On the Treatment of Acute Poisoning With Paracetamol

BACKGROUND Currently, despite the optimization of diagnostic methods in order to predict the development of liver damage, improvement of treatment protocols, paracetamol poisoning is a serious problem in medicine, being the most common cause of acute liver failure worldwide.

AIM OF STUDY To determine the indications for the use of acetylcysteine in paracetamol poisoning and evaluate the effectiveness of the 21-hour protocol for its administration.

MATERIAL AND METHODS We examined 20 patients with acute paracetamol poisoning (15 women and 5 men), the median age was 21.5 (19.8–32.3) years. ALT and AST were assessed during the entire period of stay in the hospital, the time period from the moment of taking paracetamol to hospitalization and the beginning of the administration of ACC, the concentration of paracetamol in the blood, and mortality. According to the level of ALT and AST in the blood, the patients were divided into 2 groups: Group I consisted of 14 patients, in whom the concentration of ALT and AST during the entire observation period did not exceed 50 U/L; in Group II (6 patients), an increase in the level of ALT and AST in the blood of more than 50 U/L was observed. To assess the risk of liver lesion, the Rumack-Matthew nomogram was used. To compare the concentrations of paracetamol in the blood of patients, the paracetamol index was used.

RESULTS It was found that in 10 patients with a high risk of liver damage, who were treated with a 21-hour regimen of ACC administration, no hepatotoxic effect was found. The use of ACC according to a 21-hour protocol in patients with initially elevated ALT and AST levels of more than 50 U/L (n = 4) (25%) led to a rapid positive dynamics of laboratory and clinical parameters. It was found that in 2 patients, despite the introduction of ACC, the development of liver damage was observed. At the same time, the level of paracetamol in their blood was 6.6 and 10.6 fold higher than the “therapeutic” line of the nomogram, and the time from the moment of taking the drug to the beginning of the administration of ACC was 8 and 20 hours. High risk factors for the development of hepatotoxic effect in case of paracetamol poisoning are the time range from the moment of taking the drug to the beginning of the administration of ACC and the value of the paracetamol index.

CONCLUSION Indications for the use of acetylcysteine in acute poisoning with paracetamol is a high risk of liver damage. Its criteria are high doses, increased concentrations of ALT and AST when patients are admitted to the hospital; if it is possible to determine the concentration of paracetamol in the blood, an increase in the value of the paracetamol index is more than 1. The use of a 21-hour protocol of intravenous administration of acetylcysteine is effective in case of paracetamol poisoning and its early use in the complex of treatment almost always prevents the development of acute liver failure.

1. Casey D, Geulayov G, Bale E, Brand F, Clements C, Kapur N, et al. Paracetamol self-poisoning: Epidemiological study of trends and patient characteristics from the multicentre study of self-harm in England. J Affect Disord. 2020;276:699–706. PMID: 32871703 https://doi.org/10.1016/j.jad.2020.07.091

2. Wong A, Graudins A. Risk prediction of hepatotoxicity in paracetamol poisoning. Clin Toxicol (Phila). 2017;55(8):879–892. PMID: 28447858 https://doi.org/10.1080/15563650.2017.1317349

3. Mullins ME, Yeager LH, Freeman WE. Metabolic and mitochondrial treatments for severe paracetamol poisoning: a systematic review. Clin Toxicol (Phila). 2020;58(12):1284–1296. PMID: 32762579 https://doi.org/10.1080/15563650.2020.1798979

4. Luzhnikov EA. (ed.) Meditsinskaya toksikologiya. Natsional’noe rukovodstvo. Moscow: GEOTAR-Media Publ.; 2013. (in Russ.).

5. Zotov PB, Lyubov EB, Abuzarova GR, Scriabin EG, Klyashev SM, Petrov VG. Paracetamol Among the Means of Suicidal Actions in Russia and Abroad. Suicidology. 2019;4(37):99–119. (in Russ.).

6. Hoffman RS, Nelson LS, Howland MA, Lewis NA, Flomenbaum NE, Goldfrank LR (eds.). Goldfrank’s Manual of Toxicologic Emergencies. New York: McGraw-Hill Medical; 2007. [Russ. ed.: Khoffman R, Nel’son L, Khauland M-E, L’yuin N, Flomenbaum N., Goldfrank L: Kotenko KV (ed.). Ekstrennaya meditsinskaya pomoshch’ pri otravleniyakh. Moscow: Praktika Publ.; 2010.]

7. 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. 2017;55(10):1055–1065. https://doi.org/10.1080/15563650.2017.1334915

8. Chiew AL, Isbister GK, Page CB, Kirby KA, Chan BSH, Buckley NA. Modified release paracetamol overdose: a prospective observational study (ATOM-3). Clin Toxicol (Phila). 2018;56(9):810–819. PMID: 29451045 https://doi.org/10.1080/15563650.2018.1439950

9. Pettie JM, Caparrotta TM, Hunter RW, Morrison EE, Wood DM, Dargan PI. Safety and Efficacy of the SNAP 12-hour Acetylcysteine Regimen for the Treatment of Paracetamol Overdose. EClinicalMedicine. 2019;11:11–17. PMID: 31317129 https://doi.org/10.1016/j.eclinm.2019.04.005

10. Rumack BH, Bateman DN. Acetaminophen and acetylcysteine dose and duration: past, present and future. Clin Toxicol (Phila). 2012;50(2):91–98. PMID: 22320209 https://doi.org/10.3109/15563650.2012.659252 Erratum in: Clin Toxicol (Phila). 2021;59(4):359.

11. Heard K, Dart R. Acetaminophen (paracetamol) poisoning in adults: Treatment. UpToDate. Available at: https://www.uptodate.com/contents/acetaminophen-paracetamol-poisoning-in-adults-treatment [Accessed Nov 23, 2021].

12. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55(6):871–876. PMID: 1134886

13. Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br Med J. 1979;2(6198):1097–1100. PMID: 519312 https://doi.org/10.1136/bmj.2.6198.1097

14. Antoine DJ, Dear JW, Lewis PS, Platt V, Coyle J, Masson M, et al. Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Hepatology. 2013;58(2):777–787. PMID: 23390034 https://doi.org/10.1002/hep.26294

15. Chiew AL, Gluud C, Brok J, Buckley NA. Interventions for paracetamol (acetaminophen) overdose. Cochrane Database Syst Rev. 2018;2(2):CD003328. PMID: 29473717 https://doi.org/10.1002/14651858.CD003328.pub3

16. Zobnin YuV. Otravlenie paratsetamolom: klinika, diagnostika, lechenie. Irkutsk; 2002. (in Russ.).

17. Bateman DN, Dear JW. Acetylcysteine in paracetamol poisoning: a perspective of 45 years of use. Toxicol Research. 2019;8(4):489–498. PMID: 31341611 https://doi.org/10.1039/c9tx00002j

18. Chiew AL, Reith D, Pomerleau A, Wong A, Isoardi KZ, Soderstrom J, et al. Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand. Med J Aust. 2020;212(4):175–183. PMID: 31786822 https://doi.org/10.5694/mja2.50428 PMID: 31786822

19. Bateman DN, Dear JW, Carroll R, Pettie J, Yamamoto T, Elamin M, et al. Impact of reducing the threshold for acetylcysteine treatment in acute paracetamol poisoning: The recent United Kingdom experience. Clin Toxicol. 2014;52(8):868–872. PMID: 25200454 https://doi.org/10.3109/15563650.2014.954125

20. Marks DJB, Dargan PI, Archer JRH, Davies CL, Dines AM, Wood DM, et al. Outcomes from massive paracetamol overdose: a retrospective observational study. Br J Clin Pharmacol. 2017;83(6):1263–1272. PMID: 28002875 https://doi.org/10.1111/bcp.13214

21. 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;59(10):932–936. PMID: 33620007 https://doi.org/10.1080/15563650.2021.1887493

22. Сairney DG, Beckwith HK, 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;54(5):405–410. PMID: 27108714 https://doi.org/10.3109/15563650.2016.1159309