Treatment Of Diabetic Ketoacidosis (DKA)

From: America Family Physicians

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. Blood glucose should be evaluated every one to two hours until the patient is stable, and 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.3 Cardiac monitoring may be warranted for patients with significant electrolyte disturbances. Treatment also should be directed at the underlying cause of the DKA, including antibiotics for suspected or identified infection. Although it is important to monitor urinary output, urinary catheterization is not advised routinely.

inpatient vs. outpatient treatment
Selected patients with mild DKA who are alert and taking fluids orally may be treated under observation and sent home without admission.3 The ADA admission guidelines are a plasma glucose concentration greater than 250 mg per dL (13.9 mmol per L) with an arterial pH level below 7.30, a serum bicarbonate level of less than 15 mEq per L, and a moderate or greater level of ketones in the serum or urine.27 Patients with severe DKA should be admitted to the intensive care unit.

fluids
Fluid deficits are typically 100 mL per kg of body weight.3 Fluid replacement alone will lower blood glucose. Tracer studies have found that during the first four hours of therapy for DKA, up to 80 percent of the decline in glucose concentration may be caused by rehydration.28
Fluid guidelines are summarized on the flowchart in Figure 1.3 When giving fluids, the average rate of change in effective serum osmolality ideally should not be more than 3 mOsm per hour. Patients who are able to drink can take some or all of their fluid replacement orally. Fluid intake should be modified based on urinary output. Urinary output will decrease as the osmotic diuretic effect of hyperglycemia is reduced.

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Management of Adults with Diabetic Ketoacidosis
Figure 1. Algorithm for the management of adults with diabetic ketoacidosis. (NaCl = sodium chloride; IM = intramuscular; IV = intravenous; SC = subcutaneous.)
Adapted with permission from Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, et al. Hyperglycemic crises in diabetes. Diabetes Care 2004;27(suppl 1):S96.
Management of Patients Younger than 20 Years with Diabetic Ketoacidosis* or Hyperosmolar

Hyperglycemic State†
*-Diagnostic criteria: blood glucose > 250 mg per dL, venous pH < 7.3, bicarbonate < 15 mEq per L, moderate ketonuria or ketonemia.
†-Diagnostic criteria: blood glucose > 600 mg per dL, venous pH > 7.3, bicarbonate > 15 mEq per L, and altered mental status or severe dehydration.
‡-After the initial history and physical examination, immediately obtain blood glucose, venous blood gases, electrolytes, blood urea nitrogen, creatinine, calcium, phosphorus, and urine analysis.
§-Usually 1.5 times the 24-hour maintenance requirements (about mL per kg-1 per hour-1) will accomplish a smooth rehydration; do not exceed two times the maintenance requirement.
-The potassium in solution should be 1/3 potassium phosphate and 2/3 potassium chloride or Kacetate.
When the blood glucose level has dropped below 250 mg per dL, the patient may be given fluid with 5 percent dextrose, such as 0.45 normal saline. If dextrose is not given, further ketosis may occur.

insulin
An intravenous insulin drip is the current standard of care for diabetic ketoacidosis, primarily because of the more rapid onset of action. Studies29 comparing intra-venous insulin with subcutaneous or intramuscular insulin have found a quicker decrease in glucose and ketone levels, but no improvement in morbidity and mortality. Insulin may be mixed in a standard concentration of 1 U per 10 mL of normal saline. Common adult rates are 5 to 7 U per hour. A standard regimen is given in Figure 1.3 When the blood glucose level is less than 250 mg per dL, the intravenous insulin rate usually is decreased, or the patient is switched to subcutaneous insulin to maintain plasma glucose in the range of 150 to 200 mg per dL (8.3 to 11.1 mmol per L) until metabolic control is achieved.
Regular insulin should be used intravenously. Lispro and aspart (NovoLog) insulin are more expensive and do not work faster than regular insulin when given intravenously. A newly published regimen is treatment of DKA with subcutaneous aspart or lispro insulin.29,30 In one study,30 patients who were medically stable after initial fluid resuscitation were treated with a loading dose of 0.3 U per kg of aspart insulin, followed by 0.1 U per kg every hour. There were no significant differences in outcomes between the aspart and intravenous insulin regimens. A similar study29 comparing subcutaneous lispro insulin in a medical ward with an intravenous insulin drip in the intensive care unit showed similar outcomes, except for a 40 percent reduction in cost for patients treated in the medical ward. Long-acting insulin normally is stopped during treatment of DKA. If the patient is on an insulin pump, it should be stopped, and the patient should be switched to an intravenous infusion.31
If an intravenous infusion pump is not available, insulin can be given intramuscularly. Insulin is absorbed more rapidly intramuscularly than if given subcutaneously.32 A regimen for intramuscular insulin is given in Figure 1.3 This regimen advises that an initial dose of insulin be given intravenously and intramuscularly. When intravenous access is unavailable, studies have found that giving the entire initial dose intramuscularly also is effective.33 If intramuscular insulin is used, it is important to use a needle that is long enough to ensure that the insulin is not given subcutaneously.

potassium
Whole body potassium deficits typically are 3 to 5 mEq per L (3 to 5 mmol per L). Acidosis increases potassium levels and glucose administered with insulin lowers them. Before treatment of DKA, the level of potassium usually is normal or elevated. Potassium should be started as soon as adequate urine output is confirmed and the potassium level is less than 5 mEq per L.3 Usually 20 to 30 mEq (20 to 30 mmol) of potassium is given for each liter of fluid replacement. If the potassium level is less than 3.3 mEq per L (3.3 mmol per L), potassium replacement should be given immediately and insulin should be started only after the potassium level is above 3.3 mEq per L.3

bicarbonate
Studies of patients with a pH level of 6.9 or higher have found no evidence that bicarbonate is beneficial,34 and some studies have suggested bicarbonate therapy may be harmful for these patients.35-37 The flowchart in Figure 13 advises giving no bicarbonate if the pH level is greater than 6.9. Because there are no studies on patients with a pH level below 6.9, giving bicarbonate as an isotonic solution still is recommended. Bicarbonate therapy lowers potassium levels; therefore, potassium needs to be monitored carefully.

phosphate
Although the phosphate level frequently is low in patients with DKA, good-quality studies have shown that routine phosphate replacement does not improve outcomes in DKA, and excessive replacement can lead to hypocalcemia.3,38-40 If the patient's serum phosphate level is below normal, consider giving one third to one half of the potassium may be given in the form of potassium phosphate, provided the level of serum calcium is monitored closely.3,41

magnesium
A serum deficit of 1 to 2 mEq per L (0.50 to 1 mmol per L) of magnesium usually exists. In addition to alterations in magnesium metabolism from DKA, many patients with diabetes have taken medications such as diuretics that also may lower magnesium levels. Symptoms of magnesium deficiency are difficult to recognize and overlap with symptoms caused by deficiencies of calcium, potassium, and sodium. Paresthesias, tremor, carpopedal spasm, agitation, seizures, and cardiac dysrhythmias all are reported symptoms. Checking magnesium levels and correcting low levels should be considered in patients with DKA. Patients usually are symptomatic at serum levels of 1.2 mg per dL (0.50 mmol per L) or lower.42 If the level is below normal (i.e., less than 1.8 mg per dL [0.74 mmol per L]) and symptoms are present, administration of magnesium should be considered.42

sodium
Whole body sodium deficits typically are 7 to 10 mEq per L (7 to 10 mmol per L). Serum sodium is falsely lowered by 1.6 mEq for every 100 mg per dL increase in blood glucose. Hyponatremia needs to be corrected only when the sodium level is still low after adjusting for this effect. For example, in a patient with a serum glucose concentration of 600 mg per dL (33.3 mmol per L) and a measured serum sodium level of 130, the true serum sodium level is 130 + (1.6 X 5) = 138. A high serum sodium level almost always indicates hypernatremic dehydration.

Complications
Selected patients with mild ketoacidosis who are alert and taking oral fluids may be treated under observation and sent home without hospital admission.
Common complications of DKA include hypoglycemia, hypokalemia, and recurrent hyperglycemia. These may be minimized by careful monitoring. Hyperchloremia is a common but transient finding that usually requires no special treatment.
Cerebral edema is a rare but important complication of DKA. Although it can affect adults, it is more common in young patients, occurring in 0.7 to 1.0 percent of children with DKA.3 Early signs of cerebral edema include headache, confusion, and lethargy. Papilledema, hypertension, hyperpyrexia, and diabetes insipidus also may occur. Patients typically improve mentally with initial treatment of DKA, but then suddenly worsen. Dilated ventricles may be found on CT or magnetic resonance imaging. Treatment of suspected cerebral edema should not be delayed for these tests to be completed. In more severe cases, seizures, pupillary changes, and respiratory arrest with brain-stem herniation may occur. Once severe symptoms occur, the mortality rate is greater than 70 percent, and only about 10 percent of patients recover without sequelae.3
Avoiding overhydration and limiting the rate at which the blood glucose level drops may reduce the chance of cerebral edema.3 However, some patients may present with cerebral edema before treatment is started. About 10 percent of the patients initially diagnosed with cerebral edema have other intracranial pathology such as subarachnoid hemorrhage.43 Mannitol (Osmitrol) therapy and hyperventilation have been recommended based on limited evidence.44,45
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Figure 2. Algorithm for the management of patients younger than 20 years with diabetic ketoacidosis* or hyperosmolar hyperglycemic state.† (NaCl = sodium chloride; IM = intramuscular; IV = intravenous; SC = subcutaneous.)
Adapted with permission from Kitabchi AE, Umpierrez GE, Murphy MB, Barrett EJ, Kreisberg RA, Malone JI, et al. Hyperglycemic crises in diabetes. Diabetes Care 2004;27(suppl 1):S98.
Special Situations-Young and Old Patients
The main differences in the management of children and adolescents compared with adults are the greater care in administering electrolytes, fluids, and insulin based on the weight of the patient and increased concern about high fluid rates inducing cerebral edema. A flowchart for the management of DKA in children and adolescents from the ADA guideline is shown in Figure 2.3 A growing problem is the development of type 2 diabetes in obese children. Although DKA is less common in these patients than among those with type 1 diabetes, it does occur. C-peptide levels may be helpful for determining the type of diabetes and guiding subsequent treatment. Risk factors for adolescent type 2 diabetes are hypertension and acanthosis nigricans.6
TABLE 4
Strategies to Prevent Diabetic Ketoacidosis
Diabetic education
Blood glucose monitoring
Sick-day management
Home monitoring of ketones or beta-hydroxybutyrate
Supplemental short-acting insulin regimens
Easily digestible liquid diets when sick
Reducing, rather than eliminating, insulin when patients are not eating
Guidelines for when patients should seek medical attention
Case monitoring of high-risk patients
Special education for patients on pump management
Information from references 49 through 51.
Older patients are less likely to be on insulin before developing DKA, less likely to have had a previous episode of DKA, typically require more insulin to treat the DKA, have a longer length of hospital stay, and have a higher mortality rate (22 percent for those 65 years and older versus 2 percent for those younger than 65 years).46 Causes of death include infection, thromboembolism, and myocardial infarction.47 Although concomitant diseases and high rates of morbidity need to be considered when caring for older patients with DKA, no specific treatment guidelines are available.

Transition to Standard Regimen and Prevention of Recurrence
A blood glucose concentration of less than 200 mg per dL, a bicarbonate level of 18 mEq per L or greater, and a venous pH level of greater than 7.3 indicate that the DKA has resolved.3 Typical duration of therapy is about 48 hours.3 If the patient can eat when DKA has resolved, a standard subcutaneous insulin regimen by injection or insulin pump should be started.
Intravenous insulin should continue for one to two hours after initiation of subcutaneous insulin. For patients who are unable to eat, intravenous insulin may be continued to maintain the blood glucose in a target range (i.e., 80 to 140 mg per dL [4.4 to 7.8 mmol per L]).
Prevention of another episode should be part of the treatment of DKA. Most patients with DKA will need lifetime insulin therapy after discharge from the hospital. Education about diabetes is a cornerstone of prevention that also has been found to reduce length of stay.48 Strategies for prevention are listed in Table 4.49-51

Strength of Recommendations
Key clinical recommendation
Label
References
Comments
Regular insulin by continuous intravenous infusion is preferred for moderate to severe diabetic ketoacidosis.
B
3
Although intravenous insulin infusion can be changed quickly and studies have found more rapid initial improvement in glucose and bicarbonate levels, there is no improvement in morbidity and mortality over insulin administered intramuscularly or subcutaneously.

Check beta-hydroxybutyrate rather than ketones to evaluate the degree of ketosis.
B
25
Beta-hydroxybutyrate is the main metabolic product in ketoacidosis. Levels correlate better with changes in arterial pH and blood bicarbonate levels than ketones, and were found to lead to better outcomes in one study of children.
Bicarbonate therapy should not be given to adult patients with a pH level of 7.0 or greater.
B
34, 35, 37
No studies have found improved outcomes beyond slight increases in serum pH levels after bicarbonate has been administered. A few studies suggest possible harms.
Gradual correction of glucose and osmolality and careful use of isotonic or hypotonic saline will reduce the risk of cerebral edema.
C
3
Cerebral edema is less common in adults than in children, and there are no studies in adults to report.
Phosphate should not be given routinely.
B
38, 39, 40
Low phosphate levels can cause problems, but phosphate does not need to be given routinely.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, opinion, or case series. See page 1635 for more information.
The author indicates that he does not have any conflicts of interest. Sources of funding: none reported.
Members of various family medicine departments develop articles for "Practical Therapeutics.” This article is one in a series coordinated by the Department of Family and Community Medicine at the University of Illinois at Chicago, Rockford. Guest editor of the series is Eric Henley, M.D.