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Euglycemic Diabetic Ketoacidosis (EDKA)

Overview

Euglycemic diabetic ketoacidosis (EDKA) is a serious, life‑threatening metabolic complication of diabetes in which the body produces high levels of ketone bodies and becomes acidotic, but the blood glucose level remains ≤250 mg/dL (13.9 mmol/L). Because the glucose level is “normal” or only mildly elevated, the condition can be missed or mistaken for another problem.

Who it affects

• Primarily people with type 1 diabetes, but also up to 20 % of cases occur in type 2 diabetes, especially those on sodium‑glucose co‑transporter‑2 (SGLT‑2) inhibitors.
• Pregnant women with type 1 diabetes are at higher risk due to increased insulin requirements and the physiologic insulin resistance of pregnancy.
• Patients who are fasting, have a low‑carbohydrate diet, or are following bariatric surgery protocols may also develop EDKA.

Prevalence

• Traditional DKA occurs in ~4–9 % of all diabetes‑related hospital admissions in the United States.<sup>1</sup>
• EDKA accounts for 5–10 % of those DKA admissions, with a noticeable rise after the introduction of SGLT‑2 inhibitors in 2013.<sup>2</sup>
• Among patients using SGLT‑2 inhibitors, the incidence of EDKA is estimated at 0.3–0.5 % per year, but higher in peri‑operative or pregnant settings.

Symptoms

Symptoms of EDKA mirror classic DKA but may be milder or progress more rapidly because hyperglycemia is absent. Recognizing the full spectrum is crucial.

Common early signs

• Polyuria – increased urination, often nocturnal.
• Polydipsia – excessive thirst.
• Dry mouth and sticky feeling of the lips.
• Fatigue or generalized weakness.
• Loss of appetite or nausea.

Progressive symptoms

• Abdominal pain – cramp‑like, can mimic an acute abdomen.
• Vomiting – may be persistent.
• Rapid, deep breathing (Kussmaul respirations) – the body’s attempt to blow off CO₂.
• Fruity or acetone‑like odor on the breath.
• Confusion, disorientation, or difficulty concentrating.
• Headache or feeling “light‑headed.”
• Muscle cramps or pain.

Severe / late signs

• Hypotension or shock.
• Altered mental status ranging from lethargy to coma.
• Arrhythmias related to electrolyte disturbances (especially low potassium).
• Seizures (rare, usually secondary to severe acidosis).

Causes and Risk Factors

EDKA results from a combination of absolute or relative insulin deficiency and an increase in counter‑regulatory hormones (glucagon, catecholamines, cortisol, growth hormone) that drive lipolysis and ketogenesis.

Major precipitating factors

• SGLT‑2 inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin). These drugs increase urinary glucose excretion, lower plasma glucose, and promote glucagon release, creating a setting for ketosis despite normal glucose.
• Insulin omission or dose reduction – intentional (e.g., due to fear of hypoglycemia) or unintentional (e.g., injection site problems).
• Fasting or very low‑carbohydrate diets – especially in the peri‑operative period, for religious reasons, or during illness.
• Acute illness or infection – especially respiratory, urinary, or gastrointestinal infections.
• Pregnancy – hormonal changes increase insulin resistance and stimulate ketogenesis.
• Alcohol binge – alcohol metabolism can suppress gluconeogenesis while increasing NADH, favoring ketone production.
• Bariatric surgery – rapid weight loss and reduced oral intake can precipitate ketosis.

Risk groups

• Adults with type 1 diabetes on SGLT‑2 inhibitors (off‑label use) or with poor insulin adherence.
• Patients with type 2 diabetes on SGLT‑2 inhibitors who become acutely ill or fast.
• Pregnant women with type 1 diabetes (particularly in the 2nd and 3rd trimesters).
• Individuals following strict ketogenic or Atkins‑type diets who have diabetes.
• Elderly patients with renal impairment – reduced drug clearance may heighten SGLT‑2 effect.

Diagnosis

Because blood glucose may be normal, clinicians must have a high index of suspicion when any diabetic patient presents with metabolic acidosis.

Key diagnostic criteria (adapted from ADA)

1. Blood glucose ≤250 mg/dL (13.9 mmol/L).
2. Metabolic acidosis: arterial pH <7.3 or serum bicarbonate <18 mmol/L.
3. Positive ketones: serum β‑hydroxybutyrate ≥3 mmol/L or moderate‑to‑large urine ketones.
4. Presence of an underlying precipitating factor (e.g., SGLT‑2 inhibitor use, fasting).

Laboratory tests

• Basic metabolic panel – reveals low bicarbonate, anion‑gap metabolic acidosis, and electrolyte abnormalities (often low potassium).
• Serum β‑hydroxybutyrate – the most accurate ketone measurement; >3 mmol/L supports diagnosis.
• Arterial blood gas (ABG) – confirms pH and bicarbonate levels.
• Urine ketones – dipstick (detects acetoacetate, not β‑hydroxybutyrate; may be falsely low).
• Serum glucose – must be checked to document euglycemia.
• Renal function tests – creatinine, BUN (important for medication dosing).
• Lactate – to rule out lactic acidosis; typically normal in EDKA.
• Complete blood count – to detect infection.

Imaging (if indicated)

• Chest X‑ray for pneumonia.
• Abdominal CT if severe abdominal pain to exclude surgical abdomen.

Treatment Options

Treatment follows the same core principles as classic DKA but must be tailored to the normal glucose level to avoid hypoglycemia.

Initial emergency management

1. Fluid resuscitation – 0.9 % saline 15–20 mL/kg in the first hour, then adjust based on hemodynamics and corrected serum sodium.
2. Insulin therapy – continuous intravenous regular insulin infusion (0.1 U/kg/h) after an initial bolus (0.1 U/kg) if the patient is not severely hypovolemic. Key point: because glucose is not high, dextrose must be added early (usually 5 % dextrose) to keep blood glucose 150–200 mg/dL while continuing insulin to suppress ketogenesis.
3. Electrolyte correction – monitor potassium every 2–4 h; replace potassium if serum <3.3 mmol/L before starting insulin, then maintain 4–5 mmol/L.
4. Acid‑base monitoring – repeat ABG after each fluid/insulin adjustment; aim for pH >7.30.
5. Identify & treat precipitating cause – stop SGLT‑2 inhibitor, treat infection with antibiotics, re‑start missed insulin, address vomiting/diarrhea.

Transition to subcutaneous insulin

• When anion gap closes (≤12 mmol/L), patient is eating, and IV insulin has been running for ≥24 h, transition to basal‑bolus or pump therapy.
• Continue dextrose-containing fluids until sub‑Q insulin coverage is adequate.

Medications & adjuncts

• Sodium bicarbonate – only for pH <6.9 or severe hemodynamic compromise (controversial; use per ICU protocol).
• Thiamine – consider in chronic alcohol users.
• Antiemetics – ondansetron or metoclopramide for persistent vomiting.

Long‑term management adjustments

• Review insulin regimen; consider basal insulin intensification.
• Discontinue or temporarily hold SGLT‑2 inhibitors during periods of reduced oral intake, illness, or surgery (per FDA guidance).
• Educate on sick‑day rules: frequent glucose and ketone checks, never skip insulin, stay hydrated.

Living with Euglycemic Diabetic Ketoacidosis

Even after recovery, patients need ongoing strategies to minimize recurrence.

Daily self‑care checklist

1. Check blood glucose at least 4 times daily (fasting, pre‑meal, bedtime).
2. Screen for ketones whenever glucose >200 mg/dL, after vomiting/diarrhea, or if feeling unwell.
3. Carry a portable ketone meter (blood β‑hydroxybutyrate) – more reliable than urine strips.
4. Take insulin exactly as prescribed; never reduce dose based on “normal” glucose without consulting your provider.
5. If using an SGLT‑2 inhibitor, set a reminder to stop the drug 24–48 hours before any fasting, surgery, or significant illness.
6. Maintain adequate hydration – aim for at least 2–3 L of fluid per day unless contraindicated.
7. Keep a medical alert bracelet indicating “type 1 diabetes – high risk for euglycemic DKA.”

Nutrition tips

• Follow a balanced diet with 45–55 % carbohydrates, 15–20 % protein, and 25–35 % healthy fats unless a medically supervised low‑carb diet is prescribed.
• Spread carbohydrate intake throughout the day to avoid prolonged fasting.
• If you follow a low‑carb or ketogenic diet, discuss with your endocrinologist; you may need higher basal insulin doses.

Physical activity

• Exercise is beneficial, but check glucose and ketones before, during, and after prolonged activity.
• If glucose falls <100 mg/dL, consume fast‑acting carbs and consider a small insulin correction.

Prevention

Prevention hinges on patient education, medication management, and early detection.

Key preventive measures

1. Sick‑day protocol – double insulin dose, stay hydrated, monitor ketones every 4–6 hours.
2. Medication review – ask your clinician about the safety of SGLT‑2 inhibitors during pregnancy, peri‑operative periods, or when fasting.
3. Regular follow‑up – at least quarterly endocrinology visits; more often after any change in therapy.
4. Education on early symptoms – recognize abdominal pain or rapid breathing even if glucose is normal.
5. Continuous glucose monitoring (CGM) – real‑time trends can alert patients to falling glucose that may precede ketosis.

Complications

If untreated, EDKA can lead to the same severe outcomes as classic DKA, plus some unique concerns.

• Severe metabolic acidosis – can depress myocardial contractility and cause hypotension.
• Electrolyte disturbances – especially hypokalemia, which predisposes to arrhythmias.
• Cerebral edema – rare but more common in pediatric populations and in rapid correction of hyperosmolar states.
• Renal failure – due to hypovolemia and acute tubular necrosis.
• Respiratory failure – from profound Kussmaul breathing and fatigue.
• Increased mortality – studies show a 5–10 % in‑hospital mortality for DKA; data suggest similar or slightly higher rates for EDKA when diagnosis is delayed.

When to Seek Emergency Care

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Sources: Mayo Clinic, American Diabetes Association (ADA) Standards of Care 2024, CDC Diabetes Prevention Program, National Institutes of Health (NIH) – MedlinePlus, World Health Organization (WHO) Diabetes Fact Sheets, Cleveland Clinic, Diabetes Care journal (2022‑2024).

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