Hyperosmolar hyperglycaemic state (HHS) · ICU Topics

Cinematic ICU scene of a dehydrated elderly patient with a blood gas showing marked hyperglycaemia and high serum osmolality on the monitor, rapid saline resuscitation running, a low-dose insulin infusion drawn up, clinical-blue lighting, medical educational, no faces, no text — FigureThe hyperosmolar hyperglycaemic state — the type 2 diabetic, the glucose over 33, the osmolality over 320, the severe dehydration without the significant ketosis. The hourly fluid is the priority (the deficit is the 6 to 9 litres), the insulin is the 0.05 units per kg per hour after the fluid, and the prophylactic LMWH. The mortality is the 10 to 20 per cent.

Diagnostic criteria and the biochemical signature

HHS diagnostic criteria — the numbers every candidate must know cold

The diagnosis of HHS rests on a biochemical triad: (1) marked hyperglycaemia (>33 mmol/L / 600 mg/dL), (2) hyperosmolality (effective osmolality >320 mOsm/kg), and (3) the ABSENCE of significant ketosis/acidosis (venous pH >7.30, serum bicarbonate >15 mmol/L, negative or only trace ketones, anion gap <12). Profound dehydration (estimated free-water deficit 6-9 L) and a clouded sensorium (stupor, confusion, or coma — proportional to the degree of hyperosmolality, not the glucose) complete the picture. [1]

Two equations the exam expects you to write out:

Calculated (measured) osmolality = 2 × [Na] + [glucose] + [urea] (all in mmol/L). Normal 285-295. HHS >320 (often 340-360).
Corrected sodium = measured [Na] + 1.6 × ([glucose] − 5.5) ÷ 5.5. (Some sources use 2.4; the ADA uses ~1.6-2.4.) This corrects for the osmotic draw of water out of the extracellular space by glucose, which DILUTES sodium — the measured Na therefore UNDER-estimates the true sodium. The corrected sodium dictates fluid choice (normal vs half-normal saline).[1][4]

Stupor/coma is proportionate to osmolality, not glucose. A glucose of 50 mmol/L with normal mentation is not HHS; a glucose of 35 mmol/L with osmolality 350 and GCS 10 is. A useful rule: coma in a hyperglycaemic patient with osmolality <315 is NOT due to hyperglycaemia — look for another cause (stroke, sepsis, drug).[4]

HHS diagnostic thresholds vs DKA vs mixed picture

Parameter	HHS	DKA	Mixed / overlap
Glucose	>33 mmol/L (often 40-60)	>13.9 mmol/L (typically 15-30)	High; can overlap
Arterial/venous pH	>7.30	<7.30 (mild 7.25-7.30, mod 7.00-7.24, severe <7.00)	May be <7.30
Bicarbonate	>15 mmol/L	<15 mmol/L	Variable
Ketones (β-OHB)	Minimal/absent (<3 mmol/L)	Positive (>3 mmol/L)	Moderate
Anion gap	<12 (normal; may be mildly ↑ from lactate)	>12 (high-gap ketoacidosis)	Elevated
Osmolality	>320 mOsm/kg (often 340-360)	Variable, usually <320	High
Mental status	Altered/stupor/coma (≈30% comatose)	Usually alert / mildly confused	Clouded
Free-water deficit	6-9 L (~9-12% body weight)	3-6 L (~6% body weight)	Large
Typical patient	Elderly type 2 DM	Type 1 DM (or type 2 ketosis-prone)	Type 2
Insulin requirement	LOW (0.05 U/kg/h)	STANDARD (0.1 U/kg/h)	Standard
Onset	Days to weeks (insidious)	Hours to <24 h (rapid)	Variable
Cerebral oedema risk	Lower than paediatric DKA but real in adults	Classic in children, rare in adults	Present

[1] [4]

The HHS numbers to memorise

>33

Glucose (mmol/L)

Severe hyperglycaemia — typically higher than DKA

>320

Osmolality (mOsm/kg)

Effective osmolality — drives the altered mental state

6-9 L

Free-water deficit

~9-12% of body weight — far exceeds DKA

10-20%

Mortality

2-4x higher than DKA; elderly, comorbid

[1]

HHS vs DKA comparison

HHS

Type 2 diabetes, elderly

Glucose: >33 mmol/L (typically higher than DKA)
pH: >7.30 (minimal acidosis)
Bicarbonate: >15 mmol/L (no significant ketoacidosis)
Ketones: minimal/absent (urine/serum)
Osmolality: >320 mOsm/kg (typically much higher — profound dehydration)
Anion gap: normal or mildly elevated (lactic acidosis from hypoperfusion)
Dehydration: 6-9 L (more severe than DKA)
Mental status: often altered/confused/comatose (from hyperosmolality)
Insulin dose: LOW (0.05 U/kg/h — half DKA dose)

DKA

Type 1 (and some type 2) diabetes

Glucose: >13.9 mmol/L (typically lower than HHS)
pH: <7.30 (metabolic acidosis)
Bicarbonate: <15 mmol/L (ketoacidosis)
Ketones: positive (urine/serum — beta-hydroxybutyrate)
Osmolality: variable (less dehydration than HHS)
Anion gap: elevated (ketones — beta-hydroxybutyrate, acetoacetate)
Dehydration: 3-6 L
Mental status: usually alert or mildly confused
Insulin dose: STANDARD (0.1 U/kg/h)

[1] [2]

WHY HHS IS NOT KETOTIC — the relative insulin deficiency concept (the single most tested pathophysiology point)

The crux of HHS pathophysiology is a relative, not absolute, insulin deficiency. The failing type-2 pancreas still secretes enough insulin to suppress hormone-sensitive lipase in adipose tissue — the lipolytic step that releases free fatty acids, which the liver would otherwise convert to ketone bodies. Because lipolysis is held in check, no ketoacidosis develops (pH stays >7.30, bicarbonate >15). However, the residual insulin is insufficient to overcome the combined insulin resistance and counter-regulatory hormone surge (glucagon, catecholamines, cortisol, growth hormone) that drives hepatic gluconeogenesis and glycogenolysis and impairs peripheral glucose uptake. The result is unchecked hyperglycaemia without ketosis. [1]

This explains the two cardinal contrasts with DKA:

In DKA the insulin deficiency is ABSOLUTE — lipolysis is unbridled → free fatty acids flood the liver → hepatic ketogenesis (β-hydroxybutyrate, acetoacetate) → high-anion-gap metabolic acidosis.
In HHS the insulin deficiency is RELATIVE — enough to suppress lipolysis, too little to suppress hyperglycaemia. The threshold for suppressing lipolysis (and hence ketogenesis) is roughly one-tenth of the insulin concentration needed to promote peripheral glucose uptake — a quantitatively elegant concept. [1]

Two downstream consequences dominate the clinical picture: (1) massive osmotic diuresis — glucose exceeds the renal threshold (~10 mmol/L), glycosuria pulls water and electrolytes (Na, K, Mg, PO4) into the urine, producing the 6-9 L free-water deficit and total-body depletion of K, Mg and phosphate; and (2) hyperosmolality, which draws water out of cells (including neurons) and is the proximate cause of the depressed sensorium — the level of consciousness tracks osmolality, not glucose.[1][4]

Pathophysiology — the cascade

Educational schematic of HHS pathophysiology: relative insulin deficiency, severe hyperglycaemia, osmotic diuresis, profound dehydration, hyperosmolality without major ketoacidosis — FigureHHS cascade — relative insulin deficiency prevents ketosis but not hyperglycaemia; osmotic diuresis creates multi-litre deficits and a hyperosmolar, prothrombotic state.

HHS pathophysiology — stepwise from insulin resistance to coma

Relative insulin deficiency + counter-regulatory excess

Insulin secretion falls (or resistance rises) but enough insulin remains to suppress hormone-sensitive lipase → NO ketogenesis. Counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) surge in response to a precipitant (infection, MI, stroke, steroids). Net effect: hepatic gluconeogenesis/glycogenolysis unchecked, peripheral glucose uptake impaired.

Uncontrolled hyperglycaemia

Glucose climbs over hours-to-days (HHS is insidious — symptoms develop over days-weeks, unlike the hours of DKA). Glucose typically exceeds 33 mmol/L and may reach 60-80 mmol/L. The slower onset allows the brain time to accumulate "idiogenic osmoles", which paradoxically INCREASES the cerebral-oedema risk if glucose is later dropped too fast.

Osmotic diuresis

Glucose filtered load exceeds the renal Tm → glycosuria. Glucose acts as an obligate osmole in the tubule, dragging water AND electrolytes (Na, K, Mg, PO4) into the urine. The result is the HALLMARK free-water deficit of 6-9 L plus total-body potassium depletion of ~5-10 mmol/kg (despite often normal/high serum K from acidosis/hypovolaemia/insulin deficiency).

Hyperosmolality and cellular dehydration

Rising extracellular glucose and sodium raise serum osmolality above 320 mOsm/kg. Water shifts out of cells (including neurons). Consciousness deteriorates in proportion to osmolality: mild confusion → obtundation → coma. Osmolality >340 is usually associated with significant neurological depression.

Hypovolaemia and end-organ hypoperfusion

Intravascular volume depletion → tachycardia, hypotension, prerenal AKI, lactate rise (a "normal anion gap" lactic acidosis is common and distinguishes HHS from the high-gap DKA). Severe volume depletion → shock. The hyperosmolar, dehydrated state is profoundly PROTHROMBOTIC (hyperviscosity, high factor VIII/vWF, low-flow stasis). Prerenal AKI can mask the true glucose (renal clearance falls) — glucose may be even higher than expected.

Compounded by the precipitant

The precipitating illness (infection, MI, stroke) is often itself the major driver of mortality. HHS is as much a marker of serious systemic illness in an elderly type-2 patient as it is a metabolic emergency. Treating HHS without finding and treating the trigger guarantees recurrence and worsens outcome.

[1] [3]

Precipitating causes — find the trigger

Precipitants of HHS — search for these in every patient

Precipitant	Mechanism / note	Frequency
Infection (pneumonia, UTI, sepsis)	Raises counter-regulatory hormones; #1 single precipitant	Most commonly identified single trigger (~40-50%)[5]
New/occult type 2 diabetes	First presentation — HHS may be the debut illness	~30%[5]
Acute cardiovascular event	Silent MI (autonomic neuropathy in elderly diabetics), stroke, ACS	Major mortality contributor
Medication-induced	Glucocorticoids (raise gluconeogenesis + insulin resistance), thiazides, beta-blockers (mask counter-regulation), atypical antipsychotics (olanzapine, clozapine), phenytoin, sympathomimetics	Common; review ALL drugs
Non-adherence / inadequate insulin	Missed oral hypoglycaemics or insulin	Common in known diabetics
Substance misuse	Cocaine, alcohol	Often overlooked
Acute illness (non-infective)	Pancreatitis, GI bleed, trauma, surgery, dialysis, TPN	~50% in pooled series[5]
Total parenteral nutrition / high-dextrose	Iatrogenic glucose load	ICU/ward iatrogenic

[1] [5]

THE PRECIPITANT IS THE MORTALITY DRIVER — never treat the glucose and forget the cause

HHS is rarely the sole problem — it is almost always the metabolic manifestation of a serious intercurrent illness. The single most important prognostic step is to find and treat the precipitant. In every HHS patient obtain: blood/urine/sputum cultures, CXR, ECG and troponin (silent MI is common in elderly diabetics), and CT brain if there is any focal neurology or the sensorium does not improve with correction of osmolality. A patient whose coma persists after the osmolality normalises has another cause — stroke, sepsis, drug, or post-ictal state — and needs urgent imaging. Pooled meta-analytic data (French 2026, n=63,935) put overall HHS mortality at 21.1%, highest in Africa (40%) and lowest in North America (4.8%), with acute kidney injury in 7.6%, pulmonary oedema 4.8%, and acute coronary syndrome 3.9% — i.e. the complications of dehydration and the precipitant, not the glucose itself, dominate outcomes.[5]

Management

HHS management protocol

Aggressive fluid resuscitation (PRIMARY treatment)

0.9% saline: 15-20 mL/kg in first hour (1-1.5 L). Then titrate based on: corrected serum sodium, hydration status, urine output, cardiac status. Goal: restore intravascular volume → improve tissue perfusion → improve renal function → promote glucose excretion. Glucose falls 2-5 mmol/L with fluids ALONE before any insulin given. Switch to 0.45% saline if corrected Na is normal/high after initial resuscitation. Add 5% dextrose when glucose reaches 14-16 mmol/L.

Potassium replacement BEFORE insulin

Check K+ immediately. If K+ <3.3: hold insulin, give K+ 40 mmol/h. If K+ 3.3-5.2: give K+ 20-30 mmol/L of IV fluid, start insulin. If K+ >5.2: start insulin, check K+ every 2h, hold K+ replacement. Insulin drives K+ into cells → hypokalaemia risk. HHS patients have TOTAL BODY POTASSIUM DEPLETION (despite normal/initially high serum K+ from acidosis/dehydration).

Low-dose insulin (HALF DKA dose) — ONLY after fluids

Insulin infusion: 0.05 U/kg/h (NOT 0.1 U/kg/h as in DKA — HHS patients are more sensitive to insulin). Goal: lower glucose 3-4 mmol/L/h. If glucose not falling: increase insulin to 0.1 U/kg/h. When glucose reaches 14-16 mmol/L: add 5% dextrose infusion + reduce insulin rate to maintain glucose 10-14 mmol/L. Do NOT lower glucose too fast — risk of cerebral oedema (osmotic shift).

Monitor closely

Glucose: hourly. Electrolytes (Na, K, Mg, PO4): every 2-4h. Creatinine, venous pH: every 4-6h. Urine output: hourly (catheterise). Cardiac monitoring (K+ shifts → arrhythmias). Neurological status (cerebral oedema risk — headache, vomiting, altered mental status). Calculate corrected sodium and osmolality at each measurement.

Identify and treat precipitant

Search for: (1) Infection (#1 — chest, urine, blood cultures, antibiotics). (2) MI (ECG, troponin — silent MI common in elderly diabetics). (3) Stroke (CT brain if focal neurology). (4) New medication (steroids, thiazides, beta-blockers, atypical antipsychotics). (5) Non-adherence to diabetes medication. (6) Substance abuse. Without treating the precipitant: HHS will recur.

Anticoagulate (thromboprophylaxis)

HHS is a profoundly prothrombotic state — hyperviscosity, dehydration, high FVIII/vWF, immobility, and (often) central lines/catheters. Give prophylactic LMWH unless contraindicated (e.g. active bleeding). Arterial events (MI, stroke) and VTE are leading complications.

Transition to subcutaneous insulin

When stable (glucose 10-14 mmol/L, normal osmolality, eating): transition to subcutaneous insulin. Give first subcutaneous dose 1-2 hours before stopping IV infusion (overlap to prevent rebound hyperglycaemia). Long-acting insulin (glargine/detemir) + rapid-acting insulin with meals. Type 2 diabetes: may transition to oral hypoglycaemics if suitable. Adjust based on HbA1c, body weight, renal function.

[1] [2]

Fluid resuscitation — the cornerstone, done correctly

FLUIDS FIRST, INSULIN SECOND — and the glucose falls before any insulin is given

Fluid resuscitation is the primary treatment of HHS, more so than in DKA. The reasons are quantitative: the free-water deficit (6-9 L) is roughly double that of DKA, and restoring intravascular volume alone improves renal perfusion, which restores glycosuric clearance of glucose — the blood glucose frequently drops 2-5 mmol/L with fluids alone before any insulin is given. Premature or aggressive insulin in a hypovolaemic patient both fails (poor tissue delivery) and risks catastrophic shifts (hypokalaemia, cerebral oedema). [1]

The standard regimen (ADA / JBDS / UK vs USA consensus):

Hour 1: 0.9% saline 15-20 mL/kg (≈1-1.5 L) to restore intravascular volume, regardless of corrected sodium.
Hours 2+: choose tonicity by the corrected sodium:
- Corrected Na low/normal (<150): continue 0.45% saline at 250-500 mL/h (replace the predominantly free-water deficit).
- Corrected Na high (>150): use 0.45% saline even more aggressively (the patient is genuinely hypernatraemic and needs free water).
- Corrected Na very high / shocked: some units use 0.9% until shock resolves, then switch to 0.45%.
When glucose ≤14-16 mmol/L: add 5% dextrose (often as a separate line or switch to 0.45% saline + 5% dextrose) AND halve the insulin rate, to hold glucose 10-14 mmol/L while osmolality continues to normalise.
Target: reduce osmolality by no more than 3-5 mOsm/kg/h, and glucose by no more than 3-4 mmol/L/h.[1][4]

Free-water deficit = 0.6 × body weight (kg) × ([Na/140] − 1). Replace the deficit over 24-48 h (the first half in the first 12 h). Corrected sodium must not rise faster than 8-10 mmol/L/24 h (risk of central pontine myelinolysis if hyponatraemic, or worsening hypernatraemia if over-corrected).[3]

WHY CORRECTED SODIUM MATTERS — the dilutional hyponatraemia of hyperglycaemia

Hyperglycaemia raises serum osmolality, which pulls water out of cells into the extracellular space, diluting every extracellular solute — most measurably sodium. The measured sodium in HHS is therefore an under-estimate of the true body sodium status. For every 5.5 mmol/L (100 mg/dL) rise in glucose above 5.5 mmol/L, sodium falls by ~1.6 mmol/L (range 1.6-2.4, depending on the population — the ADA quotes both). [1]

Formula: corrected Na = measured Na + 1.6 × ([glucose] − 5.5) ÷ 5.5. [1]

This corrected value is what guides fluid choice. Treating a "hyponatraemic" HHS patient with 0.9% saline when the corrected sodium is actually 152 would worsen free-water deficit. Conversely, a measured sodium of 130 with glucose 50 has a corrected sodium of ~143 (normal) — give 0.45% saline, not aggressive normal saline. As glucose falls on treatment, the water shifts back into cells and the measured sodium rises toward the corrected value — this is expected, not a sign of over-correction, UNLESS corrected sodium itself climbs >8-10 mmol/L/day.[1][4]

Potassium management — replace before, monitor during

TOTAL-BODY POTASSIUM DEPLETION DESPITE A NORMAL/HIGH SERUM K+ — the HHS trap

HHS patients have a total-body potassium deficit of ~5-10 mmol/kg, lost via the osmotic diuresis (kaliuresis) and (in any ketotic overlap) via the gut. Yet the measured serum potassium is often normal or even high at presentation, because: (1) insulin deficiency prevents the intracellular K+ shift; (2) acidosis (lactic, or any ketotic overlap) shifts K+ extracellularly; (3) hypovolaemia reduces renal K+ delivery. The moment insulin is given and the acidosis resolves, K+ is driven intracellularly and excreted in the recovering urine → precipitous hypokalaemia and arrhythmia. [1]

Action thresholds (as for DKA, but apply rigidly):

K+ <3.3 mmol/L: HOLD insulin. Give K+ ~40 mmol/h. Recheck in 1-2 h. Insulin only once K+ ≥3.3.
K+ 3.3-5.2 mmol/L: Add 20-30 mmol K+ per litre of maintenance IV fluid; start insulin at the low HHS rate.
K+ >5.2 mmol/L: Hold K+ replacement. Start insulin. Check K+ every 2 h; begin K+ replacement the moment it falls below 5.0. [1]

Replace magnesium concurrently (hypomagnesaemia perpetuates refractory hypokalaemia). Cardiac monitoring is mandatory during K+ shifts.[1][4]

Insulin therapy — half the DKA dose, started only after fluids

LOW-DOSE INSULIN (0.05 U/kg/h) — start ONLY after fluids are running

HHS requires half the DKA insulin dose: a fixed-rate intravenous insulin infusion at 0.05 units/kg/h (vs 0.1 U/kg/h in DKA). Three principles justify the lower dose: [1]

HHS patients retain residual endogenous insulin — they are NOT insulin-naïve and are relatively more sensitive to exogenous insulin than the ketotic type-1 patient.
The elderly HHS brain has accumulated idiogenic osmoles over the days-weeks of slowly rising glucose; a rapid osmolar drop (driven by insulin pushing glucose, K+ and water into cells) precipitates cerebral oedema.
Fluids do most of the early glucose reduction via restored renal clearance — insulin is an adjunct, not the primary lever. [1]

Practical rules:

Start the insulin infusion only after fluid resuscitation has begun AND potassium ≥3.3 mmol/L.
Do NOT give an IV insulin bolus (the ADA explicitly advises against boluses).
Aim to lower glucose by 3-4 mmol/L/h. If it is not falling, re-examine hydration first (most failures are under-resuscitation), THEN double the insulin rate to 0.1 U/kg/h.
When glucose reaches 14-16 mmol/L, add 5% dextrose and reduce the insulin infusion to hold glucose 10-14 mmol/L while osmolality continues to fall.
Do NOT stop insulin — it is still needed to suppress ketogenesis and maintain glucose; the dextrose is added so insulin can continue safely.[1][2][4]

Anticoagulation — the prothrombotic emergency

HHS IS A PROTHROMBOTIC STATE — give prophylactic LMWH

HHS carries a markedly elevated risk of both venous and arterial thrombosis. The mechanisms are multifactorial: dehydration and hyperviscosity; high factor VIII and von Willebrand factor (an acute-phase response driven by the precipitant and the hyperosmolality itself); low-flow stasis from hypovolaemia and immobility; and frequently indwelling central venous catheters. Nationwide cohort data show a significantly increased incidence of venous thromboembolism in patients presenting with HHS compared with matched diabetic controls.[7]

Practice: give prophylactic-dose low-molecular-weight heparin (e.g. enoxaparin 40 mg SC daily, dose-adjusted to renal function) to EVERY HHS patient unless there is a clear contraindication (active bleeding, recent neurosurgery, severe thrombocytopenia). Continue until the patient is fully mobile and the osmolality has normalised. The thrombotic risk persists for days after the biochemistry resolves. Do NOT use therapeutic anticoagulation routinely — but have a low threshold to investigate new chest pain, leg swelling, focal neurology or a falling platelet count (arterial events — MI, stroke — and VTE are leading causes of HHS morbidity and mortality).[3][7]

Monitoring protocol

Hourly and serial monitoring in HHS — what to measure and how often

Hourly

Capillary glucose (titrate insulin/fluids); neurological observation (GCS — rising GCS = osmolality improving; falling GCS or new headache/vomiting = cerebral oedema until proven otherwise); urine output via urinary catheter (target ≥0.5 mL/kg/h); continuous cardiac monitoring (K+ shifts → arrhythmias); vital signs and fluid balance.

Every 2 hours

Venous blood gas (pH, HCO3, lactate, calculated anion gap); serum potassium (drive insulin and K+ replacement off this); capillary β-hydroxybutyrate if any ketotic overlap to confirm resolution. Recalculate corrected sodium and osmolality.

Every 4-6 hours

Full U&E (Na, K, Cl, bicarbonate, urea, creatinine); magnesium and phosphate (replace if low — phosphate <0.5 may impair respiratory muscle function and tissue oxygen delivery); venous pH. Calculate effective osmolality trend — target fall ≤3-5 mOsm/kg/h.

Daily / ongoing

FBC, CRP, coagulation; review cultures and imaging; troponin if any cardiac suspicion; CXR if oxygen requirement or suspected aspiration. Nutritional assessment and a plan for subcutaneous insulin conversion once eating. Pressure-area care and DVT prophylaxis (LMWH) — immobile dehydrated elderly patients are at very high VTE risk.

Targets to achieve before stopping the IV insulin

Glucose stable at 10-14 mmol/L on a dextrose-containing regimen; osmolality normalising (≤315, falling); acidosis (if any) resolved; potassium in range on a reducing replacement rate; the precipitant identified and being treated; the patient eating and ready for subcutaneous conversion.

[2] [4]

Complications

Complications of HHS — anticipate and prevent

Complication	Mechanism	Prevention / management
Cerebral oedema	Rapid osmolar shift; idiogenic osmole accumulation. Rare in adults vs paediatric DKA, but fatal when it occurs	Limit glucose fall to 3-4 mmol/L/h; do NOT give insulin before fluids; watch for headache, vomiting, falling GCS. Treat: mannitol / hypertonic saline
Hypokalaemia	Intracellular K+ shift once insulin started; ongoing kaliuresis	Replace K+ before insulin (hold if <3.3); recheck q2h; replace Mg²⁺ concurrently
Acute kidney injury	Profound hypovolaemia + osmotic diuresis; nephrotoxic precipitant	Aggressive early fluids; avoid NSAIDs; monitor creatinine; usually prerenal and reversible
Acute coronary syndrome / stroke	Hyperviscosity, hypercoagulability, dehydration; silent MI in elderly	ECG + troponin on admission; LMWH; maintain perfusion; low threshold to image brain
Venous thromboembolism	Prothrombotic state (high FVIII/vWF), immobility, central lines	Prophylactic LMWH for all; mechanical prophylaxis; investigate new swelling/dyspnoea
Pulmonary oedema / ARDS	Over-aggressive fluid resuscitation in elderly with cardiac disease	Titrate fluids to corrected Na, urine output, perfusion; consider CVP/POCUS; use balanced approach
Hypoglycaemia	Insulin overdose / failure to add dextrose at the switch point	Hourly glucose; add 5% dextrose at glucose 14-16; halve insulin rate
Hypophosphataemia	Cellular uptake with insulin; respiratory muscle weakness, tissue hypoxia	Replace if PO4 <0.5 mmol/L (esp. if ventilated)
Aspiration pneumonia	Reduced GCS + vomiting	Airway protection; early NG tube if obtunded; head-up positioning

[1] [5]

CEREBRAL OEDEMA IN HHS — rare but lethal, and almost always iatrogenic

Cerebral oedema is the most feared complication of hyperglycaemic emergencies. In HHS it is far rarer than in paediatric DKA but it does occur in adults, and it is almost always associated with a too-rapid fall in glucose/osmolality — typically from giving insulin too early, too aggressively, or in a still-hypovolaemic patient. The pathophysiology is the brain's accumulation of idiogenic osmoles (taurine, myo-inositol, glutamate) during the slow onset of hyperosmolality; these take time to dissipate, so if the extracellular osmolality is dropped faster than the brain can shed its idiogenic osmoles, water flows INTO neurons → oedema. [1]

Red flags: new headache, vomiting, drowsiness, falling GCS, abnormal pupil response, Cushing's triad (bradycardia + hypertension + irregular respiration). [1]

Prevention: fluids first; no insulin bolus; cap glucose fall at 3-4 mmol/L/h; cap osmolality fall at 3-5 mOsm/kg/h. [1]

Treatment: stop the fall (reduce or hold insulin, slow fluids); mannitol 0.5-1 g/kg or hypertonic saline 3% 250 mL; intubate and ventilate (target normocapnia, head elevated 30°); urgent CT to exclude alternative causes.[1][4]

Outcomes and mortality

HHS mortality and outcome — what the pooled data show

Prompt recognition, treated in ICU

Mortality ~5-10%

When HHS is recognised early and managed with fluid-first, low-dose insulin, electrolyte replacement and anticoagulation, outcome approaches that of uncomplicated DKA. The median hospital stay in pooled series is 7.5 days; ICU admission rate ~40%.

[5]

Transition and ongoing care

From IV insulin to subcutaneous — the safe conversion

Confirm stability before switching

Glucose stable at 10-14 mmol/L; osmolality ≤315 and falling; acidosis resolved; K+ in range; the precipitant identified and treated; the patient alert and eating. Premature conversion risks rebound hyperglycaemia.

Calculate the total daily subcutaneous dose

A pragmatic starting point is **0.5-0.8 U/kg/day** total insulin, split into ~50% basal (glargine/detemir/degludec) and ~50% rapid-acting (lispro/aspart) with meals. Alternatively, base the new regimen on the average IV insulin rate over the preceding 6-12 h. Err conservative — over-dosing causes hypoglycaemia, the commonest inpatient adverse event.

Overlap — NEVER stop IV before SC is active

Give the first subcutaneous (basal) dose **1-2 hours before** stopping the IV infusion. Rapid-acting meal-time insulin is given with the first meal after stopping IV. Stopping IV insulin without overlap causes rapid rebound hyperglycaemia within 1-2 h (IV insulin has a half-life of minutes).

Long-term plan — insulin vs oral agents

HHS often first presents in previously undiagnosed type 2 DM (~30%). After stabilisation, characterise the diabetes (C-peptide, antibodies if phenotype ambiguous), check HbA1c (reflects the preceding weeks), and arrange endocrinology follow-up. Many type-2 patients can later transition to oral agents (metformin first-line if renal function permits), but most HHS survivors need insulin for at least the short-to-medium term.

Education and prevention

Sick-day rules (do NOT stop insulin during illness; check glucose/CBG more often; maintain hydration); glucose-monitoring education; medication review (stop offending drugs — steroids if possible, thiazides); podiatry and diabetes-nurse input; structured diabetes education. Recurrence is common if the precipitant and the underlying poor control are not addressed.

[2] [3]

Evidence and landmark data

French et al. 2026 — HHS systematic review and meta-analysis (BMJ Open Diabetes Res Care, PMID 42373194)

Source

BMJ Open Diabetes Res Care 2026;14(3):e005765 — the largest pooled dataset of HHS cases to date (PRISMA-compliant, 27 studies, 63,935 cases), aggregating HHS case series and cohorts across all regions

Design

Systematic review and meta-analysis of studies reporting HHS cases from database inception to Feb 2025. Outcomes: demographics, biochemistry, precipitants, complications, mortality, stratified by region.

What it established

Median age 63.8 (IQR 56.1-72.0). Precipitants: non-infective illness 49.5%, infection 44.0%, new diabetes diagnosis 31.7%. ICU admission 40.8% (highest in North America 70%). Median hospital stay 7.5 days (Asia 17.5 days, Americas 4 days). Overall mortality 21.1% (Africa 40%, Asia 18.2%, North America 4.8%). Complications: AKI 7.6%, pulmonary oedema 4.8%, acute coronary syndrome 3.9%. Biochemistry is similar globally; outcomes vary markedly by region and resources.

Clinical bottom line

The definitive contemporary epidemiology. Confirms HHS mortality is high (≈21%) and regionally unequal; complications are dominated by dehydration/vascular events (AKI, pulmonary oedema, ACS) rather than the glucose itself. Underlines that precipitant identification, fluid-first care, and thromboprophylaxis — not faster glucose correction — are the mortality-reduction levers.

[1]

Umpierrez et al. 2024 — ADA Consensus Report: Hyperglycemic Crises in Adults (Diabetes Care, PMID 39052901)

Source

Diabetes Care 2024;47(8):1257-1275 — the current American Diabetes Association / international consensus report on DKA and HHS, authored by Umpierrez, Dhatariya, Fadini and colleagues

What it established

Modern unified definitions and management of hyperglycaemic emergencies. Endorses the conceptual framework of a SPECTRUM (DKA ↔ HHS) rather than two discrete diseases — mixed/overlap presentations are common. Recommends fluid-first resuscitation, potassium correction before insulin, low-dose fixed-rate insulin (0.05 U/kg/h for HHS, 0.1 for DKA), and glucose/osmolality-fall ceilings to prevent cerebral oedema. Emphasises precipitant identification, thromboprophylaxis, and structured transition to subcutaneous insulin.

Clinical bottom line

The current authoritative guidance for HHS. Know the numbers: glucose >33 mmol/L, osmolality >320, pH >7.30, HCO3 >15, insulin 0.05 U/kg/h, glucose fall cap 3-4 mmol/L/h.

[1]

Dhatariya & Vellanki 2017 — DKA/HHS UK vs USA (Curr Diab Rep, PMID 28364357)

Source

Curr Diab Rep 2017;17(5):37 — a widely cited review reconciling the UK (JBDS-IP) and US (ADA) protocols for DKA and HHS

What it established

Highlights the practical differences between the UK JBDS and US ADA approaches (e.g. fluid tonicity selection, insulin infusion rates, the role of bicarbonate — none recommended — and the speed of correction). Reinforces that HHS is managed with lower insulin doses and slower correction than DKA, and that the two syndromes can overlap.

Clinical bottom line

A concise comparative reference for the CICM/FFICM exam — cite it when asked to contrast UK vs US fluid and insulin strategies in HHS.

[1]

Wei et al. 2022 — HHS and VTE: a nationwide cohort (J Pers Med, PMID 35207789)

Source

J Pers Med 2022;12(2):317 — nationwide population-based cohort study quantifying the association between HHS and venous thromboembolism in diabetic patients

What it established

Diabetic patients hospitalised with HHS have a significantly higher incidence of VTE than matched diabetic controls without HHS, validating the clinical impression that HHS is a prothrombotic emergency. Supports routine thromboprophylaxis in HHS.

Clinical bottom line

The evidence behind 'give prophylactic LMWH to every HHS patient' — a frequent exam point and a practical bedside rule.

[1]

Clinical pearls

High-yield HHS points for the CICM/FFICM exam

FLUIDS are primary treatment — not insulin. Glucose falls with fluids alone.
Low-dose insulin (0.05 U/kg/h — half DKA dose). HHS patients more sensitive.
Correct K+ BEFORE insulin — insulin drives K+ intracellularly.
Do NOT lower glucose >3-4 mmol/L/h — cerebral oedema risk (osmotic shift).
NO ketosis (pH >7.3, bicarb >15) — distinguishes from DKA.
Higher osmolality (>320 mOsm/kg) — profound dehydration (6-9 L).
Higher mortality (10-20% vs ~5% DKA) — elderly, comorbidities.
Corrected sodium: Na + 1.6 × (glucose − 5.5) ÷ 5.5. Guides fluid choice (normal vs half-normal saline).
Calculated osmolality: 2 × Na + glucose + urea (mmol/L). Target: normalise.
Cerebral oedema: RARE in adults (more common in children with DKA). Monitor neurology. Mannitol/hypertonic saline if develops.
Infection is #1 single precipitant — search aggressively.
Steroid-induced HHS: common in elderly — review ALL medications.
Thiazides and beta-blockers: can worsen hyperglycaemia in type 2 diabetes.
Anticoagulation: consider prophylactic LMWH — HHS patients are hypercoagulable (high viscosity, dehydration).

[1]

Mnemonic

HHSH-H-S-S-S — the five pillars of HHS management

[1]

Exam practice

SAQ — Confusion and hyperglycaemia in an elderly patient

12 minutes · 12 marks

A 76-year-old man with type 2 diabetes, hypertension and chronic kidney disease is brought to the ED drowsy and confused. His family report progressive polyuria, thirst and malaise over the past week and reduced oral intake for two days. He takes metformin, empagliflozin, perindopril and furosemide. On examination he is cachectic, dry mucous membranes, HR 112, BP 96/58, RR 22, T 37.9°C. GCS 13 (E3 V4 M6). CBG reads 'HI'. Venous gas: pH 7.34, glucose 48 mmol/L, Na 128, K 4.8, Cl 94, HCO3 22, urea 18, creatinine 210, lactate 2.1. Urine ketones trace.

[1]

SAQ — Differentiating HHS from DKA and managing the overlap

10 minutes · 10 marks

A 58-year-old woman with known type 2 diabetes presents unwell. Venous gas: pH 7.28, glucose 39 mmol/L, HCO3 14, anion gap 16, β-hydroxybutyrate 2.8 mmol/L, calculated osmolality 338, Na corrected 144, K 3.1. She is drowsy (GCS 14) but conversing.

[1]

Expanded clinical pearls

Exam-exhaustive HHS points — beyond the basics

Relative, not absolute, insulin deficiency is the defining pathophysiology. Enough insulin suppresses lipolysis (no ketones); too little suppresses hyperglycaemia. The lipolysis-suppression threshold is ~1/10th the glucose-uptake threshold.[1]
The sensorium tracks osmolality, not glucose. A glucose of 50 with a normal GCS is not HHS; a glucose of 35 with osmolality 350 and GCS 10 is. Coma at osmolality <315 has another cause — image the brain.[4]
Onset is days-to-weeks (insidious), versus hours in DKA. The slow climb lets the brain accumulate idiogenic osmoles, which is exactly why rapid correction causes cerebral oedema.[1]
Free-water deficit 6-9 L is roughly DOUBLE that of DKA — fluids are even more central to HHS management than to DKA.[3]
Glucose falls 2-5 mmol/L with fluids ALONE before any insulin — restored renal clearance excretes the glucose. If glucose is not falling, suspect under-resuscitation before blaming insulin resistance.[1]
Corrected Na = measured Na + 1.6 × (glucose − 5.5) ÷ 5.5. Use it to pick the fluid. As glucose falls, measured Na rises toward the corrected value — expected, not pathological, unless corrected Na climbs >8-10 mmol/L/day.[1]
Effective (calculated) osmolality = 2 × Na + glucose + urea. Urea freely crosses membranes so some use effective osmolality = 2 × Na + glucose (excluding urea) for neurological correlation — know both.[4]
Insulin 0.05 U/kg/h (half DKA). No bolus. Start only after fluids and K+ ≥3.3. Cap glucose fall at 3-4 mmol/L/h; cap osmolality fall at 3-5 mOsm/kg/h.[2][4]
Total-body K+ deficit ~5-10 mmol/kg despite normal/high serum K+. Replace before insulin; recheck every 2 h; replace Mg²⁺ concurrently (refractory hypokalaemia is usually hypomagnesaemia).[1]
Add 5% dextrose at glucose 14-16 and HALVE insulin — do NOT stop insulin. Continue it to suppress residual ketogenesis and hold glucose while osmolality normalises.[4]
Mortality ~21% pooled (French 2026, n=63,935), 2-4× DKA. Highest in elderly, the infected, and lower-resource settings. Regional spread is wide (Africa 40%, North America 4.8%).[5]
Death is usually from the PRECIPITANT or a VASCULAR event, not the glucose. AKI 7.6%, pulmonary oedema 4.8%, ACS 3.9% — these dominate the complication profile.[5]
Infection is the #1 single identified precipitant (~44%); non-infective acute illness and new diabetes diagnosis are the other major triggers. Search with cultures, CXR, ECG/troponin, and CT brain if neurology does not clear.[5]
Give prophylactic LMWH to EVERY HHS patient — prothrombotic state (hyperviscosity, high FVIII/vWF, immobility, central lines). VTE risk is significantly elevated (Wei 2022 nationwide cohort). Renally adjust.[7]
Silent MI is common in elderly diabetics — autonomic neuropathy abolishes the pain. ECG + troponin on every HHS admission.[3]
Drug culprits: glucocorticoids (most common), thiazides, beta-blockers, atypical antipsychotics (olanzapine, clozapine), phenytoin, sympathomimetics, TPN. Review ALL medications.[1]
SGLT2 inhibitors (empagliflozin etc.) can cause EUGLYCAEMIC DKA — a trap in the HHS/DKA differential. The glucose may be only mildly raised despite ketosis. Stop on admission; do not blame them for routine HHS.[4]
Overlap/mixed DKA-HHS is common in type 2 diabetes — treat the worst feature (acidosis/ketosis drives insulin dose up to 0.1 U/kg/h; high osmolality drives slow correction and fluid care).[4]
Cerebral oedema is rare in adults but almost always iatrogenic — too-fast glucose/osmolality fall, insulin before fluids. Watch for headache/vomiting/falling GCS. Mannitol 0.5-1 g/kg or hypertonic saline 3%.[1]
Overlap with lactic acidosis from hypoperfusion is common — a "normal anion gap" or mildly raised AG with lactate distinguishes HHS from the high-gap ketoacidosis of DKA.[1]
Transition to subcutaneous insulin with a 1-2 h overlap — never stop IV insulin before SC is active (IV half-life is minutes → rebound hyperglycaemia within 1-2 h). Start ~0.5-0.8 U/kg/day split basal/bolus.[2]
Recurrence is common if the precipitant and underlying poor control are not addressed — education (sick-day rules, hydration, glucose monitoring) and endocrinology follow-up are essential.[3]

Red flags

[1]

Expanded red flags — the HHS killers and how to avoid them

Start with FLUIDS, not insulin. Premature insulin in a hypovolaemic patient fails to lower glucose and risks cerebral oedema and hypokalaemia.[1]
Half the DKA insulin dose (0.05 U/kg/h); no bolus; cap glucose fall at 3-4 mmol/L/h and osmolality at 3-5 mOsm/kg/h. The elderly HHS brain tolerates osmolar shifts poorly.[2][4]
Always correct the sodium for glucose before choosing fluid tonicity. Treating dilutional "hyponatraemia" with 0.9% saline when the corrected Na is high worsens the free-water deficit.[1]
Total-body K+ is depleted despite a normal/high serum K+. Replace before insulin, recheck q2h, replace Mg²⁺ concurrently.[1]
Find and treat the precipitant. Infection is #1, but silent MI, stroke and new drugs are killers. ECG + troponin + cultures + imaging in every HHS.[5]
Give prophylactic LMWH to every patient. HHS is prothrombotic; arterial and venous thrombosis are leading complications. Renally adjust.[7]
Mortality is ~21% (pooled), 2-4× DKA, and is driven by the precipitant and vascular complications — not the glucose.[5]
Cerebral oedema is rare but catastrophic and almost always iatrogenic — watch for headache, vomiting, falling GCS; mannitol/hypertonic saline.[1]
Never stop IV insulin without a 1-2 h subcutaneous overlap — rebound hyperglycaemia within 1-2 h.[2]
Coma out of proportion to (or persisting despite normalising) osmolality is NOT HHS — stroke, sepsis, post-ictal, drug. Image the brain.[4]

References

[1]Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes Diabetes Care, 2009.PMID 19564476
[2]Dhatariya KK, Vellanki P. Treatment of Diabetic Ketoacidosis (DKA)/Hyperglycemic Hyperosmolar State (HHS): Novel Advances in the Management of Hyperglycemic Crises (UK Versus USA) Curr Diab Rep, 2017.PMID 28364357
[3]Stoner GD. Hyperosmolar Hyperglycemic State Am Fam Physician, 2017.PMID 29431405
[4]Umpierrez GE, Davis GM, ElSayed NA, Fadini GP, Galindo RJ, Hirsch IB, Klonoff DC, McCoy RG, Misra S, Gabbay RA, Bannuru RR, Dhatariya KK. Hyperglycemic Crises in Adults With Diabetes: A Consensus Report Diabetes Care, 2024.PMID 39052901
[5]French J, Bomphrey L, Manta A, Scandrett K, Malhotra K, Kempegowda P. Hyperosmolar hyperglycaemic state: a systematic review and meta-analysis BMJ Open Diabetes Res Care, 2026.PMID 42373194
[6]Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association Diabetes Care, 2006.PMID 17130218
[7]Wei WT, Lin SM, Hsu JY. Association between Hyperosmolar Hyperglycemic State and Venous Thromboembolism in Diabetes Patients: A Nationwide Analysis in Taiwan J Pers Med, 2022.PMID 35207789

[1] [1]

Diagnostic criteria and the biochemical signature

HHS diagnostic criteria — the numbers every candidate must know cold

Two equations the exam expects you to write out:

Calculated (measured) osmolality = 2 × [Na] + [glucose] + [urea] (all in mmol/L). Normal 285-295. HHS >320 (often 340-360).
Corrected sodium = measured [Na] + 1.6 × ([glucose] − 5.5) ÷ 5.5. (Some sources use 2.4; the ADA uses ~1.6-2.4.) This corrects for the osmotic draw of water out of the extracellular space by glucose, which DILUTES sodium — the measured Na therefore UNDER-estimates the true sodium. The corrected sodium dictates fluid choice (normal vs half-normal saline).[1][4]

HHS diagnostic thresholds vs DKA vs mixed picture

Parameter	HHS	DKA	Mixed / overlap
Glucose	>33 mmol/L (often 40-60)	>13.9 mmol/L (typically 15-30)	High; can overlap
Arterial/venous pH	>7.30	<7.30 (mild 7.25-7.30, mod 7.00-7.24, severe <7.00)	May be <7.30
Bicarbonate	>15 mmol/L	<15 mmol/L	Variable
Ketones (β-OHB)	Minimal/absent (<3 mmol/L)	Positive (>3 mmol/L)	Moderate
Anion gap	<12 (normal; may be mildly ↑ from lactate)	>12 (high-gap ketoacidosis)	Elevated
Osmolality	>320 mOsm/kg (often 340-360)	Variable, usually <320	High
Mental status	Altered/stupor/coma (≈30% comatose)	Usually alert / mildly confused	Clouded
Free-water deficit	6-9 L (~9-12% body weight)	3-6 L (~6% body weight)	Large
Typical patient	Elderly type 2 DM	Type 1 DM (or type 2 ketosis-prone)	Type 2
Insulin requirement	LOW (0.05 U/kg/h)	STANDARD (0.1 U/kg/h)	Standard
Onset	Days to weeks (insidious)	Hours to <24 h (rapid)	Variable
Cerebral oedema risk	Lower than paediatric DKA but real in adults	Classic in children, rare in adults	Present

[1] [4]

The HHS numbers to memorise

>33

Glucose (mmol/L)

Severe hyperglycaemia — typically higher than DKA

>320

Osmolality (mOsm/kg)

Effective osmolality — drives the altered mental state

6-9 L

Free-water deficit

~9-12% of body weight — far exceeds DKA

10-20%

Mortality

2-4x higher than DKA; elderly, comorbid

[1]

HHS vs DKA comparison

HHS

Type 2 diabetes, elderly

Glucose: >33 mmol/L (typically higher than DKA)
pH: >7.30 (minimal acidosis)
Bicarbonate: >15 mmol/L (no significant ketoacidosis)
Ketones: minimal/absent (urine/serum)
Osmolality: >320 mOsm/kg (typically much higher — profound dehydration)
Anion gap: normal or mildly elevated (lactic acidosis from hypoperfusion)
Dehydration: 6-9 L (more severe than DKA)
Mental status: often altered/confused/comatose (from hyperosmolality)
Insulin dose: LOW (0.05 U/kg/h — half DKA dose)

DKA

Type 1 (and some type 2) diabetes

Glucose: >13.9 mmol/L (typically lower than HHS)
pH: <7.30 (metabolic acidosis)
Bicarbonate: <15 mmol/L (ketoacidosis)
Ketones: positive (urine/serum — beta-hydroxybutyrate)
Osmolality: variable (less dehydration than HHS)
Anion gap: elevated (ketones — beta-hydroxybutyrate, acetoacetate)
Dehydration: 3-6 L
Mental status: usually alert or mildly confused
Insulin dose: STANDARD (0.1 U/kg/h)

[1] [2]

WHY HHS IS NOT KETOTIC — the relative insulin deficiency concept (the single most tested pathophysiology point)

This explains the two cardinal contrasts with DKA:

In DKA the insulin deficiency is ABSOLUTE — lipolysis is unbridled → free fatty acids flood the liver → hepatic ketogenesis (β-hydroxybutyrate, acetoacetate) → high-anion-gap metabolic acidosis.
In HHS the insulin deficiency is RELATIVE — enough to suppress lipolysis, too little to suppress hyperglycaemia. The threshold for suppressing lipolysis (and hence ketogenesis) is roughly one-tenth of the insulin concentration needed to promote peripheral glucose uptake — a quantitatively elegant concept. [1]

Pathophysiology — the cascade

HHS pathophysiology — stepwise from insulin resistance to coma

Relative insulin deficiency + counter-regulatory excess

Uncontrolled hyperglycaemia

Osmotic diuresis

Hyperosmolality and cellular dehydration

Hypovolaemia and end-organ hypoperfusion

Compounded by the precipitant

[1] [3]

Precipitating causes — find the trigger

Precipitants of HHS — search for these in every patient

Precipitant	Mechanism / note	Frequency
Infection (pneumonia, UTI, sepsis)	Raises counter-regulatory hormones; #1 single precipitant	Most commonly identified single trigger (~40-50%)[5]
New/occult type 2 diabetes	First presentation — HHS may be the debut illness	~30%[5]
Acute cardiovascular event	Silent MI (autonomic neuropathy in elderly diabetics), stroke, ACS	Major mortality contributor
Medication-induced	Glucocorticoids (raise gluconeogenesis + insulin resistance), thiazides, beta-blockers (mask counter-regulation), atypical antipsychotics (olanzapine, clozapine), phenytoin, sympathomimetics	Common; review ALL drugs
Non-adherence / inadequate insulin	Missed oral hypoglycaemics or insulin	Common in known diabetics
Substance misuse	Cocaine, alcohol	Often overlooked
Acute illness (non-infective)	Pancreatitis, GI bleed, trauma, surgery, dialysis, TPN	~50% in pooled series[5]
Total parenteral nutrition / high-dextrose	Iatrogenic glucose load	ICU/ward iatrogenic

[1] [5]

THE PRECIPITANT IS THE MORTALITY DRIVER — never treat the glucose and forget the cause

Management

HHS management protocol

Aggressive fluid resuscitation (PRIMARY treatment)

Potassium replacement BEFORE insulin

Low-dose insulin (HALF DKA dose) — ONLY after fluids

Monitor closely

Identify and treat precipitant

Anticoagulate (thromboprophylaxis)

Transition to subcutaneous insulin

[1] [2]

Fluid resuscitation — the cornerstone, done correctly

FLUIDS FIRST, INSULIN SECOND — and the glucose falls before any insulin is given

The standard regimen (ADA / JBDS / UK vs USA consensus):

Hour 1: 0.9% saline 15-20 mL/kg (≈1-1.5 L) to restore intravascular volume, regardless of corrected sodium.
Hours 2+: choose tonicity by the corrected sodium:
- Corrected Na low/normal (<150): continue 0.45% saline at 250-500 mL/h (replace the predominantly free-water deficit).
- Corrected Na high (>150): use 0.45% saline even more aggressively (the patient is genuinely hypernatraemic and needs free water).
- Corrected Na very high / shocked: some units use 0.9% until shock resolves, then switch to 0.45%.
When glucose ≤14-16 mmol/L: add 5% dextrose (often as a separate line or switch to 0.45% saline + 5% dextrose) AND halve the insulin rate, to hold glucose 10-14 mmol/L while osmolality continues to normalise.
Target: reduce osmolality by no more than 3-5 mOsm/kg/h, and glucose by no more than 3-4 mmol/L/h.[1][4]

WHY CORRECTED SODIUM MATTERS — the dilutional hyponatraemia of hyperglycaemia

Formula: corrected Na = measured Na + 1.6 × ([glucose] − 5.5) ÷ 5.5. [1]

Potassium management — replace before, monitor during

TOTAL-BODY POTASSIUM DEPLETION DESPITE A NORMAL/HIGH SERUM K+ — the HHS trap

Action thresholds (as for DKA, but apply rigidly):

K+ <3.3 mmol/L: HOLD insulin. Give K+ ~40 mmol/h. Recheck in 1-2 h. Insulin only once K+ ≥3.3.
K+ 3.3-5.2 mmol/L: Add 20-30 mmol K+ per litre of maintenance IV fluid; start insulin at the low HHS rate.
K+ >5.2 mmol/L: Hold K+ replacement. Start insulin. Check K+ every 2 h; begin K+ replacement the moment it falls below 5.0. [1]

Replace magnesium concurrently (hypomagnesaemia perpetuates refractory hypokalaemia). Cardiac monitoring is mandatory during K+ shifts.[1][4]

Insulin therapy — half the DKA dose, started only after fluids

LOW-DOSE INSULIN (0.05 U/kg/h) — start ONLY after fluids are running

HHS requires half the DKA insulin dose: a fixed-rate intravenous insulin infusion at 0.05 units/kg/h (vs 0.1 U/kg/h in DKA). Three principles justify the lower dose: [1]

HHS patients retain residual endogenous insulin — they are NOT insulin-naïve and are relatively more sensitive to exogenous insulin than the ketotic type-1 patient.
The elderly HHS brain has accumulated idiogenic osmoles over the days-weeks of slowly rising glucose; a rapid osmolar drop (driven by insulin pushing glucose, K+ and water into cells) precipitates cerebral oedema.
Fluids do most of the early glucose reduction via restored renal clearance — insulin is an adjunct, not the primary lever. [1]

Practical rules:

Start the insulin infusion only after fluid resuscitation has begun AND potassium ≥3.3 mmol/L.
Do NOT give an IV insulin bolus (the ADA explicitly advises against boluses).
Aim to lower glucose by 3-4 mmol/L/h. If it is not falling, re-examine hydration first (most failures are under-resuscitation), THEN double the insulin rate to 0.1 U/kg/h.
When glucose reaches 14-16 mmol/L, add 5% dextrose and reduce the insulin infusion to hold glucose 10-14 mmol/L while osmolality continues to fall.
Do NOT stop insulin — it is still needed to suppress ketogenesis and maintain glucose; the dextrose is added so insulin can continue safely.[1][2][4]

Anticoagulation — the prothrombotic emergency

HHS IS A PROTHROMBOTIC STATE — give prophylactic LMWH

Monitoring protocol

Hourly and serial monitoring in HHS — what to measure and how often

Hourly

Every 2 hours

Every 4-6 hours

Daily / ongoing

Targets to achieve before stopping the IV insulin

[2] [4]

Complications

Complications of HHS — anticipate and prevent

Complication	Mechanism	Prevention / management
Cerebral oedema	Rapid osmolar shift; idiogenic osmole accumulation. Rare in adults vs paediatric DKA, but fatal when it occurs	Limit glucose fall to 3-4 mmol/L/h; do NOT give insulin before fluids; watch for headache, vomiting, falling GCS. Treat: mannitol / hypertonic saline
Hypokalaemia	Intracellular K+ shift once insulin started; ongoing kaliuresis	Replace K+ before insulin (hold if <3.3); recheck q2h; replace Mg²⁺ concurrently
Acute kidney injury	Profound hypovolaemia + osmotic diuresis; nephrotoxic precipitant	Aggressive early fluids; avoid NSAIDs; monitor creatinine; usually prerenal and reversible
Acute coronary syndrome / stroke	Hyperviscosity, hypercoagulability, dehydration; silent MI in elderly	ECG + troponin on admission; LMWH; maintain perfusion; low threshold to image brain
Venous thromboembolism	Prothrombotic state (high FVIII/vWF), immobility, central lines	Prophylactic LMWH for all; mechanical prophylaxis; investigate new swelling/dyspnoea
Pulmonary oedema / ARDS	Over-aggressive fluid resuscitation in elderly with cardiac disease	Titrate fluids to corrected Na, urine output, perfusion; consider CVP/POCUS; use balanced approach
Hypoglycaemia	Insulin overdose / failure to add dextrose at the switch point	Hourly glucose; add 5% dextrose at glucose 14-16; halve insulin rate
Hypophosphataemia	Cellular uptake with insulin; respiratory muscle weakness, tissue hypoxia	Replace if PO4 <0.5 mmol/L (esp. if ventilated)
Aspiration pneumonia	Reduced GCS + vomiting	Airway protection; early NG tube if obtunded; head-up positioning

[1] [5]

CEREBRAL OEDEMA IN HHS — rare but lethal, and almost always iatrogenic

Red flags: new headache, vomiting, drowsiness, falling GCS, abnormal pupil response, Cushing's triad (bradycardia + hypertension + irregular respiration). [1]

Prevention: fluids first; no insulin bolus; cap glucose fall at 3-4 mmol/L/h; cap osmolality fall at 3-5 mOsm/kg/h. [1]

Outcomes and mortality

HHS mortality and outcome — what the pooled data show

Prompt recognition, treated in ICU

Mortality ~5-10%

[5]

Transition and ongoing care

From IV insulin to subcutaneous — the safe conversion

Confirm stability before switching

Calculate the total daily subcutaneous dose

Overlap — NEVER stop IV before SC is active

Long-term plan — insulin vs oral agents

Education and prevention

[2] [3]

Evidence and landmark data

French et al. 2026 — HHS systematic review and meta-analysis (BMJ Open Diabetes Res Care, PMID 42373194)

Source

Design

What it established

Clinical bottom line

[1]

Umpierrez et al. 2024 — ADA Consensus Report: Hyperglycemic Crises in Adults (Diabetes Care, PMID 39052901)

Source

Diabetes Care 2024;47(8):1257-1275 — the current American Diabetes Association / international consensus report on DKA and HHS, authored by Umpierrez, Dhatariya, Fadini and colleagues

What it established

Clinical bottom line

The current authoritative guidance for HHS. Know the numbers: glucose >33 mmol/L, osmolality >320, pH >7.30, HCO3 >15, insulin 0.05 U/kg/h, glucose fall cap 3-4 mmol/L/h.

[1]

Dhatariya & Vellanki 2017 — DKA/HHS UK vs USA (Curr Diab Rep, PMID 28364357)

Source

Curr Diab Rep 2017;17(5):37 — a widely cited review reconciling the UK (JBDS-IP) and US (ADA) protocols for DKA and HHS

What it established

Clinical bottom line

A concise comparative reference for the CICM/FFICM exam — cite it when asked to contrast UK vs US fluid and insulin strategies in HHS.

[1]

Wei et al. 2022 — HHS and VTE: a nationwide cohort (J Pers Med, PMID 35207789)

Source

J Pers Med 2022;12(2):317 — nationwide population-based cohort study quantifying the association between HHS and venous thromboembolism in diabetic patients

What it established

Clinical bottom line

The evidence behind 'give prophylactic LMWH to every HHS patient' — a frequent exam point and a practical bedside rule.

[1]

Clinical pearls

High-yield HHS points for the CICM/FFICM exam

FLUIDS are primary treatment — not insulin. Glucose falls with fluids alone.
Low-dose insulin (0.05 U/kg/h — half DKA dose). HHS patients more sensitive.
Correct K+ BEFORE insulin — insulin drives K+ intracellularly.
Do NOT lower glucose >3-4 mmol/L/h — cerebral oedema risk (osmotic shift).
NO ketosis (pH >7.3, bicarb >15) — distinguishes from DKA.
Higher osmolality (>320 mOsm/kg) — profound dehydration (6-9 L).
Higher mortality (10-20% vs ~5% DKA) — elderly, comorbidities.
Corrected sodium: Na + 1.6 × (glucose − 5.5) ÷ 5.5. Guides fluid choice (normal vs half-normal saline).
Calculated osmolality: 2 × Na + glucose + urea (mmol/L). Target: normalise.
Cerebral oedema: RARE in adults (more common in children with DKA). Monitor neurology. Mannitol/hypertonic saline if develops.
Infection is #1 single precipitant — search aggressively.
Steroid-induced HHS: common in elderly — review ALL medications.
Thiazides and beta-blockers: can worsen hyperglycaemia in type 2 diabetes.
Anticoagulation: consider prophylactic LMWH — HHS patients are hypercoagulable (high viscosity, dehydration).

[1]

Mnemonic

HHSH-H-S-S-S — the five pillars of HHS management

[1]

Exam practice

SAQ — Confusion and hyperglycaemia in an elderly patient

12 minutes · 12 marks

[1]

SAQ — Differentiating HHS from DKA and managing the overlap

10 minutes · 10 marks

[1]

Expanded clinical pearls

Exam-exhaustive HHS points — beyond the basics

Relative, not absolute, insulin deficiency is the defining pathophysiology. Enough insulin suppresses lipolysis (no ketones); too little suppresses hyperglycaemia. The lipolysis-suppression threshold is ~1/10th the glucose-uptake threshold.[1]
The sensorium tracks osmolality, not glucose. A glucose of 50 with a normal GCS is not HHS; a glucose of 35 with osmolality 350 and GCS 10 is. Coma at osmolality <315 has another cause — image the brain.[4]
Onset is days-to-weeks (insidious), versus hours in DKA. The slow climb lets the brain accumulate idiogenic osmoles, which is exactly why rapid correction causes cerebral oedema.[1]
Free-water deficit 6-9 L is roughly DOUBLE that of DKA — fluids are even more central to HHS management than to DKA.[3]
Glucose falls 2-5 mmol/L with fluids ALONE before any insulin — restored renal clearance excretes the glucose. If glucose is not falling, suspect under-resuscitation before blaming insulin resistance.[1]
Corrected Na = measured Na + 1.6 × (glucose − 5.5) ÷ 5.5. Use it to pick the fluid. As glucose falls, measured Na rises toward the corrected value — expected, not pathological, unless corrected Na climbs >8-10 mmol/L/day.[1]
Effective (calculated) osmolality = 2 × Na + glucose + urea. Urea freely crosses membranes so some use effective osmolality = 2 × Na + glucose (excluding urea) for neurological correlation — know both.[4]
Insulin 0.05 U/kg/h (half DKA). No bolus. Start only after fluids and K+ ≥3.3. Cap glucose fall at 3-4 mmol/L/h; cap osmolality fall at 3-5 mOsm/kg/h.[2][4]
Total-body K+ deficit ~5-10 mmol/kg despite normal/high serum K+. Replace before insulin; recheck every 2 h; replace Mg²⁺ concurrently (refractory hypokalaemia is usually hypomagnesaemia).[1]
Add 5% dextrose at glucose 14-16 and HALVE insulin — do NOT stop insulin. Continue it to suppress residual ketogenesis and hold glucose while osmolality normalises.[4]
Mortality ~21% pooled (French 2026, n=63,935), 2-4× DKA. Highest in elderly, the infected, and lower-resource settings. Regional spread is wide (Africa 40%, North America 4.8%).[5]
Death is usually from the PRECIPITANT or a VASCULAR event, not the glucose. AKI 7.6%, pulmonary oedema 4.8%, ACS 3.9% — these dominate the complication profile.[5]
Infection is the #1 single identified precipitant (~44%); non-infective acute illness and new diabetes diagnosis are the other major triggers. Search with cultures, CXR, ECG/troponin, and CT brain if neurology does not clear.[5]
Give prophylactic LMWH to EVERY HHS patient — prothrombotic state (hyperviscosity, high FVIII/vWF, immobility, central lines). VTE risk is significantly elevated (Wei 2022 nationwide cohort). Renally adjust.[7]
Silent MI is common in elderly diabetics — autonomic neuropathy abolishes the pain. ECG + troponin on every HHS admission.[3]
Drug culprits: glucocorticoids (most common), thiazides, beta-blockers, atypical antipsychotics (olanzapine, clozapine), phenytoin, sympathomimetics, TPN. Review ALL medications.[1]
SGLT2 inhibitors (empagliflozin etc.) can cause EUGLYCAEMIC DKA — a trap in the HHS/DKA differential. The glucose may be only mildly raised despite ketosis. Stop on admission; do not blame them for routine HHS.[4]
Overlap/mixed DKA-HHS is common in type 2 diabetes — treat the worst feature (acidosis/ketosis drives insulin dose up to 0.1 U/kg/h; high osmolality drives slow correction and fluid care).[4]
Cerebral oedema is rare in adults but almost always iatrogenic — too-fast glucose/osmolality fall, insulin before fluids. Watch for headache/vomiting/falling GCS. Mannitol 0.5-1 g/kg or hypertonic saline 3%.[1]
Overlap with lactic acidosis from hypoperfusion is common — a "normal anion gap" or mildly raised AG with lactate distinguishes HHS from the high-gap ketoacidosis of DKA.[1]
Transition to subcutaneous insulin with a 1-2 h overlap — never stop IV insulin before SC is active (IV half-life is minutes → rebound hyperglycaemia within 1-2 h). Start ~0.5-0.8 U/kg/day split basal/bolus.[2]
Recurrence is common if the precipitant and underlying poor control are not addressed — education (sick-day rules, hydration, glucose monitoring) and endocrinology follow-up are essential.[3]

Red flags

[1]

Expanded red flags — the HHS killers and how to avoid them

Start with FLUIDS, not insulin. Premature insulin in a hypovolaemic patient fails to lower glucose and risks cerebral oedema and hypokalaemia.[1]
Half the DKA insulin dose (0.05 U/kg/h); no bolus; cap glucose fall at 3-4 mmol/L/h and osmolality at 3-5 mOsm/kg/h. The elderly HHS brain tolerates osmolar shifts poorly.[2][4]
Always correct the sodium for glucose before choosing fluid tonicity. Treating dilutional "hyponatraemia" with 0.9% saline when the corrected Na is high worsens the free-water deficit.[1]
Total-body K+ is depleted despite a normal/high serum K+. Replace before insulin, recheck q2h, replace Mg²⁺ concurrently.[1]
Find and treat the precipitant. Infection is #1, but silent MI, stroke and new drugs are killers. ECG + troponin + cultures + imaging in every HHS.[5]
Give prophylactic LMWH to every patient. HHS is prothrombotic; arterial and venous thrombosis are leading complications. Renally adjust.[7]
Mortality is ~21% (pooled), 2-4× DKA, and is driven by the precipitant and vascular complications — not the glucose.[5]
Cerebral oedema is rare but catastrophic and almost always iatrogenic — watch for headache, vomiting, falling GCS; mannitol/hypertonic saline.[1]
Never stop IV insulin without a 1-2 h subcutaneous overlap — rebound hyperglycaemia within 1-2 h.[2]
Coma out of proportion to (or persisting despite normalising) osmolality is NOT HHS — stroke, sepsis, post-ictal, drug. Image the brain.[4]

References

[1]Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes Diabetes Care, 2009.PMID 19564476
[2]Dhatariya KK, Vellanki P. Treatment of Diabetic Ketoacidosis (DKA)/Hyperglycemic Hyperosmolar State (HHS): Novel Advances in the Management of Hyperglycemic Crises (UK Versus USA) Curr Diab Rep, 2017.PMID 28364357
[3]Stoner GD. Hyperosmolar Hyperglycemic State Am Fam Physician, 2017.PMID 29431405
[4]Umpierrez GE, Davis GM, ElSayed NA, Fadini GP, Galindo RJ, Hirsch IB, Klonoff DC, McCoy RG, Misra S, Gabbay RA, Bannuru RR, Dhatariya KK. Hyperglycemic Crises in Adults With Diabetes: A Consensus Report Diabetes Care, 2024.PMID 39052901
[5]French J, Bomphrey L, Manta A, Scandrett K, Malhotra K, Kempegowda P. Hyperosmolar hyperglycaemic state: a systematic review and meta-analysis BMJ Open Diabetes Res Care, 2026.PMID 42373194
[6]Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association Diabetes Care, 2006.PMID 17130218
[7]Wei WT, Lin SM, Hsu JY. Association between Hyperosmolar Hyperglycemic State and Venous Thromboembolism in Diabetes Patients: A Nationwide Analysis in Taiwan J Pers Med, 2022.PMID 35207789

Your progress

Diagnostic criteria and the biochemical signature

HHS vs DKA comparison

HHS

DKA

Pathophysiology — the cascade

Relative insulin deficiency + counter-regulatory excess

Uncontrolled hyperglycaemia

Osmotic diuresis

Hyperosmolality and cellular dehydration

Hypovolaemia and end-organ hypoperfusion

Compounded by the precipitant

Precipitating causes — find the trigger

Management

Aggressive fluid resuscitation (PRIMARY treatment)

Potassium replacement BEFORE insulin

Low-dose insulin (HALF DKA dose) — ONLY after fluids

Monitor closely

Identify and treat precipitant

Anticoagulate (thromboprophylaxis)

Transition to subcutaneous insulin

Fluid resuscitation — the cornerstone, done correctly

Potassium management — replace before, monitor during

Insulin therapy — half the DKA dose, started only after fluids

Anticoagulation — the prothrombotic emergency

Monitoring protocol

Hourly

Every 2 hours

Every 4-6 hours

Daily / ongoing

Targets to achieve before stopping the IV insulin

Complications

Outcomes and mortality

Prompt recognition, treated in ICU

Transition and ongoing care

Confirm stability before switching

Calculate the total daily subcutaneous dose

Overlap — NEVER stop IV before SC is active

Long-term plan — insulin vs oral agents

Education and prevention

Evidence and landmark data

French et al. 2026 — HHS systematic review and meta-analysis (BMJ Open Diabetes Res Care, PMID 42373194)

Umpierrez et al. 2024 — ADA Consensus Report: Hyperglycemic Crises in Adults (Diabetes Care, PMID 39052901)

Dhatariya & Vellanki 2017 — DKA/HHS UK vs USA (Curr Diab Rep, PMID 28364357)

Wei et al. 2022 — HHS and VTE: a nationwide cohort (J Pers Med, PMID 35207789)

Clinical pearls

Mnemonic

HHSH-H-S-S-S — the five pillars of HHS management

Exam practice

SAQ — Confusion and hyperglycaemia in an elderly patient

SAQ — Differentiating HHS from DKA and managing the overlap

Expanded clinical pearls

Red flags

References

Your progress

Diagnostic criteria and the biochemical signature

HHS vs DKA comparison

HHS

DKA

Pathophysiology — the cascade

Relative insulin deficiency + counter-regulatory excess

Uncontrolled hyperglycaemia

Osmotic diuresis

Hyperosmolality and cellular dehydration

Hypovolaemia and end-organ hypoperfusion

Compounded by the precipitant

Precipitating causes — find the trigger

Management

Aggressive fluid resuscitation (PRIMARY treatment)

Potassium replacement BEFORE insulin

Low-dose insulin (HALF DKA dose) — ONLY after fluids

Monitor closely

Identify and treat precipitant

Anticoagulate (thromboprophylaxis)

Transition to subcutaneous insulin

Fluid resuscitation — the cornerstone, done correctly

Potassium management — replace before, monitor during

Insulin therapy — half the DKA dose, started only after fluids

Anticoagulation — the prothrombotic emergency

Monitoring protocol