hyperglycemia is an appropriate physiologic response to maintain cellular glucose uptake in certain situations, especially by the brain, which depends, in part, on glucose delivery to maintain glucose uptake and utilization. Currently, there is little rational research data in preterm or term newborns to indicate whether hyperglycemia causes harm by itself and no evidence (short of severe hyperglycemia producing coma and other neurologic injuries) that treatment makes any difference. The most obvious approach to reducing the incidence and severity of hyperglycemia in newborns is to normalize physiology with good medical care and reduce stress. Obviously, this is easier said than done. A more direct and immediate approach is to reduce catecholamine infusions. Another option is to reduce lipid infusion rates, although this approach has not been shown to have a large or immediate effect. The most common approach to reducing hyperglycemia is simply to reduce all IV glucose infusion rates, including minimization of dextrose concentrations in medication infusions.

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risks and benets of insulin infusion to treat severe hyperglycemia in newborns. Bottino and associates (34) found only one study with sufcient strength and quality of study design to address this issue for their Cochrane Library review of neonatal hyperglycemia and insulin treatment. In this study, insulin infusion was compared with reduced glucose infusion rates to treat hyperglycemia, dened as more than 10 mmol/L (180 mg/dL), in preterm infants. There were no differences between these two approaches in terms of outcomes for death, sepsis, retinopathy of prematurity, necrotizing enterocolitis, intracranial hemorrhage, chronic lung disease, neonatal intensive care unit days, or growth. A more recent study in the United Kingdom, Belgium, The Netherlands, and Spain conrmed the lack of reduction in mortality or morbidity between groups of infants treated with early insulin therapy versus others treated conventionally. (35) In fact, in the intent-to-treat analysis, mortality at 28 days of age was higher in the early insulin group. The study did show lower glucose concentrations among the study group of preterm infants treated with insulin but also more frequently measured values consistent with their denition of neonatal hypoglycemia. The insulin-treated infants also had greater rates of water infusion and greater total amounts of carbohydrate intake. Other studies of insulin treatment of hyperglycemia have noted lower pH values, increased lactate concentrations, tachypnea, and, if used for long enough periods with high rates of glucose and lipid, fatty inltration of the liver and heart. It also is important to note that insulin does not promote glucose uptake or utilization by the brain and does not enhance neuronal growth or dendritic development. Furthermore, although insulin is an important positive regulator of growth, the metabolic effects of insulin result in negative feedback mechanisms that limit its ability to promote protein synthesis, net protein balance, and growth. Absence of insulin limits growth rate (but does not inhibit all growth), which can be restored if insulin is replaced. There is no evidence for increased growth of lean body mass (muscle, bone, cell structural elements, number of cells) when insulin is provided in excess of what produces pharmacologic concentrations, either in normal fetuses or those without insulin. (36)(37) There even is concern that use of insulin to maintain tight control of plasma glucose concentrations might have adverse effects on growth. In one study, preterm infants born at less than 30 weeks gestation or weighing less than 1,500 g who developed hyperglycemia were randomized to tight glycemic control (72.1 to 108.1 mg/dL [4 to 6 mmol/L] using insulin infusion) or standard practice (restrictive guidelines for
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starting insulin only above blood glucose concentrations of 144.1 to 180.2 mg/dL [8 to 10 mmol/L]). (38) Infants in the tight glycemic control group had decreased lower leg growth rate (P 0.05), lower plasma insulin concentrations 2 weeks after randomization (10 versus 8 mcU/mL, P 0.05), more episodes of hypoglycemia (25/43 versus 13/45, P 0.05), and longer time to reach full enteral feedings (11 versus 8 days, P 0.05).

Improved Nutrition
Higher parenteral amino acid infusion rates in young, preterm infants are associated with increased insulin concentrations. (32) Perhaps the amino acids stimulate insulin secretion, which is possibly a better approach than insulin infusions to prevent neonatal hyperglycemia. Moreover, higher plasma amino acid concentrations from IV amino acid infusions can counteract the catabolic conditions often associated with neonatal hyperglycemia. Reynolds and colleagues (39) found that increasing IV amino acid intake from approximately 1.0 to 2.5 g/kg per day in critically ill newborns after major thoracic or abdominal surgery produced a directly related increase in protein balance despite the obvious stress that the infants were experiencing. In fact, one of the most consistent observations in clinical nutritional research in preterm infants, even those born extremely preterm and of extremely low birthweight, is the production of positive protein balance with increased amino acid and protein nutrition. (39)

Summary and Recommendations (Table 4)

Evidence is lacking for improved outcomes in most neonates who have hyperglycemia and are treated with continuous insulin. Combined with the contradictory results of studies in critically ill adults who have hyperglycemia, there seems little advantage to aggressive treatment of neonatal hyperglycemia with insulin in most patients who have mild-to-moderate, short-term hyperglycemia. Good physiologic control and improved enteral and parenteral nutrition (particularly with increased amino acid nutrition) are the foundations of reducing the incidence and associated complications of hyperglycemia. Reducing stress can reduce the catabolic hormones that promote hyperglycemia. Enhancing amino acid intake can directly counter catabolic conditions as well as promote endogenous insulin and insulin-like growth factor-1 secretion and their anabolic effects. IV glucose infusion rates should be limited to just the rate that produces normal glucose concentrations. Lipid infusions should be limited during hyperglycemia. Enteral feeding should be used and advanced as promptly but as safely as

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5. Dweck HS, Cassady G. Glucose intolerance in infants of very

Summary of Recommendations for Prevention and Management of Neonatal Hyperglycemia

Table 4.

Improved physiologic control Early and increased parenteral nutrition with amino acids Early initiation of enteral feedings Limited intravenous glucose infusion rates during hyperglycemia to what is required for achieving normal glucose concentrations Limited intravenous lipid infusions during hyperglycemia Reservation of insulin therapy only for severe hyperglycemia with associated clinical signs and complications.

possible. Insulin therapy should be reserved as much as possible for severe hyperglycemia, when marked hyperglycemia with glucose concentrations greater than 500 mg/dL (27.8 mmol/L) and associated with depressed central nervous system activity occurs. There is no evidence yet to support the use of insulin to produce tight glucose control in newborns. There also is no evidence yet that prolonged hyperglycemia in neonates leads to the possible adverse morbidity noted in critically ill adults who have hyperglycemia.

American Board of Pediatrics Neonatal-Perinatal Medicine Content Specications

Know the causes, including genetic and autogenic disorders, of neonatal hyperglycemia, including transient diabetes mellitus. Know the clinical and laboratory features and approach to therapy of neonatal hyperglycemia, including transient diabetes mellitus.

References
1. Sunehag AL, Haymond MW. Glucose extremes in newborn
infants. Clin Perinatol. 2002;29:245260

2. Alsweiler JM, Kuschel CA, Bloomeld FH. Survey of the management of neonatal hyperglycaemia in Australasia. J Paediatr Child Health. 2007;43:632 635 3. Beardsall K, Ogilvy-Stuart AL, Ahluwalia J, et al The continuous glucose monitoring sensor in neonatal intensive care. Arch Dis Child Fetal Neonatal Ed. 2005;90:F307F310 4. Iglesias PI, Thio LM, Pociello AN, et al. Continuous glucose monitoring in infants of very low birth weight. Neonatology. 2009; 95:217223

low birth weight. I. Incidence of hyperglycemia in infants of birth weights 1,100 grams or less. Pediatrics. 1974;53:189 195 6. Lilien LD, Roseneld RL, Baccaro MM, Pildes RS. Hyperglycemia in stressed small premature neonates. J Pediatr. 1979;94: 454 459 7. Louik C, Mitchell AA, Epstein MF, Shapiro S. Risk factors for neonatal hyperglycemia associated with 10% dextrose infusion. Am J Dis Child. 1985;139:783786 8. Pildes RS. Neonatal hyperglycemia. J Pediatr. 1986;109: 905907 9. Zarif M, Pildes RS, Vidyasagar D. Insulin and growth-hormone responses in neonatal hyperglycemia. Diabetes. 1976;25:428 433 10. Cowett RM, Oh W, Pollak A, Schwartz R, Stonestreet BS. Glucose disposal of low birth weight infants: steady state hyperglycemia produced by constant intravenous glucose infusion. Pediatrics. 1979;63:389 396 11. Aldoretta PW, Carver TD, Hay WW Jr. Maturation of glucosestimulated insulin secretion in fetal sheep. Biol Neonate. 1998;73: 375386 12. Bazaes RA, Salazar TE, Pittaluga E, et al. Glucose and lipid metabolism in small for gestational age infants at 48 hours of age. Pediatrics. 2003;111:804 809 13. Limesand SW, Rozance PJ, Zerbe GO, et al. Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction. Endocrinology. 2006;147:1488 1497 14. Mitanchez-Mokhtari D, Lahlou N, Kieffer F, et al. Both relative insulin resistance and defective islet {beta}-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants. Pediatrics. 2004;113:537541 15. Setia S, Sridhar MG, Bhat V, et al. Insulin sensitivity and insulin secretion at birth in intrauterine growth retarded infants. Pathology. 2006;38:236 238 16. Fowden AL. Effects of adrenaline and amino acids on the release of insulin in the sheep fetus. J Endocrinol. 1980;87:113121 17. Leos RA, Anderson MJ, Chen X, et al. Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufciency and intrauterine growth restriction. Am J Physiol Endocrinol Metab. 2010;298:E770 E778 18. Savich RD, Finley SL, Ogata ES. Intravenous lipid and amino acids briskly increase plasma glucose concentrations in small premature infants. Am J Perinatol. 1988;5:201205 19. Sunehag AL. The role of parenteral lipids in supporting gluconeogenesis in very premature infants. Pediatr Res. 2003;54: 480 486 20. Sunehag A, Gustafsson J, Ewald U. Glycerol carbon contributes to hepatic glucose production during the rst eight hours in healthy term infants. Acta Paediatr. 1996;85:1339 1343 21. Sunehag A, Ewald U, Gustafsson J. Extremely preterm infants ( 28 weeks) are capable of gluconeogenesis from glycerol on their rst day of life. Pediatr Res. 1996;40:553557 22. Sunehag AL. Parenteral glycerol enhances gluconeogenesis in very premature infants. Pediatr Res. 2003;53:635 641 23. Sauer PJ, Carnielli VP, Sulkers EJ, van Goudoever JB. Substrate utilization during the rst weeks of life. Acta Paediatr Suppl. 1994;405:49 53 24. Thureen PJ, Phillips RE, Baron KA, et al. Direct measurement of the energy expenditure of physical activity in preterm infants. J Appl Physiol. 1998;85:223230 25. Alexandrou G, Skiold B, Karlen J, et al. Early hyperglycemia is
NeoReviews Vol.11 No.11 November 2010 e637

Downloaded from http://neoreviews.aappublications.org/ at Health Internetwork on April 19, 2012

endocrinology

neonatal hyperglycemia

a risk factor for death and white matter reduction in preterm infants. Pediatrics. 2010;125:e584 e591 26. Hays SP, Smith EO, Sunehag AL. Hyperglycemia is a risk factor for early death and morbidity in extremely low birth-weight infants. Pediatrics. 2006;118:18111818 27. Kao LS, Morris BH, Lally KP, et al. Hyperglycemia and morbidity and mortality in extremely low birth weight infants. J Perinatol. 2006;26:730 736 28. Das UG, Schroeder RE, Hay WW Jr, Devaskar SU. Timedependent and tissue-specic effects of circulating glucose on fetal ovine glucose transporters. Am J Physiol. 1999;276:R809 R817 29. Carver TD, Anderson SM, Aldoretta PA, et al. Glucose suppression of insulin secretion in chronically hyperglycemic fetal sheep. Pediatr Res. 1995;38:754 762 30. Horst DA, Sedenquist M, Stoll B, et al. Chronic parenteral nutrition reduces lean tissue growth and induces insulin resistance in neonatal piglets. E-PAS. 2006;59:4136.7 31. Stoll B, Puiman PJ, Burrin D. Continuous parenteral versus enteral nutrition induces glucose intolerance and hyperinsulinemia in neonatal piglets. E-PAS. 2008;63:3050.2 32. Thureen PJ, Melara D, Fennessey PV, Hay WW Jr. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res. 2003;53: 24 32

33. Van den Berghe G, Schetz M, Vlasselaers D, et al. Clinical

review: intensive insulin therapy in critically ill patients: NICESUGAR or Leuven blood glucose target? J Clin Endocrinol Metab. 2009;94:31633170 34. Bottino M, Cowett RM, Sinclair JC. Interventions for treatment of neonatal hyperglycemia in very low birth weight infants. Cochrane Database Syst Rev. 2009;1:CD007453 35. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med. 2008;359:18731884 36. Carson BS, Philipps AF, Simmons MA, et al. Effects of a sustained insulin infusion upon glucose uptake and oxygenation of the ovine fetus. Pediatr Res. 1980;14:147152 37. Fowden AL, Hughes P, Comline RS. The effects of insulin on the growth rate of the sheep fetus during late gestation. Q J Exp Physiol. 1989;74:703714 38. Alsweiler JM, Harding JE, Bloomeld FH. A randomised controlled trial of tight glycaemic control in hyperglycaemic very low birthweight preterm babies. 13th Annual Perinatal Society of Australia and New Zealand Proceedings. 2009:A30 39. Reynolds RM, Bass KD, Thureen PJ. Achieving positive protein balance in the immediate postoperative period in neonates undergoing abdominal surgery. J Pediatr. 2008;152:63 67

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NeoReviews Quiz
6. A 2-day-old neonate, who weighs 820 g at an estimated gestational age of 34 weeks, had a difcult delivery, and is receiving dopamine to maintain blood pressure, has a serum glucose concentration of 190 mg/dL (10.5 mmol/L). He is receiving an intravenous infusion of 10% dextrose solution at a rate of 80 mL/kg per day and an orogastric infusion of expressed human milk at a rate of 10 mL/kg per day. He is receiving mechanical ventilation and a fraction of inspired oxygen of 0.4. Of the following, the most likely cause of hyperglycemia in this infant is: A. B. C. D. E. Decreased insulin secretion. Decreased release of stress-related catecholamines. Increased exogenous glucose infusion. Increased gastric secretion of incretin. Increased pancreatic secretion of glucagon.

7. Neonatal hyperglycemia is associated with potential adverse effects. It is unclear, however, whether these adverse effects are related to hyperglycemia itself or to the underlying disease. Of the following, the most likely serious adverse effect of severe (glucose >500 mg/dL [27.8 mmol/L]) neonatal hyperglycemia is: A. B. C. D. E. Dilutional acidosis. Intracranial hemorrhage from hyperosmolarity. Sepsis from impaired immunity. Skin breakdown from impaired wound healing. Wasting from skeletal muscle loss.

8. A 2-day-old neonate, who weighs 640 g at an estimated gestational age of 24 weeks, has serum glucose concentrations ranging between 190 and 280 mg/dL (10.5 and 15.5 mmol/L). She is receiving an intravenous infusion of 10% dextrose and 1% amino acid at a rate of 160 mL/kg per day and an intravenous infusion of lipid at a rate of 0.5 g/kg per day. She is receiving mechanical ventilation and a fraction of inspired oxygen of 0.4. Of the following, the most common approach for correcting hyperglycemia in this infant is to: A. B. C. D. E. Decrease the amino acid infusion. Increase the lipid infusion. Limit the glucose infusion. Provide cardiac support with catecholamines. Start insulin treatment.

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Neonatal Hyperglycemia Paul J. Rozance and William W. Hay, Jr Neoreviews 2010;11;e632 DOI: 10.1542/neo.11-11-e632

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