Vol. 11 Issue 12
Hyperglycemic Hyperosmolar Nonketotic Coma
Without adequate medical intervention, patients experience a downward decline with worsening confusion, convulsions, coma and eventual death.
In the United States, most people to some extent know about the incidence of diabetes mellitus and its long-term general complications. Likewise, the direct and indirect economic costs associated with diabetes, now exceeding $132 billion yearly,1 are probably not surprising, either. People with diabetes or with family members or friends with the disease generally are well aware of the variety of medications and devices that help control glucose levels and understand that diabetes is a major cause of morbidity in this country.
Not all manifestations of diabetes are as well appreciated, however, including hyperglycemic, hyperosmolar, nonketotic (HHNK) coma, which is primarily seen in patients who have type 2 diabetes. Unlike patients with type 1 diabetes, who may develop diabetic ketoacidosis (DKA), patients with type 2 diabetes tend to develop HHNK syndrome when their blood glucose levels sharply rise. This syndrome is usually insidious in onset, with symptoms of polyuria, polydipsia, weight loss, weakness and a progressive decline in mental alertness, occurring over a period of days or weeks, and sometimes presenting in patients not previously known to have diabetes.
While the syndrome is often referred to as "coma," that is somewhat misleading, because fewer than 10% of HHNK cases actually slip into a comatose state.2 But without adequate medical intervention, patients experience a downward decline with worsening confusion, convulsions, coma and eventual death.
DKA and the hyperglycemic, hyperosmolar state (HHS) represent extremes in the spectrum of diabetic decompensation.3 The overall incidence of HHS in the United States is 17.5 per 100,000.2 Based on the estimated size of the type 2 diabetic population in the United States, one can anticipate that 1,000 to 2,000 patients will be admitted to hospitals for treatment of HHNK syndrome each year.
The underlying metabolic abnormality of HHNK syndrome, as well as of DKA, is related to an insulin deficiency, along with elevations in insulin counterregulatory hormonesnamely glucagon, catecholamines and cortisol. The elevated counter-regulatory hormone levels stimulate glycogenolysis and enhance gluconeogenesis with alterations in metabolism of carbohydrates, fats and proteins. Elevated cortisol levels result in increased amounts of amino acid precursors, aiding gluconeogenesis. The low insulin level and the increased catecholamine concentrations decrease glucose uptake by peripheral tissues. This combination of enhanced gluconeogenesis and glycogenolysis, combined with a decreased utilization of glucose in the periphery, constitutes the primary pathogenic abnormality leading to hyperglycemia in HHNK syndrome and in DKA.
It follows, then, that hyperglycemia leads to glycosuria, osmotic diuresis (polyuria) and subsequent dehydration. Dehydration leads to decreased renal perfusion, leading to less glucose clearance by the kidneys and a furthering of the hyperglycemia.
Whereas DKA is associated with ketogenesis and results from counter-regulatory hormone excess in the face of insulin lack, the reason for the absence of ketosis in the presence of insulin deficiency in HHS is unknown.4 One theory suggests that this absence might relate to lower levels of free fatty acids, or higher levels of portal vein insulin, or both.4 Certainly, free fatty acid levels frequently are normal in patients with HHS, whereas they may be markedly elevated in patients with DKA. Perhaps the liver is less capable of ketone synthesis, or perhaps simply the glucagon-to-insulin ratio does not favor ketogenesis in the pure HHNK syndrome. Elderly patients who have marked hypovolemia may also have a relative failure of the adrenergic nervous system in producing enough catecholamines to assist in lipolysis and release of free fatty acids.
In HHS, the osmotic diuresis secondary to hyperglycemia results in profound fluid loss, ranging from 7 L to 12 L, which represents a loss of about 10% to 15% of body weight.4 In a study by MacIsaac and colleagues,5 30% of presentations for diabetic hyperglycemic emergencies actually were related to a mixed state of ketoacidosis and hyperosmolarity, and mortality rates for both were influenced by age and degree of hyperosmolarity. However, the mortality rate for emergencies associated with ketoacidosis was considerably lower than the mortality rate associated with hyperosmolarity. This seems to be a consistent finding in the literature, since the HHNK syndrome is more frequently seen in elderly patients who have associated comorbidities.
The estimated mortality rate for DKA is between 4% and 10%, whereas the rate for HHS varies from 10% to 50%.4,6 This higher range is attributable to underlying illnesses.
Factors precipitating HHNK syndrome generally are similar to factors precipitating DKA and include administration of fluids high in glucose, omission of insulin doses or inadequate insulin doses, other medical conditions, concurrent infection and medications. Medical conditions that may precipitate HHNK syndrome include silent myocardial infarction (MI), cerebrovascular accident, renal insufficiency, severe burns and certain endocrine disorders.
Medications associated with HHS include corticosteroids, which antagonize the actions of insulin; potassium-wasting diuretics and phenytoin, which may suppress secretion of insulin; and a few miscellaneous drugs such as beta-blockers, diazoxide and others. In some cases, no obvious precipitating cause can be found.
Any patient presenting with dehydration and high blood glucose should be expected to have acute diabetic decompensation; however, a definitive diagnosis of DKA or HHNK syndrome must be confirmed through laboratory investigation.
Careful clinical observation can provide very helpful clues for a preliminary diagnosis. DKA usually occurs in younger patients (mean age in early 40s), whereas HHS is likelier to occur in older patients (mean onset in the 70s). The patient with HHNK syndrome is also more apt to be obese and have a history of type 2 diabetes.
Additionally, HHNK syndrome develops more slowly than DKA, usually occurring over a period of several days to weeks, and the patients at highest risk are the elderly with some degree of renal compromise and dementia who reside in nursing facilities. A preceding illness often may be identified, especially if the illness was infectious, and the patient may provide a history of fever, vomiting, diarrhea, etc. Patients with chronic medical conditions associated with dementia or immobility may have a history of consumption of inadequate quantities of fluids.
Physical examination of the patient provides helpful clues to the state of hydration, presence of chronic disorders and mental state. Patients are usually tachycardic, and if dehydration is severe, they will be hypotensive, as well. Other signs of dehydration will be evident in skin turgor, dry mucous membranes, sunken eyes, etc. Of major importance is a careful search during an in-depth physical examination for signs and symptoms of underlying infection and other catastrophic events such as MI or stroke.
Minimal initial laboratory evaluation should include serum electrolytes, serum glucose, serum osmolality and serum ketones, blood pH, serum lactate and blood urea nitrogen. These will provide quick, useful information, but with suspicion of infection or MI, for example, the laboratory investigation obviously would be broadened.
In HHS, initial serum glucose concentrations may range from 600 to 2,400 mg/dL (normal range 60 to 110 mg/dL), however, contrary to expectation, acidosis and ketosis are minimal, and plasma acetone is not routinely present.7 Serum osmolality is frequently greater than 320 mmol/kg (normal range 280 to 300 mmol/kg), which by definition is diagnostic of HHS.4 Elevation of serum osmolality above 320 mmol/kg is associated with central nervous system dysfunction, and at 400 mmol/kg, most patients are obtunded.7
Serum sodium levels may be increased, normal or decreased. Increased sodium with marked hyperglycemia indicates severe dehydration. Decreased sodium is falsely skewed because of the underlying dehydration and hyperglycemia (artifactual decrease of 1.6 mEq/L for every 100 mg/dL increase of serum glucose).7 Serum potassium may be increased (related to hyperosmolality), low (related to osmotic diuresis with urinary loss) or normal. Blood urea nitrogen will be increased 79 to 90 mg/dL (normal range 8 to 25 mg/dL) more than in DKA.
Management of the Hyperosmolar State
Since patients with HHNK syndrome or coma are in acute crisis, standard care, including airway management, intravenous access and electrocardiographic monitoring, are expected interventions. The most important element of immediate treatment, however, is fluid and electrolyte replacement, since severely dehydrated patients may have fluid losses of up to 200 mL/kg body weight.4
It is imperative that extracellular fluid volume be replaced and renal perfusion be restored. General recommendations are that the fluid loss should be replaced in the first 18 to 24 hours of therapy, and that treatment should start with normal saline, which will be hypotonic compared with the marked hypertonicity of the hyperosmolar state. Also, normal saline will produce a smaller fluid shift in tissue compartments, such as the central nervous system, and will more easily avoid development of brain edema.
Subsequent fluid replacement usually involves administration of 0.5 N saline if the patient shows clinical improvement in tissue perfusion and urine output is improving. Potassium replacement must be instituted as soon as urine output is ensured, since hypokalemia will occur during insulin therapy to correct the hyperglycemia. Serum potassium concentrations must be carefully and frequently monitored, however, because acute oliguric renal failure is a common problem of HHNK syndrome. All electrolyte deficiencies must be replaced carefully and with frequent monitoring in order to return the patient to a more nearly normal state of health.
Because of poor tissue perfusion secondary to the marked hypovolemia, regular insulin at a dose of 0.1U/kg/hour is most often administered by continuous infusion. Again, one must be careful in rapidly lowering the serum glucose, since rapid correction of hyperglycemia may be accompanied by shifts of water from extracellular to intracellular compartments, including the brain. When the plasma glucose level reaches 12 to 14 mmol/L, the insulin infusion rate may be decreased by 50% as 5% dextrose is added to the IV fluid.4 Then one adjusts the insulin infusion to maintain plasma glucose values until the hyperosmolality and other signs and symptoms in HHS have been resolved.
After resolution of the acute disorder, and when the patient can take fluids orally, maintenance therapy for diabetes must be developed and followed. Also keep in mind that rapid infusion of large volumes of fluid is contraindicated if the patient has underlying congestive heart failure.
Be on the Lookout
Hyperglycemic, hyperosmolar, nonketotic coma is one complication of type 2 diabetes that is seen more frequently with the aging population and one that can become rapidly fatal if not recognized and treated promptly and accurately. In the recent past, HHS had been associated with a mortality rate of 30% to 80%, but more recent data suggest a rate of 10% to 40%.8 Short of death, other serious complications such as seizures, thromboses and renal failure may occur. Since most patients are transferred to an emergency facility for initial evaluation, the most important role for the PA is to recognize the severity of this disorder and to involve the ED personnel in the management of such patients.
Doris Rapp is an associate professor and director of the surgical PA program at the University of Alabama at Birmingham. Patricia R. Jennings is an associate professor at the surgical PA program at the University of Alabama at Birmingham.
1. The Prevention and Treatment of Complications of Diabetes Mellitus: A Guide for Primary Care Practitioners. Atlanta, Ga: Centers for Disease Control and Prevention; 2000. Available at: http://www.cdc.gov/diabetes/pubs/complications/glycemic.htm. Accessed October 8, 2003.
2. Sagarin M, McAfee A. Hyperosmolar hyperglycemic nonketotic coma. eMedicine Web site. Available at: http://www.emedicine.com/EMERG/topic264.htm. Accessed October 8, 2003.
3. Magee MF, Bhatt BA. Management of decompensated diabetes. Diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Crit Care Clin. 2001;17:75-106.
4. Chiasson JL, Aris-Jilwan N, Belanger R, et al. Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state. CMAJ. 2003;168:859-866.
5. MacIsaac RJ, Lee LY, McNeil KJ, Tsalamandris C, Jerums G. Influence of age on the presentation and outcome of acidotic and hyperosmolar diabetic emergencies. Intern Med J. 2002;32:379-385.
6. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care. 2001;24:131-153.
7. Wallach JB. Interpretation of Diagnostic Tests. 7th ed. Philadelphia, Pa: Lippincott Williams and Wilkins; 2000:617.
8. Berger W, Keller U. Treatment of diabetic ketoacidosis and non-ketotic hyperosmolar diabetic coma. Baillieres Clin Endocrinol Metab. 1992;6:1-22.