How to manage persistent hypoglycemia in preterm infants?

Management of Persistent Hypoglycemia in Preterm Infants

Start intravenous glucose infusion immediately at 4-8 mg/kg/min on Day 1, targeting 8-10 mg/kg/min from Day 2 onwards, with blood glucose checks every 30-60 minutes until stable above 2.5 mmol/L (45 mg/dL). 1

Initial Assessment and Intervention Thresholds

Define hypoglycemia as blood glucose below 2.5 mmol/L (45 mg/dL) in preterm infants. 1, 2 However, intervention thresholds vary based on severity:

• Any single measurement <1 mmol/L (18 mg/dL) requires immediate intervention 1, 2
• Blood glucose <2 mmol/L (36 mg/dL) that remains below this value at the next measurement requires immediate intervention 1, 2
• Any single measurement <2.5 mmol/L (45 mg/dL) with abnormal clinical signs requires immediate intervention 1, 2

Preterm infants are uniquely vulnerable to hypoglycemia due to limited glycogen and fat stores, inability to generate glucose through gluconeogenesis, higher metabolic demands from relatively larger brain size, and inability to mount counter-regulatory responses. 3 Nearly 30-60% of high-risk preterm infants develop hypoglycemia requiring immediate intervention. 3

Glucose Infusion Protocol

Initial glucose infusion rates:

• Start at 4-8 mg/kg/min (5.8-11.5 g/kg/day) on Day 1 4, 1
• Target 8-10 mg/kg/min (11.5-14.4 g/kg/day) from Day 2 onwards 4, 1
• Increase stepwise to 10 mg/kg/min (14.4 g/kg/day) over the first 2-3 days to allow growth 1

Critical boundaries:

• Do not exceed 12 mg/kg/min (17.3 g/kg/day) in preterm infants, as this exceeds maximum glucose oxidation rate and causes hyperglycemia 4, 1
• Do not go below 4 mg/kg/min (5.8 g/kg/day) in preterm infants 4, 1

The rationale: When exogenous glucose is reduced from 6 to 4 mg/kg/min, endogenous glucose production increases but is often insufficient to prevent hypoglycemia. 4 The maximum rate of glucose oxidation in preterm infants is 6-8 mg/kg/min (8.6-11.5 g/kg/day), so exceeding 12 mg/kg/min provides no metabolic benefit and increases hyperglycemia risk. 4

Monitoring Strategy

Frequency of glucose checks:

• Check blood glucose every 30-60 minutes until stable above 2.5 mmol/L 1
• Hypoglycemia occurs most frequently during the first 48 hours of life 5
• In 69.64% of cases, hypoglycemic episodes last longer than 30 minutes, and in 26.78% they exceed 2 hours 5

Measurement technique:

• Use blood gas analyzers with glucose modules for most accurate measurements 1, 2
• Avoid handheld glucose meters in neonates due to significant accuracy concerns from interference by high hemoglobin and bilirubin levels 1, 2
• Continuous glucose monitoring systems (CGMS) detect hypoglycemia missed by capillary testing in 35.7% of cases 5

Management of Persistent Hypoglycemia

If standard glucose infusion rates fail to maintain euglycemia:

1. First-line: Increase glucose infusion rate up to maximum of 12 mg/kg/min 4, 1

2. Second-line pharmacologic agents:

   • Corticosteroids are indicated when glucose infusion alone is insufficient 6
   • Diazoxide is indicated when glucose infusion alone is insufficient 6

3. Avoid glucagon infusion in preterm infants - it causes severe hyponatremia, thrombocytopenia, and transient convulsions 6

Critical Pitfalls to Avoid

Repetitive and prolonged hypoglycemia ≤2.5 mmol/L (45 mg/dL) must be avoided as it is associated with impaired motor and cognitive development at 18 months in preterm newborns. 1, 2 However, the evidence shows no differences in developmental progress or physical disability at 15 years when hypoglycemia is treated to maintain levels above 2.6 mmol/L. 2

Avoid large glucose swings - both hypoglycemia and rapid rises in glucose following IV dextrose boluses are associated with poorer neurodevelopmental outcomes. 1 Use protocols to maintain stable glucose levels. 1

Monitor for hyperglycemia - avoid glucose levels >8 mmol/L (145 mg/dL) as this is associated with increased morbidity and mortality in neonatal ICU patients. 1 If glucose exceeds 10 mmol/L (180 mg/dL) despite reasonable glucose infusion rate adjustment, consider insulin therapy, though this carries significant hypoglycemia risk (risk ratio 2.99-4.93). 1

High-Risk Populations Requiring Intensive Monitoring

• Gestational age <32 weeks shows significantly higher hypoglycemia occurrence 7
• Birth weight <2 kg shows higher susceptibility to hypoglycemia 7, 5
• Small for gestational age infants have 31.7% hypoglycemia rate in first 24 hours 7
• Males are slightly more affected than females 7