Epidemiology

The precise prevalence and incidence of hyperosmolar hyperglycaemic state (HHS) is difficult to determine because of the lack of population-based studies and the multiple comorbidities often found in these patients. However, the overall prevalence is estimated at less than 1% of all diabetes-related hospital admissions.[10][11] The incidence of HHS has been estimated at a rate of 17.5 per 100,000 patient years.[7]

HHS is seen most commonly in older people and, in the US, those of African-American ethnicity with diabetes.[11] However, HHS is now being seen in younger adults and even in children/teenagers, often as the initial presentation of type 2 diabetes.[12]

Mortality rates in HHS have been reported to be 5% to 20%, a rate that is 10-fold higher than that reported for diabetic ketoacidosis.[2][13] Mortality increases significantly when the patient is above the age of 70 years.[14] A combined state of severe hyperglycaemia, hyperosmolality, and metabolic acidosis is seen in approximately 25% of all hyperglycaemic emergencies.[6][15][16]

Risk factors

Infection is the major precipitating factor, occurring in 30% to 60% of patients. Urinary tract infections and pneumonia are most commonly reported.[6][38]

Counter-regulatory hormones, particularly adrenaline (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 hyperglycaemic crises in patients with diabetes.[1][9]

Non-adherence to insulin or oral antidiabetic medication is found in 12% to 25% of patients admitted with hyperosmolar hyperglycaemic state (HHS).[6][7] In the US, this association is much higher in urban African-American patients with diabetes, in whom non-adherence is the sole reason for HHS in 42% of cases.[10]

Alcohol and cocaine misuse is a major contributing factor to non-adherence of diabetic therapy. In one study of urban, underprivileged, African-American patients with HHS, alcohol misuse 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.[1][10][9]

Underlying cardiovascular events, particularly myocardial infarction, provoke the release of counter-regulatory hormones that may result in HHS.[7][17]

Stroke, with increased levels of counter-regulatory hormones and compromised access to water and insulin, may contribute to the development of hyperglycaemic crises.[7][17]

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 co-morbid diseases further increase their risk of developing HHS.

In patients with diabetes, failure to detect hyperglycaemia or inappropriate treatment of diabetes leads to the same sequence of events.[6][14]

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., in cardiac or orthopaedic procedures).[7][39] 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.[17]

Corticosteroids,[23] thiazide diuretics,[24][25] beta-blockers,[26] and didanosine[27] are thought to induce HHS by affecting carbohydrate metabolism.[8]

Medications that have been associated with hyperglycaemia, but not directly with HHS, include phenytoin,[28] gatifloxacin,[29] and cimetidine.[30] Drug-induced hyperglycaemia has been noted increasingly in HIV clinics; the drugs commonly involved are megestrol, pentamidine, and corticosteroids.[31] The risk of severe hyperglycaemia increases with concomitant use of these medications.[32]

Atypical antipsychotic medications (in particular, clozapine and olanzapine) have also been implicated in producing diabetes and hyperglycaemic 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.[8][34]

Any person with a strong family history of diabetes is at high risk of developing HHS on TPN therapy if not treated concomitantly with insulin.[17][19]

In patients with concomitant diabetes, hypercortisolism leads to insulin resistance and promotes HHS development.[21]

Ectopic production of adrenocorticotropic hormone has been associated with HHS.[22]

Hyperthyroidism induces glucose intolerance by lowering insulin levels and peripheral insulin sensitivity.[40] A case series of HHS in hyperthyroidism has been reported.[41]

A few cases of HHS associated with acromegaly have been reported.[20]

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