Management of Adverse Reactions to N-acetylcysteine (NAC)

Paracetamol overdose is common and can lead to severe hepatotoxicity if inadequately treated. N-acetylcysteine (NAC) is the antidote of choice in paracetamol toxicity due to demonstrated efficacy and good tolerability.^[1] The 3-bag NAC regimen is most commonly used (Figure 1).

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Figure 1: 3-bag NAC regimen 

Intravenous NAC results in 14% to 18% non-allergic anaphylactic reactions (NAARs) or non-immunologic anaphylaxis, formerly known as anaphylactoid reactions.^[2,3] Unlike immunologic anaphylaxis, it is not IgE mediated and does not require prior sensitization.^[4] NAARs are dose related and are mostly seen during the initial phase of NAC administration since half the dose is given in the 1st hour. To overcome this a 2-bag regimen is proposed (Figure 2).

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Figure 2: 2-bag NAC regimen

Example of how to administer the 2-bag NAC regimen in a 70-kg patient:

• 1^st bag at 200mg/kg over 4 hours = 14 g of NAC over 4 hours
  1 ampoule of NAC = 2g/ 10mL (200mg /mL) therefore 7 ampoules will be needed, which adds up to 70mL NAC
  - If using 5% dextrose solution 500mL bag, remove 70mL solution and inject 70mL NAC into the 5% dextrose
  Run the infusion at 125mL/hr (3.5g NAC/hr)
  - If using 0.9% normal saline solution 1L bag, remove 70mL solution and inject 70mL NAC into the 0.9% solution
  Run infusion at 250 mL/hr (3.5g NAC/hr)
• 2^nd bag at 100mg/kg over 16 hours = 7g of NAC over 16 hours
  From a 1L 5% dextrose solution OR 1L 0.9% normal saline, remove 35mL solution and add 35mL NAC (3.5 ampoules) into the 1L 5% dextrose OR 0.9% normal saline bag. Run infusion at 62.5mL/hr (0.4 g NAC/hr)

A comparison of the simplified 2-bag to the conventional 3-bag regimen has been studied and demonstrates lower incidence of NAARs in the 2-bag regimen versus the 3-bag regimen.^[5–7]

Since NAARs are dose related, the reaction can be treated by reducing the rate of the infusion. In selected patient groups the administration of antihistamines may be warranted (table 1).

Table 1: Management of non-allergic anaphylactic reactions (anaphylactoid reactions)

Presentation	Management recommendation
Flushing	Reassess need for NAC Continue NAC if needed at a reduced infusion rate - Restart infusion at 25% of the dose and titrate to normal dose rate over 1 hour E.g. in a 70-kg patient, restart 1st bag infusion at 32mL/hr and titrate up to 125mL/hr over the next hour)
Urticaria	Reassess need for NAC Promethazine 0.25-0.5mg/kg/dose intravenously Continue NAC if needed at a reduced infusion rate - Restart infusion at 25% of the dose and titrate to normal dose rate over 1 hour E.g. in a 70-kg patient, restart 1st bag infusion at 32mL/hr and titrate up to 125mL/hr over the next hour)
Angioedema	Stop NAC Promethazine 0.25-0.5mg/kg/dose intravenously Reassess need for NAC  If no symptoms after 1 hour, restart NAC Restart infusion at 25% of the dose and titrate to normal dose rate over 1 hour - E.g. in a 70-kg patient, restart 1st bag infusion at 32mL/hr and titrate up to 125mL/hr over the next hour)
Respiratory symptoms or hypotension	Stop NAC infusion Assess airway, breathing and circulation: Treat symptomatically Promethazine 0.25-0.5mg/kg/dose intravenously Reassess need for NAC If no symptoms after 1 hour, restart NAC Restart infusion at 25% of the dose and titrate to normal dose rate over 1 hour - E.g. in a 70-kg patient, restart 1st bag infusion at 32mL/hr and titrate up to 125mL/hr over the next hour)

Adapted from Bailey et al.,1998^[8]

Key points:

• 2-bag NAC regimen is associated with reduced NAARs
• NAARs can be overcome by reducing the rate of the NAC infusion
• 2-bag regimen allows for easier administration in a setting with limited staff
• If NAARs are persistent, consult Clinical Pharmacologist on call

References:

1. Peterson RG, Rumack BH. Toxicity of acetaminophen overdose. J Am Coll Emerg Physicians 1978;7(5):202–5.
2. NDA. Acetadote ® (acetylcysteine) Injection Package Insert. 2004.
3. Anaphylaxis vs. Anaphylactoid Reactions | World Allergy Organization [Internet]. [cited 2019 Jul 22]; Available from: https://www.worldallergy.org/ask-the-expert/questions/anaphylaxis-vs-anaphylactoid-reactions
4. Anaphylactic and anaphylactoid reactions | Clinical Gate [Internet]. [cited 2019 Jul 22]; Available from: https://clinicalgate.com/anaphylactic-and-anaphylactoid-reactions/
5. Wong A, Graudins A. Simplification of the standard three-bag intravenous acetylcysteine regimen for paracetamol poisoning results in a lower incidence of adverse drug reactions. Clin Toxicol 2016;54(2):115–9.
6. Schmidt LE, Rasmussen DN, Petersen TS, Macias-Perez IM, Pavliv L, Kaelin B, et al. Fewer adverse effects associated with a modified two-bag intravenous acetylcysteine protocol compared to traditional three-bag regimen in paracetamol overdose. Clin Toxicol 2018;56(11):1128–34.
7. McNulty R, Lim JME, Chandru P, Gunja N. Fewer adverse effects with a modifi ed two-bag acetylcysteine protocol in paracetamol overdose. Clin Toxicol 2018;56(7):618–21.
8. Bailey B, Mcguigan MA. Management of Anaphylactoid Reactions to Intravenous N-Acetylcysteine. 1998.

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