Neonatal Hyperglycemia

Etiology

1. Prematurity and Intrauterine growth restriction 
• Inadequate insulin secretion and inability to suppress glucose production in the liver 
• Increased insulin resistance
2. 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
3. Causes related to enteral feeding 
• A delay in the initiation of enteral feeding causes decreased incretin secretion, which in turn causes hyperglycemia.[2]
• The hyperosmolar formula may lead to transient glucose intolerance in the baby. 
4. Causes related to total parenteral nutrition (TPN)
• A 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, which decrease glucose oxidation competitively by providing additional carbon substrates for oxidative metabolism. Free fatty acids and glycerol promote gluconeogenesis.[3]
5. Sepsis: Consider sepsis and necrotizing enterocolitis if hyperglycemia develops without a change in glucose infusion rate.
6. 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.
7. Transient neonatal diabetes mellitus usually occurs in small for gestational age infants. This condition is self-limited.
8. 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

Epidemiology

Hyperglycemia is more common in preterm infants than in term infants and is generally noted during the first week of life. Usually, the acute hyperglycemia resolves over 2 to 3 days in most neonates but can last up to 10 days. Hyperglycemia is less common than hypoglycemia among neonates but is associated with increased mortality and morbidity among neonates. Neonatal hyperglycemia is inversely related to birth weight and gestational age.[4] Hyperglycemia occurs in one-third of preterm and small for gestational age infants.

Pathophysiology

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.[5]

History and Physical

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

Evaluation

Considerations for workup should include:

• Serum glucose: 
  • Relying on point-of-care blood glucose testing alone yields erroneous results. A high blood glucose level must be verified by measuring the serum glucose level before starting treatment for neonatal hyperglycemia. 
  • Venous blood glucose measurement is preferred compared to capillary blood glucose measurement. Capillary blood glucose (heel stick sample) is 15% lower, and the hematocrit value affects the levels. 

• Urine glucose 2+ or higher suggests osmotic diuresis. 
• Complete blood count and C-reactive protein help in ruling out sepsis.
• Monitor serum electrolyte levels in patients with hyperglycemia. The osmotic diuresis causes electrolyte loss in urine. 
• Measure the weight of the baby to determine hydration status.
• If hyperglycemia is persistent, serum insulin level, serum, and urine C-peptide levels are used to rule out monogenic diabetes and Type 1 diabetes.

Treatment / Management

In preterm and very-low-birth-weight (VLBW) infants, ie, 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 without 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.[6]
3. Role of insulin: 
   • Hyperglycemia persisting at low GIR (4 mg/kg/min) may indicate relative insulin deficiency or resistance. 
   • The role of insulin therapy in treating hyperglycemia in neonates is controversial. Consider insulin if the blood glucose level is more than 250 mg/dl and urine glucose is more than 2+ in 2 samples obtained 4 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 maintaining the blood glucose level between 100 mg/dL and 150 mg/dL.[7]
     • 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. 
   • Monitoring serum glucose levels every 1 hour when the infant is on insulin is crucial. 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.  
(B2)

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 prevent hyperglycemia. 

1. Early initiation of enteral feedings 
2. Early supplementation of amino acids in TPN leads 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.

Differential Diagnosis

Neonatal hyperglycemia is generally associated with a clinical condition rather than a specific disorder of glucose metabolism. Neonatal hyperglycemia can be a sign of an underlying illness like sepsis, necrotizing enterocolitis, or seizures. A rare cause of neonatal hyperglycemia is neonatal diabetes mellitus. Neonatal diabetes can occur in 1 in 400,000 births.[8] Neonatal diabetes can be of 3 different types:

1. The transient form accounts for more than 50%. It is usually associated with mutations of sulfonylurea receptors. Transient neonatal diabetes manifests soon after birth and remits spontaneously in 6 months.
2. Permanent neonatal diabetes needs lifelong management. Mutations in the genes encoding the subunit of the ATP-sensitive potassium channel are the most common cause.[9]
3. Syndromic Neonatal diabetes is usually associated with syndromes like Wolfram syndrome and IPEX syndrome (immune dysregulation polyendocrinopathy X-linked syndrome).

Prognosis

Neonatal hyperglycemia, particularly in preterm neonates, is usually associated with an increased risk of mortality and morbidity. The severity of impact increases with prolonged hyperglycemia. Prompt evaluation and management of neonatal hyperglycemia decrease the impact.

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.[10] 
      • 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. Necrotizing enterocolitis [11]
   5. Retinopathy of prematurity [12]
   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.