Hypoglycaemia

A blood glucose concentration low enough to cause symptoms or signs, conventionally below 3.3 mmol/L in emergency practice, with 3.9 mmol/L used as the alert threshold in patients on glucose lowering therapy and below 3.0 mmol/L defining clinically significant hypoglycaemia.

Whipple triad, which establishes that symptoms are attributable to hypoglycaemia: symptoms consistent with hypoglycaemia, a documented low plasma glucose, and resolution of symptoms when glucose is corrected. In a non diabetic patient, the triad must be satisfied before embarking on investigation for an insulinoma or other cause.

Counterregulation and why symptoms appear when they do

• At around 4.6 mmol/L, endogenous insulin secretion is suppressed.
• At around 3.8 mmol/L, glucagon and adrenaline are released, producing the autonomic symptoms.
• At around 2.8 mmol/L, cortisol and growth hormone are released and cognitive impairment begins.
• Below around 2.5 mmol/L, severe neuroglycopenia with seizures and coma.

The brain has no glucose stores and depends on a continuous supply. Prolonged severe hypoglycaemia causes permanent neuronal injury, particularly in the hippocampus and cortex, which is why treatment is immediate and why glucose is given before any test result returns in a patient with altered consciousness.

Hypoglycaemia unawareness

Repeated hypoglycaemia blunts the counterregulatory response, so the autonomic warning symptoms are lost and the patient proceeds directly to neuroglycopenia without warning. This affects up to a quarter of patients with long standing type 1 diabetes and is a major cause of severe events. It is partially reversible by scrupulous avoidance of hypoglycaemia for several weeks, which is a specific therapeutic goal rather than general advice.

Causes

In diabetes, which accounts for most cases:

• Excess or mistimed insulin, wrong insulin type, or injection into a lipohypertrophic site with erratic absorption.
• Sulfonylureas, particularly glibenclamide and glimepiride, which cause prolonged and relapsing hypoglycaemia. Metformin, dipeptidyl peptidase 4 inhibitors and sodium glucose cotransporter 2 inhibitors do not cause hypoglycaemia alone but do so in combination with insulin or sulfonylureas.
• Missed or delayed meals, reduced carbohydrate intake, vomiting.
• Unaccustomed exercise, which increases glucose uptake for up to 24 hours afterwards.
• Alcohol, which inhibits gluconeogenesis. Alcohol induced hypoglycaemia typically occurs several hours after drinking, in a fasted or malnourished person, and is not corrected by glucagon since glycogen stores are depleted.
• Deteriorating renal function, which prolongs insulin and sulfonylurea clearance and is a frequent and under recognised cause in the elderly.
• Weight loss, resolution of an intercurrent illness, or reduction in corticosteroid dose without adjusting the diabetes regimen.

Without diabetes:

• Sepsis, which is a common cause in a critically ill patient and where hypoglycaemia is a marker of severity.
• Malaria, particularly falciparum malaria in children and in pregnancy, and quinine induced hyperinsulinaemia.
• Liver failure, advanced renal failure, cardiac failure.
• Adrenal insufficiency and hypopituitarism.
• Malnutrition, anorexia, prolonged starvation.
• Insulinoma, and non islet cell tumours secreting insulin like growth factor 2.
• Post bariatric surgery hypoglycaemia and other post prandial reactive hypoglycaemia.
• Drugs: quinine, quinolones, beta blockers, salicylates, tramadol, pentamidine.
• Factitious hypoglycaemia from surreptitious insulin or sulfonylurea use.
• Neonatal hypoglycaemia in the infant of a diabetic mother, in prematurity, in growth restriction and in sepsis.

Autonomic symptoms, from adrenergic and cholinergic activation, appearing first in the patient with intact awareness:

• Sweating, which is often profuse and is a useful objective sign.
• Tremor, palpitations and anxiety.
• Hunger, nausea, tingling around the mouth.
• Pallor.

Neuroglycopenic symptoms, from cerebral glucose deprivation:

• Difficulty concentrating, confusion and slurred speech.
• Behavioural change, aggression and irritability, which is frequently misinterpreted as intoxication or a psychiatric presentation and which delays testing.
• Visual disturbance, diplopia.
• Drowsiness, incoordination.
• Focal neurological deficit including hemiparesis and dysphasia, which mimics stroke exactly and which resolves with glucose. Every suspected stroke must have a glucose measured before thrombolysis is considered.
• Seizure.
• Coma.

In neonates and infants: poor feeding, lethargy, irritability, jitteriness, hypothermia, apnoea, cyanosis, a high pitched cry and seizures. Symptoms are non specific and glucose must be checked in any unwell neonate.

In the elderly: falls, confusion and non specific deterioration, frequently attributed to dementia or infection while the glucose is never measured.

Beta blockade masks the adrenergic symptoms except sweating, so a patient on a beta blocker may present directly with neuroglycopenia.

• Capillary blood glucose immediately in every patient with altered consciousness, seizure, focal neurological deficit, abnormal behaviour, sweating, collapse or unexplained deterioration. This is a bedside test that takes seconds and its omission causes preventable brain injury.
• Confirm with a laboratory venous glucose where possible, since meters are less accurate at low values and in shock, anaemia and hypoperfusion, but never delay treatment for the laboratory result.
• Before giving glucose in a patient without a clear cause, and where the situation permits, draw a critical sample for insulin, C peptide, beta hydroxybutyrate, cortisol, growth hormone and a sulfonylurea screen. Once glucose is given, the diagnostic opportunity is lost and the investigation becomes far harder. This applies to non diabetic hypoglycaemia and is frequently forgotten.
• Interpretation of the critical sample: raised insulin with raised C peptide indicates endogenous hyperinsulinism, that is insulinoma or sulfonylurea; a sulfonylurea screen distinguishes them. Raised insulin with suppressed C peptide indicates exogenous insulin administration. Low insulin with low C peptide and raised ketones indicates a non hyperinsulinaemic cause such as alcohol, fasting, adrenal insufficiency or liver failure.
• Supporting tests according to the clinical picture: full blood count, urea and electrolytes, creatinine, liver function, blood cultures, malaria rapid diagnostic test and blood film, cortisol, thyroid function, and toxicology.
• Imaging with computed tomography of the head where consciousness does not recover after glucose normalisation, since a coexisting structural cause or hypoglycaemic brain injury must be considered.

Immediate priorities

• Monitor and support airway, breathing and circulation. Position the unconscious patient in the recovery position.
• Check vital signs including blood pressure, pulse, respiratory rate, oxygen saturation and temperature.
• Give oxygen if saturation is below 94 percent, targeting 94 percent or above.
• Determine whether the patient can safely swallow.

Patient able to tolerate oral intake and conscious

• Give 15 to 20 g of rapidly absorbed carbohydrate: 150 to 200 mL of fruit juice or a sugary soft drink, 4 to 5 glucose tablets, 3 to 4 teaspoons of sugar dissolved in water, or a glucose gel.
• Recheck the glucose after 10 to 15 minutes and repeat the rapid carbohydrate if still below 4 mmol/L, up to three cycles.
• Once above 4 mmol/L, follow with a meal containing complex starchy carbohydrate such as rice, ugali, bread, potato or wholemeal, or a long acting snack if a meal is not due. This is the step most often omitted, and its omission causes recurrence within the hour.
• Avoid chocolate and biscuits as the initial treatment, since fat delays gastric emptying and glucose absorption.

Patient unable to tolerate oral intake, with intravenous access

• Give 50 mL of 50 percent dextrose intravenously through a large vein, followed by a saline flush. This is highly hyperosmolar at 2520 mOsm/kg and causes phlebitis and severe tissue necrosis if it extravasates, so use a large secure cannula and stop immediately if there is pain or swelling.
• An equivalent and gentler alternative is 100 mL of 20 percent dextrose or 200 mL of 10 percent dextrose, which delivers the same 20 g of glucose with far less venous irritation and is increasingly preferred.

Dextrose rule of 50 for weight based dosing

The volume in millilitres per kilogram multiplied by the dextrose percentage equals 50, which gives 0.5 g/kg of glucose.

• Neonate: 5 mL/kg of 10 percent dextrose.
• Infant: 2 mL/kg of 25 percent dextrose.
• Older child and adult: 1 mL/kg of 50 percent dextrose.

Higher concentrations cause venous sclerosis and, in neonates, rebound hyperinsulinaemic hypoglycaemia and intraventricular haemorrhage, which is why concentration is stepped down as age decreases.

Making up intermediate concentrations from 50 percent dextrose

• 50 mL of 50 percent dextrose plus 50 mL of normal saline gives 100 mL of 25 percent dextrose.
• 50 mL of 50 percent dextrose plus 150 mL of normal saline gives 200 mL of 12.5 percent dextrose.
• For 10 percent, dilute 50 mL of 50 percent dextrose to a total of 250 mL.

Patient unable to tolerate oral intake, no intravenous access

• Glucagon 1 mg subcutaneously or intramuscularly in adults and children over 25 kg, and 0.5 mg in children under 25 kg. Intranasal glucagon 3 mg is an alternative where available.
• Onset is 10 to 15 minutes. Nausea and vomiting are common afterwards.
• Glucagon acts by mobilising hepatic glycogen and therefore fails in patients with depleted glycogen: those with alcohol induced hypoglycaemia, prolonged starvation, malnutrition, liver failure and prolonged hypoglycaemia. It is also less effective in type 2 diabetes on sulfonylureas, where it stimulates further insulin release.
• Establish intravenous access as soon as possible and give 50 mL of 50 percent dextrose regardless, since the glucagon effect is short lived.

After the initial correction

• Recheck glucose after 10 to 15 minutes. Confirm symptoms have resolved and glucose is above 3.3 mmol/L, ideally above 4.4 mmol/L.
• If symptoms persist or glucose remains low, repeat the algorithm.
• After two rounds without sustained correction, start a continuous infusion of 10 percent dextrose at approximately 100 to 110 mL per hour in an adult, titrated to maintain glucose above 4.4 mmol/L. In children, run 10 percent dextrose at maintenance rates calculated by weight.
• Give a full complex carbohydrate meal as soon as the patient can eat safely. Where they cannot, the dextrose infusion continues.
• Continue hourly glucose monitoring until stable for several hours, then reduce frequency.

Thiamine

Give thiamine 100 mg intravenously before or with glucose in malnourished, alcohol dependent and chronically unwell patients, followed by 100 mg orally twice daily for at least 6 weeks. A glucose load in a thiamine deficient patient can precipitate Wernicke encephalopathy, and the sequence matters. Do not withhold glucose while waiting for thiamine in a hypoglycaemic patient; give both, thiamine first if it is immediately at hand.

Sulfonylurea induced hypoglycaemia

This is the situation that most often results in a patient being discharged and returning unconscious.

• Sulfonylureas have long durations of action, and glibenclamide in particular has active metabolites and a duration well beyond 24 hours, extended further in renal impairment and in the elderly.
• Admit every patient with sulfonylurea induced hypoglycaemia for a minimum of 24 hours, and longer for glibenclamide or renal impairment. Do not discharge on the basis of a corrected glucose.
• Repeated boluses of dextrose stimulate further insulin release and produce a cycle of rebound hypoglycaemia. Use a continuous 10 percent dextrose infusion rather than repeated boluses.
• Octreotide 50 to 100 micrograms subcutaneously every 6 to 8 hours suppresses pancreatic insulin release and is the specific antidote for refractory sulfonylurea hypoglycaemia. It substantially reduces the number of hypoglycaemic episodes and the dextrose requirement, and should be used earlier than it usually is.

Insulin induced hypoglycaemia

Duration depends on the preparation. Long acting analogues may require an infusion for 12 to 24 hours. Deliberate overdose with a depot of subcutaneous insulin may require an infusion for several days, with excision of the injection site considered in massive overdose.

Treat the underlying cause

• Treat sepsis, malaria, adrenal insufficiency with hydrocortisone 100 mg intravenously, and liver disease.
• Review and adjust the diabetes regimen. Reduce or stop the offending agent, and do not discharge a patient on the same dose that caused the event.
• Reassess renal function, since declining renal function is a common precipitant that requires dose reduction of insulin and sulfonylureas.
• Review injection technique and sites for lipohypertrophy.
• Assess for alcohol dependence, eating disorder, cognitive impairment and depression, all of which underlie recurrent events.

Before discharge

• Confirm the glucose is stable and the patient has eaten.
• Identify and correct the cause.
• Educate the patient and family on recognition and self treatment, with a glucagon kit prescribed and family members taught to use it where the patient is on insulin.
• Provide written sick day rules.
• Advise on driving regulations, which in most jurisdictions require a glucose above 5 mmol/L before driving, testing every 2 hours on long journeys, carrying carbohydrate, and reporting severe hypoglycaemia to the licensing authority. Recurrent severe hypoglycaemia or hypoglycaemia unawareness generally requires cessation of driving.
• Arrange diabetes clinic follow up, and structured education for recurrent events.
• Where hypoglycaemia unawareness is present, set a temporary target of scrupulous avoidance of any hypoglycaemia for several weeks to restore awareness, and consider continuous glucose monitoring.