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Diabetic Ketoacidosis (DKA) - Harrison's Principles of Internal Medicine, 22e (2025)

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Overview

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Pathophysiology

• Hyperglycemia - from increased hepatic gluconeogenesis and glycogenolysis, plus impaired peripheral glucose utilization
• Ketogenesis - insulin deficiency + glucagon excess activates lipolysis; free fatty acids are oxidized in the liver to ketone bodies (beta-hydroxybutyrate and acetoacetate), causing metabolic acidosis
• Osmotic diuresis - glucosuria leads to volume depletion, dehydration, and electrolyte losses
• Electrolyte shifts - total body K⁺, Na⁺, phosphate, and Mg²⁺ are depleted, even when serum levels appear normal/elevated

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Precipitating Factors ("The 5 I's")

• Infection (most common - pneumonia, UTI)
• Insulin omission or inadequate dosing (e.g., missed doses, pump failure)
• Infarction (MI, stroke)
• Ischemia/Illness (trauma, surgery, pancreatitis)
• SGLT-2 inhibitors (euglycemic DKA - see below)
• New-onset type 1 DM

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Clinical Features (Table 416-8, Harrison's)

• Abdominal pain can mimic acute pancreatitis; serum amylase may be elevated but lipase is typically NOT elevated in DKA - helps distinguish
• Kussmaul respirations = deep, labored breathing compensating for metabolic acidosis
• Cerebral edema - most serious complication, seen mainly in children
• Look for signs of infection even in the absence of fever

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Laboratory Values (Table 416-7, Harrison's)

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Diagnosis

• Elevated serum/urine ketones (beta-hydroxybutyrate >3 mmol/L preferred)
• Serum HCO₃ <18 mEq/L, pH <7.3
• Anion gap metabolic acidosis
• Glucose >250 mg/dL (may be lower in euglycemic DKA)
• The anion gap = Na - (Cl + HCO₃); elevated in DKA due to ketoacid accumulation

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Treatment (Table 416-9, Harrison's)

1. Fluid Replacement

• 1-3 L of 0.9% normal saline over the first 1-2 hours to restore hemodynamic stability
• Then switch to 0.45% saline at 250-500 mL/h depending on hydration and sodium levels
• Switch IV fluid to 5% dextrose + 0.45% saline when plasma glucose falls to 11.1-13.9 mmol/L (200-250 mg/dL)
• Typical total deficit: 3-5 L

2. Insulin

• Regular insulin IV bolus: 0.1 units/kg, then continuous IV infusion: 0.1 units/kg/h
• If glucose does not fall by at least 50-70 mg/dL in the first hour, double the infusion rate
• Continue the insulin infusion until the anion gap normalizes and acidosis resolves (NOT just until glucose normalizes)
• When glucose reaches 200-250 mg/dL, reduce infusion to 0.05-0.1 units/kg/h
• Transition to subcutaneous insulin only after the patient is eating and the anion gap is closed; overlap IV and SC insulin by 1-2 hours to prevent rebound ketoacidosis

3. Potassium Replacement

• Despite apparent normal/high serum K⁺ at presentation, all DKA patients have total body K⁺ depletion
• If K⁺ < 3.5 mEq/L: do NOT start insulin until potassium is repleted (risk of fatal hypokalemia); replace K⁺ at 40-80 mEq/h
• If K⁺ 3.5-5.0 mEq/L: add 20-40 mEq/L to each liter of IV fluid
• If K⁺ >5.0 mEq/L: hold K⁺ replacement; monitor closely every 2 hours
• Goal: maintain serum K⁺ between 4.0-5.0 mEq/L

4. Bicarbonate

• Not routinely recommended even in severe acidosis
• Consider only if pH <7.0, with careful monitoring
• Risk: paradoxical CNS acidosis, hypokalemia, delay in ketonemia resolution

5. Phosphate

• Routine phosphate replacement is not recommended
• Consider if serum phosphate <1.0 mg/dL or if patient has cardiac dysfunction/respiratory compromise

6. Treat the Precipitant

• Cultures, antibiotics for suspected infection
• ECG, cardiac enzymes for MI
• Review medications (especially SGLT-2 inhibitors)

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Monitoring During Treatment

• Blood glucose every 1 hour
• Electrolytes, BUN, creatinine, venous pH every 2-4 hours
• Urine output
• Mental status
• Target: anion gap closure, bicarbonate >18, pH >7.3

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Euglycemic DKA (SGLT-2 Inhibitor-Associated)

• Associated with SGLT-2 inhibitor use (empagliflozin, dapagliflozin, canagliflozin)
• Lab values mirror DKA (elevated ketones, anion gap, low HCO₃) but glucose is near-normal
• Mechanism: SGLT-2 inhibitors increase glucagon, reduce insulin secretion, and enhance renal ketone excretion, promoting ketogenesis even without marked hyperglycemia
• Risk is higher in type 1 DM and insulin-deficient type 2 DM
• Often missed because glucose is not markedly elevated
• Management: Same as DKA - fluids, insulin, electrolyte replacement; withhold the SGLT-2 inhibitor

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Complications to Watch For

• Hypokalemia - most dangerous, precipitated by insulin therapy; can cause fatal arrhythmias
• Cerebral edema - especially in children; associated with aggressive fluid replacement and rapid osmolality changes; treat with IV mannitol
• Hypoglycemia - if glucose monitored inadequately during insulin infusion
• Persistent acidosis - suggests ongoing infection, inadequate insulin, or concurrent condition
• Acute kidney injury - from volume depletion

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DKA vs HHS - Key Differences

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Diabetic Ketoacidosis (DKA)

Compared Across: Tintinalli's Emergency Medicine | Goldman-Cecil Medicine | Rosen's Emergency Medicine

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Epidemiology

• Annual incidence: 13.4-14.9 cases per 1,000 type 1 diabetics (UK, US, and other developed countries) - Tintinalli's
• DKA hospitalizations in the US have increased by 30% over the past decade, with ~140,000 hospitalizations/year - Tintinalli's
• Mortality: <1% in experienced centers with modern management - Tintinalli's; higher in developing countries, elderly, and those with comorbidities
• Increasingly seen in type 2 DM - especially in African Americans and Hispanics with ketosis-prone type 2 DM ("ketosis-prone diabetes") - Tintinalli's
• DKA may be the initial presentation of type 1 DM, especially in the developing world and in infants/young children - Goldman-Cecil

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Pathophysiology

The Three Pillars of DKA Pathophysiology

• Insulin deficiency → unchecked gluconeogenesis + glycogenolysis in liver
• Peripheral tissues (muscle, fat) cannot utilize glucose without insulin
• Progressive hyperglycemia exceeds renal threshold → osmotic diuresis

• Insulin deficiency activates hormone-sensitive lipase → liberation of free fatty acids (FFAs) from adipose tissue - Rosen's
• Long-chain FFAs transported to liver → converted to acetoacetate and beta-hydroxybutyrate → accumulated in blood → elevated anion gap metabolic acidosis
• Low insulin = decreased ability of brain and muscle to use ketones → worsening ketonemia - Rosen's
• Goldman-Cecil describes the "DKA triad": the D = hyperglycemia; the K = ketones ≥2+ or beta-hydroxybutyrate ≥3 mmol/L; the A = pH <7.3

• Osmotic diuresis pulls water, Na⁺, K⁺, Mg²⁺, Ca²⁺, phosphate into urine - Rosen's
• Exocrine pancreatic dysfunction parallels endocrine dysfunction → malabsorption + vomiting → further electrolyte loss - Rosen's
• Renin-angiotensin-aldosterone activation from volume depletion → further renal K⁺ losses - Tintinalli's
• Prostaglandins I₂ and E₂ from adipose breakdown → paradoxical peripheral vasodilation despite hypovolemia - Tintinalli's
• Chloride retained in exchange for ketoanion excretion → superimposed hyperchloremic acidosis - Tintinalli's

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Precipitating Factors (Goldman-Cecil Table 210-11)

• Infections (pneumonia, UTI most frequent)
• Inadequate insulin / non-adherence
• New-onset diabetes
• Acute coronary syndrome

• Cerebrovascular accident, pulmonary embolism, acute pancreatitis, mesenteric thrombosis
• Alcohol intoxication
• Endocrinopathies: Cushing syndrome, thyrotoxicosis, acromegaly
• Drugs: corticosteroids, clozapine, olanzapine, cocaine, lithium, sympathomimetics, thiazides, SGLT-2 inhibitors
• Severe burns, hyperthermia/hypothermia
• Behavioral: insulin omission for weight loss, eating disorders, depression, drug abuse - Tintinalli's / Goldman-Cecil

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Clinical Features

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Average Fluid & Electrolyte Deficits in Severe DKA (Rosen's Table 115.3)

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Diagnosis

Diagnostic Criteria (Goldman-Cecil's "DKA Triad")

1. Glucose: often 250-600 mg/dL (but can be near-normal in euglycemic DKA)
2. Urine ketones ≥2+ OR beta-hydroxybutyrate ≥3.0 mmol/L
3. pH <7.3 and/or bicarbonate <18 mEq/L with elevated anion gap

Key Lab Findings

Sodium Correction Formula

Corrected Na = Measured Na + 2.4 × [(Glucose - 100) / 100] - Tintinalli's (note: the classic 1.6 factor likely underestimates at glucose >400 mg/dL)

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Treatment

1. Fluids

• Switch to 0.45% NS after hemodynamic stabilization
• Switch to D5W + 0.45% NS when glucose reaches:
  • ≤300 mg/dL (Rosen's)
  • 200-250 mg/dL (Goldman-Cecil, Harrison's)
• Do NOT correct too rapidly in HHS (risk of neurological deterioration) - Goldman-Cecil

2. Insulin

• Do NOT start insulin until K⁺ ≥3.3-3.5 mEq/L (risk of fatal arrhythmia from worsening hypokalemia)
• Continue insulin infusion until anion gap closes - not just until glucose normalizes
• Transition to SC insulin only when patient is eating; overlap by 1-2 h to prevent rebound ketoacidosis

3. Potassium

• Goldman-Cecil: Use 0.9% NS with K⁺ 40 mEq/L (ready-mixed) if K⁺ <5.5 and urine output present
• Monitor every 2 hours during treatment

4. Phosphate

• Not routinely replaced - all three sources agree
• Consider if <1.0 mg/dL or cardiac/respiratory compromise present

5. Bicarbonate

• Not recommended even in severe acidosis - all sources
• Risks: paradoxical CNS acidosis, hypokalemia, delayed ketonemia resolution
• Some consider it only at pH <7.0

6. Magnesium

• Rosen's: correct with 1-2 g MgSO₄ - note serum levels may not reflect true body stores

7. Airway Considerations (Rosen's - unique emphasis)

• Avoid intubation if possible - patients have tremendous respiratory drive and matching ventilator to minute ventilation is challenging
• If intubation required (comatose, vomiting), maintain hyperventilation to prevent worsening acidosis
• In hypovolemic shock: aggressive fluid resuscitation before vasopressors

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Monitoring

• Anion gap closure
• pH >7.3
• Serum HCO₃ >18 mEq/L
• Patient tolerating oral intake

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Disposition (Rosen's)

• Initial pH ≥7.35
• HCO₃ ≥20 mEq/L
• Can tolerate oral fluids
• Symptoms resolved after ED treatment
• No underlying precipitant requiring admission

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Complications

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Key Textbook-Specific Insights

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