59: Hyperglycemia

The nurse reports an infant has a blood glucose level of 240 mg/dL. The incidence of hyperglycemia is higher in preterm than term infants (60–80% in extremely low birthweight [ELBW] infants). The definition and treatment of hyperglycemia is controversial. Following are some of the definitions used:

1. Whole blood glucose >120–125 mg/dL or a plasma glucose >145–150 mg/dL regardless of gestational or postnatal age or weight

2. Whole blood glucose >125 mg/dL in term and >150 mg/dL in preterm

3. Whole blood glucose >215 mg/dL (operational definition per Edmund Hey)

1. What is the serum glucose value on laboratory testing? Bedside glucose testing using reagent strips is widely used for screening. It is best to confirm a serum glucose level from the laboratory before initiating treatment. Whole blood glucose measurements are 10–15% lower than plasma glucose.

2. Is glucose being spilled in the urine (glucosuria/glycosuria)? Glucosuria (glycosuria) is not reliable for hyperglycemia since it can occur at normal glucose blood levels. Mild hyperglycemia can also be associated with mild or no glucosuria. A trace amount of glucose in the urine is accepted as normal. If the urinary glucose level is +1, +2, or greater, the renal threshold has been reached with an increased chance of osmotic diuresis. Some institutions accept a urinary glucose level of +1 without treating the patient (controversial). Some authors suggest that the presence of >1+ glucosuria suggests osmolar changes and should be treated. Note: Each 18-mg/dL rise in blood glucose causes an increase in serum osmolarity of 1 mOsm/L.

3. How much glucose is the patient receiving? High glucose intake is a common cause of hyperglycemia in a preterm infant. Levels >10–12 mg/kg/min may result in hyperglycemia, and hyperglycemia may occur at lower levels if the infant is stressed. Normal initial maintenance glucose therapy in infants not being fed orally is 6–7 mg/kg/min on day 1 to 8–9 mg/kg/min on days 2 to 7. ELBW infants should be started at 4–6 mg/kg/min (see Chapter 12).

4. Are there signs of stress? Stressful situations like surgery may cause hyperglycemia by inducing a stress response (catecholamine mediated).

5. Does the infant have necrotizing enterocolitis (NEC) or sepsis? When an infant who has had normal glucose levels develops hyperglycemia and there is no change in IV fluids, or if an infant who is being fed only enterally suddenly develops hyperglycemia, suspect either sepsis or NEC. Hyperglycemia is seen more frequently in fungal infections than in bacterial infections. In Candida sepsis, infants may have a high blood sugar for 2–3 days before any other clinical signs appear.

6. What is the birthweight of the infant? Low birthweight is the most significant risk factor for hyperglycemia at any gestational age. The incidence is ∽2% in infants >2000 g, 45% in infants <1000 g, and 80% in infants <750 g.

7. Does the infant have any of the high-risk factors for hyperglycemia? Risk factors include gestational age <37 weeks, postnatal age <72 hours, weight <2500 g (lower birthweight), hypoxia, infection, use of ionotrophs, lipid infusions, high glucose infusion rate, respiratory distress syndrome (RDS), and sepsis. These infants should have frequent monitoring of their blood sugars.

8. What medications is the infant on? Steroids (most common), vasoactive drugs, and methylxanthines can cause hyperglycemia.

Hyperglycemia can cause hyperosmolarity, osmotic diuresis, and subsequent dehydration. Hyperglycemia is very common in ELBW and premature infants and is associated with an increase in mortality, white matter reduction on the magnetic resonance image (MRI) of the brain, intracranial hemorrhage, stage II/III NEC, risk of sepsis (if hyperglycemia occurs in the first few days after birth), retinopathy of prematurity (ROP) in ELBW infants, and developmental delay. Etiologies include excess administration or production, inadequate insulin secretion or insulin resistance, glucose intolerance, and defective glucoregulatory hormone control.

1. Factitious hyperglycemia

   1. Blood drawn from an IV line containing glucose or a bolus was given when flushing a line.

   2. False bedside hyperglycemia from a glucose meter. Some glucose meters will overestimate the serum glucose in an infant with galactosemia because of the lack of specificity of the enzyme used by the assay. Always confirm with a serum sample if glucose meter is high.

2. True hyperglycemia

   1. Excess glucose administration has a major role in hyperglycemia. Giving infants more glucose than what they can handle needs to be evaluated first. Incorrect calculation of glucose levels or errors in the formulation of IV fluids may cause hyperglycemia.

   2. Inability to metabolize glucose may occur with prematurity or secondary to sepsis or stress. Most commonly, a tiny infant on total parenteral nutrition becomes hyperglycemic because of glucose intolerance.

   3. Impaired glucose homeostasis

      1. Extremely low birthweight infants (<1000 g). These infants have greater fluid requirements because of their immature renal function and increased insensible water loss. This often leads to a high volume of fluid and administering too much glucose. They also may have insulin resistance, an immature insulin response, and are unable to stop gluconeogenesis when IV glucose is given.

      2. Preterm infants/small for gestational age (SGA) infants. Preterm infants receiving a glucose challenge show variable increases in insulin levels consistent with insulin resistance. This resistance may be related to immaturity or downregulation of peripheral receptors. Transient hyperglycemia can also be seen in SGA infants from impaired glucose homeostasis.

   4. Sepsis can cause hyperglycemia. Suspect sepsis in a neonate who had normal glucose levels with no change in the rate or amount of IV glucose. The etiologies can include the stress response, a reduction in the peripheral utilization of glucose, or a decrease in release of insulin. Hyperglycemia is more frequent in fungal than bacterial sepsis in the neonate. Hyperglycemia may be the first sign in neonatal sepsis; in Candida sepsis it can appear 2 to 3 days before other signs.

   5. Hyperosmolar formula. Ask how the formula was made. An inappropriate dilution can lead to a hyperosmolar formula, which in turn can cause transient neonatal glucose intolerance. Severe dehydration from gastroenteritis can lead to hypernatremia and hyperglycemia.

   6. Lipid infusion. Infants who receive lipid infusion even with low rates of glucose administration may develop hyperglycemia. Lipids are emulsified in a Dextran solution. The lipid component may also cause a glycemic response and a decrease in peripheral glucose utilization, and may inhibit insulin's effect. One study found that giving lipid infusion increased plasma glucose concentrations by 24% over baseline values.

   7. Stress. Pain, painful procedures (venipuncture, vascular cutdowns, and others), surgical procedures (during surgery and postoperative), NEC, acute intracerebral bleeding, hypoxia, catecholamine infusions, respiratory distress, and others can all cause hyperglycemia secondary to increased cortisol.

   8. Hypoxia can cause increased glucose production.

   9. Medications such as maternal use of diazoxide can cause hyperglycemia in the infant. Drugs used in infants that have been associated with hyperglycemia include caffeine, theophylline (slight increase), steroids (common), vasoactive drugs, and phenytoin. Prostaglandin E₁ has been associated with hyperglycemia in a case report.

   10. Neonatal diabetes mellitus. It is a rare cause of diabetes and occurs when there is persistent hyperglycemia that lasts more than 2 weeks and requires insulin therapy. Neonatal diabetes occurs in infants <6 months old; it is not an autoimmune disease and is most commonly caused by genetic defects. Molecular analysis of chromosome 6 anomalies and the KCNJ11 and ABCC8 genes can provide a way of differentiating transient from permanent neonatal diabetes. Infants with neonatal diabetes mellitus can have metabolic acidosis, ketosis, and glycosuria. There are 2 types:

       1. Transient neonatal diabetes mellitus (TNDM)(50–60% of cases). A developmental disorder of the production of insulin that resolves. It is primarily a genetic disorder (chromosome 6q24 anomalies and KATP channel defects). Most infants are SGA or have intrauterine growth restriction (IUGR); they present from 2 days to 6 weeks of age with hyperglycemia and require insulin therapy. It persists for more than 2 weeks and usually resolves by 3–4 months. Common findings are hyperglycemia, dehydration, glycosuria, polyuria, progressive wasting, hypoinsulinism, ketosis, metabolic acidosis and absent ketonuria, and normal or transiently low C-peptide levels in urine and serum. There is a positive family history in ∽33% of cases. About half of these cases go on to develop insulin-dependent diabetes in adolescence or in adulthood.

       2. Permanent neonatal diabetes mellitus (PND or PNDM). (Less common than TNDM.) It develops in the neonatal period and does not go into remission. Genetic mutations are common (KCNJ11, ABCC8, and INS genes). It is not associated with IUGR.

       3. Insulin-dependent (type 1) diabetes mellitus. An autoimmune disease that occurs in children and adolescents.

   11. Idiopathic. No identifiable cause is found; a diagnosis of exclusion.

1. Physical examination and history. Is the infant premature, SGA, or IUGR? Determine if there is a family history of diabetes and ask about maternal and infant medications. Infants with hyperglycemia usually have no obvious signs. Look for dehydration, weight loss, and fever. Evaluate for subtle signs of sepsis (eg, temperature instability, changes in peripheral perfusion) or changes in gastric aspirates if the infant is feeding. Look for signs of NEC.

2. Laboratory studies

   1. Initial studies

      1. Serum glucose level. Confirm any rapid bedside paper-strip test result with a serum glucose level. It is advisable to repeat serum blood glucose before treating.

      2. Urine dipstick testing for glucose. High levels are a warning sign for osmotic diuresis.

      3. Complete blood count (CBC) with differential. A screening test for sepsis.

      4. Blood, urine, and spinal cultures. For sepsis workup if indicated.

      5. Serum electrolytes. Hyperglycemia may cause osmotic diuresis, which may lead to electrolyte losses and dehydration. Monitor serum electrolyte levels in hyperglycemic patients.

      6. Arterial blood gas. If concerned about hypoxia. Metabolic acidosis can be seen in sepsis and neonatal diabetes.

   2. Further studies

      1. Serum ketones can be positive in neonatal diabetes mellitus. Ketonuria can be absent or mild.

      2. Serum insulin level is low to normal in transient neonatal diabetes mellitus and normal to high in sepsis.

      3. Serum or urine C-peptide levels are low in transient neonatal diabetes.

      4. Molecular analysis of chromosome 6q24 anomalies and the KCNJ11 and ABCC8 genes will help to differentiate transient from permanent neonatal diabetes mellitus.

      5. Genetic testing can identify which types of permanent neonatal diabetes will respond to oral sulfonylurea therapy and which will require insulin.

3. Imaging and other studies. None are usually required; however, a chest radiograph may be useful in the evaluation of respiratory distress and sepsis and an abdominal film for NEC. Head ultrasound is recommended in premature infants to rule out a bleed.

The standard treatments of hyperglycemia are observation only or decrease the amount of glucose given or give insulin or a combination of glucose restriction and insulin. The most immediate risk is osmotic diuresis due to the glucose load. While treating hyperglycemia, maintain adequate nutrition for optimal postnatal growth because this relates to morbidity. Cochrane review states that large randomized trials are necessary to determine whether and how hyperglycemia should be treated. There was no evidence that treating hyperglycemia in very low birthweight (VLBW) infants would decrease mortality or morbidity rates. Recommended treatment is conservative since most cases are transient.

1. Initial management. Rule out factitious hyperglycemia. Make sure the infant is not receiving too much glucose. Try decreasing the amount of glucose. Treat any underlying causes of hyperglycemia (sepsis, hypoxia, pain, respiratory distress, stopping medications, checking formula dilution, and others).

2. Excess glucose administration

   1. Positive urinary glucose level. The presence of ≥1+ glucosuria may increase the risk of osmolar changes. Decrease the concentration of dextrose in IV fluids or reduce the infusion rate gradually. The rate can be safely decreased by 1–2 mg/kg/min every 2–4 hours. Most infants who are not feeding initially require 5–7 mg/kg/min of glucose to maintain normal glucose levels. Monitor with bedside glucose testing every 4–6 hours, and check for glucose in the urine with each void.

   2. Negative urinary glucose level. If glucose is being given to increase the caloric intake, it is acceptable to have a higher serum glucose level as long as glucose is not being spilled in the urine. Monitor with bedside glucose testing every 4–6 hours, and check for glucose in the urine with each void.

3. Inability to metabolize glucose. Sepsis should always be considered in an infant with hyperglycemia. If the CBC is suspicious or there are clinical signs of sepsis, it is acceptable to treat the infant for 3 days with antibiotics and stop if cultures are negative. Ampicillin and an aminoglycoside are usually given initially (for doses, see Chapter 148). Treatment of infants unable to metabolize glucose for any reason is described next.

   1. Decrease the concentration of glucose or the rate of infusion until a normal serum glucose level is present. Do not use a solution that has a dextrose concentration of <4.7%. Such a solution is hypo-osmolar and could cause hemolysis, with resulting hyperkalemia.

   2. Feed as early if possible. Either with hyperalimentation or enterally; both are associated with a decreased incidence of hyperglycemia. Even minimal enteral feeds induce insulin secretion. If the clinical situation is severe, feeding may not be possible.

   3. Insulin. If hyperglycemia persists or if an osmotic diuresis occurs, insulin may be necessary. Levels vary widely on recommendations, but many will treat the infant with insulin if the blood glucose levels are at a level from 180 to 250 mg/dL (some recommend >300 mg/dL). Guidelines are institutional dependent and controversial. Insulin administration has been used in premature infants with success and has allowed more energy intake, promotes glucose tolerance, and promotes weight gain in these infants. Mortality (higher incidence of behavioral and neurologic problems at age 2) was higher in very preterm infants with hyperglycemia treated with insulin during the neonatal period. Early insulin therapy offers little clinical benefit in VLBW infants. Cochrane review does not support the routine use of insulin to prevent hyperglycemia in VLBW infants. Insulin therapy carries a risk of hypoglycemia. Several regimens are available for insulin dosing:

      1. Bolus infusion. Insulin 0.05–0.1 U/kg/dose over 15–20 minutes every 4–6 hours PRN. Monitor glucose every 30 to 60 minutes. Consider infusion if bolus does not work after 2 to 3 doses.

      2. Continuous infusion (most common and preferred method). Insulin loading dose of 0.05–0.1 U/kg/dose IV over 15–20 minutes, then maintenance 0.01–0.1 U/kg/h continuous IV infusion. Adding albumin to the bag to prevent insulin from adhering to the plastic tubing is now considered unnecessary. By flushing the tubing with an adequate amount (>25 mL) of the insulin-containing solution, all sites in the tubing will be saturated satisfactorily before beginning the infusion. Potassium should be added to the solution to limit hypokalemia. Bedside glucose testing must be performed every 30–60 minutes until the glucose is stable.

      3. Insulin subcutaneously. 0.1–0.2 U/kg/dose every 6–12 hours. Continuous IV insulin is preferred. Bedside glucose testing must be performed every 60 minutes until the glucose level is stable.

      4. Early insulin therapy to prevent hyperglycemia. Not recommended.

      5. Amino acid and lipid administration. Provides a substrate for gluconeogenesis and helps stimulate insulin release in infants receiving glucose.

      6. Potassium and glucose levels need to be monitored when giving insulin therapy. Insulin can cause hypokalemia and hypoglycemia.

4. Transient or permanent neonatal diabetes mellitus

   1. Give IV or oral fluids and monitor the urine output, blood pH, and serum electrolyte levels.

   2. Give insulin either by constant infusion or subcutaneously (see Section V.C.3). Monitor glucose levels with bedside testing every 4–6 hours. This disease usually resolves in days to months.

   3. Continuous subcutaneous insulin infusion (CSII) is used with an insulin pump and has been used in neonates with diabetes with less variability in glucose. Guidelines are lacking because of few cases where it has been used.

   4. Oral sulfonylurea therapy may be a useful treatment option for some patients where subcutaneous insulin might be difficult for some caregivers.

   5. Repeat serum insulin values to rule out permanent diabetes mellitus. Early genetic testing should be done.

   6. KCNJ11- and ABCC8-related permanent neonatal diabetes are responsive to oral sulfonylurea therapy. GCK- and IPF1-related permanent neonatal diabetes require insulin therapy.

   7. Consult a pediatric endocrinologist.

5. Medications

   1. If the infant is receiving theophylline, the serum theophylline level should be checked to detect possible toxicity, with resulting hyperglycemia. Other signs of theophylline toxicity include tachycardia, jitteriness, feeding intolerance, and seizures. If the level is high, the dosage must be altered or the drug discontinued.

   2. With maternal use of diazoxide, the infant may have tachycardia and hypotension as well as hyperglycemia. Toxicity in the infant is usually self-limited, and only observation is usually necessary.

   3. Caffeine and phenytoin should be adjusted or discontinued if possible.

   4. Steroids. Prolonged courses and pharmacologic dosing of corticosteroids are being used in some infants with chronic lung disease. When steroid use is deemed necessary, reducing the dose or frequency may limit the hyperglycemic effects.

6. Hyperosmolarity. Rehydration is necessary. If hyperglycemia is secondary to a hyperosmolar formula, stop the formula and give detailed instructions on how to make formula using powder or concentrated formula.