Diabetic Ketoacidosis

How to Cite This Chapter: Rodríguez-Gutiérrez R, Vélez-Viveros CA, Portillo-Sanchez P, Lavalle-Gonzalez FJ, Sieradzki J, Płaczkiewicz-Jankowska E. Diabetic Ketoacidosis. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.13.3.1 Accessed September 30, 2020.
Last Updated: June 6, 2019
Last Reviewed: June 9, 2019
Chapter Information

Definition, Etiology, PathogenesisTop

Diabetic ketoacidosis (DKA) is an acute life-threatening syndrome of metabolic disturbances involving carbohydrate, fat, and protein metabolism as well as the water-electrolyte and acid-base balances that result from an acute severe insulin deficiency or insulin resistance and an elevation in the levels of counterregulatory hormones, such as glucagon, catecholamines, cortisol, and growth hormone; in particular, glucagon is elevated due to the absence of the normal suppressive effect of insulin. A typical feature is the triad of hyperglycemia, elevated anion gap metabolic acidosis, and serum and urine ketone bodies (eg, acetoacetic acid, acetone, and beta-hydroxybutyric acid). DKA has been characteristically described as a feature of type 1 diabetes mellitus (many times in new-onset diabetes); however, patients with type 2 diabetes and any other type of diabetes may develop DKA.

Regarding DKA pathogenesis, insulin deficiency or severe resistance results in excessive glucose production through hepatic gluconeogenesis and increased lipolysis, which leads to the production of ketone bodies. This in turn causes hyperglycemia, urinary glucose loss, osmotic diuresis, dehydration, electrolyte disturbances (particularly hyperkalemia with coexisting intracellular potassium deficiency), and elevated anion gap metabolic acidosis. DKA is also considered a proinflammatory state in which tumor necrosis factor alpha, interleukin (IL) 1, IL-6, IL-8, and reactive oxygen species are generated.

Precipitating factors include interruption of insulin therapy (eg, due to a gastrointestinal disease resulting in fasting) or inappropriate insulin use (most common cause in type 1 diabetes mellitus), infections (bacterial, viral, or fungal; most common cause in type 2 diabetes), acute cardiovascular events (myocardial infarction, stroke), delayed diagnosis of type 1 diabetes, acute pancreatitis, alcohol abuse, drugs (glucocorticoids, high-dose thiazide diuretics), and any conditions causing a sudden increase in insulin requirements (eg, sepsis, surgery).

Clinical FeaturesTop

1. Symptoms: Excessive thirst (polydipsia), dry mouth, polyuria, polyphagia, weakness, fatigue and somnolence, altered mental status to coma, vertigo, headache, nausea, vomiting, abdominal and/or chest pain (the latter usually associated with DKA severity).

2. Signs: Hypotension, tachycardia, rapid and deep and then shallow breathing (Kussmaul breathing), features of dehydration (weight loss, reduced skin turgor), hyporeflexia, odor of acetone on patient’s breath, facial redness, reduced eyeball turgor, abdominal guarding (similar to peritonitis).

An important feature of DKA is that all symptoms evolve rapidly (usually within 24 hours).


Initial evaluation:

1) Airway, breathing, circulation status (volume status), and mental status.

2) Fingerstick glucose levels (later confirmed with a plasma glucose test).

3) Arterial blood gases (usually including bicarbonate and lactate levels).

4) Electrocardiogram.

5) Complete blood count with differential count, serum electrolytes (sodium, potassium, and chlorine), blood urine nitrogen, and creatinine.

6) Serum and urine ketones.

7) Urinalysis.

8) Effective plasma osmolality calculated as:

Effective Posm = (2 × Na [mEq/L]) + (glucose [mmol/L or {mg/dL ÷ 18}])

Additional tests, such as chest and/or abdominal radiographs; amylase/lipase; computed tomography of the head; and cultures of urine, sputum, and blood may be evaluated, depending on the particular case.

The diagnosis of DKA and assessment of its severity are based on laboratory test results (Table 5.2-6).

Differential Diagnosis

Starvation ketosis (hyperglycemia is absent), alcoholic ketoacidosis (blood glucose levels are rarely >13.9 mmol/L [250 mg/dL], bicarbonate levels ≥18 mmol/L), lactic acidosis (blood glucose levels are not severely increased, symptoms of shock are the dominant features; elevated serum lactate levels [some moderate lactate elevation may be observed in DKA]), coma (uremic, hepatic, and cerebral coma; these may sometimes be accompanied by elevated blood glucose levels), nonrespiratory acidosis with a high anion gap >20 mEq/L (poisonings with ethylene glycol, methyl alcohol, paraldehyde, or salicylates).

With the development of new antihyperglycemic drugs, such as sodium glucose cotransporter-2 (SGLT-2) inhibitors, one of differential diagnoses to be considered is euglycemic DKA. This condition has been reported in patients with type 1 and type 2 diabetes mellitus, being more prevalent in type 1 diabetes. The risk factors for the development of euglycemic DKA include reduction or discontinuation of insulin, major surgery, alcohol consumption, and low-carbohydrate diet. Although this is a potential risk with the use of SLGT-2 inhibitors, the 2016 position statement from the American Association of Clinical Endocrinologists and American College of Endocrinology remarks that the risk-benefit ratio is in favor of continued use.


1. Fluid replacement: Large volumes of isotonic IV fluids is the mainstay therapy. The exact amount may depend on the resolution of metabolic abnormalities (particularly the anion gap) and severity of dehydration.

The fluid administered initially in most cases is 0.9% saline but balanced solutions or 0.45% saline may also be used. The choice may depend on the progression and resolution of electrolyte abnormalities, especially hyperchloremia. The aggressiveness of fluid replacement therapy will depend on the patient’s hemodynamics: state of hydration, serum electrolyte levels, and urinary output. One of the reasonable regimens, initiated while monitoring volume status and metabolic parameters, may start in the following way (following fluid balance may be more important than absolute infusion rates, as urine output may exceed the infusion rate):

1) Administer 1000 mL of 0.9% saline IV over the first hour, or at a rate of 15 to 20 mL/kg/h.

2) Administer 500 mL/h of 0.9% saline IV (or a balanced solution) over the following 4 to 6 hours.

3) Then administer 0.9% saline (or a balanced solution) as an IV infusion at a rate of 250 mL/h until the normalization of acid-base homeostasis.

4) When the blood glucose level decreases <11.1 mmol/L (200 mg/dL), add an IV infusion of 5% glucose (dextrose) to maintain serum glucose between 8.3 and 11.1 mmol/L (150-200 mg/dL) until ketoacidosis resolves.

5) After adding the glucose infusion, reduce the rate of the 0.9% saline and 5% glucose IV infusion to 150 mL/h.

6) Once the serum sodium results are available, in patients with normal to high corrected serum sodium levels, a 0.45% saline infusion can be used until hypernatremia is controlled (the actual serum sodium level may be calculated by adding 1.6 mEq/L to the measured serum sodium level for every 5.6 mmol/L [100 mg/dL] of blood glucose over 5.6 mmol/L [100 mg/dL]); more recent studies suggest that the correction factor is closer to 2.4 mEq/L. If 0.45% saline is not available, you can connect 2 infusion sets to one IV catheter: one with 0.9% saline and another with hyponatremic solution (2/3/1/3; sterile water) for IV infusion and administer both fluids at the same rate. Another option is to take away 500 mL of the 0.9% infusion and add 500 mL of sterile water to the remaining 500 mL of the 0.9% saline infusion. In patients with low corrected serum sodium levels, use 0.9% saline.

2. Reduce hyperglycemia: Start IV insulin (use a short-acting insulin):

1) Start from an IV bolus injection of 0.1 IU/kg and immediately follow with a continuous IV infusion at a rate of ~ 0.1 IU/kg/h (usually 4-8 IU/h) and monitor blood glucose levels frequently (as often as hourly).Evidence 1 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due the risk of bias, imprecision, indirectness, and lack of further recent studies. Fisher JN, Shahshahani MN, Kitabchi AE. Diabetic ketoacidosis: low-dose insulin therapy by various routes. N Engl J Med. 1977 Aug 4;297(5):238-41. PubMed PMID: 406561.

2) Alternatively, start directly (without the bolus) with an IV continuous insulin infusion at a rate of ~0.14 IU/kg/h.

3) Adjust the insulin dose to maintain a constant rate of blood glucose reduction by 2.7 to 4.1 mmol/L/h (50-75 mg/dL/h, or 10% per hour) not exceeding 5.6 mmol/L/h (100 mg/dL/h). If the expected reduction in the blood glucose level is not achieved within 1 hour, give an insulin bolus of 0.14 IU/kg and return to the previous rate of insulin infusion. Then reassess the treatment effect hourly and adjust the insulin dose as appropriate.

4) Once the serum glucose level reaches 11.1 mmol/L (200 mg/dL), reduce the infusion rate of IV insulin to 0.02 to 0.05 IU/kg/h and maintain serum glucose between 8.3 and 11.1 mmol/L (150-200 mg/dL) until DKA resolves.

5) To switch from the IV infusion to a subcutaneous insulin regimen, you may start the latter in insulin-naive patients with a dose of 0.5 to 0.8 IU/kg/d of human insulin (two-thirds of insulin isophane [NPH] and one-third of regular insulin), maintaining the insulin infusion for 1 to 2 hours after the subcutaneous regimen begins and the patient has eaten. In patients previously treated with insulin, a prior insulin regimen can be restarted.

3. Correct potassium deficit (approximate doses of replacements may differ markedly in individual patients, especially in those with impaired renal function). The treatment goal is to maintain potassium levels within 4.0 to 5.0 mEq/L:

1) In patients with serum potassium levels between 3.3 and 5.2 mEq/L, give 20 to 30 mEq per each liter of IV fluid to keep serum potassium levels in the range of 4.0 to 5.0 mEq/L.

2) In patients with serum potassium levels <3.3 mEq/L, you may decrease the insulin infusion and administer 20 to 30 mEq/h until the serum potassium level is >3.3 mEq/L.

3) In patients with serum potassium levels >5.2 mEq/L, do not administer potassium but check the serum potassium level every 2 hours. Note that potassium deficit becomes apparent with continued insulin therapy and worsens with an increase in pH (remember about potassium administration once acidosis is controlled, particularly if sodium bicarbonate is used).

4. Control acidosis:

1) Mild and moderate acidosis is gradually controlled with fluid replacement, insulin administration, and correction of water-electrolyte abnormalities.

2) Severe metabolic acidosis (with a pH level <6.9) may lead to impaired myocardial contractility, cerebral vasodilatation and coma, and several gastrointestinal complications; therefore, administration of IV sodium bicarbonate in this situation may be considered.Evidence 2 Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due the risk of bias, imprecision, indirectness, and lack of further recent studies. Morris LR, Murphy MB, Kitabchi AE. Bicarbonate therapy in severe diabetic ketoacidosis. Ann Intern Med. 1986 Dec;105(6):836-40. PubMed PMID: 3096181. Sodium bicarbonate use is open to debate and some (including some reviewers of this chapter) suggest not to use it at all. Our pattern is to administer it only in patients with an arterial blood pH <6.9. In these patients, 100 mmol of bicarbonate is infused in 400 mL of sterile water with 20 mEq of potassium chloride at an infusion rate of 200 mL/h every 2 hours until pH is >7.0. Monitor potassium levels every 2 hours, as they can decrease dangerously with the infusion.

5. Monitor and correct hypophosphatemia, especially if severe (<0.5 mmol/L). As with potassium, correction of acidosis may lead to rapid unmasking of hypophosphatemia.

6. Look for an underlying condition and start appropriate treatment (eg, antimicrobial therapy in case of infection; usually suspected with leukocytosis with cell counts >25,000 mm3).


The following points present our suggested pattern of practice.

1) If feasible, as often as every 1 hour monitor blood pressure, pulse rate, respiratory rate, mental status, capillary blood or plasma glucose levels, and fluid balance.

2) Every 2 to 4 hours monitor the serum potassium level and arterial blood gases. Every 4 hours monitor serum sodium, chloride, and (less importantly) ketone levels (beta-hydroxybutyrate), as well as phosphate and calcium levels (these may be monitored less often if the values are within the reference range or normalizing).

3) Monitor body weight and temperature as needed.

4) When the patient has voided, urinary ketone and glucose levels may be assessed (however, if judged important, the most accurate method of monitoring DKA is the quantitative determination of blood beta-hydroxybutyrate levels).

Complications Top

In the course of treatment of DKA and coma, the following adverse events may occur:

1) Sudden hypokalemia.

2) Hypernatremia that may contribute to lung edema with respiratory failure and to brain edema (brain edema may be caused by an excessively rapid reduction of blood glucose levels).

3) Hyperglycemia due to premature discontinuation of insulin infusion.

4) Hypoglycemia (most common complication).

5) Hyperchloremic metabolic acidosis (with a normal anion gap) caused by an excessive saline intake.

6) Hypophosphatemia.

7) Renal failure.

8) Thromboembolic complications.


Table 5.2-6. Diagnostic criteria of diabetic ketoacidosis





Blood glucose level in mmol/L (mg/dL)

>13.9 (>250)

>13.9 (>250)

 >13.9 (>250)

Arterial blood pH




Serum bicarbonate level (mmol/L)




Urine and serum ketones




Anion gap (mmol/L)




Altered mental status




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