Hyperosmolar hyperglycemic state

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Key Recommendations

Hyperosmolar hyperglycemic state (HHS) usually evolves insidiously over days to weeks.[1][4] The aim of initial laboratory investigations is to establish the diagnosis and assess the severity. Subsequent investigations are used to identify underlying triggers, such as infection or myocardial infarction (MI).

History and physical exam

Patients usually present with polyuria, polydipsia, weakness, and weight loss.[12] Altered mental status is frequently present on admission, and correlates with the severity of hyperglycemia and serum osmolality.[1] Coma is a very rare presentation of HHS and is associated with total serum osmolality levels >340 mOsm/kg.[3]

Important factors to consider in the patient's past or current medical history include changes or omissions of insulin therapy, recent infection, and recent or previous MI or stroke because these may precipitate HHS.[1][9]

It is essential to take a full drug history, in particular looking for recent use of corticosteroids, pentamidine, beta-blockers, thiazide diuretics, phenytoin, or atypical antipsychotics, because these affect carbohydrate metabolism and may participate in the development of hyperglycemic crises.[1][26][27][28][29][30][32][33]

Physical signs of volume depletion include dry mucous membranes, poor skin turgor, tachycardia, hypotension, and, in severe cases, shock. Volume depletion may be difficult to assess in the form of poor skin turgor in older patients. Assessment of the buccal mucosa for dryness is more informative in these patients.[8] Mild hypothermia may be observed in some patients, as a result of peripheral vasodilation.[8][46] Severe hypothermia is a poor prognostic sign.[8][46]

Abdominal pain is uncommon in HHS but frequent (>50%) in diabetic ketoacidosis (DKA).[1][12] Therefore, in patients with hyperglycemic emergencies, the presence of unexplained abdominal pain should guide the clinician toward a diagnosis of DKA rather than HHS. Occasionally, patients with HHS may present with focal neurologic signs (hemianopia and hemiparesis) and seizures (either focal or generalized).[8][12][46] This presentation can be mistaken for acute stroke. However, correction of hyperglycemia with fluid and insulin therapy leads to rapid resolution of these signs in HHS.[8][12] Epilepsia partialis continua is an unusual form of seizure that is present in 6% of patients with HHS in the early phase of HHS.[49] Seizures related to hyperglycemia in HHS are usually resistant to anticonvulsive therapy and phenytoin may further exacerbate HHS.[8]

Initial investigations

The aim of initial laboratory investigations is to establish the diagnosis and assess the severity.

Plasma glucose

Shows severe hyperglycemia (≥600 mg/dL).

Blood urea nitrogen and creatinine

Elevated due to volume depletion.

Serum electrolytes[1][8]

Serum sodium is usually low owing to the osmotic flux of water from the intracellular to extracellular space in the presence of hyperglycemia. The total sodium deficit is 5-13 mEq/kg. Hypernatremia in the presence of hyperglycemia in patients with HHS indicates profound volume depletion. To assess the severity of sodium and water deficit, the patient's corrected sodium can be calculated by adding 1.6 mEq/L of sodium to the measured value for every 100 mg/dL of glucose above 100 mg/dL.[46]
Total potassium deficit is 4-6 mEq/kg, owing to increased loss of potassium by diuresis. In spite of the total body potassium deficit, serum potassium is usually elevated. This is because insulin insufficiency, hypertonicity, and acidemia cause a large extracellular shift of potassium. A low potassium level on admission indicates severe total-body potassium deficit.[46]
Serum chloride levels are usually low. There is usually a total chloride deficit of 5-15 mEq/kg; this is secondary to the sodium deficit.
Serum magnesium levels are usually low. There is usually a total magnesium deficit of 1-2 mEq/kg, as a result of increased magnesium loss from diuresis.
Serum phosphate levels are usually low or normal on presentation. The total body phosphate deficit is 3-7 mmol/kg, as a result of increased phosphate loss from diuresis.

Serum osmolality

Total serum osmolality is total concentration of sodium, glucose, and blood urea nitrogen (BUN) in serum. [ Osmolality Estimator (serum) Opens in new window ]
Effective serum osmolality is calculated from serum concentrations of sodium and glucose.[1] BUN concentration is not taken into account, because it is freely permeable and its accumulation does not change the osmotic gradient.[46]
Elevated in all patients with HHS (total serum osmolality: >320 mOsm/kg; calculated effective serum osmolality: >300 mOsm/kg).[1]

Serum or urinary ketones

Beta-hydroxybutyrate is the main product of ketogenesis, with acetoacetic acids constituting the remainder of the ketones.
Guidelines recommend that direct measurement of beta-hydroxybutyrate by laboratory enzymatic methods or by point-of-care capillary measurement should be undertaken whenever possible.[1][50] If beta-hydroxybutyrate measurement is not available, nitroprusside reaction can be used to detect ketones.
Beta-hydroxybutyrate is converted to acetoacetate over time, which is excreted in the urine. When measuring serum ketones, the nitroprusside reaction will not detect beta-hydroxybutyrate. Thus, serum or urine ketones measured by the nitroprusside reaction may be initially negative at the time of presentation, or remain positive when DKA-HSS has resolved (giving the appearance that there are no ketones in the serum, or that DKA-HSS is not resolving).[Figure caption and citation for the preceding image starts]: Expected blood test results in HHSCreated by BMJ Digital Health [Citation ends].

Anion gap

Anion gap is calculated as (Na)-(Cl + HCO₃) (mEq/L).
The normal range of anion gap varies depending on the laboratory. Typically, levels ≥12 mEq/L signify an anion gap acidosis, which may indicate mixed DKA-HHS, lactic acidosis, or other conditions unrelated to HHS.[1][3]

Serum lactate

Lactic acid levels can be elevated in conditions such as sepsis, and in severe volume depletion in patients with diabetes.[2][46]

Urinalysis

Urine ketones are usually negative or mildly positive (<2 + on a ketone strip).
Urine glucose is positive.
If infection is present, urine will be positive for leukocytes and nitrites; urinary tract infection is a common precipitant of HHS.[3][8][9][10]

Blood gas

Arterial pH is usually ≥7.30 and arterial bicarbonate is ≥15 mEq/L. A venous pH sample is usually 0.03 units lower than arterial pH. Several studies have suggested that the difference between venous and arterial pH samples is not sufficiently significant to change clinical management.[50] Furthermore, venous pH sampling is easier, more convenient, and less painful.

Complete blood count

Leukocytosis is a common finding in patients in hyperglycemic crises.[36]
Leukocytosis of >25,000 per microliter may indicate infection and requires further evaluation.[46]

Liver function tests

Typically normal. Abnormalities may exist if underlying diseases, such as fatty liver or congestive heart failure, are present.

Additional investigations

Subsequent investigations are used to identify underlying triggers, such as infection or MI, or an alternative diagnosis.

Chest x-ray

Used to exclude pneumonia, a common precipitant of HHS.[3][8][9][10]

ECG

Should be performed if cardiovascular diseases, such as MI, are suspected as the trigger or if severe electrolyte abnormalities are present.[1] Evidence of hypokalemia (U waves) or hyperkalemia (tall T waves) may also be present.

Myocardial enzymes

Should be tested if an MI is suspected as the trigger.

Blood, urine, or sputum cultures

Used to identify precipitating infections. Further workup for sepsis should be performed if clinically indicated.[46]

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