Neonatal Hyperglycemia

Neonatal hyperglycemia is usually defined as serum glucose greater than 150 mg/dl (8.3 mmol/L) or whole blood glucose greater than 125 mg/dl (6.9 mmol/L) irrespective of gestational or postmenstrual age. Usually, the safe target for a neonate’s blood glucose level is 70 to 150 mg/dl. The cut-off for the safe target is based on the renal glucose threshold of preterm neonates.

Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/l (200 mg/dL), but symptoms may not start to become noticeable until even higher values such as 13.9–16.7 mmol/l (~250–300 mg/dL). A subject with a consistent range between ~5.6 and ~7 mmol/l (100–126 mg/dL) (American Diabetes Association guidelines) is considered slightly hyperglycemic, and above 7 mmol/l (126 mg/dL) is generally held to have diabetes. For diabetics, glucose levels that are considered to be too hyperglycemic can vary from person to person, mainly due to the person’s renal threshold of glucose and overall glucose tolerance. On average, however, chronic levels above 10–12 mmol/L (180–216 mg/dL) can produce noticeable organ damage over time.

Causes

Prematurity and Intrauterine growth restriction 
  • Inadequate insulin secretion and inability to suppress glucose production in the liver
  • Increased insulin resistance
Increased stress hormones like epinephrine and norepinephrine inhibit both insulin secretion and action. They also increase glucagon, which promotes glycogenolysis. The following conditions are associated with increased stress hormones,
  • Catecholamine infusions
  • Seizures
  • Physiologic stress caused by surgery, pain, hypoxia, respiratory distress, or sepsis
Causes related to enteral feeding 
  • Delay in the initiation of enteral feeding causes decreased incretin secretion, which in turn causes hyperglycemia.
  • The hyperosmolar formula may lead to transient glucose intolerance in the baby.
Causes related to Total parenteral nutrition (TPN)
  • Delay in supplementing parenteral amino acids in TPN delays the release of insulin-like growth factor-1, which delays the development of beta cells in the pancreas and develops hyperglycemia.
  • A high intravenous lipid infusion rate causes an increase in free fatty acids (FFA), which decrease glucose oxidation competitively by providing additional carbon substrates for oxidative metabolism. FFA and glycerol promote gluconeogenesis.
  • Sepsis: Consider sepsis and Necrotizing enterocolitis (NEC) if hyperglycemia develops without glucose infusion rate change.
  • Iatrogenic: One of the causes of hyperglycemia in the neonate is an error in the glucose infusion rate (GIR) calculation in the intravenous (IV) fluids.
  • Transient neonatal diabetes mellitus usually occurs in small for gestational age (SGA) infants. This condition is self-limited.
  • Drugs

    1. Maternal medications

      • Maternal diazoxide may cause hyperglycemia, hypotension, and tachycardia in neonates.
      • Antenatal steroids
    2. Neonatal medications

      • Dopamine, dobutamine, epinephrine infusions
      • Caffeine, theophylline
      • Phenytoin
      • Corticosteroids

Glucose is an essential source of energy for the fetus and neonate. The brain growth of the fetus exclusively depends upon glucose. In the early postnatal period, glucose homeostasis occurs via glycogenolysis and gluconeogenesis. The critical regulatory mechanisms of glucose homeostasis are sluggish in the initial days, particularly among preterm neonates. The mechanisms of neonatal hyperglycemia are multifactorial. The risk of hyperglycemia increases with the severity of the accompanying illness. The most common cause is high exogenous glucose infusion rates in preterm infants who are already at risk for hyperglycemia due to the following reasons,

  • decreased ability to suppress endogenous glucose production,
  • decreased insulin response to glucose, and
  • limited glycogen and fat stores.

Symptoms

The way in which neonatal hypoglycemia symptoms may be presented is vague or hard to tell apart from other conditions. The symptoms can be confused with:

  • hypocalcemia
  • Sepsis
  • CNS disorders
  • Cardiorespiratory problems
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Neonatal hypoglycemia can also show no symptoms in some newborns or may be life-threatening.

Some observed symptoms are (these symptoms may be transient but reoccurring):

  • Jitteriness
  • hypothermia 
  • irritability 
  • pallor 
  • tremors
  • twitching
  • weak or high-pitched cry
  • lethargy
  • hypotonia
  • generalized seizures
  • coma
  • cyanosis
  • apnea
  • rapid and irregular respirations
  • diaphoresis
  • eye-rolling
  • refusal to feed
  • hunger 

Diagnosis

There are no specific findings related to hyperglycemia. Physical examination may reveal signs of the underlying cause, for example, temperature instability and low perfusion in sepsis. The following signs, though nonspecific, may indicate hyperglycemia.

  • Increased urine output
  • Dehydration
  • Weight loss
  • Fever
  • Feeding difficulty

Considerations for workup should include:

Serum glucose:

  1. Relying on point-of-care blood glucose testing alone will yield erroneous results. A high blood glucose level must be verified by measuring the serum glucose level before starting treatment for neonatal hyperglycemia.
  2. Venous blood glucose measurement is a preferred sample compared to capillary blood glucose measurement. Capillary blood glucose (heel stick sample) is 15% lower, and the hematocrit value affects the levels.
  3. Urine glucose 2+ or higher suggests osmotic diuresis.
  4. Complete blood count and C-reactive protein will help in ruling out sepsis.
  5. Monitor serum electrolytes levels in patients with hyperglycemia. The osmotic diuresis causes electrolyte loss in urine.
  6. Measure the weight of the baby to determine hydration status.
  7. If hyperglycemia is persistent, serum insulin level, serum, and urine C-peptide levels are used to rule out monogenic diabetes and Type 1 diabetes.

The two major academic societies, the American Academy of Pediatrics (AAP) and the Pediatric Endocrine Society (PES), present conflicting guidelines for screening at-risk infants and the management of neonatal hypoglycemia. The most recent AAP guidelines recommend screening for late preterm and term infants that experience symptoms of hypoglycemia, and asymptomatic infants at highest risk for hypoglycemia in the first 12 to 24 hours of life. “At risk” infants include late preterm (34-36.6 weeks gestation), term infants who are small for gestational age, infants of diabetic mothers, and large for gestational age infants. The guidelines state that ‘routine screening and monitoring of blood glucose is not needed in healthy term infants after a normal pregnancy and delivery.’

The Pediatric Endocrine Society (PES) recommends screening all infants with risk factors for prolonged or pathologic hypoglycemia, including :

  • Symptomatic hypoglycemia
  • Large for gestational age
  • Perinatal stress

    • Perinatal hypoxia/ischemia, fetal distress
    • Maternal pre-eclampsia/eclampsia
    • Meconium aspiration syndrome, erythroblastosis fetalis, polycythemia, hypothermia
  • Premature or post-term delivery
  • Infant of diabetic mother
  • Family history of genetic hypoglycemia
  • Congenital syndrome (e.g., Beckwith-Wiedermann), abnormal physical features (e.g., midline facial malformations)

Per the PES guidelines, infants unable to maintain pre-prandial blood glucose values >50 mg/dL in the first 48 hours of life or >60 mg/dL thereafter are at risk for persistent hypoglycemia and require further workup prior to discharge home. The PES recommends that the evaluation of infants at risk for persistent hypoglycemia for an underlying etiology occur after the first 48 hours of life, to exclude those infants experiencing transient low glucose levels (i.e., transitional neonatal hypoglycemia).

The PES recommends evaluation of the following infants to exclude persistent causes of hypoglycemia :

  • Symptomatic hypoglycemia or severe hypoglycemia requiring treatment with intravenous dextrose
  • Infants unable to maintain blood glucose concentrations >50 mg/dL in the first 48 hours of life and >60 after 48 hours of age
  • Family history of a genetic form of hypoglycemia
  • Congenital syndrome (e.g., Beckwith-Wiedermann), abnormal physical features (e.g., midline facial malformations)

Point-of-care testing (POCT) offers a quick and cost-effective method for screening for hypoglycemia. However, these methods have limitations. Most standard instruments use non-enzymatic methods to measure blood glucose concentration, which is less accurate at lower glucose values than laboratory analysis using glucose oxidase methods (the gold standard). Whole blood samples (used in POCT) have 10% to 18% lower glucose concentrations than plasma, depending on the hematocrit. Therefore, abnormally low glucose values on POCT require confirmation by measuring plasma glucose concentration using clinical laboratory methods.

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More recently, the use of continuous glucose monitoring (CGM) in the detection and management of neonatal hypoglycemia is under investigation. A study published in 2010 by Harris et al. looked at the usefulness of continuous glucose monitoring in 102 infants >32 weeks gestation at risk of hypoglycemia during the first 7 days of life. Infants were screened for hypoglycemia with intermittent blood glucose measurements and started on early oral feeds or intravenous dextrose solution per clinical guidelines. Investigators found that detected hypoglycemia (blood glucose <47 mg/dL) was present in 44% of infants using continuous glucose monitoring, versus 32% of infants with intermittent blood glucose sampling. And that there is good agreement between interstitial (used in continuous monitoring) and blood glucose measurements. The study suggests that continuous glucose monitoring is safe, easy to use, and detects more episodes of hypoglycemia.

In infants with persistent hypoglycemia suspected of having an underlying disorder, measuring bicarbonate, lactic acid, beta-hydroxybutyrate, free fatty acids, insulin, and carnitine levels during hypoglycemia (blood glucose <50 mg/dL) is useful in differentiating between the metabolic causes of persistent hypoglycemia and aids in the diagnosis of hyperinsulinism and disorders of fatty acid oxidation.

Treatment

In preterm and very-low-birth-weight (VLBW) infants, i.e., infants with birth weight less than 1500 grams, a consistent blood glucose level of more than 200 mg/dL is a cause for concern. A blood glucose level measured as >200 mg/dL with a 4-hour interval and glucosuria of +2 or more necessitates treatment. Currently, hyperglycemia treatment in the absence of an increase in osmolarity and osmotic diuresis is not supported.

  1. The first step in evaluating neonatal hyperglycemia is to assess the GIR.
    GIR = IV infusion rate (mL/kg/day) x Dextrose concentration (%) / 144
    The GIR is lowered by reducing IV dextrose concentration or the infusion rate. GIR can be decreased by 1 to 2 mg/kg/min every 2 hours, with frequent glucose monitoring until the GIR reaches 4 mg/kg/min.
  2. In the case of persistent hyperglycemia, underlying causes such as sepsis, stress, and medications need to be explored and treated accordingly.
  3. Role of Insulin

    • Hyperglycemia persisting at low GIR (4 mg/kg/min) may indicate relative insulin deficiency or insulin resistance.
    • The role of insulin therapy in treating hyperglycemia in neonates is controversial. Consider insulin if blood glucose level is more than 250 mg/dl, and if urine glucose is more than 2+ in two separate samples obtained four hours apart.
    • Bolus insulin therapy has a high risk of causing hypoglycemia. So, bolus insulin therapy is usually not preferred in treating neonatal hyperglycemia.
    • Two approaches are available for using Insulin.

      • The first approach is to add insulin to maintenance fluids.
      • Another approach is to run insulin independently. This approach’s advantage is that the insulin rate can be adjusted without changing the total IV fluid rate.
    • The dosage of Insulin

      • The initial dosage for insulin infusion is 0.01 to 0.05 U/kg/hour.
      • Titrate the insulin infusion rate based on blood glucose concentrations
      • Titrate the insulin with an increment of 0.01 U/kg/h. The maximum dose can be up to 0.1 U/kg/h.
      • The target is to maintain the blood glucose level between 100 mg/dL and 150 mg/dL.
      • If the blood glucose level decreases to 180 mg/dL, insulin infusion is reduced by 50%.
      • If the blood glucose level is below 150 mg/dL, discontinue the Insulin.
    • It is crucial to monitor serum glucose levels every 1 hour when the infant is on insulin. Measure the blood glucose level half an hour after each change in insulin infusion
    • If hypoglycemia develops, discontinue the insulin infusion and give 2 ml/kg D10 IV bolus.
    • After discontinuing the Insulin, monitor for rebound hyperglycemia.
  4. Any electrolyte imbalance due to osmotic diuresis should be corrected. Sodium and potassium imbalance is very common.

Hyperglycemia needs to be prevented in all neonates, particularly among preterm infants, due to associated complications such as the increased risk for infection, impaired immunity, poor wound healing, increased morbidity, and mortality. The following preventive measures help in the practice to prevent hyperglycemia.

  1. Early initiation of enteral feedings
  2. Early supplementation of amino acids in TPN, leading to an increase in insulin secretion that prevents hyperglycemia.
  3. Targeting optimal and physiologic GIR in TPN as per the glucose monitoring
  4. Limiting IV lipid infusions during hyperglycemia
  5. A more direct and immediate approach is to decrease the catecholamine infusions as tolerated.
  6. Discontinuing catecholamine infusions and glucocorticoid treatments as soon as the infant’s condition has improved.

Complications

  1. Increased mortality risk among preterm and VLBW infants
  2. Increased morbidity among preterm infants. More severe outcomes occur with prolonged hyperglycemia. Neonates with hyperglycemia have an increased risk of following,

    1. Intracranial hemorrhage

      • Hyperglycemia may cause Intracranial hemorrhage by causing hyperosmolarity with osmotic shifts.
      • Each increment of 18 mg/dL in blood glucose concentration accounts for a rise of 1 mOsm/L in serum osmolarity.  If serum osmolarity exceeds 300 mOsm/L, rapidly shifting water may cause cerebral hemorrhage.
    2. Dehydration due to osmotic diuresis
    3. Electrolyte imbalance occurs due to osmotic diuresis. Glycosuria also increases sodium excretion.
    4. NEC
    5. Retinopathy of prematurity
    6. Bronchopulmonary disease
    7. Impaired immunity and increased risk of sepsis
    8. Poor wound healing
  3. Long term impact

    1. Adverse neurodevelopmental outcome
    2. Insulin resistance and glucose intolerance
  4. Side effects due to the management

    • Insulin infusion increases the risks of hypokalemia and hypoglycemia.

References

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