Hypoglycaemic Encephalopathy

Hypoglycaemic encephalopathy is brain dysfunction caused by severe hypoglycaemia (glucose under 3.0 mmol/L, or 54 mg/dL), ranging from confusion to seizures, coma and permanent brain injury. Severe hypoglycaemia is defined by the need for help from another person.

Epidemiology. It is mainly seen in people with diabetes treated with insulin or sulphonylureas, and is a recurrent problem in older adults and those with renal impairment.

Causes and associations.

• Insulin, sulphonylureas (glibenclamide, glimepiride, gliclazide) and meglitinides.
• Alcohol, starvation, liver failure, renal failure and sepsis.
• Adrenal insufficiency, hypopituitarism, and severe malaria (including quinine treatment).
• Insulinoma, non-islet cell tumours, post-bariatric hypoglycaemia and insulin autoimmune syndrome.
• Drugs: quinolones, pentamidine, beta blockers, salicylates, and co-trimoxazole with sulphonylureas.
• In neonates: prematurity, maternal diabetes and inborn errors.

Pathophysiology. The brain depends on glucose. As glucose falls, autonomic symptoms occur at about 3.3 mmol/L, cognitive impairment from about 3.0 mmol/L, and seizures and coma under about 2.0 mmol/L. Prolonged hypoglycaemia causes neuronal necrosis, especially in the cortex and hippocampus.

Presentation is sweating, tremor, palpitations, hunger, confusion, behaviour change, speech disturbance, focal deficits that mimic stroke, seizures and coma. Recovery after glucose is rapid in mild cases. In prolonged cases, coma may persist after glucose is normal.

Red flags.

• Coma or seizure, or no recovery 30 minutes after glucose is normal.
• Sulphonylurea or long acting insulin overdose.
• Hypoglycaemia without diabetes or drug exposure, and recurrent episodes.
• Alcohol, liver failure, adrenal insufficiency or sepsis.

Confirm with laboratory glucose. Before treatment where possible, take a critical sample for glucose, insulin, C-peptide, proinsulin, beta hydroxybutyrate and a sulphonylurea screen. Check electrolytes, creatinine, liver tests, cortisol and cultures. Do CT or MRI brain if coma persists. A supervised 72-hour fast investigates suspected insulinoma.

Differential diagnosis.

• Stroke, seizure, intoxication and encephalitis.
• Hepatic encephalopathy and sepsis.
• Opioid and sedative overdose, and psychiatric disorders.

Immediate. Glucose 50% 50 mL (25 g) IV, or glucose 20% 100 mL (20 g) IV, or glucose 10% 150 to 200 mL (15 to 20 g) IV, in a large vein to limit extravasation injury. Recheck glucose after 10 to 15 minutes and repeat if under 4.0 mmol/L. Then give a 10% glucose infusion at 100 to 125 mL/h, titrated to a glucose of 5 to 10 mmol/L.

No IV access. Glucagon 1 mg IM or SC, which may be ineffective in alcohol use disorder, liver disease, starvation, adrenal insufficiency and prolonged sulphonylurea overdose. Follow with oral carbohydrate when able to swallow.

Thiamine. 100 mg IV when alcohol misuse or malnutrition is likely, before or with glucose.

Sulphonylurea toxicity. Hypoglycaemia can recur for 24 to 72 hours or longer. Give octreotide 50 microgram SC or IV every 6 to 8 hours (doses of 50 to 100 microgram are used), and observe for at least 24 hours after glucose has normalised without treatment, longer with renal impairment or long acting agents.

Insulin overdose. Large doses may need a prolonged glucose infusion, with 20% glucose through a central line.

Adrenal insufficiency. Hydrocortisone 100 mg IV.

Persistent coma. If coma persists 30 minutes after glucose is normal, look for another cause. Treat raised intracranial pressure and seizures in the usual way.

Monitoring. Capillary glucose every 15 minutes until stable and then hourly, ECG for QT effects in sulphonylurea toxicity, potassium and neurological observations.

Referral and escalation. Admit severe episodes from sulphonylureas or long acting insulin. Endocrinology for unexplained hypoglycaemia, suspected insulinoma or recurrent episodes. Review insulin and sulphonylurea therapy, kidney function and hypoglycaemia awareness.

Special groups. In children, glucose 10% is 2 mL/kg IV, then an infusion of 5 to 8 mg/kg/min. In neonates, 10% glucose 2 mL/kg IV, then 5 to 8 mg/kg/min, with specialist directed escalation. In older adults and renal impairment, use less hypoglycaemia prone agents and relax glycaemic targets.