Initial Assessment and Management of Congenital Hyperinsulinism in Neonates

Initial Assessment and Management of Congenital Hyperinsulinism in Neonates

Flowchart

Introduction

Congenital Hyperinsulinism is the most common cause of persistent and refractory hypoglycaemia in neonatal period and infancy, due to dysregulated insulin secretion from pancreatic β- cells. Insulin suppresses mobilisation of ketones bodies during hypoglycaemia, thereby depriving the brain of primary (glucose) and secondary fuel (ketones). This places infants at high risk of hypoglycaemic brain injury and neurodevelopmental sequelae (such as cerebral palsy and seizures).

There is a separate PIER guideline for the initial investigation of hypoglycaemia which should be followed. The aim of this guideline is to provide an agreed clinical approach to neonates with persistent or recurrent hypoglycaemia requiring a glucose infusion rate of > 8mg/kg/ minute.

Scope

This guideline is to be used for paediatricians caring for neonates in the Wessex region. Any baby requiring diazoxide should be discussed with the tertiary Paediatric Endocrinology Department in Southampton (within working hours) prior to starting treatment.

Purpose

The aim of the guideline is to provide an agreed clinical approach to the initial investigation and management of congenital hyperinsulinism, provide an overview of the wide spectrum of underlying disorders and guide clinicians to the appropriate investigations including those that should be carried out prior to initiating treatment.

Definitions

Congenital Hyperinsulinism (CHI) - Severe, persistent, or recurrent hypoglycaemia due to inappropriate secretion of insulin. Suspect CHI when large amounts of intravenous dextrose infusions (>8mg/kg/min) are required to maintain normoglycaemia. Biochemically it is characterised by low levels of serum free fatty acids, low beta hydroxybutyrate and raised or detectable insulin and c-peptide levels in the presence of hypoglycaemia.

Hypoglycaemia - The definition of hypoglycaemia in neonates remains controversial and different professional bodies use different reference points. For the purpose of this guideline hypoglycaemia will be defined as a blood sugar of < 3 mmol/l.

Transitional hypoglycaemia - A hypoketotic hypoglycaemia caused by a lower glucose threshold for suppression of insulin secretion can occur in the first 48-72 hrs of life as part of the normal newborn metabolic transition.

Small for gestational age - infant born with a birth weight less that the 10th centile

Large for gestational age - Infants born with a birth weight greater than 90th centile

GIR (glucose infusion rate) - can be calculated from the rate of infusion, concentration of dextrose and body weight or by using online calculators such as Starship GIR calculator or NICU Tools.

History and Examination

Points to consider in the history and examination

The following risk factors can be associated with congenital hyperinsulinism

Maternal/ family history

Infant of diabetic mother
Maternal preeclampsia/eclampsia or hypertension
Maternal intake of betablockers
High rates of maternal glucose infusion
Family history of a genetic form of hypoglycaemia or congenital hyperinsulinism
Consanguinity
Neonatal death

Neonatal risk factors

Large for gestational age
Intrauterine growth restriction (small for gestational age)
Dysmorphic features/ congenital syndromes (e.g., Beckwith-Wiedemann) (see appendix)

Perinatal risk factors

Premature delivery
Perinatal stress

Features suggestive of endocrine causes of hypoglycaemia (Ex: hypopituitarism/adrenal insufficiency) or metabolic disorders

Jaundice
Midline defects and dysmorphic features
Microphallus
Hyperpigmentation
Hepatomegaly, lactic acidosis, raised ammonia
Family history of metabolic conditions, consanguinity, and history of neonatal death

Initial clinical approach and when to consider diagnosis of congenital hyperinsulinism (CHI)

Perform a hypoglycaemia screen when blood glucose ≤3 mmol/l (see Appendix 1). If possible, also check bedside ketones. The hypoglycaemia screen will need to be repeated if initial screen is done within first 48 – 72 hours of life as the results may reflect normal neonatal transitional hypoglycaemia.
Treat hypoglycaemia immediately with intravenous glucose: Give 2ml/kg bolus of 10% glucose followed by continuous glucose infusion to prevent rebound hypoglycaemia. Recheck blood glucose 15 mins after administration of bolus to ensure normoglycaemia (blood glucose >3.5 mmol/l).
Titrate glucose infusion/ feed rate to maintain normoglycaemia. Neonates with suspected CHI should initially preferably be managed on glucose infusions (rather than feeds) to ensure appropriate GIR can be calculated and maintained to prevent hypoglycaemia. This will also enable easier volume titration without compromising the concentration of glucose infusion, if medication such as diazoxide is required.
Calculate glucose infusion rate (GIR). The glucose requirements of a newborn baby are 4-6 mg/kg/min. A GIR > 8mg/kg/min is excessive and suggestive of hyperinsulinism.

Sugar concentration of breast milk (lactose) is 7.2%. For formula feeds, check carbohydrate content in the manufacturer’s label. The total carbohydrate content of the milk (g)/100 ml is the figure used to replace the % glucose in the above equation. The total carbohydrate concentration of Nutriprem 1 is 8.4g/100ml or 8.4% and of Nutriprem 2 is 7.2g/100ml or 7.2%.

How to calculate GIR – worked examples

Example 1

A 3kg baby on 120ml/kg/day of Nutriprem 1 (8.4%)

Rate of infusion = (120 x 3)/ 24
= 15

GIR = 8.4 x 15
3 x 6

GIR = 7 mg/kg/min

Example 2

A 3.6kg baby on 15% glucose at 150ml/kg/day

Rate of infusion = 22.5ml/hr

GIR = 15 x 22.5
3.6 x 6

GIR = 15.6mg/kg/min

5. Consider CHI if

A glucose infusion rate of > 8mg/kg/ minute and
Hypoglycaemia screen shows;
- Plasma glucose <3mmol/L
- Detectable Insulin >2mU/L or 12 pmol/L
- Elevated C-peptide levels >165.5 pmol/L
- Suppressed free fatty acids and BOHB *

*Use point of care testing in addition to sending lab samples

Exclusion of metabolic disorders (acidosis, abnormal plasma or urine organic acids, elevated ammonia or lactate, deranged liver function) is crucial

Please note that Insulin has a short half-life and may not be elevated if the hypoglycaemia screen is delayed. It is also worth noting that the level of insulin achieved during hypoglycaemia is not indicative of the severity of the condition.

Initial management

Initial management of a baby with suspected congenital hyperinsulinism: important practice points

Until biochemical diagnosis of hyperinsulinism is confirmed, initial glycaemic stabilisation should be achieved with high concentration glucose infusion. Occasionally, it may be necessary to treat suspected CHI prior to obtaining biochemical confirmation of a diagnosis. This may be due to a delay in receiving the laboratory results of a hypoglycaemia screen, difficulties associated with venesection in neonates, insufficient hypoglycaemia screens or discrepancy in results. A bedside ketone test may be helpful when considering the diagnosis.
Repeated hypoglycaemia screens are recommended each time a baby has a blood glucose < 3.0 mmol/L if HH is suspected, until the biochemical diagnosis is confirmed or if there is uncertainty in diagnosis. It is worthwhile ringing the lab in advance to let them know to expect your samples.
In the clinical context of CHI, the aim is to keep the blood glucose >3.5 mmol/l. Intervention with very frequent/ continuous feeds and/ or high concentrations of IV glucose is often required. The risk of hypoglycaemia causing seizures and subsequent brain injury is high (25-50%) in this population so a low index of suspicion and prompt treatment are essential.
Consider requirement for central venous access early (long line or umbilical venous catheter) (if concentration of glucose >12.5% is needed).

Management 0-48 hrs

Increase concentration of glucose in increments as necessary to maintain pre-feed blood glucose > 3.5 mmol/ml. Glucose concentration needs to be titrated up to reduce fluid volume, aiming to reduce total volume to 130 ml/kg/day (consider 120 mls/kg/day in preterm neonates with a greater risk of pulmonary hypertension). This is to prepare for the potential introduction of diazoxide later (usually after 24-48 hours) and will minimise the side effect of fluid retention which can be severe. Once blood glucose is stable the volume can be reduced aiming to give a similar glucose infusion rate. For example, if a 3kg baby was requiring 150ml/kg of 10% (GIR 10.4 mg/kg/min), increase the glucose concentration to 12.5% and give a volume of 130ml/kg/day and achieve a similar GIR (GIR = 11.2 mg/kg/min.
If unable to reduce fluid volume further using high concentrations of glucose, start an intravenous/subcutaneous glucagon infusion (See Appendix 2) to maintain normoglycaemia
If able to reduce volume of glucose to 130ml/kg/day without the need for glucagon and blood sugars persistently > 5-6 mmol/mol, consider weaning glucose concentration slowly (as this may represent transient hyperinsulinism). Repeat hypoglycaemia screen if blood glucose <3.0 mmol/l at any point.

Glucagon infusion calculation: See appendix

Management Beyond 48 hrs

1. First line medical therapy is diazoxide.   Checklist prior to staring diazoxide
                - contact the Paediatric Endocrine Team in Southampton during working hours
                - reduce fluids to 130 ml/kg/day (consider 120 mls/kg/day in preterm neonates
                  with a greater risk of pulmonary hypertension.
                -Baseline echocardiogram is recommended prior to starting diazoxide as
                  congenital heart disease increases the risk of diazoxide-induced pulmonary
                  hypertension. Repeat echo 10-14 days after diazoxide especially if clinical
                  concerns/existing cardiac issues
                -Counsel parents regarding side effects of diazoxide and monitor for these.
                  (See appendix 2).

2. Diazoxide should be started at a dose recommended by the Southampton Paediatric Endocrine Team after discussion of the individual patient, along with chlorothiazide to prevent diazoxide related fluid retention (See appendix 2)

3. Once diazoxide is commenced, wean glucagon infusion by halving the rate every 4-8 hours if blood glucose remains >3.5mmol/l. Glucagon can be weaned 2 hourly if blood glucose is > 8mmol/l. Once glucagon is stopped the glucose concentration can be weaned.

Note: Patients with certain genetic forms of congenital hyperinsulinism and those with focal congenital hyperinsulinism are unresponsive to diazoxide. Please discuss with the Paediatric Endocrine team in Southampton urgently if patient remains hypoglycaemic despite treatment with diazoxide or unable to wean glucagon/glucose concentrations. These children may need additional treatment such as octreotide and discussion with CHI centre (GOSH).

Chlorothiazide (3-5mg/kg twice daily) should also be started to prevent diazoxide related fluid retention.
Once diazoxide is commenced, wean glucagon infusion by halving the rate every 4-8 hours if blood glucose remains >3.5mmol/l. Glucagon can be weaned 2 hourly if blood glucose is > 8mmol/l. Once glucagon is stopped the glucose concentration can be weaned.

Criteria for discussion and or transfer to CHI centre (GOSH):

Uncertainty of diagnosis
Unable to maintain BG >3.5
Side effects of diazoxide
2nd line therapy needed as unresponsive to diazoxide
Intravenous fluid requirement>10 days and high GIR >20 mg/kg/min
Family history of CHI
Contraindications to diazoxide therapy (cardiac dysfunction and risk of necrotising enterocolitis)
Difficulties with central venous access

Case example

A 3.0kg baby is requiring 15% glucose at a rate of 150ml/kg/day to maintain blood glucose >3.5 (GIR 15.6 mg/kg/min)

Glucagon infusion started at 5micrograms/kg/hour

Able to wean volume of IV glucose to 130ml/kg/day of 15% glucose

Baseline echo normal, discussion with UHS Paediatric Endocrine Team - diazoxide commenced at 5mg/kg/day in 3 divided doses plus chlorothiazide at 3mg/kg BD.

Baby prescribed:

Diazoxide 5mg PO TDS
Chlorothiazide 9mg PO BD
Glucagon 5micrograms/kg/hour is continued

Blood glucose stabilises on diazoxide rising to between 6.8 and 7.9 mmol/mol

Glucagon is weaned (halving dose every 4 hours). Once glucagon is stopped the concentration of glucose is weaned as feeds are introduced.

Discharge planning

Prior to discharge perform a 6 hour fast. This should be done with one-to-one nursing and the baby should have IV access in situ prior to beginning the test. Blood sugar should be recorded every hour once the baby reaches their normal feed interval or sooner if the baby becomes symptomatic.

If a baby can maintain a blood glucose >3.5 for 6 hours, it is safe for them to be discharged on the current dose of diazoxide. Complete a hypoglycaemia screen If the blood sugar drops below 3 during this period and please discuss with the Paediatric Endocrinology Team in Southampton.
If a baby was treated with diazoxide and this was subsequently weaned and stopped whilst in NICU (transient hyperinsulinism suspected), please ensure a 6 hour fast is also performed prior to discharge. The baby is safe to discharge is the blood sugar remains >3.
Babies with congenital hyperinsulinism (i.e. ongoing treatment with diazoxide) require open access to their local paediatric ward.
Parents need to be trained to recognise clinical signs of hypoglycaemia and to check blood glucose. The family will need to be discharged with a blood glucose monitor and a supply of lancets, test strips, glucogel.
Following discharge, the baby will need to have their blood glucose level checked at home twice a day by parents (usually first thing in the morning and before the evening feed (blood sugar should be checked at the end of the longest period of fasting). Parents should be given strict instructions that their baby should not be fasted for more than 6 hours. If unwell, monitoring should be increased to thrice daily prefeed and when symptomatic
Parents need to be taught how to treat an episode of hypoglycaemia (BG<3.5 mmol/l) with glucogel. Should this happen at home they would need to contact their local hospital immediately for further advice (and liaison with Southampton paediatric endocrine team regarding dose adjustment) and may need to be reviewed in person if persistent hypoglycaemia or > 2 episodes in a 24-hour period.
Parents need to be informed that should blood sugars be persistently above 8 mmol/l they need to ring their local hospital and discuss as the dose of diazoxide may need to be adjusted.
Follow up should be arranged with the Paediatric Endocrine Team in Southampton in clinic. While awaiting review in UHS, local neonatal/paediatric follow up required 6 and 12 weeks after discharge for assessment of blood sugars, review of fluid volume for growth, medication adjustment with growth and review of side effects.

Prior to discharge the parents or carers need to be trained to

Recognise signs of hypoglycaemia
Check blood glucose using a bedside glucose monitor
Know that blood glucose should be kept between 3.5 – 8 mmol/l
Increase frequency of blood glucose monitoring if unwell or if concerned
Use glucogel for emergency management of hypoglycaemia
Know when to use open access

Appendix 1

Syndromes associated with Hyperinsulinaemic Hypoglycaemia

Beckwith-Wiedemann syndrome (BWS)
Kabuki syndrome (KS)
Turner syndrome (TS)
Sotos syndrome
Costello syndrome
Simpson-Golabi-Behmel syndrome
Trisomy 13 syndrome
Timothy syndrome
Usher syndrome

Hypoglycaemia screen blood tests

Laboratory blood glucose (and bedside POCT)
Plasma insulin
C- peptide
Plasma cortisol
Growth hormone
Plasma non-esterified fatty acids
Blood 3βOH-butyrate (and bedside POCT)
Blood lactate. Blood gas
Blood / plasma acylcarnitine*
Plasma ammonia*
Plasma amino acids*
Urine ketones and organic acids (First urine after hypoglycaemia)

*Maybe taken immediately after hypoglycaemia correction, if unable to take at time of hypoglycaemia

Appendix 2

Glucagon

Glucagon can be given as a subcutaneous or intravenous infusion
Dose: Start at 2.5- 5 micrograms/kg/hour (can be increased to 20 mcg/kg/hr).
Site to be rotated every 3 days. Glucagon infusion syringe/set to be changed every 12 hours.
Side effects/risks: Iv-line occlusion, Necrolytic migratory erythema

Diazoxide

Diazoxide binds to the KATP channel maintaining it in an open configuration, thereby preventing depolarisation of the b-cell and insulin release.
Dose: Initially 2-5 mg/kg/day in 3 divided doses (can be increased to 20 mg/kg/day). Preferably Proglycem preparation.
Side effects: fluid retention, hypertrichosis, coarse facial features, pulmonary hypertension, neutropenia and thrombocytopaenia, NEC
Requires monitoring of fluid balance and U+Es.
FBC to be checked prior to starting and 4-6 monthly thereafter. Discuss with Southampton Endocrine Team if neutropenia or thrombocytopaenia.

Chlorothiazide

Chlorothiazide should also be started alongside diazoxide to prevent fluid retention. Consider changing to furosemide and spironolactone on higher doses of diazoxide (as per advice of Southampton Paediatric Endocrine Team).
Dose: 7 mg/kg/day in 2 divided doses
Side effects/risk: Hyponatremia

Appendix 3: Flowchart for Hypoglycaemia screens

References

Eljamel S. Griffiths A. Evans J et al The burden of congenital hyperinsulinism in the United Kingdom: a cost of illness study. Orphanet J Rare Dis. 2018; 13: 123.
Stanley C. Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders. J Clin Endocrinol Metab. 2016 Mar; 101(3): 815–826.
Chen SC, Dastamani A, Pintus D et al. Diazoxide-induced pulmonary hypertension in hyperinsulinaemic hypoglycaemia: Recommendations from a multicentre study in the United Kingdom. Clin Endocrinol (Oxf) 2019 Dec;91(6):770-775
Thornton PS, Stanley CA, De Leon DD et al. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants, and Children. J Pediatr. 2015 Aug;167(2):238-45.
Ferrara, C. Patel, P. Becker, S. et al. Biomarkers of insulin for the diagnosis of hyperinsulinaemic hypoglycaemia in infants and children. J Pediatr. 2016, 168; 212-219
Brar P. Heksch R. Cossen K. et al. Management and appropriate use of diazoxide in infants and children with hyperinsulinism. Clin Endocrinol Metab. 2020 Dec 1; 105
Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating "transitional neonatal hypoglycemia": mechanism and implications for management. J Pediatr. 2015;166(6):1520-5.e1

Document Version:
1.0

Lead Authors:
Dr Anitha Kumaran
Dr Elizabeth Van-Boxel
Rooha Ghauri

Approving Network:
Wessex Endocrine Netwrok

Date of Approval:
09/2024

Review Due:
09/2027

GUIDELINES

How to calculate GIR – worked examples

Appendix 3: Flowchart for Hypoglycaemia screens

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