Professional Documents
Culture Documents
Back
Neonatal hyperglycemia
Authors:
Ann R Stark, MD
Rebecca Simmons, MD
Section Editors:
Steven A Abrams, MD
Joseph I Wolfsdorf, MD, BCh
Deputy Editor:
Melanie S Kim, MD
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2021. | This topic last updated: Sep 29, 2021.
INTRODUCTION Glucose supply and metabolism are of central importance for growth and
normal brain development in the fetus and newborn. Disorders in glucose availability or utilization
can result in hypoglycemia or hyperglycemia.
The causes and management of neonatal hyperglycemia are reviewed here. Neonatal hypoglycemia
is discussed separately. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)
DEFINITION
Most neonatologists become concerned about hyperglycemia when plasma glucose concentration
(the standard laboratory test) exceeds 180 to 200 mg/dL (10 to 11.1 mmol/L). However, higher levels
of hyperglycemia are required to produce the hyperosmolality and osmotic diuresis that may be
clinically important. Plasma osmolality increases by 1 mosmol/L for each 18 mg/dL increase in
plasma glucose concentration. Thus, a rise in glucose concentration from 110 to 200 mg/dL (6.1 to
11.1 mmol/L) only increases osmolality by 5 mosmol/L, which is a relatively small change.
CAUSES In general, neonatal hyperglycemia is associated with a clinical condition, rather than a
specific disorder of glucose metabolism, and occurs in infants receiving intravenous (IV; parenteral)
glucose infusions. A rare cause of hyperglycemia is neonatal diabetes mellitus.
Reduction of glucose infusion rate — Interventions to reduce the blood glucose concentration are
initiated at values above 180 to 200 mg/dL (10 to 11.1 mmol/L). The first step in management is to
decrease the parenteral glucose infusion rate. Reducing the rate to 4 to 6 mg/kg per minute usually
lowers the blood glucose concentration. In most cases, this is accomplished by reducing the
concentration of the dextrose solution from 10 to 5 percent. If provided with parenteral nutrition
solution and lipid emulsion, infants can maintain normoglycemia with the reduced glucose supply by
gluconeogenesis from the metabolism of glycerol and amino acids [20].
However, reducing the glucose infusion rate is a short-term solution because it results in decreased
caloric intake and compromises growth. Glucose tolerance typically improves when enteral feedings
are established. (See "Nutritional composition of human milk and preterm formula for the premature
infant".)
Insulin therapy — Insulin improves glucose tolerance, allows provision of more calories, and
promotes growth in infants who remain hyperglycemic at reduced glucose infusion rates. The exact
indications for insulin therapy are not well defined. Most neonatologists, including the authors, would
begin an insulin infusion in infants with persistent hyperglycemia (>200 to 250 mg/dL [11.1 to 13.9
mmol/L]) despite reductions in glucose infusion rate, and in infants who fail to thrive because of
decreased glucose administration resulting in reduced caloric intake.
Small case series support the use of continuous insulin infusion to provide higher caloric input
thereby promoting growth by safely increasing glucose infusion rates [5,21]. In infants receiving
parenteral nutrition, improvement in glucose tolerance by continuous insulin infusion appears to be
comparable with and without the addition of lipid emulsion [22].
Routine early insulin therapy — The routine early use of insulin therapy in preterm infants has
been proposed to prevent catabolism, improve glucose control, and increase energy intake, which
might improve growth. However, early insulin therapy does not appear to improve growth and,
compared with standard care, may be associated with an increased risk of hypoglycemia and
mortality at 28 days of age.
This was illustrated in a multicenter, open-label trial of 389 very low birth weight (VLBW) infants (BW
<1500 g) who were randomly selected to receive either standard care for glycemic control or a
parenteral infusion of 20 percent dextrose with early insulin therapy (0.05 units/kg per hour) starting
within 24 hours of birth until seven days of age [23]. The following findings were noted:
●The early insulin group had lower mean glucose levels compared with the standard
care group (112 versus 121 mg/dL [6.2 versus 6.7 mmol/L]), were less likely to be
hyperglycemic (defined as serum glucose greater than 180 mg/dL [10 mmol/L]) for
more than 10 percent of the first week of life (21 versus 33 percent), were able to
receive greater amounts of glucose infusion (51 versus 43 kcal/kg per day), and had
less weight loss during the first week of life.
●More patients who received early insulin had episodes of hypoglycemia (29 versus
17 percent), which was defined as serum glucose levels less than 47 mg/dL (2.6
mmol/L) for more than one hour.
●There were no differences between the groups in the primary end point of mortality at
the expected date of delivery or in the secondary end points of sepsis, necrotizing
enterocolitis, retinopathy of prematurity, and growth parameters (ie, weight, length,
and head circumference) at 28 days of age. However, the early insulin group had a
higher mortality rate at 28 days of life.
This trial was ended early because of concerns of futility with regard to outcomes and concern for
potential harm from insulin therapy. Follow-up assessment is ongoing to determine whether the
increased incidence of hypoglycemia in the early insulin group had a detrimental effect on
neurodevelopmental outcomes. (See "Management and outcome of neonatal hypoglycemia",
section on 'Neurodevelopmental outcome'.)
Based upon these data, routine insulin therapy should not be used in VLBW infants prior to reducing
glucose infusion rates. Insulin should be used to treat hyperglycemia when reducing the glucose
infusion rate to approximately 6 mg/kg per minute is ineffective or not possible.
Risk of hypoglycemia — The blood glucose concentration should be monitored frequently during
insulin infusion, although the risk of hypoglycemia appears to be small [24,25]. This was
documented in a retrospective review of 34 extremely low birth weight (ELBW) infants (BW <1000 g)
who developed hyperglycemia and glucosuria while receiving parenteral nutrition and were treated
with insulin [24]. Before therapy, mean blood glucose concentration was 195 mg/dL (11.1 mmol/L)
while receiving glucose at a mean rate of 7.9 mg/kg per min. During insulin infusion, given for 1 to 58
days, blood glucose values of 25 to 40 mg/dL (1.4 to 2.2 mmol/L) were detected in fewer than 0.5
percent of samples (26 episodes of hypoglycemia in 7368 samples) and no values <25 mg/dL were
seen. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)
Dose and target glucose levels — In neonates who receive insulin therapy, regular insulin (100
units/mL) is used and is usually diluted in normal saline to a concentration of 0.1 units/mL. In some
centers, concentration of 0.5 units/mL is used. The solution should be changed every at least every
24 hours or based on the recommendations of the hospital pharmacy.
The initial step in management of a persistently elevated glucose level is administering a bolus
insulin infusion via a syringe pump over 15 minutes at a dose between 0.05 and 0.1 units/kg. The
blood glucose level is monitored every 30 to 60 minutes, and if it remains elevated, the insulin dose
is repeated as a bolus every four to six hours. If the glucose level remains elevated after three bolus
doses, a continuous infusion is suggested at an initial rate of between 0.01 and 0.05 units/kg per
hour and is adjusted in small increments up to a maximum rate of 0.1 units/kg per hour to maintain
glucose levels of 150 to 200 mg/dL (8.3 to 11 mmol/L). Tighter glycemic control aiming for glucose
values substantially below 150 mg/dL (8.3 mmol/L) increases the risk of hypoglycemia [26].
Monitoring — The blood glucose concentration should be monitored within 30 minutes to 1 hour of
the start of the infusion and after any change in the rate of glucose or insulin infusion. Glucose
concentration should be monitored hourly until stable, and then less frequently.
Titration and discontinuation — As glucose tolerance improves, the insulin infusion should be
tapered and discontinued to avoid hypoglycemia. In general, reductions in the insulin infusion rate
can be made more rapidly than can increases. In our centers, infusion rates are decreased in
increments of 0.01 to 0.05 units/kg per hour in response to glucose levels <150 mg/dL (8.33
mmol/L). Insulin infusion can be discontinued when the glucose level remains stable below 150
mg/dL (8.33 mmol/L) at the lowest infusion rate. The glucose level should continue to be monitored
closely for the next 12 to 24 hours.
Adherence of insulin to plastic tubing — Plastic tubing used for infusion should be primed with
insulin for at least 20 minutes before treatment because insulin nonspecifically binds to the tubing,
resulting in decreased availability to the patient. In one report, recovery of insulin from effluent of
primed polyvinyl chloride tubing at a flow rate of 0.2 mL/hour was greater at one, two, four, and eight
hours compared with unprimed tubing (42, 85, 91, and 95 versus 22, 38, 67, and 75 percent,
respectively) [27].
Amino acid and lipid infusion — Insulin infusion during euglycemia reduces proteolysis and
protein synthesis in preterm infants who are not also given amino acids [28]. This is in contrast to
adults and children, in whom insulin increases protein synthesis. As a result, we suggest amino acid
solution and lipid emulsion be administered to infants receiving glucose infusion to provide substrate
for gluconeogenesis, spare glucose utilization, and stimulate insulin release, and enteral feedings
are begun as soon as possible.
Although data are limited, a retrospective study demonstrated that nutritional changes resulting in
greater protein and less fat and carbohydrates intake resulted in a lower mean blood glucose
concentration and less frequent episodes of hyperglycemia, and no changes in the risk of
hypoglycemia [29].
Enteral feeds — Enteral feeds promote the gastric release of glucose-dependent insulinotropic
peptide (GIP) and GLP-1, incretin hormones that promote insulin secretion from the pancreas
[30,31]. Gastrointestinal incretin-mediated insulin release in response to orogastric administration of
a glucose load may occur when a threshold of glucose concentration has exceeded 105 mg/dL.
(See "Approach to enteral nutrition in the premature infant".)
Our approach — In our center, for all infants receiving intravenous glucose infusions, amino acid
solution and lipid emulsion are also provided as substrate for gluconeogenesis. Enteral feeding is
initiated as soon as possible in order to wean and discontinue parenteral nutrition. (See 'Enteral
feeds' above.)
Blood glucose monitoring is initiated for all patients receiving parenteral glucose. For infants with
stable glucose concentration, daily monitoring is adequate. For ELBW, stressed, or septic infants
who may not have a stable glucose concentration, or those receiving insulin infusion, more frequent
monitoring is performed.
●Medications are reviewed and, if possible, drugs associated with high glucose levels
are discontinued. These include glucocorticoids, phenytoin, and beta adrenergic
agents.
●Patients are evaluated for possible sepsis. If clinically appropriate, blood cultures are
obtained and empiric antibiotics are administered. (See "Clinical features, evaluation,
and diagnosis of sepsis in term and late preterm infants" and "Clinical features and
diagnosis of bacterial sepsis in preterm infants <34 weeks gestation".)
●For patients who are receiving intravenous glucose infusions:
•In infants with blood glucose concentration greater than 180 to 200 mg/dL (10 to
11.1 mmol/L), the glucose infusion rate is decreased by reducing the
concentration of infused dextrose4 to 6 mg/kg per minute, as long as the
dextrose concentration does not go below 5 percent.
•Insulin therapy is initiated in neonates with persistent hyperglycemia (blood
glucose >200 to 250 mg/dL [11.1 to 13.9 mmol/L]) despite reductions in glucose
infusion rate, and in infants who fail to thrive because of decreased glucose
infusion rates resulting in reduced caloric intake. Therapy is initially administered
as a bolus of insulin administered via a syringe pump over 15 minutes as a dose
between 0.05 and 0.1 units/kg. With the initiation of insulin, blood glucose level is
monitored every 30 to 60 minutes until stable. (See 'Dose and target glucose
levels' above.)
Continuous insulin infusion is used in infants with persistent hyperglycemia
(blood glucose >200 to 250 mg/dL [11.1 to 13.9 mmol/L]) despite reductions in
glucose infusion rate and after administering three insulin boluses. Infusion
begins at a rate between 0.01 and 0.05 units/kg per hour, and is adjusted in
small increments up to a maximum rate of 0.1 units/kg per hour to maintain blood
glucose levels between 150 and 200 mg/dL. In the very preterm ill neonate,
insulin may be given safely as long as the glucose concentration is monitored
frequently because of the relatively wide heterogeneous response that occurs
with IV administration. (See 'Insulin therapy' above.)
●Infusion insulin rates are decreased in increments of 0.01 to 0.05 units/kg per hour in
response to glucose levels <150 mg/dL (8.33 mmol/L). Insulin infusion can be
discontinued when the glucose level remains stable below 150 mg/dL (8.33 mmol/L) at
the lowest infusion rate. The glucose level should continue to be monitored closely for
the next 12 to 24 hours. (See 'Titration and discontinuation' above.)
Further research, including clinical trials to clarify the role of insulin, is needed to provide a better
understanding of the consequences of hyperglycemia and determine which infants require
intervention.
ACKNOWLEDGMENT The editorial staff at UpToDate would like to acknowledge See Wai
Chan, MD, MPH, who contributed to an earlier version of this topic review.
REFERENCES
1. Louik C, Mitchell AA, Epstein MF, Shapiro S. Risk factors for neonatal hyperglycemia
associated with 10% dextrose infusion. Am J Dis Child 1985; 139:783.
2. Wilkins BH. Renal function in sick very low birthweight infants: 4. Glucose excretion. Arch Dis
Child 1992; 67:1162.
3. Cowett RM, Oh W, Schwartz R. Persistent glucose production during glucose infusion in the
neonate. J Clin Invest 1983; 71:467.
4. Kalhan SC, Devaskar SU. Disorders of carbohydrate metabolism. In: Neonatal-Perinatal
Medicine: Diseases of the Fetus and Infant, 9th ed, Martin RJ, Fanaroff AA, Walsh MC
(Eds), Elsevier Mosby, St. Louis 2011. Vol 2, p.1497.
5. Meetze W, Bowsher R, Compton J, Moorehead H. Hyperglycemia in extremely- low-birth-
weight infants. Biol Neonate 1998; 74:214.
6. 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; 113:537.
7. Sunehag A, Gustafsson J, Ewald U. Very immature infants (< or = 30 Wk) respond to
glucose infusion with incomplete suppression of glucose production. Pediatr Res 1994;
36:550.
8. Lilien LD, Rosenfield RL, Baccaro MM, Pildes RS. Hyperglycemia in stressed small
premature neonates. J Pediatr 1979; 94:454.
9. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Prevalence and determinants of
hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study. J
Pediatr 2010; 157:715.
10. Alexandrou G, Skiöld B, Karlén J, et al. Early hyperglycemia is a risk factor for death and
white matter reduction in preterm infants. Pediatrics 2010; 125:e584.
11. Kao LS, Morris BH, Lally KP, et al. Hyperglycemia and morbidity and mortality in extremely
low birth weight infants. J Perinatol 2006; 26:730.
12. Blanco CL, Baillargeon JG, Morrison RL, Gong AK. Hyperglycemia in extremely low birth
weight infants in a predominantly Hispanic population and related morbidities. J Perinatol
2006; 26:737.
13. Farrag HM, Cowett RM. Glucose homeostasis in the micropremie. Clin Perinatol 2000;
27:1.
14. White RH, Frayn KN, Little RA, et al. Hormonal and metabolic responses to glucose
infusion in sepsis studied by the hyperglycemic glucose clamp technique. JPEN J Parenter
Enteral Nutr 1987; 11:345.
15. Manzoni P, Castagnola E, Mostert M, et al. Hyperglycaemia as a possible marker of
invasive fungal infection in preterm neonates. Acta Paediatr 2006; 95:486.
16. Doyle LW, Cheong JL, Ehrenkranz RA, Halliday HL. Early (< 8 days) systemic postnatal
corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants. Cochrane
Database Syst Rev 2017; 10:CD001146.
17. Srinivasan G, Singh J, Cattamanchi G, et al. Plasma glucose changes in preterm infants
during oral theophylline therapy. J Pediatr 1983; 103:473.
18. al-Rubeaan K, Ryan EA. Phenytoin-induced insulin insensitivity. Diabet Med 1991; 8:968.
19. Rozance PJ and. Neonatal hyperglycemia. NeoReviews 2010; 11:e632.
20. Sunehag AL, Haymond MW, Schanler RJ, et al. Gluconeogenesis in very low birth weight
infants receiving total parenteral nutrition. Diabetes 1999; 48:791.
21. Collins JW Jr, Hoppe M, Brown K, et al. A controlled trial of insulin infusion and parenteral
nutrition in extremely low birth weight infants with glucose intolerance. J Pediatr 1991;
118:921.
22. Kanarek KS, Santeiro ML, Malone JI. Continuous infusion of insulin in hyperglycemic low-
birth weight infants receiving parenteral nutrition with and without lipid emulsion. JPEN J
Parenter Enteral Nutr 1991; 15:417.
23. Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. Early insulin therapy in very-low-
birth-weight infants. N Engl J Med 2008; 359:1873.
24. Binder ND, Raschko PK, Benda GI, Reynolds JW. Insulin infusion with parenteral nutrition
in extremely low birth weight infants with hyperglycemia. J Pediatr 1989; 114:273.
25. Vaucher YE, Walson PD, Morrow G 3rd. Continuous insulin infusion in hyperglycemic, very
low birth weight infants. J Pediatr Gastroenterol Nutr 1982; 1:211.
26. Alsweiler JM, Harding JE, Bloomfield FH. Tight glycemic control with insulin in
hyperglycemic preterm babies: a randomized controlled trial. Pediatrics 2012; 129:639.
27. Fuloria M, Friedberg MA, DuRant RH, Aschner JL. Effect of flow rate and insulin priming on
the recovery of insulin from microbore infusion tubing. Pediatrics 1998; 102:1401.
28. Poindexter BB, Karn CA, Denne SC. Exogenous insulin reduces proteolysis and protein
synthesis in extremely low birth weight infants. J Pediatr 1998; 132:948.
29. Tottman AC, Bloomfield FH, Cormack BE, et al. Relationships Between Early Nutrition and
Blood Glucose Concentrations in Very Preterm Infants. J Pediatr Gastroenterol Nutr 2018;
66:960.
30. Shanahan KH, Yu X, Miller LG, et al. Early Serum Gut Hormone Concentrations Associated
With Time to Full Enteral Feedings in Preterm Infants. J Pediatr Gastroenterol Nutr 2018;
67:97.
31. Lucas A, Bloom SR, Aynsley-Green A. Gut hormones and 'minimal enteral feeding'. Acta
Paediatr Scand 1986; 75:719.
32. Hays SP, Smith EO, Sunehag AL. Hyperglycemia is a risk factor for early death and
morbidity in extremely low birth-weight infants. Pediatrics 2006; 118:1811.
33. Stensvold HJ, Strommen K, Lang AM, et al. Early Enhanced Parenteral Nutrition,
Hyperglycemia, and Death Among Extremely Low-Birth-Weight Infants. JAMA Pediatr
2015; 169:1003.
34. Auerbach A, Eventov-Friedman S, Arad I, et al. Long duration of hyperglycemia in the first
96 hours of life is associated with severe intraventricular hemorrhage in preterm infants. J
Pediatr 2013; 163:388.
35. Zamir I, Tornevi A, Abrahamsson T, et al. Hyperglycemia in Extremely Preterm Infants-
Insulin Treatment, Mortality and Nutrient Intakes. J Pediatr 2018; 200:104.
36. Yoo HS, Ahn SY, Lee MS, et al. Permissive hyperglycemia in extremely low birth weight
infants. J Korean Med Sci 2013; 28:450.
37. Zamir I, Stoltz Sjöström E, Ahlsson F, et al. Neonatal hyperglycaemia is associated with
worse neurodevelopmental outcomes in extremely preterm infants. Arch Dis Child Fetal
Neonatal Ed 2021; 106:460.
38. Gonzalez Villamizar JD, Haapala JL, Scheurer JM, et al. Relationships between Early
Nutrition, Illness, and Later Outcomes among Infants Born Preterm with Hyperglycemia. J
Pediatr 2020; 223:29.
39. Tottman AC, Alsweiler JM, Bloomfield FH, et al. Long-Term Outcomes of Hyperglycemic
Preterm Infants Randomized to Tight Glycemic Control. J Pediatr 2018; 193:68.
Topic 4981 Version 32.0
Close
© 2021 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Language
Subscription and License Agreement
Policies
Support Tag
Contact Us
About Us
UpToDate News
Mobile Access
Help & Training
Demos
Wolters Kluwer Health
Emmi®
Facts & Comparisons®
Lexicomp®
Medi-Span®