History and exam

Key diagnostic factors

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 more hypernatremic than hyperglycemic in nature.

Other diagnostic factors

Symptom of hyperglycemia.

Symptom of hyperglycemia.

Symptom of hyperglycemia.

Symptom of hyperglycemia.

Sign of volume depletion.

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.[1][9]

Sign of volume depletion.

Sign of volume depletion.

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.[41]

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

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

Severe hypothermia is a poor prognostic sign.[1][9]

Sign of volume depletion.

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 over HHS.[8]

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

Risk factors

Infection is the major precipitating factor, occurring in 30% to 60% of patients. Urinary tract infections and pneumonia are most commonly reported.[1][9][2]

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.[1]

Nonadherence to insulin or oral antidiabetic medication is found in 12% to 25% of patients admitted for HHS.[5][7] 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.[10]

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 49% of patients and cocaine use was seen in 9%.[10]

Reduction in the net effective concentration of insulin produces a relative insulin deficiency. The deficiency may trigger HHS if sufficiently large.[10][1]

Underlying cardiovascular events, particularly myocardial infarction, provoke the release of counter-regulatory hormones that may result in HHS.[1]

Stroke, with increased levels of counter-regulatory hormones and compromised access to water and insulin, may contribute to the development of hyperglycemic crises.[7][9]

Restricted water intake in nursing home residents with diabetes places these patients at high risk of developing HHS.

Diabetes in these patients may go undiagnosed and their bedridden or restrained state with or without altered thirst mechanism predisposes them to severe volume depletion. Multiple comorbid diseases further increase their risk of developing HHS.[37]

In patients with diabetes, failure to detect hyperglycemia or inappropriate treatment of diabetes, leads to the same sequence of events.[5][13]

Procedure-related increase in intravenous osmotic load with dextrose-containing fluids can trigger HHS, especially in patients who receive large volumes of dextrose fluid resuscitation (e.g., cardiac bypass or orthopedic procedures).[9][7][17] Failure to initiate insulin therapy postoperatively exacerbates the risk.

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

Corticosteroids, thiazide diuretics, beta-blockers, and didanosine are thought to induce HHS by affecting carbohydrate metabolism.[22][23][24][25][26][8]

Medications that have been associated with hyperglycemia, but not directly with HHS, include phenytoin and cimetidine.[27][28] Drug-induced hyperglycemia has been noted increasingly in HIV clinics; the drugs commonly involved are megestrol, pentamidine, and corticosteroids.[29] The risk of severe hyperglycemia increases with concomitant use of these medications.[30]

Atypical antipsychotic medications (in particular, clozapine and olanzapine) have also been implicated in producing diabetes and hyperglycemic crises.[31][32] 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.[8][32]

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][18]

In patients with concomitant diabetes, hypercortisolism leads to insulin resistance and promotes HHS development.[20]

Ectopic production of adrenocorticotropic hormone has been associated with HHS.[21]

Hyperthyroidism induces glucose intolerance by lowering insulin levels and peripheral insulin sensitivity.[38] A case series of HHS in hyperthyroidism has been reported.[39]

A few cases of HHS associated with acromegaly have been reported.[19]

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