Diabetic ketoacidosis
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Diabetic Ketoacidosis (DKA)
Definition & Diagnostic Triad
DKA is defined by three core biochemical features (the "D-K-A"):
| Feature | Threshold |
|---|---|
| Hyperglycemia (D) | Blood glucose > 250 mg/dL (or known diabetes) |
| Ketonuria/Ketonemia (K) | Urine ketones ≥ 2+ or serum ≥ 3.0 mmol/L |
| Acidosis (A) | Arterial or venous pH < 7.3, bicarbonate < 18 mmol/L |
Severity is classified as mild (pH 7.20-7.30), moderate, or severe (pH < 7.00). - Goldman-Cecil Medicine, p. 2483-2484
Pathophysiology
The fundamental driver is insulin deficiency + glucagon excess. This hormonal milieu has three major consequences:
1. Hyperglycemia
- Insulin deficiency reduces peripheral glucose uptake
- Counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) drive hepatic gluconeogenesis and glycogenolysis
- Substrates for gluconeogenesis flood the liver from muscle (amino acids, lactate, pyruvate) and adipose tissue (glycerol)
2. Ketogenesis
- Insulin deficiency activates hormone-sensitive lipase in adipose tissue, releasing free fatty acids (FFAs) into the circulation
- Long-chain FFAs travel to the liver and undergo beta-oxidation, generating acetoacetate, beta-hydroxybutyrate (BHB), and acetone
- BHB is the predominant ketone (typically 3:1 ratio over acetoacetate)
- This produces a high anion-gap metabolic acidosis
3. Osmotic Diuresis and Dehydration
-
Once blood glucose exceeds the renal threshold, glycosuria ensues
-
The osmotic diuresis causes profound loss of water, sodium, potassium, magnesium, calcium, and phosphorus
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Combined with vomiting and poor intake, fluid deficits average 3-5 L in adults
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Despite appearing normal or even elevated on initial labs, total body K+, PO4, and Mg are markedly depleted
-
Rosen's Emergency Medicine, p. 2542; Goldman-Cecil Medicine, p. 2483
Precipitating Factors
Most common:
- Infection (most frequent overall - pneumonia, UTI)
- Inadequate insulin / nonadherence
- New-onset type 1 diabetes
- Acute coronary syndrome
Other precipitants:
-
Stroke, pulmonary embolism, acute pancreatitis
-
Endocrinopathies: Cushing syndrome, thyrotoxicosis, acromegaly
-
Drugs: corticosteroids, clozapine, olanzapine, cocaine, lithium, thiazide diuretics
-
SGLT-2 inhibitors (can cause euglycemic DKA - glucose may be near normal)
-
Severe burns, hyperthermia/hypothermia
-
Goldman-Cecil Medicine, p. 2484 (Table 210-11)
Clinical Features
Symptoms (hours to days of progression)
- Polyuria, polydipsia, polyphagia (early)
- Weakness, fatigue, nausea, vomiting, anorexia
- Diffuse abdominal pain (can mimic acute abdomen - due to ileus, gastroparesis, or metabolic effects)
- Fruity/acetone breath
Signs
- Kussmaul breathing - deep, rapid respirations (compensatory respiratory alkalosis)
- Tachycardia, orthostatic hypotension, dry mucous membranes
- Reduced skin turgor, sunken eyes
- Depressed mental status, up to frank coma (correlates with hyperosmolality)
Note: fever is unusual - absence of fever does not exclude infection.
Laboratory Findings
| Test | Finding |
|---|---|
| Blood glucose | Typically 250-800 mg/dL (rarely > 1000) |
| Serum bicarbonate | < 18 mmol/L (may be < 10 in severe DKA) |
| pH | < 7.3 (severe: < 7.0) |
| Anion gap | Elevated (> 12), proportional to bicarbonate fall |
| Serum potassium | Initially normal/high (acidosis shifts K+ extracellularly), but total body K+ is DEPLETED |
| Serum sodium | Often low (osmotic dilution) - correct by adding 1.6 mEq/L per 100 mg/dL glucose above 100 |
| WBC | Often elevated (even without infection - stress response) |
| Serum amylase | May be elevated (usually salivary origin, not true pancreatitis) |
| BUN/Creatinine | Elevated (prerenal azotemia) |
| Phosphate | Initially normal/high; total body depleted |
Key pitfall on ketones: Standard nitroprusside strips detect acetoacetate and acetone, but NOT beta-hydroxybutyrate. Early DKA may show "low" ketones by strip testing while BHB is markedly elevated. As treatment progresses, BHB converts to acetoacetate, and strips can paradoxically show "worsening" ketonemia. Direct BHB measurement is preferred. - Goldman-Cecil Medicine, p. 2484
Treatment
1. Fluids (most immediate priority)
- Hypovolemic shock: Isotonic crystalloid (NS or Ringer's/Plasmalyte) boluses of 20 mL/kg until SBP ≥ 80 mmHg
- Moderate-severe dehydration (no shock): 1 L NS over first hour in adults; then switch to 0.45% NS at 250-500 mL/hr
- Pediatrics: 20 mL/kg bolus in first hour
- When glucose drops to ~200-250 mg/dL: Add dextrose (D5W or D5-0.45% NS) to prevent hypoglycemia while continuing insulin
Balanced crystalloids (Plasmalyte) may reduce hyperchloremic acidosis compared to large-volume NS. - Rosen's Emergency Medicine, p. 2544
2. Insulin
- Do NOT start insulin until K+ ≥ 3.5 mEq/L (insulin drives K+ into cells and can cause fatal hypokalemia)
- Standard: Regular insulin IV infusion at 0.1 units/kg/hr (can give 0.1 units/kg bolus first)
- Target: Blood glucose fall of 50-75 mg/dL/hr
- Subcutaneous rapid-acting insulin (e.g., lispro/aspart) is an evidence-based alternative in mild-moderate DKA - multiple RCTs and a 2024 systematic review (PMID 39090718) show similar outcomes to IV infusion with potentially fewer hypoglycemic episodes
- Continue insulin until anion gap normalizes and patient can eat - then transition to subcutaneous basal-bolus regimen
- A 2026 meta-analysis (PMID 41208563) found that starting early subcutaneous basal insulin concurrently with IV insulin reduces rebound hyperglycemia at transition
3. Potassium Replacement
- K+ < 3.5 mEq/L: Replace at 40 mEq/hr IV; hold insulin
- K+ 3.5-5.5 mEq/L: Add 20-40 mEq/L to each liter of IV fluid
- K+ > 5.5 mEq/L: No potassium; recheck every 2 hours
- Monitor K+ every 1-2 hours during treatment; it will fall as insulin is given
4. Phosphate
- Routine phosphate replacement is not recommended (no proven clinical benefit)
- Consider replacement if severe hypophosphatemia (< 1 mg/dL) or if causing cardiac/skeletal muscle dysfunction or hemolytic anemia
5. Bicarbonate
- Not recommended for pH > 6.9
- May consider for pH < 6.9 with hemodynamic instability: sodium bicarbonate 100 mEq in 400 mL sterile water over 2 hours
- Risks of bicarbonate: paradoxical CNS acidosis, hypokalemia, delayed ketonemia resolution
6. Monitoring (frequency during treatment)
- Blood glucose: every 1 hour
- Electrolytes (Na, K, Cl, bicarb), pH: every 2-4 hours
- Urine output: target 1-2 mL/kg/hr
- Resolution criteria: glucose < 200-250 mg/dL AND pH > 7.3 AND bicarbonate > 18 mmol/L AND anion gap normalized
Complications of DKA and Its Treatment
| Complication | Mechanism |
|---|---|
| Cerebral edema | Most feared in children; fluid shifts with rapid glucose correction |
| Hypokalemia | Insulin drives K+ into cells; can cause arrhythmia |
| Hypoglycemia | Continued insulin without dextrose |
| Hyperchloremic acidosis | Large-volume NS; persists after ketoacidosis resolves |
| ARDS | Inflammatory cytokines; aspiration |
| Thromboembolism | Dehydration + hyperosmolality increases clotting |
| Aspiration | Gastroparesis + altered mental status |
DKA vs. Hyperosmolar Hyperglycemic State (HHS)
| Feature | DKA | HHS |
|---|---|---|
| Glucose | 250-800 mg/dL | Often > 600 mg/dL |
| pH | < 7.3 | > 7.3 |
| Bicarbonate | < 18 | > 18 |
| Ketones | Marked | Absent/trace |
| Osmolality | Mildly elevated | Markedly elevated (> 320 mOsm/kg) |
| Onset | Hours-days | Days-weeks |
| Typical patient | Type 1 DM | Elderly Type 2 DM |
| Mortality | 1-5% | 5-20% |
Some patients present with a mixed picture (especially poorly controlled Type 2 DM with illness). - Goldman-Cecil Medicine, p. 2484
Special Considerations
SGLT-2 inhibitor-associated DKA: Glucose may be near-normal (euglycemic DKA). Classic glucose threshold may not be met - maintain high suspicion in patients on empagliflozin, dapagliflozin, canagliflozin.
Pregnancy: DKA can occur at lower glucose thresholds (as low as 200 mg/dL) due to respiratory alkalosis of pregnancy reducing buffering capacity. Fetal mortality is significant. A 2025 systematic review confirmed serious adverse pregnancy outcomes associated with DKA episodes.
Airway: Avoid intubation if possible - patients generate extreme minute ventilation that is difficult to match mechanically. If intubating, maintain hyperventilation to avoid worsening acidosis.
Sources: Rosen's Emergency Medicine 10e, Goldman-Cecil Medicine (International Ed.), with supplemental data from recent systematic reviews in BMC Endocrine Disorders (2024) and Diabetes, Obesity and Metabolism (2026).
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