Diabetic Ketoacidosis

Essentials of Diagnosis

• Hyperglycemia > 250 mg/dL (13.9 mmol/L)

• Acidosis with blood pH < 7.3

• Serum bicarbonate < 15 mEq/L

• Serum positive for ketones

General Considerations

• May be the initial manifestation of type 1 diabetes

• Commonly occurs with poor compliance in type 1 diabetics, particularly when episodes are recurrent

• Develops in type 1 diabetics with increased insulin requirements during infection, trauma, myocardial infarction, or surgery

• May develop in type 2 diabetics under severe stress such as sepsis or trauma

• Common serious complication of insulin pump therapy

Demographics

• Incidence is 5 to 8 episodes per 1000 diabetic persons annually

• Incidence in insulin pump therapy is 1 per 80 patient-months of treatment

Symptoms and Signs

• May begin with a day or more of polyuria, polydipsia, marked fatigue, nausea and vomiting and, finally, mental stupor that can progress to coma

• Drowsiness is fairly common but frank coma only occurs in about 10% of patients

• Dehydration, possible stupor

• Rapid deep breathing and a "fruity" breath odor of acetone

• Hypotension with tachycardia indicates profound fluid and electrolyte depletion

• Mild hypothermia usually present; elevated or even a normal temperature may suggest infection

• Abdominal pain and tenderness in the absence of abdominal disease; conversely, cholecystitis or pancreatitis may occur with minimal symptoms and signs

Differential Diagnosis

• Lactic acidosis in type 1 diabetics, including the use of metformin

• Alcoholic ketoacidosis

• Hypoglycemia

• Hyperglycemic hyperosmolar state

• Uremia

• Starvation ketoacidosis

• Salicylate poisoning

Laboratory Tests

• Plasma glucose of 350–900 mg/dL (19.4–50 mmol/L)

• Serum ketones at a dilution of 1:8 or greater or beta-hydroxybutyrate more than 4 nmol/L

• Hyperkalemia (serum potassium level of 5–8 mEq/L)

• Slight hyponatremia (serum sodium of approximately 130 mEq/L)

• Hyperphosphatemia (serum phosphate level of 6–7 mg/dL [1.9–2.3 mmol/L])

• Elevated blood urea nitrogen and serum creatinine levels

• Acidosis may be severe (pH ranging from 6.9 to 7.2, and serum bicarbonate ranging from 5 mEq/L to 15 mEq/L)

• PCO₂ is low (15–20 mm Hg) related to hyperventilation

• Fluid depletion is marked, typically about 100 mL/kg

• Acetoacetic acid is measured by nitroprusside reagents [Acetest and Ketostix]; the more prevalent beta-hydroxybutyric acid has no ketone group and is therefore not detected by conventional nitroprusside tests

• Nonspecific elevations of serum amylase and lipase occurs in about 16–25 % of cases of diabetic ketoacidosis; an imaging study may be necessary if the diagnosis of acute pancreatitis is being seriously considered

• Serum lipase may be useful if the diagnosis of pancreatitis is being seriously considered

• Leukocytosis up to 25,000/mcL with a left shift may occur with or without associated infection

• Hyperchloremic metabolic acidosis can develop during initial therapy, as keto acids are lost in the urine and a portion of the bicarbonate deficit is replaced with chloride ions from the saline therapy. This relatively benign condition reverses over a day once intravenous saline is stopped

• Euglycemic ketoacidosis

  • Occurs in patients in whom diabetic ketoacidosis develops while receiving treatment with SGLT2 inhibitors

  • Patient can have severe acidosis and fluid depletion, but the plasma glucose levels are only modestly elevated, usually < 250 mg/day (13.9 mmol/L)

  • Ketoacidosis with lower glucose levels also occurs in pregnancy and may reflect the expanded plasma volume and the increased glomerular filtration rate

Medications

Regular insulin

• Initially in severe ketoacidosis, use only regular insulin

• Begin with loading dose of 0.1 unit/kg as intravenous bolus, followed by 0.1 unit/kg/h, continuously infused or given hourly as an intramuscular injection

• "Piggy-back" insulin into the fluid line so the rate of fluid replacement can be changed without altering the insulin delivery rate

• If plasma glucose level fails to fall at least 10% in the first hour, give repeat loading dose (0.1 or 0.14 unit/kg)

• Patients who are normally take insulin glargine or insulin detemir can be given usual maintenance doses during initial treatment of diabetic ketoacidosis

• The continuation of the subcutaneous basal insulins means that lower doses of intravenous insulin will be needed and there will be a smoother transition from intravenous insulin infusion to the subcutaneous regimen

Fluids

• Fluid deficit is usually 4–5 L

• In the first hour, give at least 1 L of 0.9% saline to reexpand contracted vascular volume

• After the first 2 L of fluid have been given, the intravenous infusion rate should be 300–400 mL/h

• Use 0.9 % ("normal") saline unless the serum sodium is > 150 mEq/L, when 0.45% ("half normal") saline solution should be used

• When blood glucose falls to ~250 mg/dL (13.9 mmol/L), use 5% glucose solutions to maintain blood glucose in 200–300 mg/dL (13.9–16.7 mmol/L) range

• Failure to give enough volume replacement (at least 3–4 L in 8 h) to restore normal perfusion affects satisfactory recovery

• Excessive fluid replacement (more than 5 L in 8 h) may contribute to acute respiratory distress syndrome or cerebral edema

Electrolytes

• Administer NaHCO₃ if the arterial blood pH is 7.0 or less

  • One or two ampules of NaHCO₃ (one ampule contains 44 mEq/50 mL) should be added to 1 L of 0.45% saline with 20 mEq KCl or to 400 mL of sterile water with 20 mEq KCl and infused over 1–2 hours (Note: Addition of NaHCO₃ to 0.9% saline produces a markedly hypertonic solution that could aggravate the hyperosmolar state already present.)

  • It can be repeated until the arterial pH reaches 7.1

  • NaHCO₃ should not be given if the pH is 7.1 or greater to avoid increased risk of rebound metabolic alkalosis

• Total body potassium loss from polyuria and vomiting may be as high as 200 mEq

  • However, initial serum potassium is usually normal or high because of extracellular shifts from acidosis

  • Potassium infusion 10–30 mEq/h should begin 2–3 h after beginning therapy, or sooner if initial serum potassium is low

  • Defer potassium replacement if serum potassium remains above 5 mEq/L, as in chronic kidney disease

• Phosphate replacement is seldom required. However, if severe hypophosphatemia of < 0.32 mmol/L (< 1 mg/dL) develops during insulin therapy, a small amount of phosphate can be replaced as the potassium salt

  • To minimize the risk of tetany from an overload of phosphate replacement, an average deficit of 40–50 mmol phosphate should be replaced by intravenous infusion at a rate not to exceed 3–4 mmol/h in 60- to 70-kg person

  • A stock solution (Abbott Laboratories) provides a mixture of 1.12 g KH₂PO₄ and 1.18 g KH₂PO₄ in a 5-mL single-dose vial representing 22 mmol potassium and 15 mmol phosphate; 5 mL of this stock solution in 2 L of 0.45% saline or 5% dextrose in water, infused at 400 mL/h, will replace the phosphate at the optimal rate of 3 mmol/h and provide 4.4 mEq potassium per hour

  • If serum phosphate remains below 2.5 mg/dL (0.8 mmol/L), a repeat 5-h infusion can be given

Subcutaneous insulin regimen

• Can be initiated once diabetic ketoacidosis is controlled and patient is awake and able to eat

• The patient should receive subcutaneous basal insulin and rapid-acting insulin analog with the first meal and the insulin infusion discontinued 1 hour later

  • The overlap of the subcutaneous insulin action and insulin infusion is necessary to prevent relapse of the diabetic ketoacidosis

  • A patient with new-onset type 1 diabetes usually still has significant beta cell function and may not need any basal insulin and only very low doses of rapid-acting insulin before meals after recovery from the ketoacidosis

  • Patients with type 2 diabetes and diabetes ketoacidosis due to severe illness may initially require insulin therapy but can often transition back to oral agents during outpatient follow-up

Therapeutic Procedures

• Use a flow sheet listing vital signs, time sequence of laboratory values (arterial pH, plasma glucose, acetone, bicarbonate, serum urea nitrogen, electrolytes, serum osmolality) in relation to therapy

• Carefully monitor serum potassium during fluid replacement

Prognosis

• Mortality rate has dropped to < 5% due to low-dose insulin infusion, fluid and electrolyte replacement, and careful patient monitoring

• However, mortality rate is still > 20% in elderly patients and in patients in profound coma in whom treatment has been delayed

• Acute myocardial infarction and infarction of the bowel following prolonged hypotension worsen the outlook

• End-stage chronic kidney disease is serious prognostic sign

• Prior kidney dysfunction worsens the prognosis considerably because the kidney plays a key role in compensating for massive pH and electrolyte abnormalities

• Symptomatic cerebral edema occurs primarily in the pediatric population

Prevention

• The patient should contact a provider for persistent ketonuria

• Compliance is particularly important for juvenile-onset diabetics, particularly in the teen years. Intensive family counseling may be needed

• Urine ketones should be measured with signs of infection or in insulin pump-treated patients when capillary blood glucose is persistently high

When to Refer

• Recurrent diabetic ketoacidosis

• Poor compliance

When to Admit

• Severe ketosis, hyperosmolality

• An intensive care unit or step-down unit is preferable for more severe cases