Case study introduction
An 8-hour-old male infant was initially reviewed on the postnatal ward due to lethargy and poor feeding. He had a blood glucose level of 0.9 mmol/L and was admitted to the neonatal unit. Intravenous access was obtained: a hypoglycaemia screen was sent, alongside a septic screen. A 2.5 mL/kg 10% dextrose bolus was given and an intravenous infusion of 10% dextrose at 60 mL/kg per day was started. Benzylpenicillin and gentamicin were also started.
Please read more of the history and examination below and answer the questions
- Born at 38 weeks’ gestation via emergency Caesarean section due to failure to progress, with a birthweight of 4.7 kg (99th centile)
- Born in good condition, no resuscitation required
- Second child of non-consanguineous parents
- Antenatal polyhydramnios
- No maternal gestational diabetes
- No maternal pre-eclampsia, no use of beta-blockers during pregnancy
- No family history of diabetes or hypoglycaemia
- Mild lethargy
- Observations within normal ranges
- Normal tone and neonatal reflexes.
- Normal cardiovascular, respiratory and abdominal examination
- No dysmorphic features
- No hepatomegaly
- No macroglossia
- Normal male external genitalia
1. What are some causes or risk factors for neonatal hypoglycaemia?
- Prematurity
- Intrauterine growth restriction
- Maternal diabetes
- Large for gestational age
- Perinatal stress e.g. maternal pre-eclampsia, sepsis
- Maternal medication, such as beta-blockers 1,2
Causes of persistent neonatal hypoglycaemia include:
- Congenital hyperinsulinism (CHI)
- Other endocrine disorders e.g. adrenal insufficiency, congenital hypopituitarism
- Syndromes such as Beckwith-Wiedemann syndrome, Sotos syndrome
- Inborn errors of metabolism e.g. glycogen storage disease, maple syrup urine disease 1, 2
A repeat blood glucose level was performed 30 minutes after the dextrose infusion had been started. The glucose level remained low at 1.2 mmol/L and the volume of the 10% dextrose was increased to 90 mL/kg per day. Repeat blood glucose levels remained low at 1.9 mmol/L.
2. What would you do next?
Increase the volume of the 10% dextrose to 120 mL/kg per day or increase the concentration of the dextrose. It would be important to repeat blood glucose levels after each change has been made.
3. How do you work out the glucose infusion rate (GIR)?
The glucose infusion rate (GIR) is a measure of how quickly glucose needs to be administered to maintain normal blood glucose levels.
For IV fluids: GIR (mg/kg per min) = rate (mL/kg per day) x % dextrose
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For oral feeds (approximate value): GIR = sugar content of milk (g/dL) x rate (mL/kg per day)
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4. Why is the GIR important to know?
A normal neonatal GIR is 4–8 mg/kg per min. A GIR of greater than 8 mg/kg per min in the context of severe and recurrent hypoglycaemia is a strong pointer to CHI and the glucose threshold used should be 3.5 mmol/L.
5. Hypoglycaemia was persisting with 120 mL/kg per day of 10% dextrose, which equated to a GIR of 8.3 mg/kg per min. What would you do next?
A peripherally inserted central catheter (PICC) can be inserted to deliver higher concentrations of dextrose (15–20%).
Glucagon can be started via intravenous infusion at 2.5–5.0 µg/kg per hour. Glucagon increases endogenous glucose production by stimulating glycogenolysis, gluconeogenesis and lipolysis. The dose can be gradually increased in steps of 2.5 µg/kg per hour (generally to a maximum of 20 µg/kg per hour) to maintain glucose levels above 3.5 mmol/L.
Another hypoglycaemia screen was taken when blood glucose levels dropped to 2.3 mmol/L and it was noted there was an issue with the PICC line delivering 20% dextrose. A new line was inserted. The introduction of glucagon at 5 µg/kg per hour allowed fluids to be gradually titrated and feeds to be introduced via a nasogastric tube. By day 6 of life, the patient was maintaining good blood glucose levels above 3.5 mmol/L on 100 mL/kg per day of 15% dextrose and 50 mL/kg per day of expressed breast milk.
The results from the hypoglycaemia screen on day 4 of life:
- Lab plasma glucose 1.2mmol/L (low)
- Insulin 388 pmol/L (raised)
- C-peptide 2384 pmol/L (raised)
- Beta-hydroxybutyrate <100 µmol/L (low)
- Free fatty acids <100 µmol/L (low)
- Lactate 2.0 mmol/L (normal)
- Ammonia 49 µmol/L (normal)
- Cortisol 377 nmol/L (normal)
Dependent on the laboratory, assay-dependent insulin cut-off levels can vary. In most cases, insulin levels above 12 pmol/L (2 mU/L) with a concurrent low plasma glucose, suppressed ketones and free fatty acids, as well as an increased GIR, points to the diagnosis of CHI.
6. How would you manage the patient now?
Discuss with regional CHI centre.
Oral diazoxide would be the first-line treatment to start at a dose of 2–5 mg/kg per day in 2–3 divided doses. Diazoxide works by opening the KATP channels of pancreatic beta cells, inhibiting the secretion of insulin.
Diazoxide can exacerbate fluid retention; pulmonary hypertension can also occur, especially in those with pre-existing cardiovascular abnormalities. Therefore, it is important to perform an echocardiogram prior to starting diazoxide to assess pulmonary artery pressures and cardiac structure. Fluid/feed volume should be restricted to 150 mL/kg per day and chlorothiazide (7 mg/kg per day in 2 divided doses) should be started at least 24 hours prior to starting diazoxide. Diazoxide use can also be associated with necrotising enterocolitis (NEC), so it should be used with caution in those with risk factors for NEC.
Octreotide can be used as second-line therapy for those that do not respond to diazoxide (diazoxide unresponsiveness can be considered when there is little improvement with doses of 15 mg/kg per day). Octreotide is a somatostatin analogue that acts through the somatostatin receptors to inhibit cAMP-mediated insulin secretion. It should only be initiated in a CHI specialist centre or regional centre with expertise.
It is important to work with the dietitians to manage feeds in infants with CHI. Infants may require carbohydrate supplements, such as glucose polymers, high energy formula or breast milk fortifiers, to facilitate weaning from intravenous dextrose to enteral feeds.
For infants that respond to diazoxide and maintain normal blood glucose levels on milk feeds, it is important to perform a 6-hour safety fast to demonstrate stability without hypoglycaemia before discharge. This gives reassurance that missing an overnight feed is tolerated whilst on diazoxide. Parents should also be trained in glucose monitoring using a glucometer.3, 4
With this case, the neonate was started on diazoxide after discussion with the regional CHI team. Despite increasing the dose of the diazoxide, he continued to have recurrent episodes of hypoglycaemia, necessitating further intervention. Genetics were sent and he was found to have a paternally inherited mutation of the ABCC8 gene. The ABCC8 gene encodes a component of the ATP-sensitive potassium (KATP) channels; these channels are important in regulating insulin secretion from the pancreatic beta cell.
Due to the mutation found, the infant had an 18F-fluorodopa PET–CT scan and a focal lesion in the pancreas was found. A surgical lesionectomy was performed with improvement in blood glucose levels.
7. What are the different types of CHI?
CHI is a rare disorder of hypoglycaemia, but the most common cause of severe and persistent hypoglycaemia. It is caused by inappropriate and dysregulated insulin secretion from the pancreas. 4,5
CHI can be divided into transient and persistent CHI. Transient CHI usually occurs with intrauterine growth restriction, prematurity, perinatal stress, maternal diabetes or maternal beta-blocker use. The increased insulin production usually occurs for a short duration of time, and most children are able to wean off diazoxide or glucose polymers within a few months.
Infants with persistent CHI tend to have either focal or diffuse histological changes in the pancreas. An 18F-fluorodopa PET–CT scan can be performed to differentiate between the different types. The scan is generally performed when there is a paternally recessive ABCC8 or KCNJ11 mutation or when the mutation status is uncertain and there is sustained medical therapy. A lesionectomy is the first-line treatment for focal CHI and can be curative. In children with diffuse CHI, first-line treatment is medical, but subtotal pancreatectomy (leaving approximately 5% of the pancreas) may be required to achieve normoglycaemia. 4,5
Summary
- Hypoglycaemia is the most common metabolic problem occurring in the neonatal period.
- A glucose infusion rate greater than 8 mg/kg per min in the context of severe and recurrent hypoglycaemia is a strong pointer to a diagnosis of CHI.
- CHI is a rare condition but the most common cause of persistent severe hypoglycaemia in the neonate. It is caused by inappropriate excess insulin secretion from pancreatic beta cells.
- Blood glucose levels should be maintained above 3.5 mmol/L in CHI to prevent the risk of hypoglycaemia-induced brain injury.
- Initial management of CHI can involve high concentrations of dextrose, glucagon, glucose polymers in feeds, and medications, such as diazoxide or octreotide.
- Surgical management may be required in those with focal or diffuse CHI.
- The British Association of Perinatal Medicine (2024). Identification and Management of Neonatal Hypoglycaemia in the Full-Term Infant (Birth -72 hours). A BAPM Framework for Practice [Accessed 9 Sept 2024]. Available here
- Abramowski A, Ward R, Hamdan AH. Neonatal Hypoglycemia. [Updated 4 Sept 2023]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Jan 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537105/
- Shaikh, MG, Lucas-Herald, AK, Dastamani A, et al. (2023). Standardised practices in the networked management of congenital hyperinsulinism: a UK national collaborative consensus. Front Endocrinol; 14: 1231043 https://doi.org/10.3389/fendo.2023.1231043
- Worth C, Yau, D, Salomon Estebanez, M, et al (2020). Complexities in the medical management of hypoglycaemia due to congenital hyperinsulinism. Clinical Endocrinol; 92: 387–395 https://doi.org/10.1111/cen.14152
- Estebanez, MS., Worth, C, Banerjee, I. (2024). Congenital Hyperinsulinism – Notes for the General Pediatrician. Indian Pediatr; 61: 578–584 https://link.springer.com/article/10.1007/s13312-024-3211-3
