Hyperosmolar Coma 

According to the nomenclature of the American Diabetes Association, the term hyperosmolar nonketotic state (HNS) is preferred to denote an acute metabolic complication of diabetes mellitus (DM) characterized by impaired mental status (MS) and elevated plasma osmolality in a patient with hyperglycemia. Criteria for HNS include serum osmolality of 320 mOsm/kg, plasma glucose level greater than 600 mg/dL (>33.3 mmol/L), profound dehydration, no ketoacidosis, pH of 7.3, HCO₃^- greater than 15 mEq/L, and the absence of severe ketosis.

HNS is the initial presentation of DM for 30-40% of patients. Most cases of HNS occur in patients with type 2 DM, characterized by insulin resistance and defective insulin secretion. HNS has been reported in patients with type 1 DM, in whom diabetic ketoacidosis (DKA) is more common. Both HNS and DKA may occur in the same individual, which suggests these 2 states of uncontrolled DM differ only in the magnitude of dehydration and the severity of acidosis.

The key pathophysiological event in HNS is relative or absolute deficiency of insulin activity. Deficient insulin activity may arise from an increase in insulin resistance or an inadequate supply of insulin, either endogenously or exogenously.

Obesity is the most prevalent cause of insulin resistance. Pregnancy is a state of insulin resistance largely due to the action of placental hormones on maternal circulation. High circulating levels of epinephrine, glucagon, growth hormone, and cortisol (the 4 major counterregulatory hormones) cause insulin resistance. Their levels increase during acute illnesses (eg, major infections, myocardial infarction [MI], pancreatitis) or stress (eg, surgery, major psychiatric illness, multiple traumas). Additionally, diseases characterized by excessive production of these hormones (eg, pheochromocytoma, glucagonoma, acromegaly, Cushing syndrome) also induce insulin resistance. Finally, parenteral nutrition and administration of some medications, notably glucocorticoids, Retin-A, antiretrovirals, antipsychotics,^{[1, 2]} and cyclosporine and other immunosuppressive agents, cause insulin resistance.

Insulin deficiency is due to autoimmune destruction of the beta cells in type 1 DM. In type 2 DM, a defect in the first-phase release of insulin occurs, which leads to relative insulinopenia. The defective insulin secretion in persons with type 2 DM is due to the direct toxic effect of glucose on beta cells. Many patients with diabetes treated with insulin become relatively insulinopenic when they fail to adjust the dose of insulin upwards during illnesses or periods of stress.

Insulin-sensitive tissues normally take up glucose during meals, when the glycemic rise of ingested carbohydrates stimulates insulin secretion. Stimulated insulin levels inhibit glucagon release from the pancreatic islets, and the ratio of plasma insulin to glucagon becomes relatively high. A high insulin-to-glucagon ratio favors storage of glucose as glycogen in liver and muscle and lipogenesis in adipocytes. Insulin-dependent transport of glucose across the cell membranes of insulin-sensitive tissues drives potassium into these cells. A high insulin-to-glucagon ratio during meals also favors amino acid uptake by muscle.

Between meals, insulin secretion is not stimulated, and the insulin-mediated glucagon inhibition in the pancreatic islets stops. The glucagon levels rise in the plasma, leading to a decrease in the ratio of plasma insulin to glucagon. The consequence of this decrease is the breakdown of glycogen in the liver and muscle and gluconeogenesis by the liver, both of which maintain the plasma glucose concentration in the normal range. A fall in the insulin-to-glucagon ratio also favors lipolysis and the formation of ketone bodies by the liver. Several tissues in the body use glucose regardless of the insulin-to-glucagon ratio. These insulin-independent tissues include the brain and the kidneys.

In the absence of adequate insulin activity, hyperglycemia develops. Decreased glucose use occurs in peripheral tissues, including adipocytes and muscles; glucose is unable to be stored as glycogen in muscle and liver; and hepatocytes under the influence of glucagon stimulate gluconeogenesis. The resulting elevation in plasma glucose concentration leads to further impairment of insulin release by pancreatic beta cells. In this setting of inadequate insulin action, the magnitude of the rise in plasma glucose concentration also depends, in part, on the level of hydration and oral carbohydrate (or glucose) loading.

Under normal circumstances, all of the glucose filtered by the kidneys is reabsorbed. When the level of glycemia reaches approximately 180 mg/dL, the proximal tubular transport of glucose from the tubular lumen into the renal interstitium becomes saturated, and further glucose reabsorption is no longer possible. The glucose that remains in the renal tubules continues to travel into the distal nephron and, eventually, the urine, carrying water and electrolytes with it. Osmotic diuresis results. The direct consequence of this osmotic diuresis is a decrease in total body water. Within the vascular space, in which gluconeogenesis and dietary intake continue to add glucose, the loss of water results in further hyperglycemia and loss of circulating volume.

Hyperglycemia and the rise in concentration of plasma proteins that follow intravascular water loss cause a hyperosmolar state. Hyperosmolarity of the plasma triggers antidiuretic hormone release, which ameliorates renal water loss. Hyperosmolarity also stimulates thirst, a defense mechanism that is impaired in people dependent on others for care.

In the presence of a hyperglycemic, hyperosmolar state, if the renal water loss is not compensated by oral water intake, then hypovolemia follows dehydration. Hypovolemia, in turn, leads to hypotension, and hypotension results in impaired tissue perfusion. Coma is the end stage of this hyperglycemic process, when severe electrolyte disturbances occur in association with hypotension. Any process that accelerates water loss, such as diarrhea or severe burns, accelerates the development of hyperosmolarity and hypotension. In this severely dehydrated and hyperosmolar state, hypotension causes a massive stimulation of the renin-angiotensin-aldosterone system and, eventually, renal shutdown. Oliguria precludes further excretion of glucose from the kidneys, which conserves circulating volume but exacerbates hyperglycemia.

Frequency

United States

No population-based studies of HNS have been conducted. According to the US National Hospital Discharge Survey funded by the National Center for Health Statistics, 10,800 annual discharges for HNS occurred from 1989-1991 in the United States. HNS affects approximately 1 of 500 patients with DM.

Mortality/Morbidity

The mortality rate for persons with HNS remains high, ranging from 14-58%. Older age, concurrent illnesses, and severity of the metabolic derangements, especially dehydration, contribute to this high mortality rate. A delay in establishing the diagnosis and a failure to treat HNS aggressively from the outset also may contribute to this high mortality rate.

• Cerebral edema: Cerebral edema is rare in HNS and is usually observed in patients much younger than the average age of 60 years. However, cerebral edema may occur from rapid lowering of glucose levels, with an ensuing rapid drop in plasma osmolarity. Brain cells, which trap osmotically active particles, preferentially absorb water and swell during rapid rehydration. Cerebral edema follows, and, given the constraints of the cranium, uncal herniation may be the cause of death in persons with HNS. However, death from cerebral edema due to HNS is rare, presumably because the older population that it affects has underlying cerebral atrophy. Thus, even with the edema of rehydration, the intracranial volume does not reach the critical level that causes uncal herniation. Aggressive correction of hyperglycemia and hyperosmolarity is indicated, especially in older patients.
• Adult respiratory distress syndrome: Always monitor pulmonary function carefully during therapy for HNS. A drop in the partial pressure alveolar oxygen during therapy for HNS may signal adult respiratory distress syndrome (ARDS), pulmonary emboli, MI, or a pneumonitis that has worsened with rehydration. ARDS may develop in association with underlying diseases, such as pancreatitis and MI. Although the precise mechanism by which ARDS develops in persons with HNS remains unclear, a likely scenario is that rapid correction of hyperglycemia and hyperosmolarity gives rise to pulmonary edema in a manner analogous to that of cerebral edema. To compensate for hypoxia and for mild acidosis, an increase in the minute ventilation with tachypnea develops. Continuing pulmonary disease may lead to acute respiratory failure requiring full respiratory support, including mechanical ventilation.
• Vascular complications: The severe dehydration of HNS leads to hypotension and hyperviscosity of the blood, both of which predispose patients to thromboembolic disease of the coronary, cerebral, pulmonary, and mesenteric beds. Disseminated intravascular coagulation also may complicate HNS. Together, these vascular syndromes account for much of the morbidity and mortality in HNS. Low-dose subcutaneous heparin is advisable for all patients without a contraindication.

Race

Data from 10,800 hospital discharges listing HNS in the United States from 1989-1991 included 6300 white patients and 2900 African American patients; the remainder of discharges were people of other races or of unknown race.

Sex

No sex predilection is noted in most published series of HNS. In the same data base as above, 3700 persons were male and 7100 were female.

Age

The average age of patients with HNS is 60 years. Most published series note an average age at diagnosis of 57-69 years. HNS may also occur in younger people. Nursing home populations are at risk of developing HNS. Underlying comorbidities that prevent adequate hydration, including immobility, advanced age, debility, dementia, agitation, and restraint use, place these patients at risk. Impaired senses, such as deafness and blindness, may lead to social isolation and also increase the risk of HNS.