29th May 2025

Hyperosmolar hyperglycaemic syndrome (HHS)

HHS is a dangerous complication of diabetes, seen most commonly in T2DM (accounting for roughly 90-95% of cases). It carries a significant mortality rate, estimated to be around 20%, which is significantly higher than diabetic ketoacidosis (DKA) (most commonly seen in T1DM and covered in that chapter). Despite this, recognition of HHS can prove challenging to clinicians and there is a much greater awareness of DKA. HHS is most commonly seen in patients with T2DM and obesity.

Pathophysiology

In T2DM, the desensitisation of the peripheral tissues to the action of insulin leads to chronic hyperglycaemia, which inhibits pancreatic beta-cell proliferation and secretion of insulin. Therefore, the amount of glucose entering cells and being metabolised is reduced, triggering the compensatory release of glucagon, cortisol, growth hormone and catecholamines to stimulate glycogenolysis and gluconeogenesis, forming a vicious cycle. Greater circulating glucose significantly increases the serum osmolality (Osmolality = 2(Na) + glucose/18 + BUN/2.8) and osmotic gradient, pulling water into the vessels from the extravascular space. Water and electrolytes are lost in the urine leading to dehydration.

The main differentiating feature from DKA is that there is very little production of ketone bodies as there is still some production of insulin, which inhibits ketogenesis. Patients therefore don’t become severely acidotic.

Diagnosis

As in DKA, there is normally a trigger to HHS, most commonly infection but any condition that can place the body under stress. Several medications including corticosteroids, diuretics and atypical antipsychotics may trigger HHS. In contrast to DKA, HHS isn’t commonly seen on diagnosis with T2DM.  The symptoms relate to dehydration and any underlying cause:

• Tachycardia with a weak, low-volume pulse. Patients may have palpitations or chest pain if there is a cardiogenic cause.
• Hypotension, reduced skin turgor, reduced capillary refill time, cool and clammy peripheries if severely dehydrated.
• At first polyuria and then oliguria as dehydration worsens.
• Focal neurological signs, reduced consciousness, delirium and coma.
• Signs of infection or sepsis such as fever, hypotension, tachycardia etc.
• Signs of cardiovascular cause such as chest pain or palpitations.

The diagnostic criteria for HHS is a plasma glucose >600mg/dL and plasma osmolarity >320mOsm/L without the presence of ketoacidosis. There is often derangement of electrolytes and their correction is an important part of the management of HHS:

• Pseudohyponatraemia – due to intravascular dilution.
• Hyper/hypokalaemia – decreased insulin can cause the movement of potassium out of cells and into the vasculature. However, as HHS progresses potassium is increasingly lost in the urine.
• Hyperphosphataemia – due to muscle breakdown.
• Hypomagnesaemia – due to intravascular dilution and urinary loss.
• Ketones and bicarbonate – will be normal due to a lack of ketogenesis and normal pH.

Other blood results that may be noted are an increase in creatinine and BUN due to a prerenal azotaemia AKI. White blood cells and acute phase reactants may be raised even in the absence of infection as part of a stress response.

Management

The most important part of treating HHS is aggressive rehydration but there are several factors to consider:

• Rehydration – using an isotonic solution, typically 0.9% saline. An initial bolus should be given followed by an infusion at around 250ml/hour.
• Correction of electrolytes – this should be approached with caution as there is concurrent intravascular dilution and depletion of electrolytes. Potassium replacement should be started when the concentration is 4 – 4.5mmol/L. Other electrolytes should be monitored closely and replaced with specialist input.
• Insulin – this should be avoided initially as it may cause too rapid of a fall in glucose, resulting in cerebral oedema. It may be started later on the advice of an endocrinologist. 
• Monitoring – glucose should be closely monitored as if it falls too fast then cerebral oedema will occur. Osmolarity should be monitored as a marker of response to treatment. Electrolytes should be closely monitored and acted upon accordingly. 
• Treatment of underlying cause – whatever this may be. 

Patients with T2DM must be educated on the symptoms of HHS, common triggering events and when to seek medical attention. If taking insulin, the importance of good compliance should be stressed as to avoid developing HHS.