Paracetamol (acetaminophen) poisoning

Abstract

Introduction

Paracetamol directly causes around 150 deaths per year in UK.

Methods and outcomes

We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of treatments for acute paracetamol poisoning? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).

Results

At this update, searching of electronic databases retrieved 127 studies. After deduplication and removal of conference abstracts, 64 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 46 studies and the further review of 18 full publications. Of the 18 full articles evaluated, one systematic review was updated and one RCT was added at this update. In addition, two systematic reviews and three RCTs not meeting our inclusion criteria were added to the Comment sections. We performed a GRADE evaluation for three PICO combinations.

Conclusions

In this systematic overview we categorised the efficacy for six interventions, based on information about the effectiveness and safety of activated charcoal (single or multiple dose), gastric lavage, haemodialysis, liver transplant, methionine, and acetylcysteine.

Key Points

Paracetamol (acetaminophen) is a common means of self-poisoning in Europe and North America, often taken as an impulsive act of self-harm in young people.

• Mortality from paracetamol overdose is now about 0.4%, although without treatment, severe liver damage would occur in many people depending on their blood paracetamol concentration.

• Ingestion of less than 75 mg/kg is unlikely to lead to hepatotoxicity. However, there are cases of hepatotoxicity with therapeutic doses of paracetamol.

• We found few RCTs, and most were old. The difficulties of undertaking RCTs in this area should not be underestimated; however, high-quality RCTs are possible.

Standard treatment of paracetamol overdose is acetylcysteine, which, based on animal studies and clinical experience, is widely believed to reduce liver damage and mortality, although few studies have been done.

• Adverse effects from acetylcysteine include rash, urticaria, vomiting, and anaphylactoid reactions, which can (rarely) be fatal.

• One RCT found that side-effects from acetylcysteine were substantially reduced with a novel dosing regimen that reduces the peak plasma acetylcysteine concentration, but further research is needed to confirm efficacy because the RCT was not powered to detect non-inferiority. At the time of publication of this overview, most patients in the UK receive the standard 21-hour intravenous acetylcysteine regimen.

• We don't know what the optimal dose, route, and duration of acetylcysteine treatment should be. However, liver damage is unlikely to occur if treatment is started within 8 to 10 hours of ingestion of a single overdose.

It is possible that methionine reduces the risk of liver damage and mortality after paracetamol poisoning compared with supportive care, but we don't know for sure.

We found no direct information from RCTs meeting our inclusion criteria about activated charcoal in the treatment of people following paracetamol poisoning.

• There is some limited evidence from studies not meeting our inclusion criteria, such as non-randomised trials and studies in volunteer participants, that activated charcoal may reduce the absorption of paracetamol, but we don't know if it improves other clinical outcomes (e.g., mortality, hepatotoxicity, or liver failure) in patients following paracetamol poisoning.

We don't know whether gastric lavage reduce the risks of liver damage after paracetamol poisoning. Gastric lavage is no longer routine clinical practice.

Liver transplantation may increase survival rates in people with fulminant liver failure after paracetamol poisoning compared with waiting list controls, but which patients benefit most is unclear.

We found no RCTs on the effects of haemodialysis.

Clinical context

General background

Paracetamol overdose is one of the most common reasons for emergency hospital admission. Around 100,000 people present to emergency departments each year in the UK with paracetamol overdose, and around half are admitted for antidote therapy with acetylcysteine.

Focus of the review

To determine the strength of evidence for current management approaches for paracetamol overdose.

Comments on evidence

We found few RCTs, and most were old. The difficulties of undertaking RCTs in this area should not be underestimated; however, high-quality RCTs are possible.

Search and appraisal summary

The update literature search for this review was carried out from the date of the last search, March 2007, to October 2014. A search dated back from 1966 was performed for the new option added to the scope at this update. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 127 studies. After deduplication and removal of conference abstracts, 64 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 46 studies and the further review of 18 full publications. Of the 18 full articles evaluated, one systematic review was updated and one RCT was included at this update. In addition, two systematic reviews and three RCTs not meeting our inclusion criteria were added to the Comment sections.

Additional information

An additional area of interest is the widely acknowledged potential of mechanistic biomarkers to improve patient treatment stratification following paracetamol overdose.

About this condition

Definition

Paracetamol poisoning occurs as a result of either accidental or intentional overdose with paracetamol (acetaminophen). In this overview, we have included studies in people with paracetamol poisoning from either accidental or intentional overdose. We have excluded studies undertaken in animals or experimental studies undertaken in volunteers.

Incidence/ Prevalence

Paracetamol is the most common drug used for self-poisoning in the UK. It is also a common means of self-poisoning in the rest of Europe, North America, and Australasia. In the UK, around 98,000 patients attend emergency departments each year with paracetamol poisoning and around 49,000 are admitted for treatment. Overdoses from paracetamol alone directly result in an estimated 150 to 200 deaths and 15 to 20 liver transplants each year in England and Wales (data from routinely collected health and coronial statistics). Pack-size restrictions instituted in the UK in 1998 resulted in modest reductions in large overdoses, liver transplants, and deaths in England and Wales. In Scotland, the reduction in admissions and mortality from paracetamol overdose was short lived.

Aetiology/ Risk factors

Most cases in the UK are impulsive acts of self-harm in young people. In one cohort study of 80 people who had overdosed with paracetamol, 42 had obtained the tablets for the specific purpose of taking an overdose, and 33 had obtained them less than 1 hour before the act.

Prognosis

The majority of patients present to hospital soon after overdose, a time when subsequent hepatotoxicity cannot be reliably excluded by current liver function tests. The need for treatment is determined by the patient’s blood paracetamol concentration, which is interpreted with regard to the time from overdose on a nomogram. In the UK, a line starting at 100 mg/L at 4 hours post overdose determines need for treatment. The position of the line is critical in determining the number of patients treated and the risk of missing a case of treatable hepatotoxicity. The nomogram used in the UK is more conservative when compared with those used in North America or Australia. The UK position was informed by a comprehensive Medicines and Healthcare products Regulatory Agency (MHRA) review that included data from RCTs, observational studies, and clinical experience. In patients with a staggered overdose (tablets taken repeatedly over more than 2 hours), the nomogram cannot be used and the decision to treat is complex, being based on clinical judgement, reported dose of paracetamol ingested, and blood results. For the majority of patients, treatment with acetylcysteine is successful. However, the prediction of the likely clinical course of the patient remains difficult. This is mainly due to marked inter-individual variation and a lack of sensitivity and specificity, as well as an indirect mechanistic basis of currently used biomarkers to diagnose paracetamol hepatotoxicity and to predict outcome. Recent evidence from both prospective and retrospective studies of paracetamol overdose patients have shown that biomarkers linked to the mechanisms of toxicity can be used to diagnose paracetamol hepatotoxicity (paracetamol-protein adducts), predict the potential to develop acute liver injury at first presentation to hospital (miR-122, Keratin-18, HMGB1), and predict patient outcome (acetyl-HMGB1, KIM-1).

Aims of intervention

To prevent liver failure, liver transplantation, or death, with minimal adverse effects.

Outcomes

Mortality, hepatotoxicity (most commonly defined by the objective criterion of blood alanine aminotransferase >1000 U/L), liver failure (includes liver transplantation [with the exception of our option on liver transplant]). For the option on haemodialysis, we have also reported on clearance of paracetamol from the circulation; and adverse effects.

Methods

Search strategy BMJ Clinical Evidence search and appraisal date October 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to October 2014, Embase 1980 to October 2014, The Cochrane Database of Systematic Reviews 2014, issue 10 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, with no minimum level of blinding (open studies included), and containing more than 20 individuals, of whom more than 80% were followed up. Trials had a minimum length of follow-up of 1 week. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the overview. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the intervention for ipecacuanha from this overview and added the new intervention for haemodialysis. Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Paracetamol (acetaminophen) poisoning.

Important outcomes	Hepatotoxicity, Liver failure, Mortality
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of treatments for acute paracetamol poisoning?
1 (50)	Mortality	Acetylcysteine versus placebo	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and methodological flaws (allocation and concealment); directness point deducted for differences between the groups (prognostic)
1 (26)	Mortality	Methionine versus usual care	4	–3	0	–1	0	Very low	Quality points deducted for sparse data, weak methods (allocation and concealment), and incomplete reporting of results; directness point deducted for small number of events (total of 1 event)
1 (19)	Hepatotoxicity	Methionine versus usual care	4	–3	0	–1	+2	Low	Quality points deducted for sparse data, and for weak methods (allocation and concealment) and no intention-to-treat analysis; directness point deducted for differences between the groups (liver biopsy); effect size points added for RR less than 0.2

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

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