Hyperosmolar hyperglycaemic state



Introduction
Epidemiology
Pathophysiology
Clinical features
Diagnosis
Differential diagnosis
Management


Introduction

Hyperosmolar hyperglycaemic state (HHS) is a medical emergency which is extremely difficult to manage and has a significant associated mortality. Hyperglycaemia results in osmotic diuresis, severe dehydration, and electrolyte deficiencies. HHS typically presents in the elderly with type 2 diabetes mellitus (T2DM), however the incidence in younger adults is increasing. It can be the initial presentation of T2DM.

Epidemiology

  • Incidence: 10.00 cases per 100,000 person-years
  • Peak incidence: 60-70 years
  • Sex ratio: 1:1
<1 1-5 6+ 16+ 30+ 40+ 50+ 60+ 70+ 80+

Pathophysiology

Pathophysiology
  • Hyperglycaemia results in osmotic diuresis with associated loss of sodium and potassium
  • Severe volume depletion results in a significant raised serum osmolarity (typically > than 320 mosmol/kg), resulting in hyperviscosity of blood.
  • Despite these severe electrolyte losses and total body volume depletion, the typical patient with HHS, may not look as dehydrated as they are, because hypertonicity leads to preservation of intravascular volume.

Clinical features

Clinical features
  • General: fatigue, lethargy, nausea and vomiting
  • Neurological: altered level of consciousness, headaches, papilloedema, weakness
  • Haematological: hyperviscosity (may result in myocardial infarctions, stroke and peripheral arterial thrombosis)
  • Cardiovascular: dehydration, hypotension, tachycardia

Diagnosis

Diagnosis
  • 1. Hypovolaemia
  • 2. Marked Hyperglycaemia (>30 mmol/L) without significant ketonaemia or acidosis
  • 3. Significantly raised serum osmolarity (> 320 mosmol/kg)
  • Note: A precise definition of HHS does not exist, however the above 3 criteria are helpful in distinguishing between HHS and DKA. It is also important to remember that a mixed HHS / DKA picture can occur.

Differential diagnosis

It is extremely important to differentiate HHS from diabetic ketoacidosis (DKA) as the management is different, and treatment of HHS with insulin (e.g. as part of a DKA protocol) can result in adverse outcomes. The first 24 hours of treatment is very labour intensive so these patients are best managed in either a medical high dependency unit.

HHS has a higher mortality than DKA and may be complicated by vascular complications such as myocardial infarction, stroke or peripheral arterial thrombosis. Seizures, cerebral oedema and central pontine myelinolysis (CPM) are uncommon but documented complications of HHS. Whilst DKA presents within hours of onset, HHS comes on over many days, and consequently the dehydration and metabolic disturbances are more extreme.

Management

The goals of management of HHS can be summarised as follows:

  • 1. Normalise the osmolality (gradually)
  • 2. Replace fluid and electrolyte losses
  • 3. Normalise blood glucose (gradually)

Fluid replacement
  • Fluid losses in HHS are estimated to be between 100 - 220 ml/kg (e.g. 10-22 litres in an individual weighing 100 kg).
  • The rate of rehydration will be determined by assessing the combination of initial severity and any pre-existing co-morbidities (e.g. heart failure and chronic kidney disease). Caution is needed, particularly in the elderly, where too rapid rehydration may precipitate heart failure but insufficient may fail to reverse an acute kidney injury.
  • Intravenous (IV) 0.9% sodium chloride solution is the first line fluid for restoring total body fluid.
  • It is important to remember that isotonic 0.9% sodium chloride solution is already relatively hypotonic compared to the serum in someone with HHS. Therefore in most cases it is very effective at restoring normal serum osmolarity.
  • If the serum osmolarity is not declining despite positive balance with 0.9% sodium chloride, then the fluid should be switched to 0.45% sodium chloride solution which is more hypotonic relative to the HHS patients serum osmolarity
  • IV fluid replacement should aim to achieve a positive balance of 3-6 litres by 12 hours and the remaining replacement of estimated fluid losses within the next 12 hours.
  • Existing guidelines encourage vigorous initial fluid replacement and this alone (without insulin) will result in a gradual decline in plasma glucose and serum osmolarity. A rapid decline is potentially harmful (see below) therefore insulin should NOT be used in the first instance unless there is significant ketonaemia or acidosis
  • The aim of treatment should be to replace approximately 50% of estimated fluid loss within the first 12 hours and the remainder in the following 12 hours. However this is just a guide, and clinical judgement should be applied, particularly in patient with co-morbidities such as heart failure and chronic kidney disease (which may limit the speed of correction).

Monitoring response to treatment
  • The key parameter in managing HHS is the osmolality to which glucose and sodium are the main contributors. Rapid changes of serum osmolarity are dangerous and can result in cardiovascular collapse and central pontine myelinolysis (CPM).
  • Guidelines suggest that serum osmolarity, sodium and glucose levels should be plotted on a graph to permit appreciation of the rate of change. They should be plotted hourly initially.
  • Not all laboratories have readily available access to serum osmolarity measurements. If not available then a calculated osmolarity can be estimated with 2Na + glucose + urea
  • Fluid replacement alone (without insulin) will gradually lower blood glucose which will reduce osmolality
  • A reduction of serum osmolarity will cause a shift of water into the intracellular space. This inevitably results in a rise in serum sodium (a fall in blood glucose of 5.5 mmol/L will result in a 2.4 mmol/L rise in sodium). This is not necessarily an indication to give hypotonic solutions. If the inevitable rise in serum Na+ is much greater than 2.4 mmol/L for each 5.5 mmol/L fall in blood glucose this would suggest insufficient fluid replacement. Rising sodium is only a concern if the osmolality is NOT declining concurrently.
  • Rapid changes must be avoided. A safe rate of fall of plasma glucose of between 4 and 6 mmol/hr is recommended. The rate of fall of plasma sodium should not exceed 10 mmol/L in 24 hours.
  • A target blood glucose of between 10 and 15 mmol/L is a reasonable goal.
  • Complete normalisation of electrolytes and osmolality may take up to 72 hours.

Insulin
  • Fluid replacement alone with 0.9% sodium chloride solution will result in a gradual decline of blood glucose and osmolarity
  • Because most patients with HHS are insulin sensitive (e.g. it usually occurs in T2DM), administration of insulin can result in a rapid decline of serum glucose and thus osmolarity.
  • Insulin treatment prior to adequate fluid replacement may result in cardiovascular collapse as the water moves out of the intravascular space, with a resulting decline in intravascular volume.
  • A steep decline in serum osmolarity may also precipitate CPM.
  • Measurement of ketones is essential for determining if insulin is required.
  • If significant ketonaemia is present (3β-hydroxy butyrate is more than 1 mmol/L) this indicates relative hypoinsulinaemia and insulin should be started at time zero (e.g. mixed DKA / HHS picture). The recommended insulin dose is a fixed rate intravenous insulin infusion given at 0.05 units per kg per hour.
  • If significant ketonaemia is not present (3β-hydroxy butyrate is less than 1 mmol/L) then do NOT start insulin.

Potassium
  • Patients with HHS are potassium deplete but less acidotic than those with DKA so potassium shifts are less pronounced
  • Hyperkalaemia can be present with acute kidney injury
  • Patients on diuretics may be profoundly hypokalaemic
  • Potassium should be replaced or omitted as required