Hyperosmolar Hyperglycaemic State: Fluid First, Insulin Later

Introduction

Hyperosmolar hyperglycaemic state (HHS) is a medical emergency characterised by severe hyperglycaemia, marked hypovolaemia and raised serum osmolality, without significant ketosis or acidosis. It was formerly called hyperosmolar non-ketotic coma, a term now abandoned because fewer than a third of patients are actually comatose.

It typically affects older people with type 2 diabetes, and in up to a third the diabetes is previously undiagnosed - HHS is the presenting event. Unlike DKA, which develops over hours, HHS evolves insidiously over days to weeks, which is why the fluid deficit is so much larger by the time the patient arrives.

It is the more dangerous of the two hyperglycaemic emergencies. Mortality is 10 to 20%, an order of magnitude higher than DKA, reflecting the older and more comorbid population, the profound dehydration, and a very high risk of arterial and venous thrombosis.

Why there is no ketosis

This is the central conceptual point and explains the whole clinical picture. In type 2 diabetes there is residual endogenous insulin secretion. The amount is insufficient to prevent hyperglycaemia, but insulin is far more potent at suppressing lipolysis than at promoting glucose uptake - so even a small residual level is enough to restrain lipolysis and therefore ketogenesis. Counter-regulatory hormone levels are also lower than in DKA.

The consequence is that hyperglycaemia is unopposed while ketoacidosis does not develop. Because there is no acidosis, there are none of the symptoms that bring a DKA patient to hospital early - no Kussmaul breathing, no vomiting from ketosis, no abdominal pain. The patient simply becomes progressively more dehydrated and drowsy over days, often unnoticed, and the osmotic diuresis continues unchecked. By presentation the fluid deficit is typically 100 to 220 ml/kg - 10 to 22 litres in a 100 kg adult.

Diagnosis

There is no single agreed numerical definition. The JBDS guidance describes a clinical picture with three components:¹

1. Hypovolaemia
2. Marked hyperglycaemia (30 mmol/L or above) without significant ketonaemia (below 3 mmol/L) or acidosis (pH above 7.3, bicarbonate above 15 mmol/L)
3. Osmolality usually 320 mosmol/kg or above

Precipitants

• Infection - the commonest, particularly pneumonia and urinary tract infection
• Myocardial infarction and stroke - both cause and consequence, and both may be silent or masked by the confusion
• Undiagnosed or undertreated type 2 diabetes
• Drugs - corticosteroids, thiazide and loop diuretics, SGLT2 inhibitors, antipsychotics, beta-blockers and phenytoin
• Reduced access to fluid - dementia, immobility, stroke, institutional care, hot weather, or simply living alone. This is a frequent and important contributor.
• High-sugar drinks consumed for thirst - a vicious cycle that accelerates the whole process
• Acute pancreatitis, trauma, burns and major surgery
• Dialysis and total parenteral nutrition

Clinical features

Symptoms

• Weeks of polyuria, polydipsia and weight loss, often unnoticed or attributed to ageing
• Progressive weakness, lethargy and confusion
• Reduced oral intake as the patient becomes more drowsy, which accelerates the deterioration
• Later oliguria as the kidneys fail to sustain the osmotic diuresis
• Visual disturbance
• Symptoms of the precipitant - cough, dysuria, chest pain

Signs

• Profound dehydration - dry mucous membranes, sunken eyes, reduced skin turgor, prolonged capillary refill and, in severe cases, hypovolaemic shock
• Reduced conscious level - present in most, coma in a minority, and correlating closely with the osmolality rather than the glucose
• Tachycardia and hypotension
• Normal respiratory pattern - there is no Kussmaul breathing and no ketotic breath, which is a useful discriminator from DKA
• Focal neurological signs - hemiparesis, hemianopia, and seizures in around a quarter, often focal and resistant to anticonvulsants. These can closely mimic a stroke and typically resolve as the osmolality is corrected.
• Signs of the precipitant - consolidation, cellulitis, a foot ulcer
• Pressure areas - examine the heels and sacrum, as these patients have often been immobile for days

Investigations

• Capillary glucose and blood ketones - immediately
• Venous blood gas - pH, bicarbonate and potassium, to confirm the absence of acidosis
• U&Es - for sodium, urea and the osmolality calculation, and to assess acute kidney injury which is almost invariable
• Serum osmolality - calculated hourly; measured if a toxic ingestion is suspected
• Full blood count, CRP, blood cultures, urinalysis and culture, chest X-ray - to find the precipitant
• ECG and troponin - for silent myocardial infarction
• Creatine kinase - rhabdomyolysis is common in HHS and is easily missed
• Coagulation screen
• Consider CT head if the conscious level does not improve as the osmolality corrects, or if focal signs persist

Management

The guiding principle is gradual correction. These patients have adapted over days to a very high osmolality, and the brain has generated intracellular osmolytes to protect itself. Lowering the osmolality too quickly draws water into brain cells and causes cerebral oedema; correcting sodium too quickly risks osmotic demyelination. The instinct to normalise the numbers rapidly is exactly wrong here.¹

Fluid

• 0.9% sodium chloride is the principal treatment and the first-line fluid throughout
• Fluid alone will lower the glucose substantially by dilution and by restoring renal perfusion and glucose excretion - which is why insulin is not needed at the outset
• Give 1 litre over the first hour, or faster if the patient is shocked
• Aim for a positive balance of 3 to 6 litres by 12 hours, then complete replacement over the next 12 hours, adjusted for age, cardiac and renal function
• Expect the measured sodium to rise as the glucose falls - this is a predictable consequence of water moving back into cells and is not in itself a reason to change fluid, provided the calculated osmolality is falling at an appropriate rate
• Only switch to 0.45% sodium chloride if the osmolality is not falling despite adequate positive fluid balance. This is a senior decision.
• Monitor for fluid overload - these are often elderly patients with limited cardiac reserve, and the balance between under- and over-filling requires frequent reassessment

Insulin

Potassium and other measures

• Potassium replacement follows the same rules as DKA - none above 5.5 mmol/L, 40 mmol/L between 3.5 and 5.5, and senior review below 3.5. Shifts are less dramatic than in DKA because less insulin is given, but total body depletion is still substantial.
• Venous thromboembolism prophylaxis with low molecular weight heparin for all patients unless contraindicated, continued for the duration of the admission. HHS is markedly prothrombotic - hyperviscosity, dehydration and immobility combine, and arterial as well as venous events are common. Some units use full anticoagulation in selected patients; this is a senior decision.
• Treat the precipitant - antibiotics for infection, and manage myocardial infarction or stroke on their own pathways
• Foot protection and pressure area care from admission - these patients are at very high risk of heel ulceration and are often immobile for days before presenting
• Urinary catheter to monitor output accurately, and consider a nasogastric tube if consciousness is impaired
• Monitor hourly - glucose, sodium, potassium, urea and calculated osmolality initially, and fluid balance throughout

After recovery

• Convert to subcutaneous insulin when the patient is eating and drinking and the osmolality has normalised
• Many patients do not need long-term insulin. Once the acute illness has resolved, a substantial proportion can be managed on oral agents or even diet alone - reassess rather than discharging everyone on insulin.
• Full diabetes education and specialist team review before discharge, particularly for those newly diagnosed
• Address the reason it happened - access to fluids, carer support, cognitive impairment, medication review and social circumstances. Recurrence is usually a failure of these rather than of the medicine.
• Recovery of full cognitive function may take days to weeks, and warn the family of this

Complications

• Arterial and venous thrombosis - myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism and mesenteric ischaemia. The dominant cause of death.
• Cerebral oedema - rare in adults but usually fatal, caused by over-rapid correction of osmolality
• Osmotic demyelination syndrome (central pontine myelinolysis) - from too-rapid correction of sodium, presenting days later with quadriparesis, pseudobulbar palsy and a locked-in state
• Seizures - occurring in around a quarter, often focal and typically resolving with correction of osmolality rather than with anticonvulsants
• Rhabdomyolysis - common, and a cause of acute kidney injury; check creatine kinase
• Acute kidney injury - almost universal, usually pre-renal and reversible with rehydration
• Fluid overload and pulmonary oedema - from over-vigorous replacement in an elderly heart
• Hypokalaemia and hypoglycaemia - from over-treatment
• Pressure ulceration and foot ulceration
• Aspiration pneumonia in the obtunded patient
• Prolonged cognitive impairment

Red flags

Prognosis

Mortality is 10 to 20%, considerably higher than DKA and rising steeply with age, degree of hyperosmolality, depth of coma and the presence of a serious precipitant such as myocardial infarction, stroke or sepsis. Most deaths are attributable to the precipitating illness and to thrombotic complications rather than to the hyperglycaemia itself.

Recovery of the metabolic state usually takes 24 to 72 hours, longer than in DKA because correction must be deliberately slow. Cognitive recovery lags behind biochemical recovery and may take days to weeks, which is worth explaining to families who understandably expect improvement to track the blood results.

For those who survive, the outlook depends largely on their underlying health. Many return to their previous level of function, and a substantial proportion of those newly diagnosed with diabetes can be managed with oral agents or lifestyle measures once the acute episode has passed. Recurrence is usually preventable, and prevention is rarely a matter of medication: the recurring themes are access to fluids, cognitive impairment, isolation and the absence of anyone noticing that an older person had been unwell for a fortnight. Addressing those before discharge does more than any adjustment of the diabetes regimen.