Epidemiology
The precise prevalence and incidence of hyperosmolar hyperglycemic 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.[5][14][15]
HHS is seen most commonly in older patients with poorly controlled type 2 diabetes.[2][3] Reported mortality rates in HHS vary.[1] In the US, from 2008 to 2018, there was a reported increase in hospitalizations for HHS in patients with type 2 diabetes; however, inpatient mortality decreased from 1.44% to 0.77%.[16] Mortality rates are higher in low- and middle-income countries, with rates reported up to 20.3% in Jamaica.[17] Mortality increases significantly when the patient is above the age of 70 years.[18] Reported mortality rates are higher for those with mixed diabetic ketoacidosis (DKA)/HHS compared with DKA or HHS alone.[1][5] A combined state of severe hyperglycemia, hyperosmolality, and metabolic acidosis is seen in approximately 24% to 33% of all hyperglycemic emergencies.[5][17][19]
Risk factors
Infection is the major precipitating factor, occurring in 40% to 60% of patients.[9] Pneumonia and urinary tract infections are most commonly reported.[3][8][9][10]
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][9]
Nonadherence to insulin or oral antidiabetic drugs is common in patients admitted for hyperosmolar hyperglycemic state (HHS).[3] One study in Taiwan found that poor adherence to diabetes treatment was the cause of HHS in 21% of patients.[40]
Reduction in the net effective concentration of insulin produces a relative insulin deficiency. If this deficiency is significant enough it can trigger HHS.[1][9]
Underlying cardiovascular events, particularly myocardial infarction, provoke the release of counter-regulatory hormones that may result in hyperosmolar hyperglycemic state.[1][9]
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.[1][8][9]
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 hyperosmolar hyperglycemic state. Other contributing factors are altered thirst mechanisms, comorbidities, polypharmacy, and possible failure to detect hyperglycemia or inappropriate treatment of diabetes.[9][41]
In patients with diabetes, failure to detect hyperglycemia or inappropriate treatment of diabetes can lead to the development of hyperosmolar hyperglycemic state.
Patients with poorly controlled diabetes who receive enteral or parenteral nutrition or dextrose-containing fluids may develop severe hyperglycemia and hyperosmolar hyperglycemic state (HHS).[8][20][42] 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.[8]
Corticosteroids, thiazide diuretics, beta-blockers, pentamidine, and phenytoin are thought to induce hyperosmolar hyperglycemic state by affecting carbohydrate metabolism.[12][26][27][28][29][30]
Atypical antipsychotics (in particular, clozapine and olanzapine) have also been implicated in producing diabetes and hyperglycemic crises.[32][33] Possible mechanisms include induction of peripheral insulin resistance; a direct influence on pancreatic beta-cell function by 5-HT1A/2A/2C receptor antagonism; and inhibitory effects through alpha2-adrenergic receptors, or by toxic effects.[12][33]
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.[43] A case series of hyperosmolar hyperglycemic state in hyperthyroidism has been reported.[44]
A few cases of hyperosmolar hyperglycemic state associated with acromegaly have been reported.[22]
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