Hyperosmolar Hyperglycemic State (HHS)

Hyperosmolar hyperglycemic state (HHS) commonly occurs in patients with type 2 diabetes who have concomitant illnesses, which cause reduced fluid intake. It is characterized by extreme hyperglycemia and hyperosmolarity without significant ketosis.

The mortality rate is higher for HHS than for DKA. This is because most patients with HHS are old and frail and usually present with comorbidities. However, the incidence of DKA is much higher than that of HHS.

Criteria for HHS

• Hypovolemia
• Marked hyperglycemia (> 30 mmol/L) without significant ketonaemia or acidosis
• Significantly raised serum osmolarity (> 320 mosmol/kg)
• Precipitating factors
  • Acute illness e.g. infection, myocardial infarction, and stroke
  • Underlying comorbidities e.g. renal dysfunction, congestive and heart failure
  • Drugs that raise serum glucose, inhibit insulin or cause dehydration:
    • Alcohol and cocaine
    • Anaesthesia
    • Antiarrhythmics: Encainide, propranolol
    • SGLTi
    • Antiepileptics: Phenytoin
    • Antihypertensives: CCBs, Diazoxide
    • Antipsychotics: Chlorpromazine, Clozapine, Olanzapine, Lithium, Risperidone, Duloxetine
    • L-asparaginase
    • Beta blockers
    • Corticosteroids
    • Thiazide and loop diuretics
    • Histamine-receptor blockers: Cimetidine
    • Immunosuppressive agents: Interferons, protease inhibitors
    • Statins
  • Non-compliance with oral hypoglycemics or insulin therapy
• Pathophysiology
  • The pathogenesis of HHS is similar to that of DKA
  • However, in HHS, there is a small amount of insulin being secreted by the pancreas
  • This insulin is sufficient to inhibit HSL activity, lipolysis, and, in turn, ketogenesis.
  • For this reason, HHS typically occurs in T2DM as it has relative insulin deficiency rather than absolute insulin deficiency as in T1DM.
  • However, DKA can occur in the advanced stages of T2DM when beta cell function has declined markedly, such that insulin levels are negligible.
• Signs and symptoms
  • Polyuria
  • Polydipsia
  • Weight loss
  • Weakness
  • Tachycardia
  • Orthostatic hypotension
  • Tachypnea
  • Hyperthermia if infection is present
  • Lethargy
  • Weak thready pulse
  • Severe dehydration
    • Poor capillary refill
    • Decreased skin turgor
    • Sunken eyes
    • Dry mucous membrane
    • Ill appearance
  • Neurological deficits
    • Altered mental status
    • Seizures – occur in 5% of patients, may be either focal or generalized
    • Coma
    • Transient hemiparesis
    • Hyperreflexia
    • Generalized areflexia
    • Lethargy → Coma
• Differentials
  • Diabetic ketoacidosis
• Investigations
  • Random blood glucose
    • 30mmol/L
  • Serum osmolality
    • 320mOsmol/kg
  • Plasma Bicarbonate
    • 15mmol
  • Arterial Blood Gases
    • PH >7.3
      • Anion gap absent
  • Urine Ketones
    • Mild ketonuria
  • Serum ketones
    • Low or absent ketones
    • CSF analysis for patients with acute alteration of consciousness and features that suggest meningitis or meningoencephalitis
  • Chest radiograph to exclude pneumonia
  • Abdominal Imaging if the patient has abdominal pain or is vomiting
  • CT scan of the head for patients with focal or global neurologic changes to exclude hemorrhagic stroke, subdural hematoma, subarachnoid bleeding, intracranial abscesses, and intracranial masses
  • Electrocardiography in all patients with HHS since myocardial infarction or pulmonary embolism can precipitate the condition
• Treatment
  • Rehydrate while maintaining electrolytes
    • Intravenous 0.9% saline to restore total body fluid
    • Switch to 0.45% if serum osmolality is not declining
    • Aim to achieve a positive balance of 3 – 6 litres by 12 hours
    • Replace the remaining losses within the next 12 hours
    • Replace or omit potassium as required
  • Correct hyperglycemia
    • Fluid replacement is enough to gradually decrease plasma glucose and serum osmolality without insulin
    • Insulin can be started initially if significant ketonemia is present at 0.05 U/kg/h
  • Treat the underlying disease
  • Monitor and assist cardiovascular, pulmonary, renal and CNS
  • Consider LMWH thromboprophylaxis if there is a risk of occlusive events
• Criteria for the resolution of HHS
  • Normalization of serum osmolality (<320 mOsm/kg)
  • Normal mental status
• Complications of HHS
  • Cardiovascular collapse may be caused by administering insulin before adequate fluid resuscitation
  • Hypoglycaemia due to inappropriate insulin administration
  • Hypokalaemia due to inappropriate insulin and bicarbonate administration
  • Cerebral oedema due to a sharp drop in plasma osmolarity when insulin is given to lower blood glucose
  • Acute respiratory distress syndrome
  • Thromboembolism due to hyperviscosity and immobilization