The neonatal brain utilises two substrates for metabolism – glucose and ketone bodies. Hyperinsulinaemic hypoglycaemia leads to inappropriately high levels of insulin causing hypoglycaemia AND low ketone bodies. These babies are therefore at particularly high risk of permanent neurological damage and intervention is recommended at a higher blood glucose level than in babies without hyperinsulinism.
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 the management of neonates with hyperinsulinaemic hypoglycaemia
Hyperinsulinaemic hypoglycaemia is characterised by persistent or recurrent hypoglycaemia in association with the following:
At the time of a blood glucose < 3 mmol/l:
Detectable/ inappropriately raised insulin levels with raised C-peptide levels
Absent or low urine ketones and
Low levels of serum free fatty acids and beta-hydroxybutyrate
A glucose infusion rate (GIR) of > 8mg per kg per minute
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. The aim of the guideline is to provide an agreed clinical approach to the initial investigation and management of hyperinsulinaemic hypoglycaemia, 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.
Hyperinsulinaemic hypoglycaemia (HH) Severe persistent or recurrent hypoglycaemia due to inappropriate secretion of insulin. Suspect HH when large amounts of intravenous glucose infusions (>8mg/kg/min) are required to maintain normoglycaemia and if there is an inability to consistently maintain preprandial glucose concentration. Biochemically it is characterised by low ketones, low levels of serum free fatty acids, and raised or detectable insulin and c-peptide levels in the presence of hypoglycaemia (BG <3 mmol/L).
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 glucose of < 3 mmol/l.
Transitional neonatal glucose regulation: A hypoketotic hypoglycaemia caused by a lower glucose threshold for suppression of insulin secretion can occur in the first 48 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.
GIR (glucose infusion rate): see calculation below
History and Examination
Points to consider in the history and examination
The following risk factors can be associated with hyperinsulinaemic hypoglycaemia (HH)
Maternal/ family history
Infant of diabetic mother
Maternal preeclampsia/eclampsia or hypertension
Maternal intake of betablockers
Family history of a genetic form of hypoglycaemia
Consanguinity and neonatal death
Neonatal risk factors
Large for gestational age
Intrauterine growth restriction (small for gestational age)
Features suggestive of other endocrine causes of hypoglycaemia (eg congenital hypopituitarism) or metabolic disorders
Midline defects and dysmorphic features
Family history of metabolic conditions, consanguinity and history of neonatal death
Initial approach and when to consider diagnosis of hyperinsulinaemic hypoglycaemia (HH)
Perform a hypoglycaemia screen when blood glucose ≤3 mmol/l (see PIER hypoglycaemia guideline). 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 glucose regulation.
Treat hypoglycaemia immediately with intravenous glucose: Give 2ml/kg bolus of 10% glucose, rechecking blood glucose 15 mins after administration of bolus to ensure normoglycaemia (blood glucose >3 mmol/l).
Titrate glucose infusion/ feed rate to maintain normoglycaemia. Neonates with suspected hyperinsulinaemic hypoglycaemia should 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 5-8mg/kg/min. A GIR > 8mg/kg/min is excessive and suggestive of hyperinsulinism.
% Glucose x rate of infusion (ml/hr) GIR = --------------------------------------------- Birth weight (kg) x 6
Sugar concentration of breast milk (lactose) is 7.1% (as is most term formula). Please refer to the manufacturer’s label if your patient is having formula milk. The total carbohydrate content of the milk 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
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
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
Consider hyperinsulinaemic hypoglycaemia (HH) If
GIR is greater > 8mg/kg/min AND
hypoglycaemia screen shows
blood glucose < 3mmol/L
no evidence of acidosis,
insulin NOT suppressed in context of low blood sugar (ie insulin is detectable)
raised C-peptide levels (low C-peptide and raised insulin levels are associated with exogenous insulin administration)
decreased free fatty acids and BOHB (betahydroxybutyrate)
The hypoglycaemia screen MUST be rechecked after 48 – 72 hours of life as initial results may simply be due to normal neonatal transitional glucose regulation
Initial management of a baby with suspected hyperinsulinaemic hypoglycaemia (HH): important practice points
It may be necessary to treat suspected HH prior to obtaining biochemical confirmation of a diagnosis. There is frequently a delay in getting the laboratory results of a hypoglycaemia screen, and due to difficulties associated with venesection in neonates, hypoglycaemia screens can often be insufficient. 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. It is worthwhile ringing the lab in advance to let them know to expect your samples as insulin deteriorates quickly.
In the clinical context of HH 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 UVC) (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 in order to reduce fluid volume, aiming to reduce total volume to 130ml/kg/day. This is to prepare for the potential introduction of diazoxide later (usually after 48 hours) and will minimise the side effect of fluid retention which can be severe. Once blood glucose of the baby 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), you could increase the glucose concentration to 12.5% and give a volume of 130ml/kg/day and achieve a similar GIR (in the second case GIR = 11.2)..
If unable to reduce fluid volume using high concentrations of glucose, start an intravenous glucagon infusion.
If able to reduce volume of glucose to 130ml/kg/day without the need for glucagon 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
First line medical therapy for hyperinsulinaemic hypoglycaemia is treatment with diazoxide. Prior to staring diazoxide consider contacting the Paediatric Endocrine Team in Southampton during working hours
Before starting diazoxide, ensure fluid requirements are reduced to 130ml/kg/day. Fluid restriction is necessary to reduce the risk of pulmonary hypertension and cardiac failure from fluid retention.
A baseline echocardiogram is recommended prior to starting diazoxide as congenital heart disease increases the risk of diazoxide-induced pulmonary hypertension.
Diazoxide should be started at a dose recommended by the Southampton Paediatric Endocrine Team after discussion of the individual case (starting dose usually 3-5mg/kg/day in three divided doses).
Counsel parents regarding side effects of diazoxide and monitor for these. (See appendix).
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 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 quaternary teams.
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.
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 plus chlorothiazide at 3mg/kg BD.
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
Glucagon is weaned (halving dose every 4 hours). Once glucagon is stopped the concentration of glucose is weaned as feeds are introduced.
Prior to discharge perform a 6 hour controlled fast. This is done to provide information on the effectiveness of diazoxide treatment and to provide parents information on how long their baby is able to safely maintain normal blood glucose for home management. The controlled fast should be carried out with one to one nursing and the baby should have IV access in situ prior to beginning the test. Blood glucose should be recorded every hour once the baby reaches their normal feed interval or sooner if the baby becomes symptomatic.
If a baby is able to maintain a blood glucose >3.5mmol/l for 6 hours, it is safe for them to be discharged home on their current dose of diazoxide. Complete a hypoglycaemia screen if the blood glucose drops below 3 mmol/l during this 6 hour period and discuss with the Paediatric Endocrinology Team in Southampton. If the blood sugar drops to between 3 and 3.5 during the fast please discuss with the Southampton Endocrine Team as the dose of diazoxide may need to be titrated.
If a baby has been weaned off diazoxide whilst still an inpatient on NICU (transient HH suspected), please ensure a 6 hour controlled fast is also performed prior to discharge. The baby is safe to discharge if the blood glucose remains >3 mmol/l.
Babies treated for HH will require open access to their local paediatric ward to be arranged prior to discharge.
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
The family will need to be discharged with a blood glucose monitor and a supply of lancets, test strips and glucogel
Following discharge the baby will need to have their blood glucose level checked at home (prefeed) twice a day by parents. Blood glucose should be checked at the end of the longest period of fasting. This is usually first thing in the morning and before the evening feed. 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 at least three times daily or pre feeds and when symptomatic.
Parents need to be taught how to treat an episode of hypoglycaemia (blood glucose <3.5 mmol/l) with glucogel. Should this happen at home they would need to contact their local hospital immediately for further advice and may need to be reviewed in person.
Parents need to be informed that should blood glucose be persistently > 8 mmol/l they need to call their local hospital for advice as the dose of diazoxide may need to be reduced. Over-treatment with diazoxide can lead to diabetic ketoacidosis.
Outpatients follow up should be arranged with the Paediatric Endocrine Team either for the Southampton clinic or the local paediatric endocrine outreach clinic.
Syndromes associated with hyperinsulinaemic hypoglycaemia (HH)
Beckwith-Wiedemann syndrome (BWS)
Kabuki syndrome (KS)
Turner syndrome (TS)
Trisomy 13 syndrome
Hypoglycaemia screen blood tests
Laboratory blood glucose
Plasma non-esterified fatty acids
Blood / plasma carnitine and acylcarnitine species
Plasma amino acids
Urine ketones and organic acids
Calculating GIR (glucose infusion rate)
% Glucose x rate of infusion (ml/hr) GIR = --------------------------------------------- Birth weight (kg) x 6
Dose: 3 – 15mg/kg/day. Consider starting dose as 3 - 5mg/kg/day in three divided doses. Side effects: fluid retention, hypertrichosis, coarse facial features, pulmonary hypertension, neutropaenia and thrombocytopaenia, can taste bitter. Requires monitoring of fluid balance and U+Es. Chlorothiazide is recommended with diazoxide, however consider changing to furosemide and spironolactone if on higher doses of diazoxide (as per advice of Southampton Paediatric Endocrine Team). Full blood count (FBC) to be checked prior to starting, 5 days after starting diazoxide and at least 3 monthly after this. Discuss with Southampton Endocrine Team if neutropaenia or thrombocytopaenia noted.
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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
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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