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Modified release paracetamol overdose: a prospective observational study (ATOM-3)
Angela L Chiew1,2,3, Geoffrey K Isbister3,4, Colin B Page5,6
1a Clinical Toxicology Unit/Emergency Department , Prince of Wales Hospital , Randwick , NSW , Australia.
Background:
Modified-release (MR) paracetamol is available in many countries as 665 mg tablets of which 69% is MR and 31% is immediate release. There are concerns that MR paracetamol overdose has higher rates of liver injury despite standard treatment algorithms. The objective of this study was to describe the clinical characteristics and outcomes of acute MR paracetamol overdose.
Methods:
Prospective observational study, recruiting patients from January 2013 to June 2017, from five clinical toxicology units and calls to two Poisons Information Centres in Australia. Included were patients >14 years who ingested ≥10 g or 200 mg/kg (whichever is less) of MR paracetamol. Data collected included demographics, ingestion history, pathology results, treatments, and outcomes including hepatotoxicity (ALT >1000 U/L).
Results:
In total, 116 patients were recruited, 85(73%) were female. The median dose ingested was 32 g (IQR: 20-49 g) and median time to presentation was 3 h (IQR: 2-9 h). 78(67%) had an initial paracetamol concentration above the nomogram line (150 mg/L at 4 h). A further 12(10%) crossed the nomogram after repeat paracetamol measurements, of which five crossed after two non-toxic levels 4 h apart. Six had a double paracetamol peak, in three occurring >24 h post-ingestion. 113(97%) received acetylcysteine of which 67 received prolonged treatment beyond the standard 21 h. This was because of an elevated paracetamol concentration at the completion of acetylcysteine in 39 (median paracetamol concentration 25 mg/L, IQR: 16-62 mg/L). 21 (18%) developed hepatotoxicity, including six treated within 8 h of ingestion. Activated charcoal and double doses of acetylcysteine did not significantly decrease the risk of hepatotoxicity.
Conclusions:
Drug regulatory authorities are considering restrictions on MR paracetamol preparations. Following an acute MR paracetamol overdose, this study found that many patients had a persistently elevated paracetamol concentrations, many required prolonged treatment and some developed liver injury despite early acetylcysteine treatment. Furthermore, activated charcoal and increased acetylcysteine did not appear to significantly alter the risk of liver injury. Hence, research into better treatment strategies is required.
Trial Registration:
Australian Toxicology Monitoring (ATOM) Study - Australian Paracetamol Project: ACTRN12612001240831 (ANZCTR) Date of registration: 23/11/2012.
Insights
Modified-release (MR) paracetamol overdose can lead to liver injury even with standard treatment. This study found prolonged elevated paracetamol levels and a need for extended treatment in many patients, highlighting the need for improved strategies.
Area of Science:
- Toxicology
- Pharmacology
- Clinical Medicine
Background:
- Modified-release (MR) paracetamol, a common formulation, raises concerns regarding increased liver injury risk in overdose cases.
- Standard treatment algorithms may be less effective for MR paracetamol overdoses, necessitating further investigation.
Purpose of the Study:
- To characterize the clinical presentation and outcomes of acute modified-release paracetamol overdose.
- To evaluate the effectiveness of current treatment protocols for MR paracetamol toxicity.
Main Methods:
- A prospective observational study conducted from January 2013 to June 2017 in Australia.
- Recruited patients aged over 14 years with significant MR paracetamol ingestion (≥10g or 200mg/kg).
- Collected data on demographics, ingestion details, laboratory results, treatments, and hepatotoxicity outcomes.
Main Results:
- 116 patients were included; 73% were female, with a median ingested dose of 32g.
- 67% had initial paracetamol levels above the nomogram, and 18% developed hepatotoxicity.
- Prolonged acetylcysteine treatment was required for 67 patients due to persistent elevated paracetamol levels; activated charcoal and increased acetylcysteine doses did not significantly reduce hepatotoxicity risk.
Conclusions:
- Acute MR paracetamol overdose frequently results in prolonged elevated paracetamol concentrations and necessitates extended treatment.
- Hepatotoxicity can occur despite early acetylcysteine administration, and current adjunct therapies show limited benefit.
- Further research is essential to develop more effective treatment strategies for MR paracetamol overdose.
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