Hyperglycaemic crisis

Hyperglycaemic crisis covers diabetic ketoacidosis (DKA) and the hyperosmolar hyperglycaemic state (HHS). Both are life threatening complications of insulin deficiency with osmotic diuresis, dehydration, electrolyte loss and a precipitating illness. They share treatment principles (fluids, insulin, potassium, precipitant) but differ in tempo and fluid strategy.

Diabetic ketoacidosis.

• Glucose over 11 mmol/L or known diabetes, plus capillary ketones 3.0 mmol/L or more (or urine ketones 2+), plus venous pH under 7.3 or bicarbonate under 15 mmol/L.
• Severity: mild pH 7.25 to 7.30, moderate 7.00 to 7.24, severe under 7.00.
• Features of severe disease: bicarbonate under 5 mmol/L, or Glasgow Coma Scale under 12, or potassium under 3.5 mmol/L on admission, or systolic pressure under 90 mmHg, or anion gap over 16 mmol/L, or heart rate over 100 or under 60 beats/min.
• Euglycaemic DKA: ketoacidosis with glucose under 11 mmol/L, typically with sodium glucose cotransporter 2 inhibitors, pregnancy, starvation, alcohol use, or liver disease.

Hyperosmolar hyperglycaemic state. Glucose over 30 mmol/L, effective serum osmolality over 320 mOsm/kg, ketones under 3.0 mmol/L, pH over 7.3, bicarbonate over 15 mmol/L, with marked dehydration. It develops over days and mostly affects older adults with type 2 diabetes.

Calculations.

• Effective osmolality = 2 x (sodium + potassium) + glucose (all in mmol/L). Total osmolality includes urea.
• Corrected sodium is sodium + 0.3 x (glucose minus 5.5) in mmol/L.
• Anion gap = sodium minus (chloride + bicarbonate).

Mechanisms. Absolute or relative insulin deficiency raises glucagon, cortisol and catecholamines, causing gluconeogenesis, glycogenolysis, lipolysis and ketone production (DKA). HHS has enough insulin to prevent ketosis but not to control hyperglycaemia. Osmotic diuresis causes total body deficits of water (6 to 9 L in DKA, 8 to 12 L in HHS), sodium, potassium (3 to 5 mmol/kg), phosphate and magnesium.

Key distinctions. Serum potassium on admission is normal or raised despite a large total deficit, and it falls rapidly with insulin and fluids. Pseudohyponatraemia occurs with hypertriglyceridaemia. Amylase, creatinine and white cell count may be raised without pancreatitis or infection.

History. Polyuria, polydipsia, weight loss, vomiting, abdominal pain, breathlessness, drowsiness, and symptoms of the precipitant (fever, cough, urinary symptoms, chest pain, neurological symptoms). Diabetes type, insulin doses and omissions (including pump failure), recent illness, new medicines (corticosteroids, thiazides, sodium glucose cotransporter 2 inhibitors, atypical antipsychotics, immune checkpoint inhibitors), alcohol, drugs (cocaine), eating disorder, pregnancy.

Examination.

• Hydration (dry mucosa, skin turgor, hypotension, tachycardia), Kussmaul breathing, ketotic breath, temperature (fever is infection until proven otherwise, since DKA causes hypothermia), conscious level.
• Abdominal tenderness (often from DKA itself, but exclude pancreatitis, appendicitis and perforation), signs of infection, focal neurological signs, cardiac and respiratory signs.

Red flags.

• Systolic pressure under 90 mmHg, Glasgow Coma Scale under 12, pH under 7.0, bicarbonate under 5 mmol/L, ketones over 6 mmol/L.
• Potassium under 3.5 mmol/L or over 6.0 mmol/L, oliguria, sepsis, chest pain, pregnancy, age under 18 years or over 70 years, and heart or kidney failure.
• Osmolality over 350 mOsm/kg, sodium over 160 mmol/L (HHS).

Special groups.

• Children: calculate fluid by weight, give only 10 mL/kg isotonic saline bolus if shocked, replace the deficit over 48 hours, avoid hypotonic fluids and watch for cerebral oedema (headache, falling heart rate, rising blood pressure, drowsiness, new incontinence).
• Pregnancy: DKA occurs at lower glucose and carries foetal loss; manage with obstetric and diabetes teams.
• Older adults: slower fluids and close monitoring for heart failure.
• Kidney or heart failure: smaller boluses with frequent reassessment.
• Region specific: undiagnosed type 1 diabetes in children, ketosis prone type 2 diabetes and infections such as tuberculosis and malaria as triggers.

Precipitants and causes of hyperglycaemic crisis.

• New onset type 1 diabetes, insulin omission or pump failure, ketosis prone type 2 diabetes.
• Infection: pneumonia, urinary tract infection, sepsis, cellulitis, tuberculosis, malaria, COVID-19.
• Cardiovascular: myocardial infarction, stroke, mesenteric ischaemia, pulmonary embolism.
• Acute pancreatitis, trauma, surgery, burns, pregnancy.
• Drugs: corticosteroids, thiazide diuretics, sodium glucose cotransporter 2 inhibitors, atypical antipsychotics, cocaine, immune checkpoint inhibitors.
• Endocrine: Cushing syndrome, acromegaly, thyrotoxicosis, phaeochromocytoma.
• Alcohol misuse, eating disorders, and psychological distress.

Other causes of high anion gap acidosis and ketosis (with or without hyperglycaemia). Alcoholic ketoacidosis, starvation ketosis, lactic acidosis, salicylate poisoning, methanol poisoning, ethylene glycol poisoning, chronic kidney disease with uraemia, and pyroglutamic acidosis.

Other causes of altered consciousness with hyperglycaemia. Stroke, sepsis, meningitis, hypoglycaemia (rebound), and hepatic encephalopathy.

Immediate. Capillary glucose and ketones (blood ketones are preferred to urine), venous blood gas (pH, bicarbonate, potassium, lactate), urea, creatinine, electrolytes with chloride, glucose, calculated osmolality and anion gap, full blood count, CRP, ECG, urinalysis, pregnancy test, blood cultures and cultures from suspected sources.

Precipitant search. Chest radiograph, troponin, lipase, HbA1c, liver tests, creatine kinase, magnesium and phosphate, CT head for focal signs or unexplained coma, and malaria tests where relevant.

Interpretation.

• Hypokalaemia on admission (under 3.5 mmol/L) means severe total deficit and requires potassium before insulin.
• Serum sodium rises as glucose falls. A corrected sodium over 145 mmol/L in DKA or rising despite treatment suggests free water deficit.
• Lactate over 4 mmol/L suggests hypoperfusion, sepsis or metformin.
• Ketones fall by at least 0.5 mmol/L/hour, glucose by 3 mmol/L/hour and venous bicarbonate rises by at least 3 mmol/L/hour on effective treatment.

Limitations. Urine ketone dipsticks detect acetoacetate only and may lag. Capillary glucose meters read inaccurately in severe acidosis, hypoperfusion or very high glucose, so confirm with laboratory glucose. Venous pH is about 0.03 lower than arterial pH, and arterial sampling is not needed for monitoring.

Immediate steps. Airway, oxygen if saturation under 94%, two IV lines, continuous ECG, urinary catheter in severe cases or when output cannot be measured, nasogastric tube if drowsy and vomiting, and search for a precipitant. Involve the diabetes team early.

Diabetic ketoacidosis in adults.

• Fluids (balanced or isotonic crystalloid; isotonic saline 0.9% is widely used, and balanced crystalloid reduces hyperchloraemia):
• If systolic pressure under 90 mmHg, give 500 mL over 10 to 15 minutes and repeat once if needed, looking for other causes of shock.
• Otherwise 1 L over the first hour, then 1 L over 2 hours, 1 L over 2 hours, 1 L over 4 hours, 1 L over 4 hours, and 1 L over 6 hours, reassessing at each step.
• Take care in older adults and in heart or kidney failure.
• Potassium (start with the second litre once urine output is established):
  • potassium over 5.5 mmol/L: give none and recheck in 2 hours
  • 3.5 to 5.5 mmol/L: add 40 mmol/L to each litre of fluid
  • under 3.5 mmol/L: delay insulin and give 10 to 20 mmol/hour IV (central line when over 10 mmol/hour) until over 3.5 mmol/L, with senior help
• Maximum potassium 20 mmol/hour; monitor ECG and potassium every 2 hours (hourly if replacing fast); reduce the rate in kidney impairment.
• Insulin:
  • fixed rate intravenous soluble insulin 0.1 units/kg/hour, started after the first hour of fluids and when potassium is 3.5 mmol/L or more
  • continue long acting basal insulin at the usual dose
  • maximum of about 15 units/hour by infusion
  • monitor glucose hourly and ketones hourly
  • if glucose falls under 14 mmol/L, add glucose 10% 125 mL/hour while continuing insulin and fluids
  • if the glucose falls under 4.0 mmol/L, give glucose 10% 150 to 200 mL IV over 15 minutes and review insulin
  • if the ketone fall is under 0.5 mmol/L/hour or bicarbonate rise under 3 mmol/L/hour, check the infusion and increase insulin by 1 unit/hour
  • reduce doses in renal impairment only with specialist input
• Bicarbonate: only for pH under 6.9 after the first hour of treatment, sodium bicarbonate 100 mmol in 400 mL sterile water with 20 mmol potassium chloride over 2 hours, repeated until pH over 7.0.
• Evidence of benefit from bicarbonate is limited, and it can worsen hypokalaemia and cerebral oedema in children.
• Phosphate and magnesium: replace only for severe hypophosphataemia (under 0.30 mmol/L) with respiratory or cardiac impairment, or haemolysis, using IV potassium phosphate 4.5 mmol over 6 hours (monitor calcium); magnesium sulphate 2 g IV over 20 minutes for hypomagnesaemia with arrhythmia.
• Venous thromboembolism prophylaxis: enoxaparin 40 mg subcutaneously once daily from admission (20 mg if CrCl 15 to 30 mL/min; unfractionated heparin 5000 units subcutaneously every 8 to 12 hours if CrCl under 15 mL/min).
• Antibiotics for suspected infection after cultures (for example ceftriaxone 2 g IV once daily, maximum 4 g daily), reassessed at 48 hours.
• Stop sodium glucose cotransporter 2 inhibitors permanently when they cause DKA.

Resolution. DKA is resolved when ketones are under 0.6 mmol/L, venous pH over 7.3 and bicarbonate over 18 mmol/L. Then change to subcutaneous insulin: give the first dose of rapid acting insulin with a meal, continue the IV insulin for 30 to 60 minutes afterwards, and continue basal insulin. Total daily insulin is calculated by weight and review. Resume sodium glucose cotransporter 2 inhibitors only on specialist advice (usually not).

Hyperosmolar hyperglycaemic state.

• Fluids: isotonic saline 0.9%, 1 L over the first hour (500 mL over 10 to 15 minutes if hypotensive), then aim for a positive balance of 3 to 6 L over the first 12 hours and the remainder over the next 12 to 24 hours.
• Use slow rates in older adults and cardiac or renal disease. Use 0.45% saline only when the corrected sodium is rising despite falling glucose.
• Targets: glucose fall of 4 to 6 mmol/L/hour (do not exceed 5 mmol/L/hour), osmolality fall of 3 to 8 mOsm/kg/hour, and sodium fall of no more than 10 mmol/L in 24 hours (rapid shifts cause cerebral oedema and osmotic demyelination).
• Insulin: delay until the first hour of fluids is given. Start fixed rate insulin 0.05 units/kg/hour (reduced rate because the risk of a rapid fall is high) if ketones are 1.0 mmol/L or more (mixed state) or glucose is not falling by over 5 mmol/L/hour after fluids.
• Add glucose 10% 125 mL/hour when glucose is under 14 mmol/L and ketones are present.
• Potassium:
  • over 5.5 mmol/L: give none and recheck in 2 hours
  • 3.5 to 5.5 mmol/L: add 40 mmol/L to each litre of fluid
  • under 3.5 mmol/L: delay insulin and give 10 to 20 mmol/hour IV until over 3.5 mmol/L (maximum 20 mmol/hour; monitor ECG and potassium every 2 hours)
• Total potassium losses are usually larger than in DKA, so requirements are often higher.
• Enoxaparin 40 mg subcutaneously once daily for every patient (20 mg if CrCl 15 to 30 mL/min; unfractionated heparin 5000 units subcutaneously every 8 to 12 hours if CrCl under 15 mL/min) (HHS carries a high risk of thrombosis).
• Treat the precipitant, and review feet and pressure areas.

Children (summary).

• Isotonic saline 10 mL/kg over 30 minutes only for shock, then replace the deficit evenly over 48 hours with maintenance.
• Start insulin 0.05 to 0.1 units/kg/hour after fluids have been running for 1 hour.
• Potassium 40 mmol/L in fluids when potassium is under 5.5 mmol/L.
• No bicarbonate; watch for cerebral oedema.
• If cerebral oedema occurs, give mannitol 0.5 to 1 g/kg IV over 20 minutes or 3% sodium chloride 2.5 to 5 mL/kg over 10 to 15 minutes, restrict fluids and arrange urgent critical care.

Complications. Hypoglycaemia, hypokalaemia, hyperchloraemic acidosis, cerebral oedema, pulmonary oedema, acute respiratory distress syndrome, acute kidney injury, venous thromboembolism, rhabdomyolysis, aspiration and recurrence.

Monitoring.

• Capillary glucose and ketones hourly, venous gas with bicarbonate and potassium at 1 hour, 2 hours and then every 2 hours until resolving, then every 4 to 6 hours.
• Urea, creatinine, electrolytes, calcium, magnesium and phosphate every 4 to 6 hours, hourly fluid balance, Glasgow Coma Scale, heart rate and blood pressure hourly.
• Continuous ECG for potassium disturbance.

Referral and escalation. Critical care or high dependency unit for severe DKA (pH under 7.0), Glasgow Coma Scale under 12, shock, severe hypokalaemia or hyperkalaemia, pregnancy, HHS with osmolality over 350 mOsm/kg, sodium over 160 mmol/L, or any patient needing vasopressors. Diabetes specialist team for every patient. Obstetrics and paediatric endocrinology where relevant.

Admission criteria. All patients with DKA or HHS are admitted. Mild uncomplicated DKA may be managed on a ward or in an ambulatory unit with a diabetes team.

Discharge and safety netting. Discharge when eating, ketones are under 0.6 mmol/L, pH is over 7.3, a subcutaneous insulin regimen is established and the precipitant has been addressed. Review by the diabetes team before discharge and within 1 week.

Give education on sick day rules: never stop basal insulin, check glucose every 2 to 4 hours, check ketones when glucose is over 14 mmol/L or unwell, increase fluids, and seek help for ketones 1.5 mmol/L or more, vomiting, or abdominal pain.

Also give access to ketone strips, insulin technique, injection site care, and psychological support for insulin omission.