Approach

HHS usually evolves insidiously over days to weeks.[1] 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 examination

Patients usually present with polyuria, polydipsia, polyphagia, weakness, and weight loss.[8] 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. Typically, coma is associated with serum osmolality levels >330 to 340 mOsm/kg and is most often hypernatremic rather than hyperglycemic in nature.

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]

It is essential to take a full medication history, in particular looking for recent use of corticosteroids, pentamidine, didanosine, sympathomimetic agents or thiazides, or second-generation (atypical) antipsychotic agents, because these affect carbohydrate metabolism and may participate in the development of hyperglycemic crises.[1][31][32]

Physical signs of volume depletion include dry mucus 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.[1][9] Mild hypothermia may be observed in some patients, as a result of peripheral vasodilation.[1][9] Severe hypothermia is a poor prognostic sign.[1][9]

Abdominal pain is uncommon in HHS but frequent (>50%) in diabetic ketoacidosis (DKA).[1][8] Therefore, in patients with hyperglycemic emergencies, the presence of unexplained abdominal pain should guide the clinician toward a diagnosis of DKA rather than HHS.[8] Occasionally, patients with HHS may present with focal neurologic signs (hemianopia and hemiparesis) and seizures (either focal or generalized).[1][8][9] This presentation can often be mistaken for acute stroke. However, correction of hyperglycemia with fluid and insulin therapy leads to rapid resolution of these signs in HHS.[8][9] Epilepsia partialis continua is an unusual form of seizure that is present in 6% of HHS patients in the early phase of HHS.[41] Seizures related to hyperglycemia in HHS are usually resistant to anticonvulsive therapy and phenytoin may further exacerbate HHS.[9]

Initial investigations

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

Plasma glucose

  • Usually shows severe hyperglycemia (>600 mg/dL).

Blood urea nitrogen and creatinine

  • Elevated due to volume depletion.

Serum electrolytes[1][9]

  • 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 to 13 mEq/kg. Hypernatremia in the presence of hyperglycemia in HHS patients 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.[1] Coma, if present, is most often due to hypernatremia rather than hyperglycemia.

  • Total potassium deficit is 4 to 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.[1]

  • Serum chloride levels are usually low. There is usually a total chloride deficit of 5 to 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 to 2 mEq/kg, as a result of increased magnesium loss from diuresis.

  • Serum calcium levels are usually low. There is usually a total calcium deficit of 1 to 2 mEq/kg, as a result of increased calcium loss from diuresis.

  • Serum phosphate levels are usually low. The total body phosphate deficit is 3 to 7 mmol/kg, as a result of increased phosphate loss from diuresis.

Serum osmolality

  • Effective serum osmolality is calculated as 2 (measured Na [mEq/L]) + (glucose [mg/dL])/18 = mOsm/kg.[1] BUN concentration is not taken into account, because it is freely permeable and its accumulation does not change the osmotic gradient.[1]

  • Elevated in all patients (≥320 mOsm/kg).

Serum or urinary ketones

  • Beta-hydroxybutyrate is the main product of ketogenesis, with acetoacetic acids constituting the remainder of the ketones.

  • Guidelines recommend that, in addition to using the nitroprusside reaction to detect ketones, direct measurement of beta-hydroxybutyrate should be undertaken whenever possible.[1][42]

  • 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).com.bmj.content.model.Caption@61751ba3[Figure caption and citation for the preceding image starts]: Expected blood test results in HHSCreated by BMJ Knowledge Centre [Citation ends].

Anion gap

  • Anion gap is calculated as (Na)-(Cl + HCO3) (mEq/L).[1]

  • Levels ≥10 to 12 mEq/L signify an anion gap acidosis (i.e., lactic or ketoacidosis).[1]

Serum lactate

  • Lactic acid levels can be elevated if concomitant lactic acidosis is present.[1]

Urinalysis

  • Urine ketones are usually negative or only mildly positive.

  • 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.[1][9][2]

Blood gases

  • 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.[42] Furthermore, venous pH sampling is easier, more convenient, and less painful.

Complete blood count

  • Leukocytosis is present in hyperglycemic crises.

  • Leukocytosis of >25,000 per microliter may indicate infection and requires further evaluation.[1]

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.[1][9][2]

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 hypo- (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.[1]

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