Hyperglycaemic hyperosmolar state (HHS)

Contents

Definition and Diagnostic Criteria

Hyperglycaemic hyperosmolar state (HHS) is a life-threatening acute diabetic emergency characterised by:

Criterion Value
Blood glucose >30 mmol/L
Serum osmolality >320 mOsm/kg
pH >7.3 (no significant acidosis)
Bicarbonate >15 mmol/L
Ketones <3 mmol/L (serum) or absent in urine
No ketonaemia/acidaemia (or mild only — see mixed picture)

Serum osmolality (calculated) = 2 × (Na⁺ + K⁺) + glucose + urea (all in mmol/L)

HHS develops more slowly than DKA (typically over days to weeks); occurs predominantly in type 2 diabetes, often older patients, and carries higher mortality than DKA (~10–15% vs ~1%).

Pathophysiology

Why No Ketosis?

In type 2 diabetes, there is enough residual insulin secretion to:

  • Suppress lipolysis (hepatic fatty acid delivery)
  • Inhibit hepatic ketogenesis
  • But insufficient to prevent hyperglycaemia

Contrast with DKA (type 1 or absolute insulin deficiency): no residual insulin → unchecked lipolysis → FFA delivery to liver → ketone body production → ketoacidosis.

Why Extreme Hyperglycaemia and Hyperosmolarity?

  1. Relative insulin deficiency → unchecked hepatic glucose production + impaired peripheral glucose uptake
  2. Glycosuria → osmotic diuresis → urinary free water loss — glucose acts as an osmotic diuretic, pulling water into the tubules and causing profound free water depletion
  3. Reduced thirst or inability to drink (elderly, cognitively impaired, nursing home residents) prevents compensatory fluid intake
  4. Progressive hyperglycaemia → ↑ serum osmolality → water moves from intracellular to extracellular compartment → cellular dehydration → neurological impairment
  5. Urinary Na⁺ loss concurrent with free water loss — but proportionally more water than Na⁺ is lost → hypernatraemia (corrected Na⁺ may be high even when measured Na⁺ appears normal)

Corrected Sodium

In hyperglycaemia, measured Na⁺ is falsely lowered by the dilutional effect of water drawn into plasma by glucose. Corrected Na⁺ = measured Na⁺ + 2.4 × [(glucose − 5.5) / 5.5] mmol/L. In HHS, corrected Na⁺ is often markedly elevated (>150 mmol/L), indicating severe free water deficit.

HHS vs DKA

Feature HHS DKA
Onset Slow (days–weeks) Rapid (hours)
Diabetes type Usually type 2 Usually type 1 (or type 2 with precipitant)
Glucose Usually >30 mmol/L Usually 15–30 mmol/L
Osmolality >320 mOsm/kg Often 290–310
Ketones Absent or minimal Markedly elevated (≥3 mmol/L)
Acidosis No (pH >7.3) Yes (pH <7.3)
Fluid deficit 8–10+ litres (larger) 3–5 litres
Na⁺ Elevated (corrected) Low (dilutional; rises with treatment)
Mortality ~10–15% ~1%
CNS symptoms Common (confusion, coma) Less prominent
Mixed picture Possible (HHS with mild ketosis) —

Clinical Presentation

Typical Patient

  • Elderly type 2 diabetic, often in care home
  • Precipitating event: infection (most common — urinary, respiratory), stroke, MI, new medications (steroids, diuretics, antipsychotics), poor compliance, reduced oral intake from intercurrent illness

Symptoms

  • Polydipsia, polyuria (prolonged, days to weeks)
  • Progressive cognitive impairment: confusion → stupor → coma (related to hyperosmolarity — neurological symptoms correlate with serum osmolality)
  • Profound weakness, lethargy

Signs

  • Severe dehydration: dry mucous membranes, reduced skin turgor, tachycardia, hypotension
  • Neurological: confusion, focal neurology, seizures, coma
  • Signs of precipitant: fever, localised infection

Investigations

  • Glucose: >30 mmol/L
  • Serum osmolality (measured or calculated): >320 mOsm/kg
  • U&E: sodium, potassium, urea, creatinine — calculate corrected Na⁺
  • Ketones: blood ketones <3 mmol/L; urine negative or trace
  • Blood gas: pH >7.3, bicarbonate >15 mmol/L (mild metabolic acidosis possible from AKI or lactic acidosis)
  • FBC, CRP, cultures: identify precipitant (blood cultures, urine culture, CXR)
  • ECG: hypokalaemia, MI as precipitant
  • HbA1c: newly diagnosed diabetes

Management

Glucose Targets

Unlike DKA, the immediate priority is osmolality, not glucose. Rapid falls in glucose → rapid falls in serum osmolality → cerebral oedema (water moves back into cells). Target glucose fall: 3–4 mmol/L per hour — no faster.

Fluid Replacement

First 1 hour: 1 litre 0.9% NaCl IV rapidly (haemodynamic resuscitation if shocked)

Subsequent hours: continue with 0.9% NaCl — note this is isotonic but will be hypotonic relative to the patient's hyperosmolar plasma, so it is relatively appropriate.

Target: Replace estimated fluid deficit over 48 hours (not 24h as in DKA). Estimated deficit 8–10 litres.

Osmolality monitoring: Check serum osmolality every 1–2 hours. Rate of osmolality fall should not exceed 3–8 mOsm/kg/hour — too rapid risks cerebral oedema.

Avoid hypotonic fluids (0.45% NaCl) initially — rapid osmolality correction risks cerebral oedema. If osmolality not falling despite 0.9% NaCl (e.g., serum Na⁺ rising), then switch to 0.45% NaCl cautiously.

Potassium

  • Potassium deficit is large (total body K⁺ depleted by osmotic diuresis) but serum K⁺ may appear normal or elevated (K⁺ shifts extracellularly in absence of insulin, and in acidosis)
  • Add potassium to IV fluids once urine output confirmed and K⁺ <5.5 mmol/L
  • Monitor K⁺ every 1–2 hours

Insulin

A critical difference from DKA: insulin is NOT started immediately in HHS.

  • Start insulin only once blood glucose is no longer falling with fluid alone — or if ketones present (mixed HHS/DKA)
  • Rate: fixed rate insulin infusion (FRII) 0.05 units/kg/h (half the DKA rate) — lower rate reduces risk of rapid osmolality fall
  • Reason to delay insulin: insulin drives glucose into cells, rapidly lowering serum osmolality → risk of cerebral oedema
  • Target: glucose fall of 3–4 mmol/L/hour

Note — NICE-SUGAR relevance: the evidence for tight glycaemic control in the ICU comes from NICE-SUGAR (target 4.5–6.0 mmol/L → ↑ mortality from hypoglycaemia). ICU glucose target is 6–10 mmol/L. In HHS, the gradual reduction in glucose also minimises hypoglycaemia risk.

Anticoagulation

  • Prophylactic LMWH mandatory: HHS is a highly prothrombotic state — hyperosmolarity, immobility, dehydration → ↑ thrombosis risk; DVT and PE are major complications
  • Thrombosis (venous and arterial) is a leading cause of death in HHS

Monitoring

  • Glucose hourly; osmolality 1–2-hourly; electrolytes 2-hourly; fluid balance 1-hourly
  • Neurological observations; GCS changes signal osmolality shifts

Complications

Complication Notes
Thromboembolism Major cause of mortality; DVT, PE, arterial thrombosis (stroke, MI)
Cerebral oedema From rapid osmolality correction; more common in young patients and if osmolality falls >3–8 mOsm/kg/h
AKI From profound dehydration; may be pre-renal → intrinsic; monitor creatinine
Rhabdomyolysis From profound dehydration, immobility; monitor CK
Hypoglycaemia From over-rapid insulin or inadequate glucose monitoring
Hyponatraemia If hypotonic fluids given too rapidly or if SIADH supervenes

Viva Questions

1. Why does HHS cause such severe dehydration compared to DKA?

In HHS, the hyperglycaemia develops slowly over days to weeks — there is usually sufficient residual insulin to prevent ketogenesis, but not enough to normalise blood glucose. As glucose climbs progressively, it exerts increasing osmotic pressure in the renal tubules, causing glycosuria and an osmotic diuresis that dumps large volumes of free water in the urine. Over days, urinary losses can reach 8–10+ litres. Unlike DKA — where the illness is acute, the patient is usually younger and can communicate thirst, and presentation typically occurs within hours to a day or two — HHS patients are often elderly, cognitively impaired, institutionalised, or have impaired thirst mechanisms. They cannot compensate for the ongoing water loss. The result is more extreme dehydration, more extreme hyperosmolarity, and paradoxically a much larger total fluid deficit than DKA despite glucose levels that may appear similarly severe.

2. Why is rapid correction of hyperglycaemia and osmolality dangerous in HHS, and how do you avoid it?

Brain cells adapt to chronic hyperosmolarity by generating idiogenic osmoles (organic osmolytes — taurine, myo-inositol, betaine, and others) that prevent intracellular water loss and protect against cellular shrinkage. If serum osmolality is corrected rapidly, these osmolytes persist within brain cells temporarily — creating an osmotic gradient that draws water into the brain → cerebral oedema. This is particularly dangerous in young patients and those with the most extreme hyperosmolarity. Avoidance: replace fluid deficit over 48 hours (not 24 hours); target osmolality fall of no more than 3–8 mOsm/kg/hour; monitor osmolality every 1–2 hours; delay insulin until glucose is no longer falling with fluids alone, then use at half the DKA rate (0.05 units/kg/h); avoid hypotonic fluids early; aim for glucose fall of only 3–4 mmol/L/hour. Any neurological deterioration (worsening GCS, new seizures) during treatment warrants urgent reassessment of the rate of osmolality correction and consideration of osmotic therapy.

3. What is the role of anticoagulation in HHS and why?

Thromboembolism is a leading cause of mortality in HHS. The prothrombotic state results from several concurrent factors: profound dehydration → haemoconcentration → polycythaemia → increased blood viscosity; hyperosmolarity → platelet activation and endothelial injury; immobility (elderly, confused, bedbound during the prolonged illness); and the hypercoagulable effects of hyperglycaemia and inflammation. Both venous thromboembolism (DVT, PE) and arterial events (stroke, MI) are significantly increased. LMWH thromboprophylaxis (e.g., enoxaparin 40 mg SC once daily, renally adjusted) is mandatory in all HHS patients without absolute contraindication. Unlike DKA — where thromboprophylaxis is recommended but the acute illness is shorter and the risk lower — the prolonged nature of HHS and the patient's typical frailty make anticoagulation an essential component of management, not just a standard VTE bundle item.