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Three Part Question

[In patients with elevated risk of liver injury with paracetamol overdose] is [high dose NAC better than standard care with NAC at standard dos] at [decreasing incidence of liver injury, decreasing incidence of liver failure, decreasing length of hospital stay, decreasing incidence of death and improving patient experience]

Clinical Scenario

55 y/o women presents after taking 100 x 500mg paracetamol tablets. She has been found at home with the empty packets of tablets. On questioning she admits to taking the medication 10 hours ago. You immediately gain IV access and start NAC as per the SNAP protocol. Her paracetamol level comes back as >300mcg/ml. Given the high dose of paracetamol she has ingested you wonder if the standard dose of NAC will be enough and if there is any evidence to support increasing it?

Search Strategy

Medline from 1966 to 2022 using pubmed interface
Results were filtered to include only papers that were full text, English and involved humans.

(Paracetamol OR acetaminophen OR paracetamol sulphate OR paracetamol derivative) AND (drug overdose OR overdose OR poisoning OR suicide) AND (calmangafodipir) AND (toxicity OR hepatotoxicity OR liver injury OR liver failure)

Search Outcome

286 results were identified of which 5 were identified as relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Cairney et al 2016 UK	727 treated with intravenous NAC following a single acute paracetamol overdose treated within 24 hours	Retrospective observational study	Acute liver injury and hepatoxicity	More common despite NAC in higher paracetamol level overdoses	Single centre study with retrospective design. Incomplete data for each patient Timing of overdose reliant on patient history
Chiew et al 2017 Aus	200 Immediate-release paracetamol overdoses with >40 g ingested under 8 h	Observational study	Paracetamol ratio (initial level ÷ 150mg/L)	72 had level >2. 43 of these had increased NAC	Uncontrolled. Partly retrospective in design. No randomisation of participants. Bias of recruitment due to use of poison centre databases to identifying participants
			Hepatotoxicity (ALT >1000 U/L).	Increased NAC decreased risk of hepatotoxicity [OR:0.27 (95% CI: 0.08-0.94)]
Marks et al 2017 UK	Patients with non-staggered paracetamol overdoses treated with NAC	Retrospective observational study	Liver injury	>30 gram overdoses - Higher peak serum ALT (r = 0.212, P < 0.0001)	Retrospective study Single centre Reliance on accurate patient history to record initial paracetamol dose. Potential inconsistent NAC dosing as administered by clinical teams.
			Kidney injury	>30 gram overdoses - Higher peak creatinine (r = 0.138, P = 0.002)
Downs et al 2021 USA	104 Patients admitted with massive paracetamol overdose (>300mg/ml at 4hrs) treated with NAC	Single centre retrospective cohort observation	Hepatotoxicity	79 cases (76%) had no acute liver injury or hepatotoxicity, and 25 (24%) developed hepatoxicity.	Single centre retrospective design. Timing of overdose reliant on patient history
Lewis et al 2022 USA	373 patients with acute massive paracetamol ingestion received one of the three NAC regimens: standard dose IV NAC, oral (PO) NAC, or high dose IV NAC.	Retrospective cohort observational	Risk of hepatotoxicity	Study unable to detect a difference between groups	Retrospective data collection. Not randomised. Timing of overdose reliant on patient history

Comment(s)

Current treatment for paracetamol overdose with NAC is based only the weight of the patient and is irrespective of the total dose ingested. Case series have demonstrated increasing incidence of hepatotoxicity in relation to initial paracetamol levels with current NAC treatment suggesting potential under dosing(1,3). Though absolute increases are modest they have been recorded irrespective of timing of NAC. In paracetamol overdose overall hepatotoxicity rates of 3.6-4.3% have been reported (6). This compares to 10.2-15% and 13.6-30.8% in those with the largest overdoses (1,3). These papers suggest that in the case of large overdoses an increased dose of NAC could be considered. This would not be without issue as reactions to NAC infusions are common and dose related. It remains unclear at what point additional NAC would be beneficial, some authors suggest increased risk with paracetamol levels over 300mcg/ml but there is no consensus (1). The term “massive overdose” is often used to describe this group but there is no evidence available to define it. On the basis of the work of Chiew et al who reported decreased toxicity in massive overdose with increased dose of NAC, Australia and New Zealand recommend this for these patients (2,7). However evidence from an 2021 observational US case series that directly compared outcomes in high dose NAC vs standard dosing did not identify benefit (5). This conflicting and often low quality evidence that lacks randomisation demonstrates that work is required to better stratify risk of hepatotoxicity in patients with paracetamol overdose. This would facilitate the development of high quality multi-centre prospective trials to better explore variable NAC dosing.

Clinical Bottom Line

While there is a suggestion that high dose NAC may be beneficial in massive paracetamol overdose there are no high quality studies that define which patients should receive it or any potential benefits.

References

1. Cairney DG, Beckwith HKS, Al-Hourani K, Eddleston M, Bateman DN, Dear JW. Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine Clin Toxicol (Phila) 2016 May 27 [cited 2022 Jun 29];54(5):405–10.
2. Chiew AL, Isbister GK, Kirby KA, Page CB, Chan BSH, Buckley NA Massive paracetamol overdose: an observational study of the effect of activated charcoal and increased acetylcysteine dose (ATOM-2). Clin Toxicol (Phila) 2017 Nov 26 [cited 2022 Jun 29];55(10):1055–65
3. Marks DJB, Dargan PI, Archer JRH, Davies CL, Dines AM, Wood DM, et al Outcomes from massive paracetamol overdose: a retrospective observational study British Journal of Clinical Pharmacology 2017 Jun 1 [cited 2022 Jun 29];83(6):1263–72.
4. Downs JW, Cumpston KL, Kershner EK, Troendle MM, Rose SR, Wills BK. Clinical outcome of massive acetaminophen overdose treated with standard-dose N-acetylcysteine. Clin Toxicol (Phila) 2021 [cited 2022 Jun 29];59(10):932–6
5. Lewis JC, Lim M, Lai L, Mendoza E, Albertson TE, Chenoweth JA Evaluation of N-acetylcysteine dose for the treatment of massive acetaminophen ingestion. Clin Toxicol (Phila) 2022 [cited 2022 Jun 29];60(4):507–13