Hyperosmolar Hyperglycemic State (HHS)

Last updated: March 18, 2026Bookmark

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

Reference Intervals ›

Biochemistry

ACTH	P: <80 ng/L
ALT	P: 5–35 U/L
Albumin	P: 35–50 g/L
Aldosterone	P: 100–500 pmol/L
Alk. phosphatase	P: 30–130 U/L
α-Amylase	P: 0–180 IU/dL
α-Fetoprotein	S: <10 kU/L
Angiotensin II	P: 5–35 pmol/L
ADH	P: 0.9–4.6 pmol/L
AST	P: 5–35 U/L
Bicarbonate	P: 24–30 mmol/L
Bilirubin	P: 3–17 μmol/L
BNP	P: <50 ng/L
CRP	P: <10 mg/L
Calcitonin	P: <0.1 mcg/L
Calcium (ionized)	P: 1.0–1.25 mmol/L
Calcium (total)	P: 2.12–2.60 mmol/L
Chloride	P: 95–105 mmol/L
Cholesterol	P: <5.0 mmol/L
VLDL	P: 0.128–0.645 mmol/L
LDL	P: <2.0 mmol/L
HDL	P: 0.9–1.93 mmol/L
Cortisol AM	P: 450–700 nmol/L
Cortisol Midnight	P: 80–280 nmol/L
CK ♂	P: 25–195 U/L
CK ♀	P: 25–170 U/L
Creatinine	P: 70–100 μmol/L
Ferritin	P: 12–200 mcg/L
Folate	S: 2.1 mcg/L
FSH	P: 2–8 U/L ♂; >25 menopause
GGT ♂	P: 11–51 U/L
GGT ♀	P: 7–33 U/L
Glucose (fasting)	P: 3.5–5.5 mmol/L
Growth hormone	P: <20 mu/L
HbA1C (DCCT)	B: 4–6%
HbA1C (IFCC)	B: 20–42 mmol/mol
Iron ♂	S: 14–31 μmol/L
Iron ♀	S: 11–30 μmol/L
Lactate (venous)	P: 0.6–2.4 mmol/L
Lactate (arterial)	P: 0.6–1.8 mmol/L
LDH	P: 70–250 U/L
LH	P: 3–16 U/L
Magnesium	P: 0.75–1.05 mmol/L
Osmolality	P: 278–305 mosmol/kg
PTH	P: 0.8–8.5 pmol/L
Potassium	P: 3.5–5.3 mmol/L
Prolactin ♂	P: <450 U/L
Prolactin ♀	P: <600 U/L
PSA	P: 0–4 mcg/mL
Protein (total)	P: 60–80 g/L
Red cell folate	B: 0.36–1.44 μmol/L
Renin (erect)	P: 2.8–4.5 pmol/mL/h
Renin (recumbent)	P: 1.1–2.7 pmol/mL/h
Sodium	P: 135–145 mmol/L
TBG	P: 7–17 mg/L
TSH	P: 0.5–4.2 mU/L
T4	P: 70–140 nmol/L
Free T4	P: 9–22 pmol/L
TIBC	S: 54–75 μmol/L
Triglycerides	P: 0.50–2.3 mmol/L
T3	P: 1.2–3.0 nmol/L
Troponin T	P: <0.1 mcg/L
Urate ♂	P: 210–480 μmol/L
Urate ♀	P: 150–390 μmol/L
Urea	P: 2.5–6.7 mmol/L
Vitamin B12	S: 0.13–0.68 nmol/L
Vitamin D	S: 50 nmol/L

Arterial Blood Gases

pH	7.35–7.45
PaCO₂	4.7–6.0 kPa
PaO₂	>10.6 kPa
Base excess	±2 mmol/L

Urine

Cortisol (free)	<280 nmol/24h
Hydroxyindole acetic acid	16–73 μmol/24h
Hydroxymethylmandelic acid	16–48 μmol/24h
Metanephrines	0.03–0.69 μmol/mmol cr.
Osmolality	350–1000 mosmol/kg
17-Oxogenic steroids ♂	28–30 μmol/24h
17-Oxogenic steroids ♀	21–66 μmol/24h
17-Oxosteroids ♂	17–76 μmol/24h
17-Oxosteroids ♀	14–59 μmol/24h
Phosphate (inorganic)	15–50 mmol/24h
Potassium	14–120 mmol/24h
Protein	<150 mg/24h
Protein/creatinine ratio	<3 mg/mmol
Sodium	100–250 mmol/24h

Haematology

WCC	4.0–11.0 ×10⁹/L
RBC ♂	4.5–6.5 ×10¹²/L
RBC ♀	3.9–5.6 ×10¹²/L
Hb ♂	130–180 g/L
Hb ♀	115–160 g/L
PCV ♂	0.4–0.54 L/L
PCV ♀	0.37–0.47 L/L
MCV	76–96 fL
MCH	27–32 pg
MCHC	300–360 g/L
RDW	11.6–14.6%
Neutrophils	2.0–7.5 ×10⁹/L (40–75%)
Lymphocytes	1.0–4.5 ×10⁹/L (20–45%)
Eosinophils	0.04–0.44 ×10⁹/L (1–6%)
Basophils	0–0.10 ×10⁹/L (0–1%)
Monocytes	0.2–0.8 ×10⁹/L (2–10%)
Platelets	150–400 ×10⁹/L
Reticulocytes	0.8–2.0% / 25–100 ×10⁹/L
Prothrombin time	10–14 s
APTT	35–45 s

Paediatric

Pulse Rate (bpm)
Neonate	140–160
Infant <1yr	120–140
1–5 years	110–130
5–12 years	80–120
>12 years	70–100
Respiratory Rate (tachypnoea)
0–2 months	≥60/min
2–12 months	≥50/min
1–5 years	≥40/min
>5 years	≥30/min
Blood Pressure (mmHg)
Term	65/45
1 year	75/50
4 years	85/60
8 years	95/65
10 years	100/70
Weight Formulas
3–12 months	(a + 9)/2 kg
1–6 years	2a + 8 kg
>6 years	(7a − 5)/2 kg
Haemoglobin (g/dL)
Term newborn	13–20
1 month	11–18
2 months	10–15
1–2 years	10–13
>2 years	11–14
MUAC (6 months–5 years)
Obese	>17.5 cm
Normal	13.5–17.4 cm
At risk	12.5–13.4 cm
Moderate malnutrition	11.5–12.4 cm
Severe malnutrition	<11.5 cm
Developmental Milestones
Social smile	1.5 months
Head control	4 months
Sits unsupported	7 months
Crawls	10 months
Stands unsupported	10–12 months
Walks	12–13 months
Talks	18 months
CSF WBC (/mm³)
Term newborn	0–25
>2 weeks	0–5

Calculator ›

Leave a ReplyCancel Reply