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

exp date isn't null, but text field is

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):

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 (<10th 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.

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

Editorial Information

Last reviewed: 03 July 2020

Next review: 01 July 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.

Co-Author(s): Other specialists consulted (previous drafts): Fiona Anderson, Pharmacist, PRM; Stephen Bowhay, Pharmacist, Royal Hospital for Children, Glasgow; Dr Jane McNeilly, Principal Biochemist, Royal Hospital for Children, Glasgow; Dr Bernd Schwahn, Consultant Metabolic Medicine, RHSC, Yorkhill; Dr Peter Robinson, Consultant Metabolic Medicine, Royal Hospital for Children, Glasgow.

Approved By: West of Scotland Managed Clinical Network Neonatology