Diabetic Ketoacidosis (DKA)

1. Pathogenesis

Core Hormonal Mechanism

• Insulin deficiency impairs glucose uptake into cells
• Glucagon excess stimulates hepatic glycogenolysis and gluconeogenesis
• Substrates delivered to the liver include amino acids and lactate from muscle, and free fatty acids/glycerol from adipose tissue
• Glucose is produced and released faster than it is used

• Insulin deficiency activates hormone-sensitive lipase in adipose tissue
• Long-chain free fatty acids (FFAs) are released into circulation in abundance
• In the liver, FFAs are partially oxidized and converted to ketone bodies: acetoacetate, β-hydroxybutyrate, and acetone
• The ratio of β-hydroxybutyrate to acetoacetate rises significantly in established DKA (explains why nitroprusside-based dipstick tests can underestimate ketosis - they only detect acetoacetate)
• Ketones accumulate faster than peripheral tissues can utilize them, causing ketonemia and ketonuria

• Hyperglycemia exceeds the renal threshold, causing glycosuria
• Glucose in renal tubules draws water, sodium, potassium, magnesium, calcium, and phosphorus into the urine
• This osmotic diuresis, combined with poor intake and vomiting, causes profound dehydration and electrolyte loss
• Average deficits in severe DKA: fluid 70-120 mL/kg, Na 8-10 mEq/kg, K 5-7 mEq/kg

• Accumulating ketoacids consume bicarbonate, producing a high anion gap metabolic acidosis
• The body compensates with Kussmaul breathing (deep, rapid respirations) to exhale CO₂
• Severe acidosis worsens insulin resistance and depresses mental status directly
• Cerebrospinal fluid pH falls more slowly than blood pH, so bicarbonate administration can paradoxically worsen CNS acidosis

Common Precipitants

2. Clinical Features

Symptoms (Hours to Days of Deterioration)

• Polyuria, polydipsia, polyphagia - classic osmotic symptoms
• Nausea, vomiting - very common; may cause or worsen dehydration
• Abdominal pain - present in ~50% of patients (especially children); usually resolves with metabolic correction. In adults, pain should raise suspicion for a real abdominal precipitant (e.g., pancreatitis, appendicitis)
• Weakness, weight loss, anorexia
• Visual blurring
• Lethargy progressing to altered consciousness or frank coma in severe cases

Signs

Key Laboratory Findings

• Mild: pH 7.20-7.30, HCO₃ 15-18, anion gap >10
• Moderate: pH 7.10-7.19, HCO₃ 10-14
• Severe: pH <7.10, HCO₃ <10

3. Management

Step 1: Stabilize and Assess Airway

• Avoid intubation if possible - patients have tremendous respiratory drive and matching ventilator settings is difficult
• Intubate if comatose, especially if vomiting (aspiration risk)
• Hypovolemic shock: aggressive isotonic crystalloid before vasopressors

Step 2: Intravenous Fluids (Most Important Initial Step)

• First 1-3 hours: 1-2 L of 0.9% normal saline (NS)
  • Children: 20 mL/kg NS in first hour
• This alone can lower glucose ~18% by improving renal perfusion and transporting residual insulin
• Improves acidosis by restoring tissue perfusion and reducing lactate production
• After initial resuscitation: switch to 0.45% NS to continue correcting free water deficit
• Target urine output: 1-2 mL/kg/hour

Step 3: Insulin

• Do NOT start insulin until K⁺ ≥ 3.3 mEq/L (risk of fatal hypokalemia)
• Start regular insulin IV infusion at 0.1 units/kg/hour (fixed rate)
• Once glucose falls to ≤250-300 mg/dL:
  • Switch IV fluid to D5W / 0.45% NS to allow continued insulin infusion without causing hypoglycemia
  • Reduce insulin to 0.05 units/kg/hour to prevent hypoglycemia and hypokalemia
• Continue insulin until ketosis is resolved (ketones <1.0 mmol/L, pH normalized, anion gap closed) - do not rely on glucose normalization alone

• Once patient is eating and ketoacidosis resolved, restart usual SC insulin regimen
• Maintain 1-2 hour overlap between SC dose and stopping IV infusion to prevent rebound ketosis

Step 4: Potassium Replacement

• K⁺ < 3.3 mEq/L: Replace aggressively before starting insulin (20-40 mEq/hr IV); hold insulin
• K⁺ 3.3-5.5 mEq/L: Add 20-40 mEq KCl to each liter of IV fluid
• K⁺ > 5.5 mEq/L: Do not add K; monitor closely; levels will fall with insulin
• Use corrected K formula: subtract 0.6 mEq/L for every 0.1 decrease in pH below normal
  • Example: reported K 5.0 mEq/L with pH 6.94 → corrected K ≈ 2.0 mEq/L (severe hypokalemia masked)

Step 5: Bicarbonate - Generally NOT Recommended

• IV fluids and insulin alone are sufficient for most cases
• Risk: paradoxical CNS acidosis; may worsen hypokalemia; delays diagnosis of resolution
• Consider only if: pH < 7.0, not responding to fluids and insulin, with profound acidosis
• Administer as NaHCO₃ 50-100 mEq slowly over 1-2 hours if used

Step 6: Phosphate and Magnesium

• Total body phosphate is depleted but routine IV replacement is NOT recommended
• Replace phosphate only if <1.0 mg/dL with muscle weakness or other complications
• Magnesium: correct with 1-2 g MgSO₄ if deficient (serum levels often don't correlate with body stores)

Step 7: Monitor Progress Closely

• Serum glucose, K⁺, HCO₃⁻, anion gap
• pH (venous acceptable)
• Fluid input and urine output
• ECG for potassium changes

Step 8: Identify and Treat Precipitating Cause

• Cultures, ECG, chest X-ray
• Treat infection, ACS, pancreatitis, etc.
• Key point: Do not stop insulin during illness in type 1 DM

Resolution Criteria

1. Blood glucose < 200-250 mg/dL
2. Serum bicarbonate ≥ 15 mmol/L
3. Venous pH > 7.3

Prognosis

• Subcutaneous vs IV insulin meta-analysis (PMID 39090718) - found subcutaneous insulin comparable to continuous IV infusion in adults with DKA
• Early SC basal insulin with IV infusion meta-analysis (PMID 41208563) - 2026 RCT meta-analysis supports early addition of SC basal insulin to reduce rebound DKA risk at transition