Hypoglycaemia: quick reference for emergency management

Emergency overview

Measure the plasma glucose immediately in everyone with a reduced level of consciousness, seizures, confusion, a change in behaviour, collapse or an acute neurological deficit. Hypoglycaemia can cause hemiparesis, aphasia and radiological changes resembling ischaemic stroke. Glucose measurement is therefore always part of the initial stroke assessment [1].

Treat immediately when there are symptoms and a low glucose. Do not wait for the venous laboratory result.

1. Assess and stabilise the airway, breathing and circulation.
2. Measure the capillary or venous glucose.
3. Give a rapid-acting carbohydrate orally if the patient can swallow safely.
4. Give intravenous glucose if the patient has a reduced level of consciousness, is having seizures or cannot swallow.
5. If there is no intravenous access, give glucagon and establish access at the same time.
6. Measure the glucose again after 10 to 15 minutes and repeat treatment until the patient has recovered.
7. Follow up with a meal or with continued glucose administration adapted to the cause.
8. Identify drugs, renal failure, alcohol, a missed meal, physical activity and any other precipitating factor.

Thresholds

The thresholds below are used above all in diabetes. The severity of the symptoms and the patient's need for help matter more than a single measured value [2].

Level 3 can occur even when the glucose has already begun to rise by the time it is measured, for example after relatives have given carbohydrate or glucagon.

In a person without diabetes, a hypoglycaemic disorder is defined primarily by Whipple's triad:

1. Symptoms or signs consistent with hypoglycaemia.
2. A documented low plasma glucose during the symptoms.
3. Resolution of the symptoms when the glucose is normalised [3].

A healthy person without diabetes therefore does not normally need investigation on the basis of an isolated, asymptomatic low sensor reading alone.

Symptoms

Autonomic symptoms

Early warning symptoms are due to sympathetic activation:

• sweating
• tremor
• palpitations
• hunger
• anxiety
• pallor
• paraesthesiae

Neuroglycopenic symptoms

An inadequate supply of glucose to the brain can cause:

• difficulty concentrating
• irritability or abnormal behaviour
• slurred speech
• visual disturbance
• confusion
• focal neurological signs
• drowsiness or unconsciousness
• seizures
• coma

The symptom threshold varies. After prolonged hyperglycaemia the patient may experience hypoglycaemia-like symptoms at a normal glucose. With frequent hypoglycaemia the warning symptoms may instead be absent until the glucose has become very low [4].

Sampling and measurement error

A capillary glucose is sufficient to start emergency treatment, but abnormal or unexpected values should be confirmed with a laboratory-analysed plasma glucose when the situation allows.

Glucose meters are less reliable in the hypoglycaemic range. Poor peripheral circulation, cold fingers, sampling errors and contamination can give erroneous values. If the measured value does not fit the clinical picture, repeat the sample and send a venous plasma glucose, but do not delay treatment of a neurologically compromised patient.

Continuous glucose monitoring reflects interstitial glucose and lags behind the blood glucose during rapid changes. Pressure on the sensor, for example during sleep, can give falsely low values. When there are symptoms or an unexpected sensor value, the glucose should therefore be checked with a capillary or venous measurement [5].

Treatment

The awake patient who can swallow safely

Give 15 to 20 g of rapid-acting carbohydrate orally. Suitable options are:

• glucose tablets or dextrose with a stated carbohydrate content
• a glucose solution
• juice or a sugar-sweetened drink

Measure the glucose again after about 15 minutes. Give a further 15 to 20 g if the glucose is still below 3.9 mmol/L or if clear symptoms persist. Oral glucose is the first-line treatment in an awake and cooperative patient [6].

Chocolate, pastries and other fatty foods are unsuitable as initial treatment, since fat delays carbohydrate absorption. They may, however, form part of a later meal.

Do not give food or drink to a patient who is drowsy, is having seizures, is vomiting or cannot protect the airway.

The patient with a reduced level of consciousness or who cannot swallow

1. Secure the airway and give oxygen if needed.
2. Place the patient in the recovery position if appropriate.
3. Establish intravenous or intraosseous access.
4. Give intravenous glucose according to the local emergency drug protocol.
5. Check the glucose and the neurological status after 10 to 15 minutes.
6. Repeat the glucose if needed.
7. Start a glucose infusion if the cause has a long duration or the glucose falls again.

Different units use different glucose concentrations. Follow the local protocol for the volume, the concentration and the infusion rate. The aim is to reverse the neuroglycopenia and then keep the glucose stable, not to induce marked hyperglycaemia.

Monitor the potassium with large or prolonged glucose administration. The combination of an excess of insulin and glucose treatment can lower the plasma potassium [7].

No intravenous access

Give glucagon intramuscularly, subcutaneously or intranasally according to the summary of product characteristics and the local protocol. At the same time establish intravenous access if the patient is severely affected.

Glucagon is a temporary rescue treatment. Its effect depends on available hepatic glycogen and may be insufficient in:

• prolonged fasting or marked malnutrition
• alcohol-related hypoglycaemia
• severe liver disease
• recurrent hypoglycaemia with depleted glycogen stores

Nausea and vomiting are common after glucagon. Protect the airway and give carbohydrate as soon as the patient is awake and able to swallow.

Ready-to-use and intranasal glucagon preparations are easier for relatives to administer than traditional preparations that must first be reconstituted. In studies, intranasal and injected glucagon have usually raised the glucose within 15 to 30 minutes, but intravenous glucose is faster and more predictable when access is available [8].

After the patient regains consciousness

Once the patient can swallow safely, give a meal or a snack that provides a more sustained supply of carbohydrate. Combining carbohydrate with protein and ordinary food is preferable.

Such a meal is particularly important if the next regular meal is a long way off, if the patient has taken basal insulin, or if physical activity has contributed. It does not, however, replace a glucose infusion, an antidote or observation in sulfonylurea toxicity, insulin overdose or any other persisting drug effect.

Check the glucose repeatedly. A single normal value immediately after treatment shows only that the glucose given has had an effect, not that the risk of recurrence has passed.

Thiamine in alcohol use and malnutrition

Where there is a risk of thiamine deficiency — for example prolonged harmful alcohol use, severe malnutrition, prolonged vomiting or suspected Wernicke's encephalopathy — give parenteral thiamine as soon as possible according to the local protocol.

Emergency glucose treatment must, however, never be delayed while awaiting thiamine. The evidence does not support a requirement for thiamine before a single dose of glucose. The risk relates chiefly to continued or repeated glucose administration in a patient with untreated thiamine deficiency. Thiamine can therefore be given before, at the same time as, or immediately after glucose, depending on what is practically fastest [9].

Specific causes

Rapid-acting insulin

Hypoglycaemia after a mealtime dose is often due to:

• too high a dose
• the wrong insulin preparation
• a missed or delayed meal
• incorrect carbohydrate counting
• vomiting or malabsorption
• physical activity
• alcohol
• a reduced insulin requirement, for example after weight loss or in renal failure

Establish which preparation was given, the dose, the time, and whether the patient may have confused mealtime and basal insulin. Also check the dose history of the insulin pump if one is used.

Long-acting insulin and insulin overdose

Long-acting insulin can cause recurrence over many hours. After a large subcutaneous overdose the absorption can become unpredictable and the hypoglycaemia persist considerably longer than the normal duration of action of the preparation. The patient needs frequent monitoring, nutrition and often a continuous glucose infusion.

An intentional overdose, an unclear dose, the wrong preparation, marked renal failure or a need for repeated intravenous glucose all argue for admission and monitoring [7].

Sulfonylureas and glinides

Sulfonylureas, above all glibenclamide and glimepiride, can cause prolonged and recurrent hypoglycaemia. The risk increases with old age, reduced food intake, renal failure, liver disease and drug interactions. Even therapeutic doses can cause serious hypoglycaemia in a vulnerable patient [10].

Glucose stimulates insulin release from beta cells under the influence of a sulfonylurea. The patient may therefore improve after a bolus of glucose but become hypoglycaemic again as the effect of the glucose wears off.

Management:

1. Correct the acute hypoglycaemia with oral or intravenous glucose.
2. Admit the patient for repeated monitoring.
3. Give a meal if the patient is awake.
4. Contact your national or regional poison control centre in overdose, unclear exposure or recurrent hypoglycaemia.
5. Consider octreotide according to toxicological advice and the local protocol.
6. Continue observation after the glucose infusion and any octreotide have been stopped.

Octreotide inhibits insulin release and reduces the risk of further hypoglycaemia after a sulfonylurea. The evidence rests on small studies and clinical series, but the treatment is established in recurrent or severe sulfonylurea-induced hypoglycaemia [7,11].

Glucagon is less suitable as repeated treatment in sulfonylurea-induced hypoglycaemia, since it may be followed by further insulin release and recurrence [11].

Renal failure

Renal failure increases the risk through:

• reduced elimination of insulin
• a prolonged effect of certain sulfonylureas and their active metabolites
• reduced renal glucose production
• malnutrition and reduced food intake
• more severe concurrent illness

An insulin regimen that has previously worked well can therefore become excessive when renal function deteriorates acutely. Insulin and other high-risk drugs must be reviewed before discharge [2,12].

Alcohol

Alcohol inhibits hepatic gluconeogenesis. Isolated hypoglycaemia is uncommon in a well-nourished person with normal glycogen stores, but the risk clearly increases with fasting, malnutrition, liver disease and concomitant insulin treatment. Intoxication can in addition mask the warning symptoms and impair the patient's ability to treat themselves [5].

Critical illness

In a patient without known diabetes, hypoglycaemia may be a sign of serious illness, for example:

• sepsis
• severe hepatic impairment
• renal failure
• circulatory failure
• severe malnutrition
• adrenal insufficiency
• extensive malignant disease

Treat both the hypoglycaemia and the underlying disease. Recurrent falls in glucose despite treatment are a marker of a continuing pathological process and warrant monitoring [5].

Observation and disposal

There is no observation period that is safe for everyone. The disposal is determined by the cause, the duration of action of the drug, renal and hepatic function, the treatment required, comorbidity and the patient's access to continued supervision.

After an insulin overdose or sulfonylurea-induced hypoglycaemia, observation should continue after the glucose infusion and any octreotide have been stopped. A toxicological review gives at least about 12 hours after the end of treatment as a general starting point, but a longer period is required with long-acting preparations, modified-release formulations, renal failure, a large dose or previous recurrence [7].

Requirements for discharge

All of the following should be met:

• the patient has fully recovered
• the glucose is stable on repeated measurement without intravenous administration
• the patient has eaten and is able to continue eating
• the cause is established and is not associated with a prolonged drug effect
• insulin or other glucose-lowering treatment has been reviewed
• the patient or a relative is able to measure the glucose
• continued supervision is available where needed
• clear advice has been given about recurrence and when to seek emergency help
• follow-up has been arranged

An intentional overdose additionally requires a psychiatric risk assessment once the patient is medically stable.

Hypoglycaemia in a person without diabetes

Hypoglycaemia in adults without diabetes is uncommon and must not be dismissed if Whipple's triad is fulfilled [3,5].

Take a critical sample during the hypoglycaemia

If it can be done without delaying treatment, take samples while the patient is still hypoglycaemic:

• laboratory-analysed plasma glucose
• insulin
• C-peptide
• proinsulin
• beta-hydroxybutyrate
• screening for sulfonylureas and other insulin secretagogues
• insulin antibodies where relevant

Add cortisol, liver function tests, renal function tests, electrolytes, infection markers and other targeted analyses according to the clinical question.

The critical sample should preferably be taken before intravenous glucose. Attempts at sampling must, however, never delay treatment of seizures, unconsciousness or other serious neuroglycopenia.

Interpretation in principle

The insulin level need not lie above the laboratory reference range. When the glucose is low, insulin secretion that has not been adequately suppressed is pathological.

Differential diagnoses

• alcohol in combination with fasting or malnutrition
• sepsis and other critical illness
• severe hepatic or renal failure
• adrenal insufficiency
• hypopituitarism
• insulinoma
• other endogenous hyperinsulinism
• exogenous insulin
• a sulfonylurea or glinide
• an adverse drug effect
• hypoglycaemia after bariatric surgery
• insulin antibody syndrome
• tumour-related hypoglycaemia, including that mediated by insulin-like growth factor 2

A systematic review has linked a large number of other drugs to hypoglycaemia, but the evidence is often weak. Among the more frequently reported agents are quinolones, pentamidine, quinine and beta blockers [12].

Suspected insulinoma

An insulinoma usually causes fasting hypoglycaemia, but postprandial episodes occur. When spontaneous sampling has not captured an episode, a supervised fast may be needed within specialist care. Imaging of the pancreas must be performed only after endogenous hyperinsulinism has been demonstrated biochemically. Starting with CT or MRI without a biochemical diagnosis risks finding insignificant incidentalomas [3,13].

After bariatric surgery

Post-bariatric hypoglycaemia usually occurs one to three hours after a meal, often after rapidly absorbed carbohydrate. Fasting hypoglycaemia is not typical and should lead to investigation of other causes, including insulinoma. Continuous glucose monitoring can demonstrate the pattern but is not sufficient on its own for the diagnosis [5].

Prevent the next episode

A severe hypoglycaemia has not been fully treated when the glucose has normalised. The episode must be used to reduce the risk of recurrence.

Review the precipitating factors

Ask specifically about:

• the wrong dose or the wrong insulin preparation
• changed meals or a reduced food intake
• vomiting or diarrhoea
• physical activity the same day or the previous evening
• alcohol
• weight loss
• deteriorating renal function
• new drugs
• nocturnal episodes
• practical problems with vision, memory, injection technique or the insulin pump
• fear of hypoglycaemia and deliberate over-correction with food

Review the treatment

• Reduce or redistribute insulin where the requirement has demonstrably fallen.
• Stop or change a sulfonylurea where possible after a severe hypoglycaemia.
• Simplify complicated regimens in frail older people.
• Individualise glucose and HbA1c targets.
• Ensure that mealtime and basal insulin cannot be confused.
• Check pump settings and dose history.

Older people with renal failure, cognitive impairment, an irregular food intake or polypharmacy are at particularly high risk. The treatment target should then prioritise safety over strict glycaemic control [12].

Impaired awareness of hypoglycaemia

Ask whether the patient usually experiences autonomic warning symptoms before cognitive impairment develops. Impaired awareness of hypoglycaemia increases the risk of severe hypoglycaemia around sixfold [14].

Measures:

• temporarily higher glucose targets
• active avoidance of further hypoglycaemia
• structured diabetes education
• continuous glucose monitoring with alarms
• a review of the insulin regimen
• contact with the diabetes team

Two to three weeks of consistently avoiding hypoglycaemia can improve the symptom threshold in some patients. Structured education, close follow-up and diabetes technology give the best results in combination [2,4,14].

Continuous glucose monitoring and insulin pumps

Continuous glucose monitoring reduces severe hypoglycaemia in type 1 diabetes and can reduce the time spent below 3.0 mmol/L. Sensor-augmented pumps and automated insulin delivery can slow or stop insulin delivery when the glucose is low or is predicted to fall [2,15].

The patient's own sensor can be used as supplementary information during a hospital stay, but acute treatment decisions should be confirmed with the hospital's own glucose measurement when the sensor value is unexpected or does not fit the symptoms.

Glucagon at home

People with type 1 diabetes and other patients at clear risk of severe hypoglycaemia should have access to glucagon. Relatives must receive practical training and know that:

• glucagon is given when the patient cannot treat themselves safely
• emergency help must be summoned in unconsciousness or if there is no response
• the patient must be placed in the recovery position because of the risk of vomiting
• carbohydrate must be given once the patient has woken and can swallow
• the expiry date and storage must be checked

Guidelines prefer ready-to-use preparations that do not need to be reconstituted before use, since they are simpler and less prone to error in an emergency [2].

Driving

Explain that severe or repeated hypoglycaemia and impaired awareness of hypoglycaemia can affect medical fitness to hold a driving licence. The patient should not drive until the glucose and cognitive function have returned to normal. Current Swedish driving licence regulations and any duty to notify the authorities must be checked separately, since international guidelines do not replace Swedish law.

Red flags

• A sulfonylurea, a glinide, long-acting insulin or an unknown insulin dose.
• An intentional overdose.
• Repeated falls in glucose after an initial improvement.
• A need for an intravenous glucose infusion.
• Renal failure, liver failure, sepsis or malnutrition.
• Hypoglycaemia in a person without diabetes.
• Seizures, trauma or prolonged unconsciousness.
• Persistent focal neurological signs or a reduced level of consciousness after the glucose has normalised.
• Suspected adrenal insufficiency with hypotension, hyponatraemia or hyperkalaemia.
• Inadequate supervision, or an inability to manage medication and glucose measurement at home.

Common pitfalls

• Not measuring the glucose in a patient with a reduced level of consciousness, confusion or a neurological deficit.
• Allowing glucose treatment to be delayed by sampling or by giving thiamine.
• Giving food or drink to a patient who cannot protect the airway.
• Regarding the patient as fully treated after a single normal glucose value.
• Discharging a patient with sulfonylurea-induced hypoglycaemia after a temporary improvement.
• Failing to recognise that long-acting insulin and large insulin depots can cause late recurrence.
• Giving repeated boluses of glucose in sulfonylurea toxicity without considering octreotide.
• Trusting a low sensor value uncritically in the absence of symptoms or a confirmatory measurement.
• Dismissing persistent focal neurological signs as merely post-hypoglycaemic. Hypoglycaemia and stroke can occur at the same time.
• Routinely requesting a CT of the brain simply because the patient has been hypoglycaemic. Imaging is guided by persistent neurological findings, trauma, seizures, suspected stroke or another clinical question.
• Neglecting prevention. The prescription, renal function, meal pattern, awareness of hypoglycaemia and capacity for self-care must all be reviewed before discharge.

References

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10. Freeman J. Management of hypoglycemia in older adults with type 2 diabetes. Postgraduate Medicine 2019. PMID: 30724638
11. Lheureux PE et al. Bench-to-bedside review: Antidotal treatment of sulfonylurea-induced hypoglycaemia with octreotide. Critical Care 2005. PMID: 16356235
12. Murad MH et al. Clinical review: Drug-induced hypoglycemia: a systematic review. Journal of Clinical Endocrinology and Metabolism 2009. PMID: 19088166
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