Diabetic ketoacidosis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Medical Therapy

The United States (US) and United Kingdom (UK) follow slightly different guidelines for the management of diabetic ketoacidosis but the basic principles are same.

Basic principles

The basic principles of diabetic ketoacidosis treatment (DKA) are:

• Rapid restoration of adequate circulation and perfusion with intravenous fluids.
• Gradual rehydration and restoration of depleted electrolytes (especially sodium and potassium), even if serum levels appear adequate.
• Insulin to reverse ketosis and lower glucose levels.
• Careful monitoring to detect and treat complications.

US guidelines

The American Diabetes Association (ADA) recommends the following therapy for diabetic ketoacidosis (DKA):

Fluid therapy

• Initial fluid therapy is aimed towards expansion of the intravascular, interstitial, and intracellular volume, all of which are reduced in hyperglycemic crises.
• Fluid restoration also leads to increased renal perfusion and improves renal function.
• The following options may be used for fluid restoration:
  • Isotonic saline (0.9% NaCl) is infused at a rate of 15–20 ml/kg/h or 1–1.5 L during the first hour. It may also be infused at a rate of 250-500 ml/h if serum sodium is low.
  • Subsequent choice for fluid replacement depends on hemodynamics, the volume status of the body (signs and symptoms of dehydration), serum electrolyte levels, and urinary output.
  • Half normal saline (0.45% NaCl ) infused at 250–500 ml/h is beneficial if the corrected serum sodium is normal or increased.
• Successful progress with fluid replacement is judged by, blood pressure monitoring, measurement of fluid input/output, laboratory values, and clinical examination.
• Fluid replacement usually leads to successful treatment of volume deficit within the first 24 hours.
• In patients with renal or cardiac compromise, monitoring of serum osmolality and frequent assessment of cardiac, renal, and mental status must be performed during fluid resuscitation to avoid iatrogenic fluid overload.
• Aggressive rehydration with subsequent resolution of the hyperosmolar state has been shown to be linked to a better response to low dose insulin. 
• Once the plasma glucose is ∼ 200 mg/dl, 5% dextrose should be added to replacement fluids to allow continued insulin administration. 

Insulin therapy

• Insulin therapy helps control hyperglycemia, hyperkalemia and ketosis.
• The following routes and rates of insulin administration may be used:
  • Route: Intravenous route is preferred because of rapid onset of action, although subcutaneous route can also be used.
  • Rate of administration: An initial intravenous dose of regular insulin (0.1 units/kg) followed by the infusion of 0.1 units/kg/h insulin.
  • The initial bolus of insulin may be skipped, if patients receive an hourly insulin infusion of 0.14 units/kg body weight (equivalent to 10 units/h in a 70 kg patient).
  • Low-dose insulin infusion protocols decrease plasma glucose concentration at a rate of 50–75 mg/dl/h.
  • Titration:If plasma glucose does not decrease by 50–75 mg from the initial value in the first hour, the insulin infusion should be increased every hour until a steady glucose decline is achieved.
  • When the blood glucose level reaches 200 mg/dl, the rate of insulin infusion should be changed to 0.02 units/kg/h - 0.05 units/kg/h and dextrose may be added to the IV fluids.

Potassium replacement

• Potassium replacement is started when the levels fall below the upper limit of normal (5.0-5.2 mEq/L).
• Goal is to maintain serum potassium levels within the normal range of 4–5 mEq/L.

Bicarbonate

• Bicarbonate is administered if arterial pH is < 6.9 to prevent acidotic complications.
• 100 mmol sodium bicarbonate (two ampules) in 400 ml sterile water (an isotonic solution) with 20 mEq KCI administered at a rate of 200 ml/h for 2 h until the venous pH is >7.0.

Phosphate

• Phosphate therapy may be given to avoid potential cardiac and skeletal muscle weakness and respiratory depression due to hypophosphatemia.
• Phosphate replacement may sometimes be indicated in patients with cardiac dysfunction, anemia, or respiratory depression and when serum phosphate concentration is <1.0 mg/dl.
• Aggressive phosphate replacement may lead to hypocalcemia.

Criteria for resolution

• According to American Diabetes Association, the following criteria must be met for labeling resolution of DKA:
  • Blood glucose <200mg/dl

PLUS

• Any two of the following:
  • Bicarbonate greater than equal to 15 mEq/L
  • Venous pH > 7.3
  • Anion gap less than equal to 12 mEq/L
• Bicarbonate level should not be relied upon to assess the resolution of DKA. This is because high volumes of 0.9 % saline (NaCl) may lead to hyperchloremia in patients. The hyperchloremic acidosis will lower the bicarbonate and thus lead to difficulty is assessing whether the ketosis has resolved. The hyperchloremic acidosis may cause renal vasoconstriction and be a cause of oliguria.
• DKA usually resolves in 24 hours with appropriate treatment.

Differences in management between US and UK

• American Diabetes Association guidelines in the US recommend treating DKA based on the severity.
• Joint British Diabetes Societies in the UK recommend treating DKA based on rate of fall of glucose and serum ketones, with a corresponding rise in bicarbonate.

The following are differences in management of DKA between the US and UK:

Region	Treatment
	Insulin	Intravenous fluids	Bicarbonate
United states	Use regular insulin Use a bolus (priming dose) of 10 U after fluid therapy and then continue at a rate of 0.1U/kg/h	Normal saline (0.9 %) at a rate of 15-20 ml/kg/h (1-1.5 L) Switch to 5 % dextrose with half normal saline (0.45 %) when serum glucose reaches 150-200mg/dl	Use bicarbonate if pH < 6.9
United Kingdom	Mainly use regular insulin but also advocate the use of long acting basal insulin to prevent rebound hyperglycemia Do not advocate the use of bolus (priming dose)	Normal saline (0.9 %) at a rate of 1 L in each of first 2 hours	Do not advocate use of bicarbonate

Contraindicated medications

Diabetic ketoacidosis is considered an absolute contraindication to the use of the following medications:

• Glipizide
• Glyburide
• Glyburide and Metformin
• Linagliptin and Metformin hydrochloride
• Repaglinide
• Saxagliptin hydrochloride and Metformin hydrochloride