Persistent or refractory hypoglycaemia in the neonate : a guideline for management

Objectives

This document is applicable to all medical, nursing and midwifery staff caring for the newborn in the West of Scotland. For advice on screening for hypoglycaemia and the management of transient neonatal hypoglycaemia, staff should refer to the guidelines entitled ‘Hypoglycaemia: term infants’ or 'Hypoglycaemia preterm infants' as appropriate.

This guideline should be used for infants who require high levels of glucose intake to maintain normoglycaemia (>8mg/kg/min), or whose hypoglycaemia fails to resolve in the usual timescale of 2 days. The document should be used with reference to the appropriate pharmacy monographs.

Introduction

Transient hypoglycaemia is common in the newborn period. Cases of hypoglycaemia which are recurrent or resistant to treatment should be investigated further, because inadequate treatment can result in poor neurological outcomes (Menni et al., 2001). The most common cause of persistent hypoglycaemia is hyperinsulinism, accounting for up to 50% of cases (Dacou-Voutetakis et al., 1998). The aetiology of this condition is diverse however, and investigations should be carried out at the time of hypoglycaemia if possible.

For the purpose of this guideline, persistent hypoglycaemia is defined as being present if the patient remains hypoglycaemic for >3 days despite treatment, as detailed in the WoS Guidelines ‘Hypoglycaemia: term infants’ and 'Hypoglycaemia preterm infants'. If the neonate is requiring high infusion rates of dextrose (>10mg/kg/minute) to maintain normoglycaemia hyperinsulinism should be considered, irrespective of age.

Hypoglycaemia is severe if a glucose requirement >8mg/kg/min is required to maintain euglycaemia. Normal glucose requirements are 4-6mg/kg/min. This can be calculated using the following equations (Kuschel and Knight, 2007):

image showing calculations for glucose intake

The following table demonstrates rates of intravenous glucose in mg/kg/minute from standard dextrose concentrations.

Infusion rate (ml/kg/day)	10% dextrose	12.5 % dextrose	15% dextrose	20% dextrose
60	4 mg/kg/min	5 mg/kg/min	6 mg/kg/min	8 mg/kg/min
75	5 mg/kg/min	7 mg/kg/min	8 mg/kg/min	11 mg/kg/min
90	6 mg/kg/min	8 mg/kg/min	9 mg/kg/min	13 mg/kg/min
120	8 mg/kg/min	10 mg/kg/min	13 mg/kg/min	17 mg/kg/min
150	10 mg/kg/min	13 mg/kg/min	16 mg/kg/min	21 mg/kg/min

For babies who are on a combination of different fluids +/- milk there is a handy online calculator at http://nicutools.org/

History and Examination

Initial discussion should be undertaken with the attending Neonatal Consultant.
Full clinical history and examination of the neonate should be carried out to include:

History:

Maternal history of ingestion of medications which can induce hypoglycaemia, for example labetalol
Maternal history of diabetes
Feeding patterns since birth and relationship with hypoglycaemia
Family history of consanguinity and sudden infant death
History of prolonged jaundice
Birth weight centile (<10^th centile)
Preterm (<37 weeks)
Severe illness e.g. sepsis, hypoxia, rhesus disease

Examination (Robinson et al., 2009)

Small penis, midface abnormalities with or without prolonged jaundice suggestive of panhypopituitarism
Macrosomia – hyperinsulinism, infants of diabetic mothers
Ambiguous genitalia or virilisation or a pigmented scrotum in a Caucasian infant – congenital adrenal hyperplasia
Progressive liver enlargement in the first week of life – disorders of gluconeogenesis or glycogen storage disease
Hypotension – cortisol deficiency
Abnormal ear lobes, macroglossia, hemi-hypertrophy, umbilical hernia – Beckwith-Wiedemann syndrome

Investigations

Refractory hypoglycaemia (requiring >8mg/kg/min Glucose to maintain normoglycaemia) in the first few days after birth will usually be caused by hyperinsulinism. For such babies, the investigations outlined in bold in the table below should be prioritised. These investigations should be carried out at the time of hypoglycaemia.

Babies with persistent hypoglycaemia (more than 2 days), or with atypical presentation (babies with no clear cause for the hypoglycaemia such as maternal diabetes or beta blockers), should be discussed with the Neonatal Consultant on call and consideration given to undertaking the extended list of investigations as below.
Note that some investigations may be hard to interpret in the first few days after birth due to normal physiological hormonal changes after delivery.

If you wish to discuss which investigations are needed, discuss with the Endocrine Consultant on Call at the Royal Hospital for Children, Glasgow.

In total, you should take 2 lithium heparin blood bottles, a grey top fluoride/oxalate bottle, a blood spot card and a urine sample during hypoglycaemia and send them to Biochemistry.

These tests are performed in different laboratories throughout Glasgow. If you wish to discuss how these tests should be sent, please discuss with the On Call Biochemist.

Table 1. Investigations required for neonates with refractory or persistent hypoglycaemia at time of hypoglycaemia

Type of specimen and investigation		How do you do it?	Where does it go? (GG&C)	Guide to interpretation
Blood	Glucose	DURING HYPOGLYCAEMIA Fluoride/oxalate (grey top) bottle	Send to biochemistry	<4 days of age abnormal if <2.2mmol >4 days of age abnormal if <2.6mmol
Blood	Capillary blood gas	Take in capillary tube	Blood gas machine	Metabolic acidosis in severe ketosis, lactic acidosis or organic acidaemia
Blood	β-hydroxybutryate and free fatty acids	DURING HYPOGLYCAEMIA Lithium heparin bottle Sample should be transported to the local laboratory & separated within 0 mins of collection,. Store frozen	Send to biochemistry	Hyperinsulinism: FFA<1.0mmol/l and FFA:β-hydroxybutyrate ratio <1.0 Fatty acid oxidation defect: FFA>1.0mmol/l and FFA: β-hydroxybutyrate ratio >1.4
Blood	Insulin and C-peptide	DURING HYPOCLYAEMIA Lithium heparin sample Samples must be collected on ice, transported to the local laboratory and separated within 30 mins of collection. Store frozen	Send to biochemistry	Insulin >2.0mU/l when hypoglycaemia present consistent with hyperinsulinism or insulinoma Increased insulin with low C-peptide suggests exogenous insulin administration
Urine	Ketones	Urinalysis	On ward	Evidence of ketonuria
Blood	Lactate	DURING HYPOGLYCAEMIA Fluoride/oxalate (grey top) bottle or blood gas tube	Send to biochemistry or analyse on blood gas machine	Ref range neonate 0.5-3mmol/l Causes of high lactate: Venous stasis on sampling Tissue hypoxia and ischaemia Disorders of gluconeogenesis Glycogen storage disease type I Primary lactic acidosis (resp chain defects, pyruvate dehydrogenase deficiency)
Blood	Cortisol	DURING HYPOGLYCAEMIA Lithium heparin sample	Send to biochemistry	Cortisol >250nmol/l excludes disorder of hypothalamic-pituitary axis Cortisol 150-250nmol/l check GH level (if >6 ug/l significant pituitary pathology unlikely) Cortisol <150nmol/l +/- GH <6 ug/l needs further investigation for pituitary/adrenal disorders
Blood	Growth Hormone	Lithium heparin sample	Send to biochemistry	GH level >10µg/L excludes hypopituitarism in infant <3 months of age (Note units: 1µg/L=3mU/L)
Blood	Ammonia	Lithium heparin sample Sample should be transported to Yorkhill ASAP Laboratory MUST be informed	Send to biochemistry	<100umol/L in term infants normal <180umol/L in preterm/SGA infants Raised in: Fat oxidation disorders Reyes syndrome Organic acidaemia (associated with hypoglycaemia and acidosis)
Blood	Urea and electrolytes	Lithium heparin sample	Send to biochemistry	Looking for evidence of: Severe dehydration Low K in organic acidaemia Renal disease Low Na +/- high K in adrenal disease
Blood	AST/ALT CK	Lithium heparin sample	Send to biochemistry	Deranged in GSD type I, Reye’s syndrome, fat oxidation defects and GSD type III
Blood	Thyroid function tests	Lithium heparin sample	Send to biochemistry	Low free T4 and TSH in hypopituiarism
Blood	Testosterone	ONLY IN MALES <4 MONTHS Lithium heparin bottle	Send to biochemistry	Absent normal postnatal surge of testosterone in panhypopituitarism
Blood	Amino acids	DURING HYPOGLYCAEMIA Lithium heparin bottle Sample should be separated by local laboratory within 2hr of collection and frozen.	Send to biochemistry	Low alanine in ketotic hypoglycaemia and starvation. High alanine in lactic acidosis
Blood	ACTH	Only if cortisol response equivocal/low Lithium heparin bottle Samples must be transported to local laboratory within 30 mins of collection. Store frozen	Send to biochemistry	Ref range 7-51ng/L Normal/low ACTH excludes adrenal pathology High ACTH with low cortisol suggests adrenal pathology and requires Synacthen test
Blood	Acyl-carnitine	DURING HYPOGLYCAEMIA Blood spots on card	Send to biochemistry	May show abnormalities in MCAD deficiency and long chain fatty acid oxidation disorders
Urine	Organic acids	First urine sample passed following hypoglycaemia episode. Freeze.	Send to biochemistry	Evidence of abnormalities in organic acid disorders, fatty acid oxidation defects. Ketosis excludes endogenous hyperinsulinism.

Treatment of persistent hypoglycaemia

Whilst investigating possible underlying causes, treatment should continue as per the WoS guidelines entitled ‘Hypoglycaemia: term infants’ or 'Hypoglycaemia preterm infants'. If an underlying cause is identified, advice should be sought from the endocrine/metabolic team.

The aim of treatment is to maintain BM>3.0 mmol/l in the first 48h and 3.5 mmol/l thereafter, this reduces the risk of hypoglycaemia and subsequent neurological impairment.

Treatment of refractory hypoglycaemia

If concerns re ongoing hypoglycaemia, blood sugars should be monitored at least 4-6 hourly, ideally pre-feed. Closer monitoring will be required after any change in therapy, particularly if reduction in glucose delivery. Blood sugars should be taken using the blood gas analyser machine, as bedside BM monitors are not accurate with glucose levels <3mmol/l. There should be early consideration of central access for the neonate.

Escalation and de-escalation of therapy management flowchart

*If unable to keep Glucose >3.0 mmol/l in the first 48h or >3.5 mmol/l thereafter, consider escalation of therapy and discussion with endocrine/metabolic team.

Drugs which may be recommended by the Metabolic/Endocrine service:

For doses please see relevant pharmacy monographs

Drug	Prior to initiation	Route	Side effects
Glucagon	Consider central IV access	IV/IM bolus OR IV infusion	GI disturbance, decreased gastric acid and pancreatic enzyme production, increased myocardial contractility.
Diazoxide	Echocardiogram Reduce fluids to 130ml/kg/day for at least 24 hours prior to commencement.	Oral	Pulmonary hypertension, fluid retention, hyponatraemia, heart failure, hyperuricaemia, hypertrichosis, leucopoenia, thrombocytopenia.
Chlorthiazide		Oral	Electrolyte imbalance.
Maxijul / Polycal		Oral	Constipation

Preparation for discharge

All patients who have required medication to treat refractory hypoglycaemia should have a ‘Fasting Challenge’ performed prior to discharge to ensure they would tolerate a missed feed in the community. During this challenge, one of the usual 3 hourly feeds should be omitted and glucose should be monitored hourly after the scheduled omitted meal until 6 hours post feed. The following observations should also be noted on an hourly basis:

Level of consciousness (responsive and can be roused)
Tone (normal)
Temperature (36.5-37.5 degrees Celsius)
Respiration (consistently >30, <60)
Colour (pink)

If this is satisfactory, the baby can be safely discharged. The parents should however be advised that they must feed their infant at a minimum of every 3 hours. The parents should also be advised of the symptoms to watch for which may signify hypoglycaemia (jitteriness, lethargy, high pitched cry) and to seek medical advice if they have any concerns.

NB – if the blood glucose falls below 2.6mmol/l , the baby should be fed and the fasting test abandoned. Regular 3hly feeds should be recommenced and the test repeated after an interval (interval to be determined by the medical team).

Appendix 1: Neonatal Hypoglycaemia Results Sheet

Neonatal Hypoglycaemia Results Sheet (pdf)

Appendix 2: Example care plan for discharge of babies who have refractory hypoglycaemia

Example care plan for discharge of babies who have refractory hypoglycaemia (pdf)
(please discuss with endocrine team)

Last reviewed: 03/07/2020

Next review date: 01/07/2023

Author(s): Dr Angela Lucas-Herald, Clinical Research Fellow, Royal Hospital for Children, Glasgow; Dr Guftar Shaikh, Consultant Endocrinologist, Royal Hospital for Children, Glasgow; Dr Alison Cozens, Consultant in Inherited Metabolic Diseases, Royal Hospital for Children, Glasgow; Dr Andrew Powls, Consultant Neonatologist, PRM..

Approved By: West of Scotland Managed Clinical Network Neonatology

Related resources

Useful websites:
IMD Scotland website www.imd.scot.nhs.uk

References

Dacou-Voutetakis, C., Psychou, F. and Maniati-Christidis (1998). Peristenthyperinsulinaemic hypoglycaemia of infancy: long-term results. Journal of Pediatric Endocrinology and Metabolism, 11, 131-141.

Kuschel, C. and Knight, D. (2007). Newborn Services Clinical Guideline, Fluid and Glucose Requirements.

Menni, F., de Lonlay, P., Sevin, C., Touati, G. Peigne, C., Barbier, V., Nihoul-Fekete, C., Saudubray, J-M and Robert, J-J (2001). Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinaemic hypoglycaemia. Pediatrics, 107, 476-479.

Robinson, P., Kirk, J., Schwahn, B., Farmer, G., Galloway, P. IMD Protocols Subgroup, Jackson, L. and Simpson, J. (2009). IMD Scotland guideline, Investigation of hypoglycaemia in neonates, infants and young children.