Although hypoglycaemia is one of the most common paediatric emergencies, consensus on a definition and investigations have not been reached. Even the definition of hypoglycaemia itself is a contentious subject. Specific guidance regarding intervention thresholds and investigation indications vary across countries and institutions.
Given the lack of consensus guidelines, a straightforward, structured approach to investigation and management is paramount to ensure accurate diagnosis and timely, appropriate management.
Please note: This article will focus mainly on hypoglycaemia beyond the early neonatal period and in the non-diabetic patient.
What is hypoglycaemia?
Hypoglycaemia is a blood glucose level (BGL) low enough to cause signs and/or symptoms of impaired brain function and neurogenic response. This response varies between individuals, age groups and developmental stages, so a single plasma concentration cannot be defined. As such, thresholds for intervention remain under debate and vary across different hospitals and countries.
Confirmation of the Whipple’s triad is valuable in older children:
- Symptoms and signs consistent with hypoglycaemia
- An accurately measured low plasma glucose concentration and
- Relief of symptoms and signs when plasma glucose concentration is returned to normal.
For infants older than 48 hours of life and young children who cannot communicate, you should consider treatment if BGL <3.3mmol/L or 60mg/dL. You can use Whipple’s triad for older children who can communicate their symptoms. For neonates under 48 hours old, the definition of hypoglycaemia is particularly contentious – however, it is essential to note that a BGL of 2.6mmol/L or 44mg/dl warrants immediate intervention. Again, this is a general guide only. When interpreting BGLs, it is important to check your local policy and discuss with a senior colleague if you are unsure.
How does the body maintain a normal blood glucose level?
Understanding how the body maintains a normal BGL (i.e. glucose homeostasis) is the first step in conquering hypoglycaemia.
Glucose is the primary source of fuel for our cells. It is the primary energy source for both anaerobic and aerobic metabolism. Several different pathways work in concert to maintain glucose homeostasis. As the brain can only store trivial amounts of glucose in the form of glycogen, it depends on a continuous supply of glucose for optimal functioning. In response to fasting, key changes in the endocrine system are triggered to feed that hungry brain.
First up, there is a decrease in insulin release from the pancreas. Next comes a barrage of counter-regulatory hormones (including glucagon, cortisol, growth hormone and adrenaline), which activate three metabolic “fasting systems”:
- Glycogenolysis (breaking down glycogen)
- Gluconeogenesis (making new glucose)
- Lipolysis and ketogenesis (breakdown of fat to make ketones)
The first two processes, glycogenolysis and gluconeogenesis, occur mainly in the liver. If fasting is prolonged, the body changes tactics and targets adipose tissue as fuel. Lipolysis and ketogenesis lead to an increase in free fatty acids (FFAs) and ketone bodies – beta-hydroxybutyrate (measured in blood) and acetoacetate (measured in urine).
As glucose production declines and ketones increase, the brain gradually switches to ketones as its primary fuel. However, it is important to note that although ketone bodies can act as a complementary energy source in times of glucose shortage, they do not replace the need for glucose; they take time to generate and, at higher levels, are associated with ketoacidosis.
A problem at any step in these pathways can result in recurrent hypoglycaemia.
Learning point: Understanding the different processes and substances involved in the counter-regulatory response informs our approach to investigating hypoglycaemia and helps construct our differential diagnosis.
Why are infants and young children more predisposed to hypoglycaemia than adults?
The adult brain accounts for more than half of total glucose consumption. Because of their disproportionately larger brain size relative to body mass, infants and younger children have a 2-3-fold higher glucose use rate than adults. Multiple other factors, including infant and children’s increased metabolic rate, surface area to body mass ratio, thermoregulation demands and glycogen stores, are also implicated.
Why do we worry about hypoglycaemia?
As the brain has only a few minutes’ worth of stored fuel reserves in the form of glycogen, interruption of glucose delivery can have devastating consequences. Although recovery from brief periods of hypoglycaemia is usually complete, severe and prolonged hypoglycaemia can cause permanent brain injury. The developing brain is particularly vulnerable to injury and long-term effects in younger children.
Infants and children can use ketones for cerebral metabolism. However, free fatty acids and ketone levels are suppressed by insulin. This explains the increased risk of brain injury in infants with hyperinsulinaemic hypoglycaemia (e.g. congenital hyperinsulinism). But more on that later…
Learning point: Brains have a natural sweet tooth and demand a constant energy supply. Severe and prolonged hypoglycaemia can cause permanent brain injury making timely identification and management a top priority.
What are the clinical signs and symptoms of hypoglycaemia?
Hypoglycaemia in neonates is often tricky to recognise clinically. They may be asymptomatic initially and tend to be picked up through targeted surveillance of high-risk infants (e.g. prematurity, intrauterine growth restriction (IUGR), macrosomia or infants of diabetic mothers). Signs and symptoms in this group are often non-specific and can include irritability, hypotonia, lethargy, jitteriness, temperature instability, poor feeding, vomiting, apnoea and seizures.
We can group clinical signs and symptoms of hypoglycaemia in older infants and children into three categories: adrenergic, neuroglycopaenic and behavioural:
- Neurogenic (autonomic) symptoms: tremor, pallor, tachypnoea, tachycardia and diaphoresis – think fight or flight response;
- Neuroglycopaenic symptoms: fatigue, lethargy, headache, drowsiness, unconsciousness, coma and seizures – think a hungry brain whose function is being impacted due to lack of fuel;
- Behavioural symptoms: irritability, jitteriness, quietness/tantrums (most common in young children).
How do I measure hypoglycaemia in the ED?
While point-of-care meters provide a very convenient screening method for detecting hypoglycaemia, their accuracy is limited to approximately +/- 0.6-0.8mmol/L in the hypoglycaemic range.
If there is clinical concern for hypoglycaemia, plasma glucose concentration should be measured. The sample should be run urgently in the lab as delays in processing and assaying glucose can reduce the glucose concentration by up to 0.3mmol/L/hr.
Learning point: Take a plasma glucose sample and ask the lab to run it urgently – time is sugar!
What are the causes of hypoglycaemia?
The differential diagnosis for hypoglycaemia is broad, so a systematic approach is essential. If we don’t think about it, we won’t diagnose it! The table shows some causes of hypoglycaemia, but this is not an exhaustive list.
Case 1
Joey is a two-year-old boy with a two-day history of vomiting, diarrhoea, and reduced oral intake. He is lethargic and pale. His vitals show mild tachycardia and tachypnoea, and his blood pressure is normal. His capillary BGL is 2.5 mmol/L. His finger-prick ketone level is 5.4mmol/L.
Thinking pause: Are you confident in calling this a simple case of gastroenteritis with resultant ketotic hypoglycaemia, or do you need more information?
While your colleague prepares for cannulation and a dextrose bolus, you continue your assessment of Joey, filling in some critical gaps…
- Is there a good history of infective gastroenteritis? “He had a sudden onset vomiting and large volume foul smelling diarrhoea with some mucous. He has also had intermittent fever.”
- Are there any sick contacts? “Yes, Joey’s older sibling had same symptoms a couple of days ago.”
- Relationship to feeding/fasting: “He hasn’t eaten anything since yesterday, today he has just been taking sips of plain water.”
- Any medications Joey could have gotten hold of? E.g. Granny’s gliclazide? “No, there are no medications in the house or potential access to medications.”
- Previously well child? “Yes, he’s never been sick before.”
- Birth history? “He was born at full term, via vaginal delivery. Pregnancy was uncomplicated and he was well after birth. His birth weight was 3.5kg.”
- Have there been any previous episodes of hypoglycaemia? “No, never before.”
- Any growth or developmental concerns? “No, he had his 2 year developmental check with Public Health Nurse and is meeting all of his milestones. They are no concerns regarding his growth.”
- Any family history* of metabolic/endocrine disease? “Not that I know of.”
*Of note: A history of unexplained deaths in infancy and childhood, including sudden infant death, can point towards fatty acid oxidation defects. A history of consanguinity is important to consider when looking at metabolic disorders.
Physical examination: Joey is well-grown. His systemic examination is normal, apart from signs of dehydration. He is lethargic but alert. There are no signs of hyperpigmentation or dysmorphic features. He has no midline defects (e.g. repaired cleft palate) or organomegaly, and his genitalia are normal in appearance.
Thinking pause: OK, Joey’s history fits with gastroenteritis and he doesn’t have any red flags that would point you towards an underlying metabolic or endocrine disorder. With his low BGL and elevated ketones, a diagnosis of ketotic hypoglycaemia is top of your differential diagnosis. But does he need further investigation?
You check your local guidelines. They advise that, in this case, further investigation is not warranted. However, it would be best if you still corrected Joey’s hypoglycaemia. As Joey is vomiting, an IV cannula is inserted, and Joey is administered a bolus of 2ml/kg 10% dextrose. Within minutes, he is feeling better, and his repeat BGL is 4.1mmol/L. Phew…!
There’s lots to unpack in this first case, with many key learning points. So let’s take it step by step…
What is idiopathic ketotic hypoglycaemia (IKH)?
IKH (accelerated starvation) is the most common form of childhood hypoglycaemia. It is a physiological response triggered by decreased oral intake/vomiting due to intercurrent illness and/or prolonged fasting. It usually affects children between 18 months and five years old, who are otherwise well with average growth, development and physical exam.
All children should have outgrown it by ten years old. In general, management centres around education focusing on avoiding prolonged fasts (<12hrs) and emphasising low threshold for admission to hospital if the child is not eating or is vomiting.
What are the key features to consider that may point towards underlying metabolic/endocrine disease?
History – key features
- Any history of hypoglycaemia in the neonatal period?
- Previous stressors: How did the child cope with illness, and fasting previously?
- Relationship of the event to last food intake (inborn errors of metabolism (IEM) often occur after a prolonged fast e.g. with intercurrent illness)
- Specific content of last food intake: E.g. large protein load
- Dietary history: How long do they fast at night? Are they ‘symptomatic’ in the mornings before breakfast?
- Sudden unexplained death including sudden infant death (metabolic disorder – Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
- Birth history including birth weight (history of macrosomia associated with hyperinsulinism)
- Growth and development: Any evidence of poor growth, overgrowth, developmental delay or regression?
Examination – key features
What are the components of a hypoglycaemia screen?
- Plasma glucose
- Beta-hydroxybutyrate (i.e. ketones measured in blood; lack of ketones indicates hyperinsulinism or MCAD deficiency)
- Insulin (should be undetectable. Elevated or detectable levels in the context of hypoglycaemia = hyperinsulinism)
- Growth hormone, cortisol (should both be increased as part of counterregulatory response; no rise = possible deficiency and warrants further investigation)
- Liver function tests
- Blood gas with lactate
- Metabolic work-up: ammonia, serum amino acids, acylcarnitine profile
- Urine organic acids (taken as close to the event as possible).
I could only get a small amount of blood…which tests are the most important?
The most important blood samples are glucose, beta-hydroxybutyrate and insulin, followed by cortisol, blood gas with lactate, and growth hormone. These need to be taken before administering dextrose. The remainder of the investigations can be done when the patient is normoglycaemic if blood sampling is challenging. However, if blood is tough to obtain, do not delay correcting the hypoglycaemia.
What are the criteria for sending a hypoglycaemia work-up?
This is another point where guidelines disagree, and there is no clear consensus. While most reference a BGL of ≤2.6mmol/L as the cut-off for considering a hypoglycaemia workup, the criteria beyond that vary between institutions. Many guidelines recommend a work-up for all children below this threshold.
But considering that accelerated starvation, or ketotic hypoglycaemia, is the most common cause of hypoglycaemia in children – are we at risk of over-investigating children who fit the ‘profile’ of idiopathic ketotic hypoglycaemia?
Some guidelines have aimed to address this by including recommendations for this specific scenario, advising that a hypoglycaemia screen is not warranted. So, you’ll need to take time to review your local guideline. Nevertheless, guidelines do not replace clinical judgement, so detailed history and examination are crucial, explicitly identifying pointers towards an underlying disease.
Learning point: The exact indications for investigation of hypoglycaemia remain up for debate, particularly when it comes to cases consistent with idiopathic ketotic hypoglycaemia. Nevertheless, certain circumstances will always warrant further investigation. These include:
* Infants <1 year old
* Severe hypoglycaemia (defined as a condition with serious cognitive dysfunction, such as convulsion or coma, requiring external help from other persons)
* Recurrent hypoglycaemia
* Hypoketotic hypoglycaemia
* Unexplained hypoglycaemia (no history of prolonged fast or intercurrent illness).
Case 2
You’re called next door to the adjacent bay where Jamie has just landed. He is a four-month-old baby boy who has also presented with vomiting and lethargy. His blood glucose at triage was 2.4mmol/L, with a ketone level is 2.1mmol/L.
You take a focused history, remembering to ask about the key features and find important clinical details. He doesn’t have any diarrhoea or fever. He has no sick contacts. He has been vomiting on and off for the last ten days.
On further questioning, Mum tells you that he has also been having periods of lethargy and sweatiness, which seem to resolve with a feed (Hmm…sounds a bit like Whipple’s Triad). He can also be very unsettled and frequently wakes at night for a feed. Mum brought him to the GP last week, who felt it was colic or reflux. He is exclusively breastfed.
He was born at full term, normal vaginal delivery. Pregnancy was uncomplicated, and he was well after birth. His birth weight was 3.4kg—no known history of hypoglycaemia as a neonate.
His mum is concerned about his development. When she puts him prone, he can barely lift his head and can’t lift himself on his forearms. She also worries about his growth and feels he has not gained much weight in recent weeks.
You take a moment to digest what Mum has told you so far. Even though the presenting issue of vomiting is the same as our first case, this one is very different. Alarm bells are ringing in your head for a potential underlying metabolic or endocrine disorder. It seems as if Jamie could be having recurrent bouts of unexplained hypoglycaemia. His history also has several red flags, including poor growth and developmental delay.
On examination, Jamie’s heart rate is mildly elevated and moderately tachypnoeic. He has poor subcutaneous fat stores with a distended abdomen. On palpation of his abdomen, you can feel significant hepatomegaly.
You insert the cannula, take baseline bloods and a hypoglycaemia screen, and give Jamie a 2ml/kg 10% dextrose bolus. You advise repeating the blood glucose in 15 minutes to ensure it has normalised.
His blood results show:
His biochemistry shows elevated urate and deranged liver function tests with elevated AST/ALT.
Jamie’s acidaemia with elevated lactate, deranged LFTs, and elevated urate is consistent with a glycogenosis. Off you head to call the metabolic consultant on call for further advice for Jamie’s acute management. Later in the week, you get an update from the metabolic team advising that Jamie has been diagnosed with glycogen storage disease I and to commend you for picking up on the key history and exam findings.
Learning point:
* Metabolic disorders are rare individually but are collectively relatively common.
* Adrenal insufficiency, growth hormone deficiency and several metabolic disorders can cause hypoglycaemia WITH ketosis and are at risk of being misdiagnosed as idiopathic ketotic hypoglycaemia.
Case 3
You’re about to finish your shift when you get called in to resus to see John, an eight-year-old boy who has come in with a two-day history of vomiting.
‘Not this again,’ – you think to yourself as you gown up for what feels like the millionth time tonight.
John’s mum gives you the lowdown – he’s been vomiting for two days, and she feels he is getting worse. She brought him to ED because he complained of weakness and dizziness, and she was worried about his hydration. However, as they were walking in, he collapsed.
His mum reports that he hasn’t been well for the last few months, with low energy levels, nausea, and fatigue. He has been intermittently vomiting over the previous three weeks. He has also lost weight. He was seen by his GP a month ago, who felt it might be post-viral. He hasn’t had any bloods done.
You know the drill at this point, and while performing your ABCDE assessment, you notice John is sallow. You find patches of hyperpigmentation on the extensor surfaces of his knees, elbows and knuckles. His gums are also hyperpigmented. He is tachycardic, tachypnoeic and hypotensive with a prolonged capillary refill time and poor peripheral perfusion. He is hypoglycaemic with a BGL of 2.5mmol/L and ketones of 2.6mmol/L.
An IV line is inserted and baseline bloods and hypoglycaemic screen are sent. John receives a 2ml/kg dextrose bolus to correct his hypoglycaemia and a 10ml/kg bolus for his hypovolaemia.
You’re handed the John’s VBG which shows:
John has an uncompensated metabolic acidosis with elevated lactate, hyponatraemia and hyperkalaemia. He is also hypoglycaemic with high ketones.
All signs for John are pointing towards an acute adrenal crisis. You manage John acutely with IV fluids and IV hydrocortisone, calling the endocrine consultant on call, who is delighted to hear that you have sent off a cortisol level before giving the IV hydrocortisone. Later you get an update that John’s cortisol level was very low, and his adrenal autoantibodies were positive. He has been diagnosed with Addison’s Disease and feels much better on his maintenance steroid therapy.
Learning point: Adrenal insufficiency is an insidious diagnosis, presenting with non-specific symptoms, particularly in earlier stages. Depending on the presenting symptoms, it may be misdiagnosed as a variety of conditions, including psychiatric disorders, e.g. anorexia nervosa, depression, viral illness, post-viral fatigue, acute abdomen, cardiovascular disorders and sepsis.
What’s all this fuss about ketones?
All of the cases so far have featured ketotic hypoglycaemia. Although we have learned the vital role ketones play in cerebral metabolism at times of glucose shortage, what role do they play in helping us form a differential diagnosis?
When considering the differential diagnosis the questions to ask are:
- Is this ketotic or hypoketotic?
- Is the hypoglycaemia appropriate for the degree of fasting or ‘metabolic stress’?
- Does the child have any clinical features to suggest this is not “idiopathic ketotic hypoglycaemia”?
The answers to these three questions will aid you in reaching a preliminary diagnosis in many cases of hypoglycaemia after the neonatal period. The list in the table below covers many of the causes but is not exhaustive.
Conclusion
Although each case we encountered began with a history of vomiting and ketotic hypoglycaemia, the underlying causes ranged from classic idiopathic ketotic hypoglycaemia to metabolic disease and life-threatening endocrine disorders.
Our journey through these cases highlights how a structured approach to history, examination and investigations in cases of hypoglycaemia will enable us to form a preliminary differential diagnosis and manage the patient appropriately and promptly.
And as for idiopathic ketotic hypoglycaemia, the jury is still out on whether investigation and follow-up are necessary. To omit further investigation and follow-up, cases must fit the classical picture of idiopathic ketotic hypoglycaemia (occurs in the context of prolonged fast with diarrhoea and vomiting for >24 hours in an otherwise well child > one year old).
Outside of this, all patients should have appropriate investigation and follow-up. A referral is also warranted if the hypoglycaemia is recurrent, severe or occurs after minimal provocation or fasting, or there are any concerning features in the family or patient history or examination.
Next time you encounter unexplained hypoglycaemia in the ED, remember the importance of a focused history and exam. Having a good knowledge of the broad differential diagnoses for hypoglycaemia is vital. If you don’t think about it, you won’t diagnose it! And although we have discussed the importance of sending a hypoglycaemia screen before correcting the hypoglycaemia – remember patient safety is the priority. DO NOT delay correcting the hypoglycaemia if blood is difficult to obtain or the patient is obtunded.
Article peer-reviewed by Dr Niamh McGrath, Consultant Paediatric Endocrinologist in Galway University Hospital, Ireland
References
Casertano A, Rossi A, Fecarotta S, Rosanio FM, Moracas C, Di Candia F, et al. An overview of hypoglycemia in children including a comprehensive practical diagnostic flowchart for clinical use. Frontiers in Endocrinology. 2021;12.
Causes of hypoglycaemia table adapted from Perth Children’s Hospital. Hypoglycaemia. Available at: https://pch.health.wa.gov.au/For-health-professionals/Emergency-Department-Guidelines/Hypoglycaemia).
Donaldson MDC, Gregory JW, Vliet VG, Wolfsdorf JI. Practical endocrinology and diabetes in children. Hoboken: Wiley-Blackwell; 2019.
Starship Child Health. Hypoglycaemia in childhood. 2018. Available at: https://starship.org.nz/guidelines/hypoglycaemia-in-childhood/
Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, et al. Recommendations from the Pediatric Endocrine Society for evaluation and management of persistent hypoglycemia in neonates, infants, and children. The Journal of Pediatrics. 2015;167(2):238–45.
Urakami T. Severe hypoglycemia: Is it still a threat for children and adolescents with type 1 diabetes? Frontiers in Endocrinology. 2020;11.
