Signs and symptoms will vary on a case-by-case basis but will be similar in presentation with a hyperglycemic DKA presentation, although perhaps without polyuria, polydipsia, or as severe mental status changes. EDKA patients can present with nausea, vomiting, shortness of breath, generalized malaise, lethargy, loss of appetite, fatigue, or abdominal pain. Patients may or may not have polydipsia or polyuria since serum glucose is normal. The onset can be more insidious compared to hyperglycemic DKA, due to the mechanism of subacute starvation required to induce ketosis and dehydration. There may or may not be an inciting infection or stressor, such as pregnancy, surgery, pancreatitis, alcohol use, or fasting.

Patients may present with deep, rapid breathing known as Kussmaul respirations, which represents respiratory compensation for severe metabolic acidosis. They may have a fruity odor to their breath due to the loss of acetone. Tachycardia, hypotension, altered mentation, increased skin turgor, and delayed capillary refill, are all signs of total body fluid losses. In severe cases, severe dehydration and metabolic derangement can lead to hypovolemic shock, lethargy, respiratory failure, coma, and death. 

An ill-feeling patient with diabetes with symptoms such as malaise, dyspnea, nausea, or vomiting should undergo screening with serum pH and blood or urine ketone testing.[3][26]

The initial laboratory evaluation of EDKA includes basic electrolytes, glucose, calcium, magnesium, creatinine, BUN, serum and urine ketones, beta-hydroxybutyric acid, arterial, or venous blood gas analysis, lactic acid, chest radiograph, and electrocardiogram. Urine screening for ketones with nitroprusside reagent does not measure beta-hydroxybutyrate but does detect acetone and acetoacetate.  Serum levels of beta-hydroxybutyrate are typically greater than 3 mmol/L in EDKA (normal values less than 0.5 mmol/L). If an infection is on the differential, consider CBC with differential white blood cell count and blood cultures. Serum osmolality, to assess for an osmolar gap, and toxic alcohols should be sent to rule out toxic alcohol ingestion when suspected in any patient with severe, unexplained anion gap metabolic acidosis. Close attention should be paid to the anion gap, to help narrow direct diagnosis, workup, and management.

As described previously, the patient will have normoglycemia (capillary blood glucose less than 250 mg/dL) in the presence of metabolic acidosis (pH less than 7.3), and a total decreased serum bicarbonate (less than 18 mEq/L). Serum and urine ketones must be elevated to make the diagnosis of EDKA. Lactic acid may be elevated, but should not account entirely for the elevation in anion gap. Leukocytosis may be present in the case of a concurrent infection; however, it is nonspecific and could also be due to hemoconcentration or stress, among other causes. Potassium levels will vary, but great attention should be paid to the level before starting therapy, as total body potassium is usually depleted. Hypomagnesemia and hypophosphatemia can be seen in the starvation state due to decreased total intake and increased losses. Mild hyponatremia may also be seen but is generally less severe than the “pseudo-hyponatremia” seen in profound hyperglycemic states.

Initial management should be directed toward fluid resuscitation, as patients usually present profoundly dehydrated. Begin with the administration of isotonic saline or lactated ringers solution. The American Diabetes Association (ADA) recommends 1 to 1.5 L/hr isotonic fluids during the first 1 to 2 hours. Continuous insulin infusion should follow fluid replacement, contingent on serum potassium levels greater than 3.3 mEq/L, starting at a rate of 0.05 to 0.1 U/kg/hr.  In contrast to DKA management, since serum glucose in EDKA is less than 250 mg/dL, dextrose 5% should be added initially to the fluids to avoid hypoglycemia and hasten clearance of ketosis.[27] Consider increasing the amount of dextrose to 10% if ketoacidosis persists on D5%.[23] Potassium should be carefully monitored as well, as total body potassium levels will likely be depleted, and IV supplementation of potassium and other electrolytes may be needed.  Blood glucose levels should be checked hourly and electrolytes every four hours at a minimum, as is the standard for the treatment of DKA. Patients taking SGLT2 inhibitors should have these medications discontinued as soon as the diagnosis is recognized and held until recovery from the acute illness.[8] Sodium bicarbonate infusions are not indicated and even use in the setting of severe acidemia of pH less than 6.9 is controversial. Patients will generally require ICU admission for close hemodynamic and laboratory monitoring as well as frequent titration of insulin infusion.[2][28] Treatment with IV fluid resuscitation should continue until the anion gap closes, and acidosis has resolved.

In patients who present with anion gap metabolic acidosis, a variety of considerations must be employed early on. Infections, including pneumonia, genitourinary infection, bacteremia, must be ruled out early. In patients presenting with abdominal pain, consider intraabdominal infection and pancreatitis. Consider toxic alcohol (methanol, ethylene glycol) or paraldehyde ingestion, salicylate overdose, lactic acidosis, starvation ketosis, and pregnancy in the appropriate clinical setting. Note that patients may have also recently administered insulin, contributing to the euglycemic presentation. The presentation is very similar to alcoholic ketoacidosis (AKA), except EDKA patients have diabetes, and AKA patients present after an alcohol binge, more commonly have hypoglycemia and can be successfully resuscitated with crystalloid and dextrose without the requirement for insulin.

Most patients with EDKA recover well with prompt recognition and treatment. Delayed diagnosis and inadequate treatment, especially involving hydration without dextrose/insulin infusion, can lead to persistent acidosis, vomiting, and prolonged hospitalization. Prognosis is worse for small children and pregnant women. Rarely, severe cases, respiratory failure, hypovolemic shock, coma, and death.  Death is rare in most EDKA cases; however, pregnant women are at greater mortality risk than the general population.

Euglycemic DKA can result in persistent vomiting, dehydration, hypoglycemia, hypovolemic shock, respiratory failure, cerebral edema, coma, seizures, infection, thrombosis, myocardial infarction, and death.[29] Maternal EDKA can increase the rate of fetal (up to 9%) and maternal mortality.[30][31]

Consider consultation with a critical care intensivist and endocrinologist for severe cases. Pregnant women suffering from EDKA benefit from involvement with obstetric and maternal-fetal medicine consultants.

Vigilant monitoring of capillary or urine ketones by patients with diabetes, especially if on SGLT2 inhibitors, or during episodes of nausea or illness, can diagnose EDKA before it becomes severe.

Patients with T1D should not take SGLT2 inhibitors because of the high risk of EDKA.

Successful diagnosis is dependent on early screening with serum or urine ketones, even when serum glucose is normal, whenever EDKA is suspected.

After volume expansion with crystalloid, the foundation of therapy is a combination of dextrose (5% to 10%) and insulin (0.05 to 0.1 u/kg/hr) infusion until acidosis resolves.

Insulin infusion should not be avoided due to normal glucose levels, but instead are essential to successful treatment.

Ketosis does not resolve with intravenous crystalloid hydration alone.

SGLT2 inhibitor treatment should be discontinued as soon as EDKA is diagnosed.

Sodium bicarbonate infusion is not indicated.

Euglycemic DKA is becoming more prevalent with the appearance of the new SGLT2 inhibitors. However, it is important to recognize the variety of etiologies of a potentially fatal condition. Early diagnosis and initiation of treatment can significantly improve morbidity and mortality. In patients presenting with a euglycemic anion gap acidosis, great care must be taken to rule out other causes, including sepsis, toxic alcohol ingestion, alcoholic ketoacidosis, among others. Early IV crystalloid and prompt initiation of insulin and dextrose infusion are the primary treatment.

Treatment requires a team of interprofessional healthcare workers, possibly including consultation with a critical care intensivist as well as an endocrinologist. Emergency and critical care nurses monitor patients, administer ordered treatments, and report changes to the physicians so treatment can be optimized. The clinicians can also consult with the pharmacy regarding appropriate interventions, as well as having them run a full medication reconciliation to check for drug interactions or agents that may contribute to EDKA. These interprofessional interventions are crucial to achieving better patient outcomes. [Level 5]