Endgames Case Report

A hypoglycaemic baby on the postnatal ward

BMJ 2010; 341 doi: http://dx.doi.org/10.1136/bmj.c4626 (Published 27 October 2010) Cite this as: BMJ 2010;341:c4626

This article has a correction. Please see:

  1. Sagarika Ray, specialty training registrar (st5), paediatrics
  1. 1Northampton General Hospital, Northampton NN1 5BD
  1. Correspondence to: S Ray sagarikaray{at}hotmail.com

A baby girl, weighing 3520 g (91st centile) was born at 38+1 weeks’ gestation by instrumental delivery. Apgar scores were normal. The pregnancy had been uneventful with no history of maternal diabetes mellitus. She was taking breast and bottle feeds well. The midwife on the postnatal ward noted that she was jittery and sweating excessively at 34 hours of age and referred her to the paediatric team on call.

Examination on the neonatal unit showed that she was jittery and sweaty with mid-facial hypoplasia, “cherubic” facies, abnormal ear lobe creases, neonatal teeth, and right hemi-hypertrophy. Her occipito-frontal circumference measured 32.5 cm (9th centile). Other observations were oxygen saturations 95% in air, respiratory rate 45-60 breaths/min (normal range 35-55), heart rate 133-140 beats/min (normal range 100-150),1 and blood pressure 83/39 mm Hg (50th centile for systolic and diastolic cuff blood pressure measurement at this age is 70 mm Hg and 55 mm Hg, respectively).2 A capillary blood gas showed mild respiratory acidosis. The bedside blood glucose concentration was 0.8 mmol/l. She was given an intravenous dextrose bolus and a dextrose infusion was started. Despite this, she remained hypoglycaemic.

Questions

  • 1 What are the causes of hypoglycaemia in neonates?

  • 2 How would you manage a neonate with hypoglycaemia?

  • 3 What other relevant investigations should be performed?

  • 4 On the basis of the clinical findings, what is the baby’s likely diagnosis?

  • 5 What are the long term implications of neonatal hypoglycaemia?

Answers

1 What are the causes of hypoglycaemia in neonates?

Short answer

Causes of neonatal hypoglycaemia can be broadly grouped into those related to a lack of substrate (ketotic) and those related to excess insulin (non-ketotic). Ketotic causes include prematurity, being small for gestational age, sepsis, polycythaemia, hypoxic ischaemic encephalopathy, maternal labetalol intake, and enzymatic defects that affect glucose metabolism. Non-ketotic causes include maternal diabetes, fatty acid oxidation defects, and transient or persistent states of hyperinsulinism.

Long answer

Hypoglycaemia in the neonate can be broadly classified into two groups: ketotic and non-ketotic.

In the ketotic group, a lack of insulin and subsequent lipolysis can lead to formation of ketones. This is often seen in conditions where there is a lack of substrate, such as small for gestational age babies, prematurity, birth asphyxia, infection, polycythaemia, and enzymatic defects affecting gluconeogenesis or glycogenolysis. Hypoglycaemia is often transient and resolves after appropriate treatment, except in babies with inborn errors of metabolism.

The non-ketotic group may have inappropriately high concentrations of circulating insulin. This is often seen in infants with Beckwith-Wiedemann syndrome, congenital hyperinsulinism, islet cell adenomas, rhesus isoimmunisation, and fatty acid oxidation defects, in addition to babies whose mothers have diabetes. It is usually caused by a transient increase in insulin secretion in response to a hyperglycaemic fetal environment. Some babies may be resistant to treatment, and hyperinsulinism is the most common cause of persistent hypoglycaemia in infancy.1

2 How would you manage a neonate with hypoglycaemia?

Short answer

Any acutely unwell baby will need initial assessment and resuscitation according to the ABC (airway, breathing, circulation) mnemonic. The method used to restore euglycaemia will depend on the baby’s clinical status and the suspected aetiology. Mild hypoglycaemia in asymptomatic babies can be treated initially by enteral feeds and pre-feed blood glucose monitoring. Symptomatic hypoglycaemia or refractory hypoglycaemia are indications for treatment with intravenous dextrose. Babies with hyperinsulinaemia will need high concentration infusions of dextrose via central venous access and possibly glucagon infusions.

Long answer

Management of neonatal hypoglycaemia should be directed towards keeping blood glucose concentrations above 2.5 mmol/l in babies with abnormal clinical signs.3 The operational threshold for clinical intervention in neonates who are “at risk” of hypoglycaemia is 2 mmol/l.4 Mild hypoglycaemia in asymptomatic babies can be initially treated by enteral feeds and pre-feed blood glucose monitoring. Symptomatic hypoglycaemia or refractory hypoglycaemia that fails to respond to enteral feeds requires treatment with intravenous dextrose. Symptomatic infants should be given a bolus of 2 ml/kg body weight of 10% dextrose over five to 10 minutes. This rapidly increases glucose concentrations in the short term but does not cause rebound hypoglycaemia as a result of pancreatic β cell stimulation.5 At the same time, a continuous dextrose infusion should be started or its rate increased (box). Blood glucose should be checked 30 minutes after an intravenous bolus, then every one to two hours until at least two readings above the therapeutic threshold of 2.5 mmol/l are obtained.6 7 If this goal is maintained, the intravenous drip can be weaned off gradually and blood glucose can then be checked four to six hourly during the first 48 hours.7 The therapeutic threshold is higher than the operational threshold to leave a high margin of safety in the absence of data. Enteral feeds should be reintroduced as soon as feasible.

Calculation for glucose requirements

  • Amount of glucose (mg/kg/min)=(concentration of dextrose (%)×ml/h×0.167)/weight (kg)

  • Preterm infant requirement: 6-8 mg/kg/min

  • Term infant requirement: 4-6 mg/kg/min6

Glucose utilisation rates of more than 10 mg/kg/min may suggest hyperinsulinism, pending the results of blood insulin measurement.3 In babies with hyperinsulinism, it is advisable to keep the blood glucose concentration above 3.5 mmol/l because they will have low concentrations of alternative substrates, such as ketones, for brain metabolism.3 They will need infusions of high concentration (12.5-20%) dextrose, which may cause damage to peripheral veins, so central venous access (umbilical venous catheter or percutaneously inserted long line) is required. The glucose requirement may range between 15 mg/kg/min and 20 mg/kg/min.

Glucagon infusions are beneficial in problematic neonatal hypoglycaemia of various causes.8 Glucagon can also be given as an intramuscular bolus (100-200 μg/kg) during temporary lapses in venous access.3 To avoid paradoxical insulin secretion, vary the rate of infusion between 1 μg/kg/h and 10 μg/kg/h.9

Hyperinsulinaemic hypoglycaemia may require longer term treatment with oral antihypoglycaemic agents like diazoxide (which stops insulin secretion via interaction with K-ATP channels in the pancreatic β cell membrane)10 along with chlorothiazide, which counteracts its fluid retention property.11 Octreotide can be used temporarily, but occasionally pancreatectomy is required.11

3 What other relevant investigations should be performed?

Short answer

Bedside blood glucose concentrations below 2.6 mmol/l must be verified by a laboratory test. If the infant does not respond to intravenous dextrose infusions, initial investigations should include testing for the presence of urinary ketones and a blood gas to detect acidosis. The results may indicate further tests to investigate hyperinsulinism (blood for insulin measurement), inborn errors of metabolism (blood for ketones, lactate, ammonia, β hydroxybutyrate, and acylcarnitine; urine for organic acids, reducing substances, and ketones), and endocrine disorders (cortisol, growth hormone).

Long answer

Bedside blood glucose concentrations will need to be confirmed by laboratory methods.6 Once this is established, testing urine for ketones can help to differentiate between ketotic and non-ketotic causes. Further investigations should be undertaken during an episode of hypoglycaemia and should be tailored to the clinical situation—for example, high glucose utilisation rates may indicate hyperinsulinism, history of parental consanguinity may indicate investigations for inborn errors of metabolism, and physical findings may indicate endocrine causes (table).

Initial investigations in symptomatic or severe neonatal hypoglycaemia* 7

View this table:

4 On the basis of the clinical findings, what is the likely diagnosis in this baby?

Short answer

Beckwith-Wiedemann syndrome is a possible diagnosis in view of the subtle dysmorphic features and hyperinsulinaemic hypoglycaemia.

Long answer

This child probably has Beckwith-Wiedemann syndrome. This is a congenital overgrowth syndrome with an incidence of 1:15 000 births that is clinically and genetically heterogeneous.12 It is caused by mutations in the chromosome 11p15.5 region, close to the genes for insulin, two subunits of the K-ATP channel (SUR and KIR 6.2), and insulin-like growth factor 2. The genetics of this syndrome are complex; sporadic or familial incidence of duplications and genetic imprinting from a defective or absent copy of the maternally derived gene are involved in the variable features and patterns of transmission. Currently, diagnosis is made by clinical evaluation and not by genetic testing, which is available for only 70% of genetic mechanisms.13

These children may present clinically with macrosomia, macroglossia, abnormal ear creases, anterior abdominal wall defects (exomphalos), visceromegaly, genitourinary anomalies, and hemihypertrophy.

Hyperinsulinaemic hypoglycaemia occurs in about 50% of such children and may be due to abnormalities in the K-ATP channels and diffuse pancreatic islet cell hyperplasia. It usually resolves with medical treatment over weeks to six months,1 although some patients will need pancreatectomy.1 The prognosis with regard to hypoglycaemia is usually excellent, although there are other associated complications. Microcephaly and retarded brain development may occur independently of hypoglycaemia. There is a predisposition to embryonal malignancies, with Wilms’s tumour and hepatoblastoma being the most common.

5 What are the long term implications of neonatal hypoglycaemia?

Short answer

Babies with symptomatic hypoglycaemia may have adverse neurodevelopmental outcomes that often depend on the degree or duration of hypoglycaemia. Specific changes may also be noted on computed tomography and magnetic resonance imaging of the brain.

Long answer

No conclusive data are available on the long term effects of asymptomatic hypoglycaemia in term infants.6 Neonatal onset congenital hyperinsulinism is a major risk factor for the development of severe mental retardation and epilepsy because of the lack of alternative substrates for the brain to use.11 14 15 “Severe” hypoglycaemia is that which satisfies Whipple’s triad—namely, clinical features typical of hypoglycaemia, evidence of low plasma glucose by accurate methods, and resolution of clinical features soon after normoglycaemia is established. It does not imply that neurological impairment is inevitable.16 Selective neuronal necrosis in multiple brain regions has been noted in severe hypoglycaemia.6 Computed tomography and magnetic resonance imaging have shown that hypoglycaemic brain injury affects the superficial cortical layers, especially in the occipital areas as opposed to the frontal areas.17 The temporal areas are least affected and the brain stem and dentate nucleus are spared.18 19 Electrophysiological changes occur in the brain when blood glucose is below 2.6 mmol/l,20 but the duration of hypoglycaemia is more strongly associated with lower developmental scores at 18 months of age.21

Patient outcome

Despite the initial infusion of 120 ml/kg/day of peripheral intravenous 12.5% dextrose (providing 10.4 mg/kg/min of glucose), she remained hypoglycaemic. The blood glucose concentration later stabilised on 20% dextrose infusion. She also required an exogenous glucagon infusion for four days. She was gradually weaned off of dextrose infusions, which were stopped when she established full enteral feeds on day 17. Oral diazoxide and chlorothiazide were started on day 10. A trial of stopping diazoxide on day 23 was unsuccessful and she has continued taking this drug since day 25. Differential diagnoses were Beckwith-Wiedemann syndrome and congenital hyperinsulinism.11 Hyperinsulinaemic hypoglycaemia was confirmed by investigations: true laboratory glucose <1.1 mmol/l, insulin 107 pmol/l (normal range 0-60 pmol/l), cortisol 1351 mmol/l (120-620 mmol/l), 3 hydroxybutyrate <0.1 mmol/l, free fatty acids 0.5 mmol/l, lactate 3.6 mmol/l, ammonia 82 mmol/l (5-100 mmol/l), and haematocrit 67%. Chromosomal analysis showed that mosaic paternal isodisomy of 11p15 was unlikely and may not be detectable when levels of isodisomy are very low. A diagnosis of Beckwith-Wiedemann syndrome was made on the basis of the clinical findings because about 30% of cases cannot be confirmed on genetic testing.

Notes

Cite this as: BMJ 2010;341:c4626

Footnotes

  • Competing interests: The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declares: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.

References