Paracetamol (acetaminophen) poisoning

Paracetamol (acetaminophen) poisoning Search date March 2007 Nick Buckley and Michael Eddleston ABSTRACT INTRODUCTION: Mortality from paracetamol overdose is now about 0.4%, although severe liver damage occurs without treatment in at least half of people with blood paracetamol levels above the UK standard treatment line. In adults, ingestion of less than 125 mg/kg is unlikely to lead to hepatotoxicity; even higher doses may be tolerated by children without causing liver damage. METHODS AND OUTCOMES: We conducted a systematic review and aimed 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 March 2006 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 24 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: activated charcoal (single or multiple dose), gastric lavage, ipecacuanha, liver transplant, methionine, N-acetylcysteine.

QUESTIONS What are the effects of treatments for acute paracetamol poisoning?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 INTERVENTIONS TREATING ACUTE PARACETAMOL POISONING Beneficial

Unknown effectiveness Activated charcoal (single or multiple dose) . . . . . . . 7

Acetylcysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Gastric lavage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Ipecacuanha . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Likely to be beneficial

Liver transplant New . . . . . . . . . . . . . . . . . . . . . . . 11

Methionine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

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 occurs in at least half of people with blood paracetamol levels above the UK standard treatment line. In adults, ingestion of less than 125 mg/kg is unlikely to lead to hepatotoxicity; even higher doses may be tolerated by children without causing liver damage. • 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 anaphylaxis which can, rarely, be fatal. We don't know what the optimal dose, route, and duration of acetylcysteine treatment should be. However, liver damage is less likely to occur if treatment is started within 8 to 10 hours of ingestion. • 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 don't know whether activated charcoal, gastric lavage, or ipecacuanha reduce the risks of liver damage after paracetamol poisoning. The rapid absorption of paracetamol suggests that a beneficial effect from treatments that reduce gastric absorption is unlikely in many cases. • Liver transplantation may increase survival rates in people with fulminant liver failure after paracetamol poisoning compared with waiting list controls, but long-term outcomes are unknown. DEFINITION

Paracetamol poisoning occurs as a result of either accidental or intentional overdose with paracetamol (acetaminophen).

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. There has been an exponential rise in the number of hospital admissions caused by paracetamol poisoning in England and Wales from 150 in 1968 to a peak of 41,200 in 1989 to 1990, before falling to around 25,000 [2] in 2001 to 2002. Overdoses from paracetamol alone 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

© BMJ Publishing Group Ltd 2007. All rights reserved.

[1]

.................... 1 ....................

Clinical Evidence 2007;12:2101

Poisoning

..................................................

[3]

[4]

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, [3] [4] the reduction in admissions and mortality from paracetamol overdose was short lived. [1]

[5]

AETIOLOGY/ Most cases in the UK are impulsive acts of self-harm in young people. In one cohort study RISK FACTORS of 80 people who had overdosed with paracetamol, 42 had obtained the tablets for the specific [5] purpose of taking an overdose, and 33 had obtained them less than 1 hour before the act. PROGNOSIS

People with blood paracetamol concentrations above the standard treatment line (defined in the UK as a line joining 200 mg/L at 4 hours and 30 mg/L at 15 hours on a semilogarithmic plot) have [6] [7] [8] [9] a poor prognosis without treatment (see figure 1, p 13 ). In one cohort study of 57 untreated people with blood concentrations above this line, 33/57 (58%) developed severe liver [7] damage and 3/57 (5%) died. People with a history of chronic alcohol misuse, use of enzyme inducing drugs, eating disorders, or multiple paracetamol overdoses may be at risk of liver damage [9] with blood concentrations below this line. In the USA, a lower line is used as an indication for [10] treatment, but we found no data relating this line to prognostic outcomes. More recently, a modified nomogram specifically designed to estimate prognosis (not need for treatment) has been [11] developed by modelling data from a large cohort. This takes into account time to initiation of acetylcysteine treatment, and the effect of alcohol use. However, it has not yet been validated, and is not widely used. Reversible renal injury occurs in some people, most commonly (but not always) in association with hepatic injury. Dose effect: The dose ingested also indicates the risk of hepatotoxicity. One case series showed that people ingesting less than 125 mg/kg had no significant [12] hepatotoxicity, with a sharp dose-dependent rise for higher doses. The threshold for toxicity after acute ingestion may be higher in children, where a single dose of less than 200 mg/kg has [13] not been reported to lead to death and rarely causes hepatotoxicity. The higher threshold for [14] toxicity in children may relate to different metabolic pathways or their larger relative liver size. For people who present later than 24 hours, or an unknown time after ingestion, several other prognostic indicators have been proposed, including prothrombin time, and abnormal liver function [15] [16] tests. These have not been validated prospectively. Slow release preparations: Pharmacokinetic studies of small overdoses of slow-release paracetamol formulations in healthy volunteers showed that peak plasma concentrations usually still occur within 4 hours, and the apparent halflife is the same as or only slightly longer than that of conventional paracetamol preparations. The [17] [18] [19] bioavailability was not increased. The nomogram has not specifically been validated for these formulations. However, only a small proportion of cases of slow release preparation ingestion have resulted in initial non-toxic levels and subsequent toxic levels on the usual nomograms. [20] [21] In just one case, with other risk factors, the use of the nomogram led to treatment being [21] ceased, and this may have contributed to a fatal outcome. Children and repeated supratherapeutic doses: There are reports of major dosing errors leading to severe hepatotoxicity in children. Of more concern are other cases of apparent toxicity with repeated doses only slightly above the current maximum recommended doses (around 75 mg/kg/day). There are possibly ad[22] [23] ditional risk factors in these cases, but these have not been established.

AIMS OF To prevent liver failure, liver transplantation, or death, with minimal adverse effects. INTERVENTION OUTCOMES

Mortality, hepatotoxicity (most commonly defined by the objective criterion of blood aspartate aminotransferase greater than 1000 U/L), liver failure (includes liver transplantation [with the exception of our option on liver transplant]).

METHODS

Clinical Evidence search and appraisal March 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2007, Embase 1980 to March 2007, and The Cochrane Library (all databases) 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — all databases, Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, including non-blinded or "open" studies, and containing at least 20 individuals of whom more than 80% were followed up. The minimum length of follow-up required to include studies was one week. We also did a search for observational studies on all the interventions. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, 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). We have performed a GRADE evaluation of the quality of evidence for interventions included in this


........................................................... 2

Poisoning

Paracetamol (acetaminophen) poisoning

review (see table, p 14 ). 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). QUESTION

What are the effects of treatments for acute paracetamol poisoning?

OPTION

ACETYLCYSTEINE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

•

For GRADE evaluation of interventions for Paracetamol (acetaminophen) poisoning, see table, p 14 .

•

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 anaphylaxis which can, rarely, be fatal.

•

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

•

We found no direct information from RCTs comparing different regimens of acetylcysteine or acetylcysteine compared with methionine in the treatment of people with paracetamol poisoning. Benefits and harms

Acetylcysteine versus no treatment: RCTs comparing acetylcysteine versus no treatment are now likely to be considered unethical. Acetylcysteine versus placebo: [24] [25] We found one systematic review (search date 2001), which identified one small RCT. We also found ten [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] studies reporting on adverse effects of acetylcysteine. Mortality Acetylcysteine compared with placebo Acetylcysteine may be more effective at reducing mortality in people with established paracetamol-induced liver failure and receiving conventional intensive liver care compared with placebo after 21 days (very low-quality evidence). Ref (type)

Population

Outcome, Interventions

Results and statistical analysis

Effect size

Favours

Mortality [25]

RCT

50 people with es- Mortality , 21 days tablished paraceta13/25 (52%) with acetylcysteine mol-induced liver (150 mg/kg over 15 minutes, failure 50 mg/kg over 4 hours, and then [24] In review 100 mg/kg diluted in 5% dextrose over 16 hours) 20/25 (80%) with placebo (5% dextrose)

ARR 28% 95% CI 3% to 53% P = 0.037 Possible bias due to sealed envelope allocation; for full details, see further information on studies

acetylcysteine

Acetylcysteine was continued until death or recovery Everyone also received conventional intensive liver care

Hepatotoxicity No data from the following reference on this outcome. © BMJ Publishing Group Ltd 2007. All rights reserved.

[24]

[25]

...........................................................

3

Poisoning


Liver failure No data from the following reference on this outcome.

[24]

[25]

Adverse effects Ref (type)

Population



Effect size

Favours

Adverse effects [25]

50 people with es- Adverse effects tablished paracetawith acetylcysteine (150 mg/kg mol-induced liver over 15 minutes, 50 mg/kg over failure 4 hours, and then 100 mg/kg di[24] In review luted in 5% dextrose over 16 hours)

RCT

with placebo (5% dextrose) Acetylcysteine was continued until death or recovery Everyone also received conventional intensive liver care The RCT did not specifically assess adverse outcomes and reported that no adverse effects were seen [26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

Population details not reported

Adverse effects with acetylcysteine Eight studies, including one RCT, found that the incidence of adverse effects from intravenous acetylcysteine was 4% to 45%; for full details, see further information on studies

Treatment-related mortality [34]

[35]


Treatment-related mortality with acetylcysteine Three deaths were reported; two followed a 10-fold miscalculation of the dose of acetylcysteine, and the other occurred in a person with severe asthma.

Vomiting [29]


Vomiting with oral acetylcysteine Vomiting is common after oral acetylcysteine and was reported to have occurred in 63% of people, despite previous administration of metoclopramide

Acetylcysteine versus methionine: See option on methionine, p 5 . © BMJ Publishing Group Ltd 2007. All rights reserved.

...........................................................

4

Poisoning


Further information on studies [25]

[26]

Allocation was concealed but treatment was not blinded. The RCT used a sealed-envelope method to allocate people to treatment, which is considered less effective at concealing allocation than a centralised computer allocation process, and may have increased the risk of bias. There were differences between the groups in prognostic variables (prothrombin time, coma grade) and other treatments, but a possible confounding effect could not be assessed adequately because of the small size of the study. [27]

[28]

[29]

[30]

[31]

[32]

[33]

Adverse effects reported were predominantly rash, urticaria, and occasionally more serious anaphylactoid reactions occurring with the initial “loading” dose. In most or all cases in the studies identified, adverse effects responded to temporary stopping of infusions and symptomatic treatment, and did not recur when treatment recommenced. Adverse reactions were more common in people with asthma and those who had non-toxic paracetamol concentrations. Oral acetylcysteine can also cause hypersensitivity and anaphylactoid reactions.

Comment:

Widespread adoption of intravenous acetylcysteine for paracetamol poisoning coincided with a [2] marked drop in overall case fatality ratio from around 3% in the early 1970s to 0.4% in the 1980s. [1] [36] There are clear animal data, observational evidence, and clinical experience that the introduction of acetylcysteine has dramatically changed the natural history of paracetamol poisoning [9] favourably. The optimal dose, route, and duration of treatment are unknown, and assessment by RCTs is required. One observational study evaluated the effects of intravenous acetylcysteine [7] in people presenting early to hospital. It found that people treated within 10 hours of ingestion were less likely to develop liver damage than were untreated historical controls (1/62 [2%] with treated people v 33/57 [58%] with untreated people). Early versus delayed treatment: [26] [7] Pooled analysis of case series and one additional case series suggested that overall hepatotoxicity was worse if treatment was delayed beyond 8 to 10 hours. Oral versus intravenous treatment: We found no RCTs. Pooled analysis of case series comparing oral versus intravenous administration [26] of acetylcysteine, and two subsequent observational studies comparing different protocols for [37] [38] intravenous and oral acetylcysteine, did not find marked differences in outcomes between groups, but these findings require confirmation by RCTs. Duration of infusion: We found one RCT (223 people, 180 [81%] evaluated; allocation by slips of paper in a closed box) comparing rates of drug-related adverse events with intravenous acetylcysteine infusion over 60 minutes versus infusion over the standard 15 minutes. It found limited evidence of no significant difference between groups (drug-related adverse events: 49/109 [45%] with 15 minutes v 27/71 [32] [38%] with 60 minutes; mean difference +7, 95% CI −8 to +22), although methodological problems make it difficult to draw any reliable conclusions from these results, and properly conducted RCTs are required. The RCT used a sealed-envelope method to allocate people to treatment, which is considered less effective at concealing allocation than a centralised computer allocation process, and may have increased the risk of bias. Groups were not comparable at baseline, and the 15-minute group was much larger that the 60-minute group (109 people in the 15-minute group v 71 people in the 60-minute group).

OPTION

METHIONINE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

•

For GRADE evaluation of interventions for Paracetamol (acetaminophen) poisoning, see table, p 14 .

•

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 about methionine compared with acetylcysteine in the treatment of people with paracetamol poisoning.


...........................................................

5

Poisoning


Benefits and harms Methionine versus usual care: [24] [39] We found one systematic review (search date 2001), which identified one small RCT. Mortality Methionine compared with usual care Methionine may be no more effective at reducing mortality in people with paracetamol poisoning compared with supportive care (low-quality evidence). Ref (type)

Population



Effect size

Favours

Mortality [39]

RCT 3-armed trial

40 people with blood concentrations of paracetamol above the UK standard treatment line (see figure 1, p 13 ) In review

[24]

Mortality

Reported as not significant

0/13 (0%) with methionine (2.5 g P value not reported 4-hourly for 4 doses) Possible bias due to sealed enve1/13 (8%) with usual care lope allocation; for full details, see further information about studies Everyone received gastric lavage plus supportive care (usual care)

Not significant

The remaining arm evaluated intravenous mercaptamine

Hepatotoxicity Methionine compared with supportive care Methionine may be more effective at reducing hepatotoxicity in people with paracetamol poisoning compared with supportive care (very low-quality evidence). Ref (type)

Population



Effect size

Favours

Hepatic necrosis [39]

RCT 3-armed trial

40 people with blood concentrations of paracetamol above the UK standard treatment line (see figure 1, p 13 ) In review

[24]

Grade III hepatic necrosis

P

Paracetamol (acetaminophen) poisoning

Paracetamol (acetaminophen) poisoning

Suggest Documents