By: Mohamed Dungersi, Associate Student Editor

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What is diabetic ketoacidosis (DKA)?

Diabetic ketoacidosis (DKA) is an acute complication of uncontrolled diabetes or hyperglycemia. It is usually observed in cases of extreme hyperglycemia (usually in excess of 500 mg/dl, though it can occur over 250 mg/dl).^1,2  It is usually characterized by the presence of hyperglycemia, ketosis, and acidosis, but underlying conditions may be present as well. The diagnostic criteria for DKA include a serum glucose >250 mg/dl, arterial pH <7.3, serum bicarbonate <18 mEq/l, and moderate ketonuria or ketonemia.¹  This article aims to provide a brief understanding of the epidemiology, pathogenesis, and treatment of DKA.

Who does DKA normally affect?

DKA is more common in young (<65 years) female diabetic patients.^2,3,4  The National Diabetes Surveillance Program of the Centers for Disease Control (CDC) estimated that there were 120,000 hospital discharges for DKA in 2005 in the United States, compared to 62,000 in 1980.³  On the other hand, DKA mortality per 100,000 diabetic patients declined between 1985 and 2005 with the greatest reduction in mortality among those 65 years of age and older.³  The prognosis of DKA is substantially worse at the extremes of age and in the presence of coma and hypotension.²  In summary, the number of cases of DKA is rising with increasing levels of obesity and increasing diagnosis of Diabetes Mellitus (DM).  However, mortality is declining despite the increase in prevalence.  This possibly indicates that DKA is better understood than in the past, which in turn led to more effective treatment.  It is important to keep in mind that mortality from DKA is primarily due to the underlying precipitating illness and only rarely due to the metabolic complications of hyperglycemia or ketoacidosis.⁵

What causes DKA?

The most common causes of DKA include inadequate insulin treatment from non-adherence; new –onset or undiagnosed diabetes; cardiovascular disease, especially myocardial infarction (MI); and infections, particularly pneumonia, urinary tract infections, and sepsis.⁴  Other causes of DKA include insulin resistance, acanthosis nigricans, pancreatitis, cererbrovascular accidents, and hyperthyroidism.⁴  DKA may also be caused by medications such as corticosteroids and sympathomimetic agents (e.g. albuterol, glucagon, atypical antipsychotics).⁴  Treatment of DKA will therefore also involve treatment of underlying conditions.

Two hormonal abnormalities are largely responsible for the development of hyperglycemia and ketoacidosis in patients with uncontrolled diabetes: insulin deficiency and/or resistance, and glucagon excess, which may result from absence of the normal suppressive effect of insulin.⁶  Glucagon excess is not required for DKA to occur, but is a contributory factor.⁶   Normally, when hyperglycemia occurs, insulin restores normoglycemia via two mechanisms: increasing glucose uptake by skeletal muscle and adipose tissue, and diminishing hepatic glucose production by reducing both glycogenolysis and gluconeogenesis.⁶  Insulin inhibits glucagon secretion and further reduces hepatic glucose production by directly inhibiting the glucagon gene in the pancreatic alpha cells.⁶  In cases of low levels of insulin and/or insulin resistance, hepatic glucose production and glucagon secretion are not inhibited.⁶

The basic mechanism underlying DKA  is a reduction in the effective action of circulating insulin, with concomitant elevation of counterregulatory hormones, primarily glucagon, but also catecholamines, cortisol, and growth hormone.^1,6  As a result, an increase in lipolysis occurs, which leads to free fatty acid conversion into ketone bodies in the liver.  Acetoacetic acid is the initial ketone formed; it may then be reduced to beta-hydroxybutyric acid, which is also an organic acid, or nonenzymatically decarboxylated to acetone, which is chemically neutral.  Ketones provide an alternate source of energy when glucose utilization is impaired.⁶  The development of DKA requires a specific alteration in hepatic metabolism so that free fatty acyl CoA can enter the mitochondria, where conversion to ketones occurs.^7,8  The presence of ketones in the blood causes hyperketonaemia and ketoacidosis.

What are the signs and symptoms of DKA?

Patients with DKA usually present with polyuria, polydipsia, polyphagia, weakness, and Kussmaul’s respirations. Often, the patient’s breath has a fruity odor.^1,6   Nausea and vomiting are present in 50—80% of patients, and abdominal pain is present in about 30%.⁶  Coffee-ground emesis, usually from hemorrhagic gastritis, occurs in about 25% of vomiting patients.  Body temperature usually is normal or low, even with an infection.  If the patient’s temperature is elevated, infection is invariably present.⁶  Signs of dehydration, such as dry mucous membranes, tachycardia, and hypotension, often are found. Most patients are dehydrated by about 10% and consciousness ranges from alert to confused to comatose in less than 20%of patients.⁶

How should DKA be treated?

The most important goals for treatment of DKA include repletion of fluid deficits, resolving hyperglycemia, resolving acidosis, and normalizing levels of potassium.¹²  Other serum levels such as magnesium, sodium, anion gap, etc. may or may not be of importance depending on the case at hand.  If an underlying condition is present, treatment for the underlying condition will also be of importance.  A priority of treatment should be to protect and maintain the airway, particularly in the obtunded patient, and to treat shock if present.  Patients should be monitored closely and frequently with the blood glucose being evaluated every one to two hours until the patient is stable.¹  Also, the blood urea nitrogen, serum creatinine, sodium, potassium, and bicarbonate levels should be monitored every two to six hours depending on the severity of DKA.¹  Cardiac monitoring may be warranted for patients with significant electrolyte disturbances.¹

The average fluid loss in DKA is 3—6 liters due largely to osmotic diuresis that occurs from excreting excess glucose; this is usually initially treated with isotonic saline (0.9 percent sodium chloride).^2,4  This will replace the fluid deficit, correct the extracellular volume depletion, lower the plasma osmolality (since it is still hypoosmotic to the patient), and reduce the serum glucose concentration both by dilution and by increasing urinary losses as renal perfusion is increased.⁹  The exact regimen will depend on the hydration status of the individual patient.  In cases of severe hypovolemia, normal saline is initially used.¹¹  In cases of mild dehydration, corrected sodium levels are evaluated, and therapy is dependent upon the sodium concentration. If Sodium levels are low, normal saline is used.  If sodium levels are high, half normal saline is used.¹¹  It is important to note that once the blood glucose level reaches 200 mg/dl, the patient will receive dextrose along with half normal saline.  Since the aim of therapy is to replete the extracellular fluid volume without inducing cerebral edema due to too rapid reduction in the plasma osmolality.^2,4

Treatment of hyperglycemia comprises of insulin therapy. Insulin lowers the serum glucose concentration (primarily by decreasing hepatic glucose production rather than enhancing peripheral utilization), diminishes ketone production (by reducing both lipolysis and glucagon secretion), and  may also augment ketone utilization [9,12]. The only indication for delaying insulin therapy is a serum potassium below 3.3 meq/L, since insulin will worsen the hypokalemia by driving potassium into the cells.¹¹  A continuous intravenous infusion of regular insulin is the treatment of choice, proceeded by a larger initial bolus dose. Uncomplicated DKA, may be treated sub-cutaneously.^1,11  Blood glucose values must be closely monitored to ensure that levels are dropping or else the insulin doses need to be increased.  Once blood glucose levels reach 200 mg/dl, dextrose is started with the saline solution in order to prevent hypoglycemia and cerebral edema.^2,4

Almost all patients with DKA have a substantial potassium deficit due to urinary, and in some cases gastrointestinal, losses.^1,9  The increase in renal potassium excretion is primarily related to the glucose osmotic diuresis and to hypovolemia-induced hyperaldosteronism.^1,9  However, because of a shift in potassium out of the cells due to insulin deficiency and hyperosmolality, the serum potassium is often elevated at presentation. In such patients, potassium repletion is not begun until serum potassium concentrations fall below 5.3 meq/L.⁹  The serum potassium should be maintained between 4.0 and 5.0 meq/L.⁹  Potassium repletion is more urgent in patients with massive potassium deficits who are hypokalemic prior to therapy; such patients require aggressive potassium replacement.  Since insulin will worsen the hypokalemia, insulin therapy should be delayed until the serum potassium is above 3.3 meq/L to avoid possible arrhythmias, cardiac arrest, and respiratory muscle weakness due to worsening hypokalemia .^4,9

Bicarbonate is used to treat acidosis if pH < 6.90. The venous pH should be monitored every two hours, and bicarbonate given until the pH rises above 7.^1,11  Additionally, treatment of underlying conditions is a priority i.e. the treatment of infections or cardiovascular disease. The American Diabetes Association (ADA) has identified the following criteria for resolved DKA: serum glucose below 200 mg/dL (11.1 mmol/L), serum anion gap <12 meq/L (or less than the upper limit of normal for the local laboratory), serum bicarbonate ≥18 meq/L, and venous pH >7.30.¹¹

The role of pharmacists in preventing DKA

Pharmacists play an important role in preventing patients from developing DKA, especially if patients are on diabetic medications. Diabetic education is vital and can help prevent non-adherence to insulin therapy or other medications.  Educating patients to regularly monitor blood glucose levels can prevent hyperglycemia and ultimately help prevent DKA.  Additionally, a sick-day-management plan will help prevent secondary DKA from occurring.  Some patients may require supplemental short acting insulin regimens and/or reduced insulin intake instead of completely eliminating it, when patients are not eating.  In such cases, recommendations should be made to the physicians.  Certain patients may also find home monitoring of blood ketones to be beneficial in preventing repeated DKA.  Regardless of the method employed, education of patients can help prevent many cases that would otherwise occur due to lack of education.  With DKA incidence and the number of patients with diabetes both rising, pharmacists must ensure patients are well educated to help prevent modifiable complications.

SOURCES:

1. Trachtenbarg DE. Diabetic ketoacidosis. Am fam physician 2005;71:1705—14.
2. Kitabchi AE, Umpierrez GE, Murphy MB, et al. Management of hyperglycemic crises in patients with diabetes. Diabetes Care 2001; 24:131.
3. National Center for Health Statistics. National hospital discharge and ambulatory surgery data. Available at www.cdc.gov/nchs/nhds.htm. Accessed May 17, 2012.
4. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care 2009; 32:1335.
5. Centers for Disease Control and Prevention: Diabetes Data & Trends. Available at http://www.cdc.gov/diabetes/statistics/dkafirst/fig1.htm. Accesssed May 17, 2012.
6. Kitabchi AE, Nathan DM, Wolfsdorf JI, et al. Epidemiology and pathogenesis of diabetic ketoacidosis and hyperosmolar hyperglycemic state. In: UpToDate, Mulder, JE (Ed), UpToDate, Waltham, MA, 2012.
7. Rose, BD, Post, TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001, p. 794.
8. Foster DW. Banting lecture 1984, From glycogen to ketones–and back. Diabetes 1984; 33:1188.
9. Wiggam MI, O’Kane MJ, Harper R, et al. Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management. A randomized controlled study. Diabetes Care 1997; 20:1347.
10. Luzi L, Barrett EJ, Groop LC, et al. Metabolic effects of low-dose insulin therapy on glucose metabolism in diabetic ketoacidosis. Diabetes 1988; 37:1470.
11. Kitabchi AE, Rose BD. Treatment of diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults. In: UpToDate, Nathan , DM (Ed), UpToDate, Waltham, MA, 2012.

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