Hyperosmolar Hyperglycaemic State

Two hyperglycaemic emergencies representing a continuum rather than distinct entities, with around a third of patients having features of both.

Diagnostic criteria

Diabetic ketoacidosis, all three required:

• Serum ketones 3 mmol/L or above, or urine ketones 2 plus or greater.
• Blood glucose above 11 mmol/L, or known diabetes. Euglycaemic ketoacidosis occurs with sodium glucose cotransporter 2 inhibitors, in pregnancy, in starvation and after insulin has been given before arrival, and a normal glucose does not exclude the diagnosis.
• pH below 7.3 or bicarbonate below 18 mmol/L.

Hyperosmolar hyperglycaemic state:

• Glucose 33.3 mmol/L or above, often far higher.
• Serum osmolality above 300 mOsm/kg, and typically above 320.
• pH 7.3 or above and bicarbonate 15 mmol/L or above, with no significant ketosis.
• Marked hypovolaemia and altered consciousness.

Pathophysiological difference

In ketoacidosis, absolute insulin deficiency permits unrestrained lipolysis, with free fatty acids oxidised in the liver to acetoacetate and beta hydroxybutyrate, producing a raised anion gap metabolic acidosis. Beta hydroxybutyrate predominates in a ratio of roughly 3 to 1 and is not detected by the nitroprusside reaction used in urine ketone sticks, which detect acetoacetate.

This means urine ketones underestimate severity at presentation and paradoxically appear to worsen during successful treatment as beta hydroxybutyrate is converted back to acetoacetate. Blood beta hydroxybutyrate measurement is therefore preferred for both diagnosis and monitoring.

In hyperosmolar state, residual insulin is sufficient to suppress lipolysis but not to permit glucose uptake, so hyperglycaemia becomes extreme over days to weeks, with an osmotic diuresis producing profound dehydration. Fluid deficits are larger, typically 100 to 220 mL/kg or 8 to 12 litres in an adult, compared with 5 to 7 litres in ketoacidosis, and evolve over a longer period.

Deficits at presentation

Ketoacidosis: water 5 to 7 litres, sodium 7 to 10 mmol/kg, potassium 3 to 5 mmol/kg, chloride 3 to 5 mmol/kg, phosphate 1 mmol/kg.

The potassium point is critical. Total body potassium is depleted by hundreds of millimoles, but acidosis and insulin deficiency shift potassium extracellularly so the serum value is normal or high at presentation. Treatment with insulin and fluid drives potassium back into cells and the serum value falls precipitously. Hypokalaemia is a leading cause of death in ketoacidosis and is entirely preventable.

Diabetic ketoacidosis

• Onset over hours to a day or two.
• Polyuria, polydipsia and weight loss.
• Nausea, vomiting and abdominal pain, the last correlating with acidosis severity and often mimicking an acute abdomen.
• Kussmaul respiration: deep, sighing, laboured breathing representing respiratory compensation. Its disappearance in a deteriorating patient indicates exhaustion and impending respiratory failure, not improvement.
• Ketotic breath.
• Dehydration with tachycardia, hypotension and reduced skin turgor.
• Drowsiness progressing to coma, correlating with osmolality rather than pH.
• Younger patients, often type 1, and frequently a first presentation.

Hyperosmolar hyperglycaemic state

• Onset over days to weeks with progressive polyuria and polydipsia.
• Older patients, usually type 2, often with limited access to fluid because of immobility, dementia or institutional care, which is why the dehydration becomes so profound.
• Marked dehydration.
• Altered consciousness, ranging from confusion to coma, which is more prominent than in ketoacidosis.
• Focal neurological signs, hemiparesis and seizures, which resolve with correction and which are commonly misdiagnosed as stroke.
• Absence of Kussmaul breathing and of ketotic breath.
• Higher mortality than ketoacidosis, at 5 to 20 percent compared with under 5 percent, reflecting age, comorbidity and the severity of dehydration.

Severity markers indicating high dependency or intensive care

• pH below 7.0 or bicarbonate below 5 mmol/L.
• Blood ketones above 6 mmol/L.
• Anion gap above 16 mmol/L.
• Potassium below 3.5 mmol/L on admission.
• Glasgow Coma Scale below 12.
• Oxygen saturation below 92 percent on air.
• Systolic blood pressure below 90 mmHg.
• Pulse above 100 or below 60 beats per minute.
• Osmolality above 320 mOsm/kg.

• Capillary glucose and blood ketones at the bedside.
• Venous blood gas for pH, bicarbonate, potassium and lactate, repeated at 1, 2, 4, 8, 12 and 24 hours during treatment.
• Urea, electrolytes, creatinine, calculated osmolality, corrected sodium and anion gap.
• Full blood count, with the caveat about stress leucocytosis.
• Urinalysis and culture, blood cultures, chest radiography.
• Twelve lead electrocardiogram in all patients, both for silent myocardial infarction and to assess for the electrocardiographic manifestations of hyper and hypokalaemia. Tall tented T waves, a widened QRS and a flattened P wave indicate hyperkalaemia; flattened T waves, U waves and ST depression indicate hypokalaemia.
• Troponin, recognising that mild elevation occurs without infarction.
• Amylase, lipase and abdominal imaging where abdominal pain persists after correction of the acidosis.
• Malaria testing, HIV testing and tuberculosis screening in endemic settings.
• Pregnancy test in women of reproductive age.
• HbA1c.
• Serum phosphate and magnesium.

Useful formulas

• Anion gap equals sodium minus the sum of chloride and bicarbonate.
• Corrected sodium equals measured sodium plus 1.6 times the quantity glucose minus 5.6, all divided by 5.6.
• Potassium correction for acidaemia: measured potassium falls by approximately 0.6 mmol/L for every 0.1 unit rise in pH, so the corrected value equals measured potassium minus 0.6 multiplied by the quantity 7.4 minus measured pH, multiplied by 10.
• Calculated total osmolality equals 2 times the sum of sodium and potassium, plus glucose, plus urea, all in mmol/L.
• Total body water deficit in litres equals 0.6 for men and children, or 0.5 for women, multiplied by body weight in kilograms, multiplied by the quantity serum sodium divided by 140, minus 1.

Three simultaneous protocols, in a strict order of priority: fluid first, potassium second, insulin third. Insulin is never the first intervention.

Identify and treat the precipitant

Simultaneously with resuscitation. Consult a physician early. Antimicrobials for infection, management of acute coronary syndrome, and treatment of whatever else has driven the episode.

Fluid protocol

Fluid replacement alone lowers glucose substantially, restores renal perfusion and improves acidosis before any insulin is given.

• Ringer lactate or balanced crystalloid is preferred to 0.9 percent sodium chloride, since large volumes of saline produce hyperchloraemic acidosis which prolongs the apparent acidosis and confuses assessment.
• Severe hypovolaemia with systolic blood pressure below 90 mmHg: give 1000 mL over the first 15 to 30 minutes and repeat until the systolic pressure exceeds 90 mmHg, then continue at approximately 1000 mL per hour over the first 2 to 4 hours, adjusting to clinical response.
• Mild to moderate hypovolaemia: aim to replace approximately 50 percent of the estimated deficit over the first 8 to 12 hours, with the remainder over the following 12 to 24 hours.
• Slow the rate in the elderly, in cardiac failure, in renal failure and in children, in whom over rapid correction risks pulmonary oedema and cerebral oedema.
• 0.45 percent sodium chloride is used only if the osmolality is failing to fall in a hyperosmolar state despite adequate volume and insulin, and it must be used with caution given the cerebral oedema risk. The target rate of osmolality fall is 3 to 8 mOsm/kg per hour.
• Markers of successful fluid therapy: improving haemodynamics, resolving tachycardia, improving pH, urine output of 1 to 2 mL/kg/hour, and clinical improvement.
• Insert a urinary catheter where the patient is anuric, obtunded or requires accurate hourly output measurement.
• Insert a nasogastric tube in the obtunded patient with vomiting, given the risk of aspiration from gastroparesis.
• Consider central venous access and invasive monitoring in the elderly, in cardiac disease and in shock.

Potassium protocol

Check potassium before starting insulin and every 1 to 2 hours initially.

• Do not give potassium if the patient is anuric or the serum potassium is above 5.0 mmol/L. Recheck every 2 hours and add potassium once it falls below 5.0.
• Potassium 3.5 to 5.0 mmol/L: add 10 to 20 mmol of potassium chloride to each litre of fluid, aiming to maintain the serum value between 4.0 and 5.0 mmol/L.
• Potassium below 3.5 mmol/L: hold insulin. Give 10 to 20 mmol of potassium per hour with continuous cardiac monitoring, and do not start or restart insulin until the potassium is above 3.5 mmol/L. Starting insulin in a hypokalaemic patient can cause fatal arrhythmia within minutes.
• Rates above 10 mmol per hour require cardiac monitoring, and rates above 20 mmol per hour require central administration and intensive care.
• Check magnesium, since hypomagnesaemia causes refractory hypokalaemia and must be corrected in parallel with magnesium sulphate 2 g intravenously.
• Phosphate falls during treatment. Routine replacement does not improve outcome and risks hypocalcaemia, so it is reserved for a phosphate below 0.3 mmol/L with respiratory muscle weakness, cardiac dysfunction or haemolysis.

Insulin protocol

• Do not give insulin until the potassium is known and is above 3.5 mmol/L.
• Give 0.1 units/kg of soluble insulin as an intravenous bolus, then a continuous intravenous infusion at 0.1 units/kg per hour. Some protocols omit the bolus and start directly at 0.14 units/kg per hour, which is equally effective.
• Prepare the infusion as 50 units of soluble insulin in 50 mL of 0.9 percent sodium chloride, giving 1 unit per mL, and prime the line, since insulin adsorbs to plastic and the first millilitres deliver less than intended.
• Monitor capillary glucose hourly.
• Target a glucose fall of 3 to 4 mmol/L per hour. Faster falls risk cerebral oedema, particularly in children.
• If the glucose does not fall by at least 3 mmol/L in the first hour, give a further bolus of 0.1 units/kg and continue the infusion, having first confirmed that the infusion is actually running and that fluid replacement is adequate.
• Once the venous glucose falls below approximately 14 mmol/L, add 5 or 10 percent dextrose to the fluid regimen and reduce the insulin infusion to 0.05 units/kg per hour. Do not stop the insulin, since insulin is required to clear the ketones and the ketoacidosis will not resolve without it. This is the point at which the treatment shifts from lowering glucose to clearing ketosis, and stopping insulin here is a common and serious error.
• Maintain glucose between 8.3 and 11.1 mmol/L in ketoacidosis, and 11.1 to 13.8 mmol/L in hyperosmolar state, continuing insulin and fluids until the ketosis or the hyperosmolality has resolved.
• Continue the patient's usual long acting basal insulin throughout, which smooths the transition off the infusion and reduces rebound ketosis.

Subcutaneous alternative for mild ketoacidosis

In mild uncomplicated ketoacidosis without shock, without altered consciousness and without significant comorbidity, subcutaneous rapid acting insulin analogue at 0.1 units/kg every hour, or 0.2 units/kg every 2 hours, is effective and avoids the need for intensive care. This is a genuinely useful option in resource limited settings, but it requires reliable hourly monitoring and adequate subcutaneous perfusion, and it is not appropriate in shock, where absorption is unpredictable.

Resolution criteria

• Diabetic ketoacidosis: blood ketones below 0.6 mmol/L, venous pH above 7.3, bicarbonate above 15 mmol/L, and the patient eating and drinking.
• Hyperosmolar hyperglycaemic state: osmolality normalised, clinical and cognitive recovery, and glucose controlled. Resolution takes longer, typically 24 to 72 hours.

Transition to subcutaneous insulin

• Only when the resolution criteria are met and the patient can eat.
• Give the subcutaneous rapid acting dose and continue the intravenous infusion for a further 30 to 60 minutes before stopping it, since intravenous insulin has a half life of minutes and stopping it before the subcutaneous dose is absorbed causes immediate rebound ketosis. This overlap is the single most frequently omitted step in the transition.
• Restart the patient's previous regimen where control was adequate, or calculate 0.5 to 0.8 units/kg per day divided into basal and prandial components in a newly diagnosed patient.
• Involve the diabetes team before discharge.

Bicarbonate

Not routinely indicated. It does not improve outcome, and it causes paradoxical cerebrospinal fluid acidosis, worsened hypokalaemia, a leftward shift of the oxygen dissociation curve, delayed ketone clearance and, in children, an increased risk of cerebral oedema. It may be considered in extreme acidaemia with pH below 6.9 with haemodynamic compromise, as 50 to 100 mmol in 400 mL of water infused over 2 hours with added potassium, but the evidence even here is weak.

Complications and their management

• Hypokalaemia and hyperkalaemia, both of which cause fatal arrhythmia and both of which are prevented by frequent measurement.
• Hypoglycaemia from failure to add dextrose when the glucose falls.
• Cerebral oedema, which is predominantly a paediatric complication occurring in around 0.5 to 1 percent of paediatric ketoacidosis with a mortality of 20 to 25 percent. It presents 4 to 12 hours into treatment with headache, deteriorating consciousness, irritability, bradycardia with hypertension and abnormal breathing pattern. Risk factors are young age, new diagnosis, severe acidosis, marked hypocapnia, high urea, bicarbonate administration and rapid fluid or osmolality correction. Treatment is immediate: reduce the fluid rate by a third, elevate the head, and give mannitol 0.5 to 1 g/kg intravenously over 20 minutes or hypertonic 3 percent sodium chloride 2.5 to 5 mL/kg over 15 minutes, with intensive care involvement and imaging only after treatment has been started.
• Venous thromboembolism, since hyperosmolar states are strongly prothrombotic. Give prophylactic low molecular weight heparin to all patients in the absence of contraindication, and consider therapeutic anticoagulation in hyperosmolar state where the risk is highest.
• Aspiration pneumonia in the obtunded patient with gastroparesis.
• Acute kidney injury.
• Hyperchloraemic acidosis from saline, which prolongs the apparent acidosis after ketones have cleared. Recognise it by a normalised anion gap with persistent low bicarbonate, and do not respond by giving more insulin.
• Rhabdomyolysis, particularly in hyperosmolar state.
• Adult respiratory distress syndrome.
• Mucormycosis and other opportunistic infection in the acidotic diabetic, with facial pain and black nasal eschar demanding immediate assessment.

Monitoring schedule

Hourly capillary glucose and urine output. Hourly ketones where available. Venous gas with potassium at 1, 2, 4, 8, 12 and 24 hours. Urea, electrolytes and creatinine every 4 to 6 hours. Continuous cardiac monitoring in severe disease and in all patients receiving potassium at rates above 10 mmol per hour. Neurological observations, particularly in children.

Before discharge

Establish and address the precipitant, particularly insulin omission and its reasons. Reinforce sick day rules, which prevent recurrence more effectively than any other intervention. Provide ketone testing strips and teach their use to all patients with type 1 diabetes. Arrange diabetes team review within days, and identify recurrent presenters, in whom the underlying issue is usually psychosocial, financial or an eating disorder rather than educational.