Danielle Leemon (Paediatric ST7), Pamela Slevin (Paediatric SAS Doctor), Shilpa Shah (Paediatric Consultant). 

Peer review Dr Sam Thompson (Paediatric Consultant)  Craigavon Hospital, Southern Health & Social Care Trust, Northern Ireland. 

 

Introduction 

Young children and babies often present to the emergency department with febrile illnesses. Most presentations are mild to moderate and do not require proonged hospitalisations or protracted investigations. Due to their higher catabolic rate, smaller glycogen stores and feed refusal during illnesses they are at a higher risk of becoming hypoglycaemic. It is a challenge to recognise the true cause of hypoglycaemia and safely ascribe it to the acute illness rather than an underlying endocrine or metabolic defect. 

In this problem-solving article we explore the causes and stepwise approach to investigating hypoglycaemia in a toddler. We conclude by highlighting some of the limitations and pitfalls in the investigations and top tips. 

Meet Candy…

She is a previously very well 13 month old. She presents to the emergency department with cough and a high temperature of 38°C. She has non-bilious vomiting for the last few hours and hasn’t been able to keep her food down. She has passed urine and has no diarrhoea. 

There are no past medical problems and her birth, immunisation and developmental history are normal. 

Dr Sweet is the F2 trainee who assesses her. Candy’s examination shows:

Airway		Patent
Breathing	Resp rate:	30/min
	Work of breathing:	No increase
Circulation	Heart rate:	160 bpm (raised)
	Capillary refill time:	Normal
	Mucous membranes:	Dry
	Blood pressure:	86/55mmHg (50th centile)
Disability		Awake and alert but slightly withdrawn
		No signs meningism
	Temperature:	38°C
Exposure		No rashes
ENT		Inflamed posterior pharynx with no pus
Systemic examination		Normal Normal growth No dysmorphic features
Impression: “Viral upper respiratory tract illness with gastritis”.

---

She receives symptomatic treatment with paracetamol, topical analgesic spray and a dose of anti-emetic medication before a trial of oral fluid is initiated. 

Sister Zucker checks Candy’s blood sugar via a point-of-care meter and finds it is only 1.8mmol/Litre. She arranges treatment with Gluco-juice (a fast acting oral carbohydrate) orally but reminds Dr Sweet to send investigations for hypoglycaemia before treatment is initiated if possible. 

What is hypoglycaemia? 

Hypoglycaemia is a plasma glucose level that is low enough to cause signs and symptoms of brain dysfunction (neuroglycopenic symptoms). As this response can differ between individuals hypoglycaemia cannot be defined as a single plasma concentration.

It is important to recognise that different guidelines exist for: neonates, children, and diabetics. Thresholds for intervention are currently under debate and vary between hospitals and countries, but as a general guide, you should consider treatments if BGL <2.6mmol/L for neonates, <3.4mmol/L for children, and <4.0mmol/L for diabetics.  So check your local policy, or discuss with senior colleagues if you are unsure.  

How does it present?

Symptoms

Many neonates are initially asymptomatic and detection of hypoglycaemia is reliant on surveillance of high-risk infants such as prematurity, intrauterine growth retardation (IUGR) or infant of diabetic mothers

Babies may present with irritability, jitteriness, hypotonia, lethargy, temperature instability, poor feeding, vomiting, apnoea and seizures.

Hypoglycaemic symptoms in infants and children may be adrenergic, neuroglycopenic and behavioural.

• Adrenergic symptoms: tremor, pallor, tachycardia, tachypnoea and diaphoresis
• Neuroglycopenic symptoms: fatigue, lethargy, headache, drowsiness, unconsciousness, coma and seizures.
• Behavioural symptoms: irritability, jitteriness, quietness, or tantrums and are most common in young children.

What are the causes of hypoglycaemia in a toddler? 

Glucose being the main fuel of life, there are a number of different pathways to manage plasma levels.  These are both endocrine and metabolic, involving the liver, muscle and pancreas as the main organs of control as demonstrated in this diagram:

Figure 1: Normal physiological response to hypoglycaemia

So, in a normal physiological response to low glucose you get:

• Increased glucagon and decreased insulin
• Adreno-cortical axis activation
• Release of alternative substrates from muscle and adipose tissue
• Glycogenolysis and gluconeogenesis 
• Fatty acid oxidation in mitochondria
• Release of byproducts 

And every pathway here can have a defect resulting in signs and symptoms alongside hypoglycaemia.  Eg. Glycogen storage disorders, growth hormone deficiency, hyperinsulinaemia, and many others  

For a full overview see this ADC article. 

But these disorders a relatively rare, so what is more likely in little children?

Idiopathic ketotic hypoglycaemia (Accelerated starvation)

• caused by reduced oral intake following gastro intestinal infections, vomiting or prolonged fast. 
• often resolves by 6yo 
• should be a diagnosis of exclusion since endocrine diseases and Glycogen Storage Disease can present with ketotic hypoglycaemia. 

• However it is reasonable to hold off extensive work-up of endocrinopathy or metabolic disorders in a previously healthy child with normal growth and development, a first episode of symptomatic fasting hypoglycemia (either in the setting of an infection or reduced oral intake) with ketonuria, without hepatomegaly and with resolution of symptoms upon administration of glucose (3)

REMEMBER Other causes

• Sepsis
• Accidental ingestions-oral hypoglycaemic agents, beta-blockers, insulin
• Malnutrition, starvation, prolonged fasting.

 

Investigations 

As recommended in the National Metabolic Biochemistry Network best practice guideline for the investigation of hypoglycaemia, some laboratories across the country have special packs containing specimen tubes and request forms for investigating non-diabetic hypoglycaemic episodes in children.  (4).

These bespoke packs are termed ‘Hypopack’ (5) they may differ from region to region but the overarching principles are the same. 

Bottle	Test	Interpretation
Bottle A Fluoride oxalate tube	Blood sugar Lactate & 3 hydroxy-butyrate 1ml blood required	Normal lactate < 0.5-1mmol/L. If elevated consider sepsis, glycogen storage disorder
Bottle B Plain clotted tube	Insulin, Cortisol, Growth hormone, Amino-acids  3ml blood required	If glucose < 2.6mmol/L then: – Cortisol should be more than 450mmol/L – Insulin should be undetected or very low in hypoglycaemia.   – Growth Hormone usually delayed rises (if < 3ng/L then assessment for GH deficiency advised).   Haemolysis can affect levels of several aminoacids so interpret with caution.Increased valine, isoleucine and leucine and decreased proline are consistent with initial metabolic response to hypoglycaemia
Gutherie card	Acyl-carnitine profile 2-3 spots of blood	Elevated levels are consistent with a lipolytic and ketogenic response to hypoglycaemia (this would be considered normal)
Bottle C Universal urine container	Urine Organic Acids 2ml Urine required	Lactic acid, 3-OH butyrate, acetoacetate and medium chain fatty acids are elevated in appropriate response to hypoglycaemia. Must be obtained as soon as possible after the hypoglycaemic episode. Catheterization may be required if clinical suspicion is high

Laboratory challenges

• Inform laboratory when sending a Hypo pack.
• Rapid transfer to the laboratory will prevent delay in management and unnecessary further venepunctures if samples are unsuitable due to incurred delay. 

• Threshold for use (to avoid wasting resources):

•  Blood Sugar < 2.6mmol/L ( non-type 1 diabetes infant or child where an underlying metabolic or endocrine cause is suspected.) 

• enter as much clinical detail as possible to help laboratories interpret the results including the use of a dextrose bolus given before bloods were obtained. This is extremely important to interpret insulin result.

• Signs of encephalitis? Send additional tests such as Ammonia, Liver and Renal functions. This is irrespective of hypoglycaemia. Standard Hypo packs do not contain these. Ammonia samples need to be sent over ice which itself can be a logistic challenge!

Back to Candy:

Her initial blood gas showed:

• normal PH 
• lactate of 1.1.
• Her point of care ketone check was 2.6 (this is raised) 

She received oral treatment for hypoglycaemia, paracetamol for fever and ondansetron for vomiting. She was observed on the ward for 8 hours where her oral intake improved, her vomiting subsided, her heart rate, temperature and blood sugar showed sustained improvement to normal range. 

She was discharged home with safety netting advice of feeding little and often and continue fluids. 

Red flags such as bilious vomiting, lethargy or new onset petechiae were explained. 

Candy’s hypo pack results (results commonly take days to weeks to come back)

Test	Result	Interpretation
Cortisol	592 nmol/L	This is appropriately elevated in response to hypoglycaemia
Insulin	<1 mU/L	This is appropriately low in response to hypoglycaemia
Growth Hormone	6.5ng/L	This is mildly elevated in response to hypoglycaemia
3-hydroxy butyrate	3.98 mmol/L (ref range 0.03-0.30)	This is appropriately elevated due to hypoglycaemia
Amino acid profile	mild elevation of glucogenic aminoacids	This is an appropriate response
Urine organic acid	mild elevation is medium chain fatty acids	appropriate response to hypoglycaemia

Final diagnosis therefore is Idiopathic ketotic hypoglycaemia of infancy

Subsequent management:

Phone review was undertaken after 2 weeks.  She continues to do well. Her mother Mrs Baker was informed about the results and no further review is planned. 

 

A note on ketones & blood v urine tests:

• Blood ketones in tests are 3 hydroxy-butyrate
  • This has higher sensitivity and specificity for blood ketosis so are preferred. In some hospitals, as blood ketones sticks are expensive, they may be saved for known diabetics or high blood sugar cases (to help manage DKA).
• Urinary ketone tests measure acetoacetate 

 

Resources

Check out the following hypoglycaemia in children guidelines. You might find some useful pearls in there. Of course your own region may have bespoke guidelines too

• Royal Children’s Melbourne Guideline

• Scottish Paediatric Hypoglycaemia Guideline 

 You may find a Podcast from the makers of “2 Paeds in a Pod “episode 49 where Dr Ian Lewins talks all things hypoglycaemia with Dr Rachel Smith very useful. Some top tips in there. This is free to download and worth a listen. 

References

1. Mark A. Sperling. Nelson Textbook of Pediatrics, Chapter 111, 848-862.e1

2. Sperling MA. Editor. Pediatric Endocrinology. 3rd edition. Philadelphia: Elsevier/Saunders, 2008. 

3. Pershad J, Monroe K, Atchison J. Childhood hypoglycemia in an urban emergency department: epidemiology and a diagnostic approach to the problem. Pediatr Emerg Care. 1998;14:268–71.

4. Losty H. National Metabolic Biochemistry Network: Guidelines for the Investigation of Hypoglycaemia in Infants and Children. See [www.metbio.net]

5. Lang T, Cardy D, Carson D, Loughrey C etal. Audit of acute hypoglycaemia in children: re-audit of procedures for diagnosis. Ann Clin Biochem 2008; 45: 486–488. DOI: 10.1258/acb.2008.008037

6. Glucose Regulation.  Associate Degree Nursing Physiology Review. Auston Community College

7. Ghosh A, Banerjee I, Morris AAM. Recognition, assessment and management of hypoglycaemia in childhood.  Archives of Disease in Childhood 2016;101:575-580.

8. Jae-Seung Yun, Seung-Hyun Ko.  Avoiding or coping with severe hypoglycemia in patients with type 2 diabetes. The Korean Journal of Internal Medicine 2015;30(1):6-16.

 

Published May 2020