Diabetic Ketoacidosis (DKA)

Definition, Etiology, PathogenesisTop

Diabetic ketoacidosis (DKA) is a life-threatening hyperglycemic emergency requiring prompt recognition, diagnosis, and treatment.

DKA has been characteristically described as a feature of type 1 diabetes mellitus (with an incidence of 4.6-8.0/1000 patient-years); however, patients with type 2 diabetes may also develop DKA (with an incidence of 0.32-2.0/1000 patient-years), in addition to patients with ketosis-prone diabetes (KPD), formerly known as Flatbush diabetes.

Regarding the pathogenesis of DKA, extracellular fluid (ECF) volume depletion results from hyperglycemia-induced urinary losses of water and electrolytes, which are caused by absolute or relative insulin deficiency and by increased levels of glucagon and other counterregulatory hormones (catecholamines, cortisol, and growth hormone). These counterregulatory hormones promote hepatic gluconeogenesis. Marked insulin deficiency leads to increased activity of hormone-sensitive lipase, which promotes the breakdown of triglycerides into glycerol and free fatty acids. Free fatty acids are oxidized in the liver to ketone bodies. This process is predominantly stimulated by glucagon and leads to high anion gap metabolic acidosis. Hyperglycemia and hyperketonemia both contribute to osmotic diuresis, resulting in volume depletion and decreased glomerular filtration, thereby further exacerbating hyperglycemia.

It is important to identify and treat the underlying cause of DKA.

Precipitating factors include new-onset type 1 diabetes or KPD, omission or errors of insulin therapy, acute infection (eg, urinary tract infection or pneumonia), cardiovascular or respiratory event (eg, myocardial infarction, stroke, or pulmonary embolism [PE]), continuous subcutaneous insulin infusion (CSII) therapy malfunction, abdominal crisis (eg, pancreatitis), thyrotoxicosis, trauma, drugs (eg, atypical antipsychotic agents, cocaine, glucocorticoids, possibly interferon, sodium-glucose cotransporter 2 [SGLT-2] inhibitors), and pregnancy.

Clinical FeaturesTop

1. Symptoms: Polydipsia, polyuria, weakness, fatigue, nausea, vomiting, abdominal pain, decreased level of consciousness, symptoms of precipitating illness.

2. Signs: Hypotension, tachycardia, Kussmaul (deep, labored) breathing, features of dehydration, hyporeflexia (due to hypokalemia), “fruity” breath (due to exhaled acetone), abdominal guarding (similar to peritonitis or acute abdomen), other signs from precipitating illness.

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

DiagnosisTop

DKA should be suspected in any acutely ill patient with hyperglycemia. Although there are no definitive criteria, the diagnosis of DKA is based on an arterial blood pH ≤7.3, serum bicarbonate ≤18 mmol/L, anion gap >10 mmol/L, and ketosis.

Formula for calculating the anion gap: see Alcohols.

Blood glucose levels in DKA are typically >13.9 mmol/L (250 mg/dL). However, DKA with normal or mildly elevated blood glucose levels (euglycemic DKA) can be seen under certain conditions, such as in pregnancy, in patients with impaired gluconeogenesis (eg, alcohol abuse or liver failure), or in patients treated with SGLT-2 inhibitors. Therefore, the degree of hyperglycemia does not necessarily determine the severity of DKA.

The predominant ketone body in untreated DKA (particularly in severe DKA) is beta-hydroxybutyrate. However, most laboratory tests (using the nitroprusside reaction) can only detect acetoacetate and acetone. Therefore, negative serum ketones, urine ketones, or both do not necessarily exclude DKA. If available, direct measurement of serum beta-hydroxybutyrate levels is preferable. The diagnosis of DKA and assessment of its severity are based on laboratory test results as well as on clinical criteria (Table 1).

Initial evaluation:

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

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

3) Arterial blood gases, usually including bicarbonate and lactate levels (may be elevated in DKA).

4) Serum electrolytes, blood urea nitrogen (BUN), and creatinine.

5) Serum and urine ketones (or serum beta-hydroxybutyrate, if available).

Differential Diagnosis

The differential diagnosis of DKA includes fasting (starvation) ketosis (hyperglycemia is absent), acute alcoholic ketoacidosis (blood glucose levels are rarely >13.9 mmol/L [250 mg/dL] or can even be normal), pregnancy-induced ketosis, and euglycemic DKA in the setting of SGLT-2 inhibitor use. As the level of lactic acid may be elevated in DKA, other causes of metabolic acidosis should be kept in mind (see Metabolic Acidosis).

TreatmentTop

Priorities of DKA management:

1) Fluid resuscitation.

2) Resolution of acidosis.

3) Correction of electrolyte imbalances (especially hypokalemia).

4) Correction of hyperglycemia.

5) Identification and treatment of precipitating factors.

The order of priorities should be tailored to the clinical situation.

The recommended monitoring parameters include blood pressure (BP), heart rate (HR), respiratory rate (RR), and level of consciousness (to be monitored every 1-2 h); fluid balance (every 1-2 h); body temperature (every 8 h); blood glucose (every hour); electrolytes (every 4 h); blood gases (every 4 h); as well as serum ketones, urine ketones, or both, at baseline. Potassium should be monitored more frequently (every 2 h) if abnormal.

In other words, adjust sodium level up by 2 mmol/L for each 5.6 mmol/L (or 100 mg/dL) of excess glucose (or by ~3.5 mmol/L per 10 mmol/L of excess glucose).

The treatment schedules for fluids and insulin presented below are suggestions only, with careful follow-up required to guide dosages.

1. Fluid resuscitation: This is the first critical step in the management of DKA. The total water deficit is ~100 mL/kg of body weight and it should be corrected within 24 to 48 hours. Restoring ECF volume improves tissue perfusion and lowers blood glucose levels (via dilution) as well as increased urinary glucose losses.

Consider the following fluid regimen (to be used with caution in patients with cardiovascular disease [CVD] or renal disease and in the elderly):

1) Administer 1000 to 2000 mL/h of 0.9% NaCl IV until hypotension/shock is corrected.

2) Administer 500 mL/h of 0.9% NaCl over the following 4 hours.

3) Then administer 250 mL/h of 0.9% NaCl (if corrected [Na+] is low) or 0.45% NaCl (if corrected [Na+] is normal or high) over the following 4 hours, followed by 150 mL/h until acid-base homeostasis is restored.

4) When blood glucose decreases to ≤14 mmol/L (252 mg/dL), add an IV infusion of 5% glucose (dextrose) starting at 100 mL/h, with the goal of maintaining serum glucose between 12 and 14 mmol/L (216-252 mg/dL) until ketoacidosis resolves.

5) In order to reduce the risk of cerebral edema due to rapid reduction in plasma osmolality, it is recommended to lower blood glucose level no faster than by 2.8 to 3.9 mmol/L/h.

2. Resolution of acidosis: Insulin is crucial to stop ketoacid production, in addition to reducing hepatic gluconeogenesis and suppressing lipolysis. There is no conclusive evidence suggesting superior outcomes with an initial bolus of IV insulin, although most treatment algorithms recommend a bolus infusion of 0.1 IU/kg/h. Although there are small randomized controlled trials demonstrating the safety and efficacy of subcutaneous insulin in mild to moderate DKA, IV infusion of regular human insulin is preferable for critically ill patients.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to limited sample size and patient selection. Umpierrez GE, Cuervo R, Karabell A, Latif K, Freire AX, Kitabchi AE. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diabetes Care. 2004 Aug;27(8):1873-8. doi: 10.2337/diacare.27.8.1873. PMID: 15277410. Umpierrez GE, Latif K, Stoever J, et al. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. Am J Med. 2004 Sep 1;117(5):291-6. doi: 10.1016/j.amjmed.2004.05.010. PMID: 15336577.  Karoli R, Fatima J, Salman T, Sandhu S, Shankar R. Managing diabetic ketoacidosis in non-intensive care unit setting: Role of insulin analogs. Indian J Pharmacol. 2011 Jul;43(4):398-401. doi: 10.4103/0253-7613.83109. PMID: 21844993; PMCID: PMC3153701. It is important to ensure that hypokalemia is corrected before starting insulin; otherwise insulin will exacerbate hypokalemia. The standard insulin infusion rate is 0.1 IU/kg/h. The rate should be adjusted based on anion gap normalization (ie, resolution of ketosis). Once the glucose level decreases to <14 mmol/L (252 mg/dL), the insulin infusion rate should be reduced gradually to 0.05 IU/kg/h and dextrose should be added to the IV fluids in order to avoid hypoglycemia, while still monitoring the patient for ketosis, in which case the IV insulin may have to be increased again and correction of the precipitant may be needed.

As mentioned above, subcutaneous insulin may be considered in the treatment of mild to moderate DKA. This involves an initial injection of rapid-acting insulin, followed by subcutaneous injections every hour (0.1 IU/kg) or every 2 hours (0.2 IU/kg). The advantage of using subcutaneous insulin outside of an intensive care unit (ICU) is that it may be more cost effective compared with treatment with IV insulin in an ICU setting.

With severe acidosis (pH <7.0), 50 mmol/h of sodium bicarbonate is considered by some until the pH is ≥7.0.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. PMID: 3096181. The issue remains controversial. Otherwise, bicarbonate is not recommended. In addition, potential complications of administering bicarbonate include hypokalemia as well as cerebral edema.

3. Correction of electrolyte imbalances:

1) Potassium: The potassium deficit in DKA is ~3 to 5 mmol/kg. Our pattern of practice is generally to start potassium supplementation (oral or IV) once the serum potassium level is <5.0 mmol/L and urine output is established. This tends to occur with the second liter of IV fluids. If [K+] is >5.0 mmol/L, avoid KCl administration and check [K+] every 2 hours. If [K+] is between 3.3 and 5.0 mmol/L, add 20 to 40 mmol KCl/L of IV fluid, targeting a serum [K+] of 4 to 5 mmol/L. If [K+] is <3.3 mmol/L, hold or delay the insulin infusion (since this shifts K+ intracellularly and worsens hypokalemia) and give KCl at a rate of 10 to 20 mmol/h until serum [K+] is ≥3.3 mmol/L.

Note that IV potassium administration of >15 mmol/h should be performed preferably through a central venous line or through 2 peripheral veins.

2) Phosphate: There is no clear evidence supporting standard phosphate supplementation in DKA. However, given that severe hypophosphatemia (<0.5 mmol/L) may be associated with rhabdomyolysis, phosphate measurement and as-needed administration of potassium phosphate should be considered in such cases. Otherwise, mild hypophosphatemia tends to resolve once the patient resumes eating.

4. Correction of hyperglycemia: Hyperglycemia should be corrected through fluid resuscitation, IV insulin, and resolution or correction of the precipitant, as outlined above.

5. Identification and treatment of precipitating factors: In addition to a thorough history and physical examination, a complete blood count (CBC), urinalysis, and electrocardiography with or without cardiac enzymes are recommended.

Additional tests (eg, chest and/or abdominal radiographs; beta human chorionic gonadotropin [beta-hCG]; lipase; computed tomography [CT] of the head; and cultures of urine, sputum, blood, or all of these) may be considered, depending on the clinical picture.

As already mentioned, SGLT-2 inhibitors may increase the risk of DKA. This is related to increased ketogenesis as a result of the increased glucagon to insulin ratio. Patients taking SGLT-2 inhibitors have a 2.6 to 5.3 times increased risk of DKA. There are a number of potential precipitants, including infection, persistent vomiting, insulin reduction or omission, prolonged fasting or markedly decreased caloric intake, dehydration, insulin pump failure, acute pancreatitis, bariatric surgery, excessive alcohol consumption, ketogenic diet, chronic liver disease, and pregnancy. Although euglycemic DKA may occur in any patient taking an SGLT-2 inhibitor, it often develops within the first 2 months of treatment. The most common symptoms include nausea, abdominal pain, and vomiting. Blood glucose levels are typically <13.9 mmol/L (250 mg/dL), and therefore infusion of 5% or 10% glucose often needs to be administered along with insulin in order to prevent hypoglycemia. The SGLT-2 inhibitor should be withheld until DKA has resolved and the precipitating factor has been addressed. If no precipitant is identified, the SGLT-2 inhibitor should not be restarted.

Transitioning to subcutaneous insulin may occur when DKA is resolved (ie, plasma glucose <13.8 mmol/L [248 mg/dL] on <2 IU/h of IV regular insulin, normalization of the anion gap) and the patient is alert and able to eat. It is important to continue IV insulin for 1 to 2 hours after restarting subcutaneous short-acting insulin in order to prevent recurrence of ketoacidosis as well as rebound hyperglycemia.

PREVENTIONTop

Patients should be educated on how to adjust their insulin during periods of illness. It should be stressed that insulin should never be discontinued. Adequate hydration should be encouraged when patients are hyperglycemic.

With respect to SGLT-2 inhibitor use, Health Canada, the Food and Drug Administration (FDA), and the European Medicines Agency have all issued statements warning that SGLT-2 inhibitors may increase the risk of DKA. The risk is higher in patients with type 1 diabetes or latent autoimmune diabetes in adults (4-5/100 patient-years) compared with type 2 diabetes (0.1-0.8/1000 patient-years). A precipitating factor can be identified in the majority of cases (eg, inappropriate insulin dose reduction or omission, low-carbohydrate diet, alcohol abuse, infection, or surgery).

ComplicationsTop

In the course of treatment of DKA, a number of adverse events may occur. These include hyperkalemia, hypokalemia, volume overload, heart failure, cerebral edema, hyperglycemia (due to premature discontinuation of insulin infusion), hypoglycemia (most common complication), hypocalcemia (if phosphate is used), stroke, acute kidney injury, and thromboembolic complications (eg, deep vein thrombosis or pulmonary embolus).

Mortality from DKA is ~0.65% to 3.3% and is increased in patients with recurrent DKA. In 50% of instances, mortality occurs within the first 48 to 72 hours and is generally due to the underlying cause, electrolyte disturbances (particularly related to potassium), or cerebral edema.

TablesTop