In the three‑bag N‑acetylcysteine regimen for acetaminophen overdose, which diluent should be used and what are the recommended dilutions and infusion volumes?

N-Acetylcysteine Three-Bag Regimen: Diluent Selection and Dilutions

For the standard three-bag intravenous N-acetylcysteine regimen, use 5% dextrose in water (D5W) as the primary diluent, with 0.45% sodium chloride or sterile water for injection as acceptable alternatives, following specific dilution protocols for each of the three sequential doses. 1

Standard Three-Bag Dosing Protocol

The FDA-approved regimen consists of three separate sequential doses totaling 300 mg/kg over 21 hours 1:

Loading Dose (Bag 1)

• Dose: 150 mg/kg administered over 15 minutes to 1 hour 2, 1
• Dilution: Dilute in 200 mL of diluent for patients ≥40 kg; adjust volume proportionally for smaller patients 1
• Concentration considerations: The undiluted NAC solution is 200 mg/mL and hyperosmolar (2600 mOsmol/L), requiring dilution before administration 1

Second Dose (Bag 2)

• Dose: 50 mg/kg administered over 4 hours 2, 1
• Dilution: Dilute in 500 mL of diluent for patients ≥40 kg 1

Third Dose (Bag 3)

• Dose: 100 mg/kg administered over 16 hours 2, 1
• Dilution: Dilute in 1000 mL of diluent for patients ≥40 kg 1

Diluent Options and Osmolarity Considerations

Three diluents are FDA-approved for NAC administration 1:

• 5% Dextrose in Water (D5W) - Most commonly used
• 0.45% Sodium Chloride (half-normal saline) - Preferred in pediatric patients to prevent hyponatraemia 3
• Sterile Water for Injection - Use with caution due to hypotonic nature 1

Osmolarity by Diluent Type

The final osmolarity varies significantly based on diluent choice and NAC concentration 1:

• At 7 mg/mL NAC concentration:

  • Sterile water: 91 mOsmol/L (hypotonic - requires caution)
  • 0.45% NaCl: 245 mOsmol/L (physiologically safer)
  • D5W: 343 mOsmol/L (isotonic range)

• At 24 mg/mL NAC concentration:

  • Sterile water: 312 mOsmol/L
  • 0.45% NaCl: 466 mOsmol/L
  • D5W: 564 mOsmol/L

Critical Pediatric Considerations

In children, use 0.45% sodium chloride plus 5% dextrose to prevent symptomatic hyponatraemia 3:

• Standard i.v. NAC dosing in D5W alone has been shown to cause symptomatic hyponatraemia in pediatric patients 3
• Adjust osmolarity to a physiologically safe level (generally not less than 150 mOsmol/L in pediatric patients) 1
• A retrospective review of 40 pediatric patients (mean age 9.5 years) using 0.45% NaCl with 5% dextrose showed maintained normal serum sodium levels (mean 140 mmol/L, range 133-152) 3

Preparation and Storage Guidelines

Proper preparation is essential for patient safety 1:

• Visually inspect for particulate matter and discoloration before administration 1
• The diluted solution color ranges from colorless to slight pink or purple after stopper puncture - this does not affect product quality 1
• Storage: Diluted solutions can be stored for 24 hours at room temperature 1
• Stability data: NAC 60 mg/mL diluted in 0.9% NaCl, 0.45% NaCl, or D5W stored in PVC bags at 25°C maintains at least 98.7% of initial concentration for 72 hours 4
• Discard unused portions; do not use previously opened vials for intravenous administration 1

Common Pitfalls and Safety Considerations

Avoid these critical errors:

• Never administer undiluted NAC - the hyperosmolar nature (2600 mOsmol/L) can cause severe adverse reactions 1
• Loading dose administration rate errors are most common - 11 rate-related and 8 dose-related errors occurred in one institutional review 5
• In pediatric patients, avoid D5W alone - use 0.45% saline-containing solutions to prevent hyponatraemia 3
• Do not delay NAC administration while preparing exact dilutions if acetaminophen overdose is confirmed - begin treatment immediately 2, 6

Alternative Simplified Regimen

While the three-bag method is FDA-approved, some institutions use a simplified two-stage regimen 3, 5:

• 150 mg/kg loading dose over 1 hour
• Followed by continuous infusion of 10-14 mg/kg/hour for 20 hours
• Prepared as NAC 30 g in 1 L of D5W 5
• This approach reduces medication errors but is off-label 5

However, the standard FDA-approved three-bag regimen remains the recommended approach for most clinical scenarios 1.