History and exam

Key diagnostic factors

common

altered mental status

Altered mental status is frequently present on admission, and correlates with the severity of hyperglycemia and serum osmolality.[2]​​

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 more hypernatremic than hyperglycemic in nature.

Other diagnostic factors

common

polyuria

Symptom of hyperglycemia, may develop over days to weeks.[5]

polydipsia

Symptom of hyperglycemia, may develop over days to weeks.[5]

weight loss

Symptom of hyperglycemia.

weakness

Symptom of hyperglycemia.

dry mucous membranes

Sign of volume depletion.

poor skin turgor

Sign of volume depletion. 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.​[9]

tachycardia

Sign of volume depletion.

hypotension

Sign of volume depletion.

seizures

Seizures are seen in up to 25% of patients and can be either focal or generalized.

Epilepsia partialis continua is an unusual form of seizure that is present in 6% of HHS patients in the early phase of HHS.[46]

Seizures related to hyperglycemia in HHS are usually resistant to anticonvulsive therapy and phenytoin may further exacerbate HHS.[9]

uncommon

hypothermia

Although concomitant infection is common in HHS, patients are usually normothermic or hypothermic owing to peripheral vasodilation.[2]

Severe hypothermia is a poor prognostic sign.[2]​[9]

shock

Sign of volume depletion.

abdominal pain

Abdominal pain is uncommon in HHS but frequent (>50%) in diabetic ketoacidosis (DKA).[2]​[13]​ Therefore, in patients with hyperglycemic emergencies, the presence of unexplained abdominal pain should guide the clinician toward a diagnosis of DKA over HHS.[13]

focal neurologic signs

Focal neurologic signs in HHS can be in the form of hemianopia or hemiparesis at presentation.[2]​​[9][13]

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.​[9][13]

Risk factors

strong

infection

Infection is the major precipitating factor, occurring in 40% to 60% of patients.[10]​ Pneumonia and urinary tract infections are most commonly reported.[4]​​[9]​​[10][11]

Counter-regulatory hormones, particularly epinephrine, are increased as a systemic response to infection. They induce insulin resistance, decrease insulin production and secretion, and increase lipolysis, ketogenesis, and volume depletion, thereby contributing to the hyperglycemic crises in patients with diabetes.[2]​​[10]

inadequate insulin or oral antidiabetic therapy

Nonadherence to insulin or oral antidiabetic medication is common in patients admitted for HHS.​​ This association is much higher in urban African-American patients with diabetes, in whom nonadherence is the sole reason for HHS in 42% of cases.[15]

Alcohol and cocaine abuse is a major contributing factor to nonadherence of diabetic therapy. In one study of urban, underprivileged, African-American patients with HHS, alcohol abuse was seen in 44% of patients and cocaine use was seen in 9%.[15]

Reduction in the net effective concentration of insulin produces a relative insulin deficiency. If this deficiency is significant enough it can trigger HHS.​[2]​​[10]

acute illness in a known patient with diabetes

Underlying cardiovascular events, particularly myocardial infarction, provoke the release of counter-regulatory hormones that may result in HHS.[2]​​[10]

Acute stroke is associated with increased levels of counter-regulatory hormones and compromised access to water and insulin, which may contribute to the development of hyperglycemic crises.[2]​​​[9][10]

nursing home residents

Nursing home residents are often bedridden or have restricted mobility, which reduces their access to water intake and increases the risk of volume depletion and HHS. Other contributing factors are altered thirst mechanisms, comorbidities, polypharmacy, and possible failure to detect hyperglycemia or inappropriate treatment of diabetes.[10][40]

failure to detect hyperglycemia

In patients with diabetes, failure to detect hyperglycemia or inappropriate treatment of diabetes can lead to the development of HHS.

weak

post-operative state

Patients with poorly controlled diabetes, who receive enteral or parenteral nutrition or dextrose-containing fluids, may develop severe hyperglycemia and HHS.[9][20][41]​ Failure to initiate insulin therapy postoperatively to correct hyperglycemia exacerbates the risk.

Neurosurgical procedures are also associated with increased risk of HHS, although it remains unclear whether this is a result ​of direct central nervous system injury, solute load, or treatment with drugs such as glucocorticoids or phenytoin.[9]

precipitating medications

Corticosteroids, thiazide diuretics, beta-blockers, phenytoin, and didanosine are thought to induce HHS by affecting carbohydrate metabolism.[13][13][26][27][28][29][30]​​

Atypical antipsychotic medications (in particular, clozapine and olanzapine) have also been implicated in producing diabetes and hyperglycemic crises.[33][34]​ Possible mechanisms include induction of peripheral insulin resistance; a direct influence on pancreatic beta-cell function by 5-HT1A/2A/2C receptor antagonism; inhibitory effects through alpha2-adrenergic receptors, or by toxic effects.[13][34]

total parenteral nutrition (TPN)

Any patient with a strong family history of diabetes is at high risk of developing HHS on TPN therapy if not treated concomitantly with insulin.[9][21]

Cushing syndrome

In patients with concomitant diabetes, hypercortisolism leads to insulin resistance and promotes HHS development.[24]

Ectopic production of adrenocorticotropic hormone has been associated with HHS.[25]

hyperthyroidism

Hyperthyroidism induces glucose intolerance by lowering insulin levels and peripheral insulin sensitivity.[23] Circulating thyroid hormones affect glycogenolysis and enhance gluconeogenesis in the liver, which can contribute to the development, and exacerbation of, diabetes.[42]​ A case series of HHS in hyperthyroidism has been reported.[43]

acromegaly

A few cases of HHS associated with acromegaly have been reported.[22]

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