interventions for paracetamol (acetaminophen)...

Interventions for paracetamol (acetaminophen) overdose

(Review)

Brok J, Buckley N, Gluud C

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 3

http://www.thecochranelibrary.com

Interventions for paracetamol (acetaminophen) overdose (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Charcoal haemoperfusion versus no intervention (randomised trials), Outcome 1 Mortality. 61

Analysis 2.1. Comparison 2 Cysteamine versus no intervention (randomised trials), Outcome 1 Mortality. . . . . 62

Analysis 2.2. Comparison 2 Cysteamine versus no intervention (randomised trials), Outcome 2 Hepatotoxicity (aspartate

aminotransferase > 1000 IU/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Analysis 3.1. Comparison 3 Cysteamine versus dimercaprol (randomised trials), Outcome 1 Mortality. . . . . . 63

Analysis 3.2. Comparison 3 Cysteamine versus dimercaprol (randomised trials), Outcome 2 Maximum alanine

aminotransferase (IU/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Analysis 4.1. Comparison 4 Cysteamine versus methionine (randomised trials), Outcome 1 Mortality. . . . . . 64

Analysis 4.2. Comparison 4 Cysteamine versus methionine (randomised trials), Outcome 2 Hepatotoxicity (aspartate

aminotransferase > 1000 U/L). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Analysis 5.1. Comparison 5 Methionine and supportive treatment versus supportive treatment (randomised trials),

Outcome 1 Mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Analysis 5.2. Comparison 5 Methionine and supportive treatment versus supportive treatment (randomised trials),

Outcome 2 Hepatotoxicity (aspartate aminotransferase > 1000 U/L). . . . . . . . . . . . . . . . 65

Analysis 6.1. Comparison 6 Initial dose over 15 min versus 60 min of intravenous N-acatylcysteine (randomised trials),



Outcome 2 Hepatotoxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66


Outcome 3 Any adverse event. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Analysis 7.1. Comparison 7 Charcoal haemoperfusion in patients with fulminant hepatic failure (randomised trials),


Analysis 8.1. Comparison 8 5 h versus 10 h of charcoal haemoperfusion in patients with fulminant hepatic failure

(randomised trials), Outcome 1 Mortality. . . . . . . . . . . . . . . . . . . . . . . . . 68

Analysis 9.1. Comparison 9 Intravenous N-acatylcysteine versus ’placebo’ in patients with fulminant hepatic failure

(randomised trials), Outcome 1 Mortality. . . . . . . . . . . . . . . . . . . . . . . . . 68

68APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iInterventions for paracetamol (acetaminophen) overdose (Review)


[Intervention Review]

Interventions for paracetamol (acetaminophen) overdose

Jesper Brok1, Nick Buckley2, Christian Gluud1

1Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet,

Copenhagen University Hospital, Copenhagen, Denmark. 2Professorial Medicine Unit, POWH Clinical School, University of NSW,

Randwick, Australia

Contact address: Jesper Brok, Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, De-

partment 3344, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DK-2100, Denmark. [email protected].

[email protected]. (Editorial group: Cochrane Hepato-Biliary Group.)

Cochrane Database of Systematic Reviews, Issue 3, 2009 (Status in this issue: Unchanged)


DOI: 10.1002/14651858.CD003328.pub2

This version first published online: 19 April 2006 in Issue 2, 2006.

Last assessed as up-to-date: 21 February 2006. (Help document - Dates and Statuses explained)

This record should be cited as: Brok J, Buckley N, Gluud C. Interventions for paracetamol (acetaminophen) overdose. CochraneDatabase of Systematic Reviews 2006, Issue 2. Art. No.: CD003328. DOI: 10.1002/14651858.CD003328.pub2.

A B S T R A C T

Background

Poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Inhibition of absorption,

removal from the vascular system, antidotes, and liver transplantation are interventions for paracetamol poisoning.

Objectives

To assess the benefits and harms of interventions for paracetamol overdose.

Search strategy

We identified trials through electronic databases, manual searches of bibliographies and journals, authors of trials, and pharmaceutical

companies until December 2005.

Selection criteria

Randomised clinical trials and observational studies were included.

Data collection and analysis

The primary outcome measure was all-cause mortality plus liver transplantation. Secondary outcome measures were clinical symptoms,

(eg, hepatic encephalopathy, fulminant hepatic failure), hepatotoxicity, adverse events, and plasma paracetamol concentration. We used

Peto odds ratios and odds ratios with 95% confidence intervals (CI) for analysis of outcomes. Random- and fixed-effects meta-analyses

were performed.

Main results

Ten small and low-methodological quality randomised trials, one quasi-randomised study, and 48 observational studies were identified.

It was not possible to perform relevant meta-analyses of randomised trials that have addressed our outcome measures. Activated charcoal,

gastric lavage, and ipecacuanha are able to reduce the absorption of paracetamol, but the clinical benefit is unclear. Of these, activated

charcoal seems to have the best risk-benefit ratio. N-acetylcysteine seems preferable to placebo/supportive treatment, dimercaprol, and

cysteamine, but N-acetylcysteine’s superiority to methionine is unproven. It is not clear which N-acetylcysteine treatment protocol offers

the best efficacy. No strong evidence supports other interventions for paracetamol overdose. N-acetylcysteine may reduce mortality in

1Interventions for paracetamol (acetaminophen) overdose (Review)


mailto:[email protected]

mailto:[email protected]

http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/DatesStatuses.pdf

patients with fulminant hepatic failure (Peto OR 0.26, 95% CI 0.09 to 0.94, one trial). Liver transplantation has the potential to be

life saving in fulminant hepatic failure, but refinement of selection criteria for transplantation and long-term outcome reporting are

required.

Authors’ conclusions

Our results highlight a paucity of randomised trials on interventions for paracetamol overdose. Activated charcoal seems the best

choice to reduce absorption. N-acetylcysteine should be given to patients with overdose but the selection criteria are not clear. No N-

acetylcysteine regime has been shown to be more effective than any other. It is a delicate balance when to proceed to liver transplantation,

which may be life-saving for patients with poor prognosis.

P L A I N L A N G U A G E S U M M A R Y

Evidence on interventions for paracetamol (acetaminophen) overdose patients is weak

Poisoning with paracetamol (acetaminophen) is a common cause of hepatic injury. The evidence for all interventions for paracetamol

overdose is weak. Activated charcoal, gastric lavage, and ipecacuanha are able to reduce absorption of paracetamol if started within

one to two hours of paracetamol ingestion, but the clinical benefit is unclear. Activated charcoal seems to be the best choice if the

patient is compliant. N-acetylcysteine seems superior to no intervention and other antidotes (dimercaprol, cysteamine) and should be

administered to patients at significant risk of hepatic damage. However, N-acetylcysteine superiority to methionine is unclear. Liver

transplantation will clearly benefit patients with irreversible hepatic failure. However, identifying such patients early is problematic and

the long-term outcomes in this group of patients have not been reported. Other interventions have not shown any clinical benefit for

paracetamol overdose.

B A C K G R O U N D

Paracetamol (acetaminophen) is a mild analgesic and antipyretic

agent, which is used frequently worldwide (O’Grady 1997). In

therapeutic doses (500 mg to 1000 mg, three to four times per

day) it is known to have very few adverse events (Koch-Weser

1976). However, an overdosage can result in severe hepatotoxicity.

In general, a single dose of 150 mg/kg or more carries a risk of

liver damage, but smaller doses may also cause liver damage (

Kwan 2005). Currently paracetamol overdose is the leading cause

of acute liver failure in many countries (Lee 2004; Morgan 2005).

There are different types of interventions for paracetamol over-

dose. First, to inhibit absorption of the ingested paracetamol. Sec-

ond, to remove paracetamol from the blood after the drug is ab-

sorbed. Third, to prevent the conversion of paracetamol by cy-

tochrome P-450 2E1 to the hepatotoxic metabolite N-acetyl-p-

benzo-quinoneimine (NAPQI). Fourth, to detoxify NAPQI or to

prevent toxic effects due to this metabolite once it has been formed.

Fifth, only in severe cases, to treat fulminant hepatic failure.

Both gastric lavage, activated charcoal, and ipecacuanha (ipecac

syrup (an emetic)) may reduce paracetamol absorption within the

first few hours after ingestion (Underhill 1990; Buckley 1999a).

However, delaying these interventions wanes the potential benefi-

cial effect. Once absorbed, it has been suggested that paracetamol

can be removed from the blood with charcoal haemoperfusion (

O’Grady 1988; Higgens 1996).

Cimetidine has been suggested because it is an inhibitor of the cy-

tochrome P-450 that catalyses the activation of the toxic metabo-

lite NAPQI (Speeg 1995). However, Burkhart et al (Burkhart

1995) found no beneficial effect of adding cimetidine to N-acetyl-

cysteine in a quasi-randomised study.

Several antidotes (methionine, cysteine, cysteamine, and dimer-

caprol) that detoxify NAPQI have been assessed. Of these, cys-

teamine or methionine decreased the risk of developing liver dam-

age after a paracetamol overdose in randomised trials (Douglas

1976; Hamlyn 1981). In an observational study N-acetylcysteine

seemed equally effective as cysteamine and methionine and notice-

ably free of adverse effects (Prescott 1979). Ever since, N-acetyl-

cysteine has been accepted as the antidote of choice for paraceta-

mol overdose. Subsequently N-acetylcysteine was also found to

reduce mortality in patients with fulminant hepatic failure after

paracetamol overdose (Keays 1991).

Treatment with N-acetylcysteine is usually based on the patients’

paracetamol concentration. Different risk lines for hepatotoxicity

in graphs plotting concentration versus time are used to initiate

treatment. These ’nomograms’ are known as the high risk- (300

line), the probable risk- (200 line), and the possible risk-line (150



line) (Rumack 1975; Prescott 1979; Smilkstein 1991). If parac-

etamol levels are not available or not used, treatment is started if

more than 150 mg/kg (or more than 10 g) have been ingested.

The ultimate intervention for irreversible liver damage following

paracetamol overdose is liver transplantation. However, which cri-

teria to use for transplantation are debated (Bailey 2003). Further-

more, the decision to proceed to liver transplantation may have

to be taken in the context of a deliberate suicidal attempt, often

upon a background of mental illness and/or alcohol abuse (Bernal

1998).

This updated systematic review tries to assess the benefits and

harms of interventions for paracetamol overdose.

O B J E C T I V E S

To assess the benefits and harms of interventions for paracetamol

overdose.

M E T H O D S

Criteria for considering studies for this review

Types of studies

We included randomised trials examining interventions for parac-

etamol overdose regardless of sources of publication and language.

We expected that few randomised trials had been conducted.

Therefore, randomised trials with human volunteers, quasi-ran-

domised studies, and non-randomised studies were also included.

However, evidence of this kind has been reported under ’Ex-

ploratory analyses’ in the result section and was interpreted con-

servatively.

Several observational studies have evaluated the efficacy of N-

acetylcysteine and other antidotes. Inclusion criteria, number

of patients included, and outcome measures varied substantially

among the studies. Accordingly, we decided to specify four study

inclusion criteria regarding intervention with N-acetylcysteine and

other antidotes (Buckley 1999b) as follows:

(1) Consecutive, unselected patients with the majority of the pa-

tients not being referred from other centres for treatment.

(2) At least 20 patients.

(3) Mortality data or number of patients with an aspartate amino-

transferase (AST) or alanine aminotransferase (ALT) more than

1000 units IU/L.

(4) Data stratified by time from ingestion to antidote intervention.

Randomised trials or other studies examining interventions for

drug poisoning (which often included many patients who had

ingested paracetamol) were not included in this review.

Types of participants

Patients who have ingested a paracetamol overdose.

The definition of a paracetamol overdose is not a clear cut-off and

the risk depends on many factors eg, age, weight, co-morbidities,

medical treatment, etc. Patients are unlikely to develop hepatotox-

icity if they have ingested less than 150 mg/kg (Vale 2004) or less

than 10 g in adults (Buckley 1999a). However, the prediction of a

patient’s risk based on reported dose of paracetamol may be lim-

ited as patients or relatives are often unaware of the exact amount

ingested.

The plasma paracetamol concentration stratified by time from

ingestion indicates the risk of developing hepatotoxicity. This can

be used to define a paracetamol overdose and whether to initiate

treatment with antidotes. Three ’nomograms’ have been suggested:

• the high risk-line (300 line) that joins plots of 300 mg/L

of paracetamol at four hours and 10 mg/L at 24 hours

on semi-logarithmic graph (Smilkstein 1991).

• the probable risk-line (200 line) (200 mg/L at four hours

and 7 mg/L at 24 hours) (Rumack 1975; Prescott 1979).

• the possible risk-line (150 line) (150 mg/L at four hours

and 5 mg/L at 24 hours) (Smilkstein 1991).

Types of interventions

• Intervention with gastric lavage, ipecacuanha, or acti-

vated charcoal in any dose or duration compared with

placebo/no intervention or with each other.

• Intervention with charcoal haemoperfusion compared

with placebo/no interventions or other interventions

for paracetamol overdose.

• Intervention with antidotes (cimetidine, cysteamine,

methionine, dimercaprol, and N-acetylcysteine) com-

pared with each other, with placebo/no interventions,

or other interventions for paracetamol overdose.

• Different doses, durations, or way of administration

(peroral or intravenously) of N-acetylcysteine compared

with each other.

• Intervention with liver transplantation compared with

conservative treatment for paracetamol-induced hepatic

failure.

Co-interventions were allowed if received equally in the interven-

tions arms.

We did not want to examine other interventions for liver failure

(eg, different types of liver support) and secondary complications

to liver failure such as hepato-renal failure, hepatic encephalopathy,

and cerebral oedema.

Types of outcome measures



Primary outcome measure:(1) Mortality plus liver transplantation.

Secondary outcome measures:(2) Clinical symptoms, ie, hepatic encephalopathy, fulminant hep-

atic failure, and renal failure.

(3) Hepatotoxicity (defined as number of patients with serum

aspartate aminotransferase or serum alanine aminotransferase >

1000 IU/L).

(4) Adverse events.

(5) Plasma paracetamol concentration (eg, plasma paracetamol

above a risk line (nomogram)), fall in plasma paracetamol versus

time, absorption of paracetamol measured as area under the curve

(AUC) of the plasma (or urine) concentration versus time curve.

Search methods for identification of studies

As described in ’Appendix 1’, we searched The Cochrane Hepato-Biliary Group Controlled Trials Register and Miscellaneous Database,The Cochrane Central Register of Controlled Trials (CENTRAL) in

The Cochrane Library , MEDLINE, EMBASE, and Science Ci-tation Index Expanded (Royle 2003). Trials were also identified

through manual searches of bibliographies in relevant articles,

hand searches of Liver International, Journal of Hepatology, Hepa-tology, Journal of Viral Hepatitis, Gastroenterology, and Gut. We also

wrote to authors of included trials and pharmaceutical companies.

Searches were performed by December 2005.

Data collection and analysis

JB and NB evaluated whether the trials fulfilled the inclusion crite-

ria and extracted data. Disagreements were resolved by discussion.

Excluded trials were listed with the reason for exclusion. We wrote

to the principal investigator of included trials to ask for relevant

data if such were not presented in the published reports.

Methodological quality

Randomisation and blinding were extracted as markers of method-

ological quality (Schulz 1995; Moher 1998; Kjaergard 2001; Jüni

2001; Als-Nielsen 2004). We assessed them as follows:

Allocation sequence generation

• Adequate if a computer, table of random numbers, coin

tossing, or similar was used to generate a sequence for

the allocation of patients.

• Unclear if the trial was described as randomised, but

the methods used for the allocation sequence generation

were not described.

• Inadequate if a system involving dates, names, admit-

tance numbers or similar were used for the allocation

of patients. These trials were classified as quasi-ran-

domised.

Allocation concealment

• Adequate if the allocation of patients involved a central

independent unit, sealed envelopes, on-site locked com-

puter, or identically appearing numbered drug bottles

or containers prepared by an independent pharmacist.

• Unclear if the trial was described as randomised, but the

methods used for the allocation sequence concealment

were not described.

• Inadequate if the allocation sequence was known to the

investigators who assigned participants eg, open table

of random numbers or similar.

Blinding

• Adequate if the trial claimed to be double blind and

ribavirin placebo tablets were used.

• Unclear if the trial claimed to be double blind but the

method of blinding was not described.

• Inadequate if the trial was not double blind.

Statistical methods

The analyses were performed in Review Manager version 4.2 (

RevMan 2003). Data were analysed by intention-to-treat includ-

ing all patients irrespective of compliance or follow-up.

Binary outcomes were expressed as odds ratios (OR) and con-

tinuous outcomes as weighted mean differences (WMD) with

95% confidence intervals (CI). Rare events (mortality plus liver

transplantation) were estimated by Peto odds ratio (Deeks 1998).

Data were analysed by both a random-effects model (DerSimonian

1986) and a fixed-effect model (DeMets 1987). If the results of

both analyses gave the same overall result regarding significance,

only the results of the fixed-effect model analysis is reported. Re-

gression analyses were performed to estimate funnel plot asymme-

try (Egger 1997). Heterogeneity was explored by chi-squared test

with significance set at P-value less than 0.10 and the quantity of

heterogeneity was measured by I2 (Higgins 2002).

We intended to assess the methodological quality of the included

trials in sensitivity analyses: adequate versus unclear or inadequate

generation of allocation sequence, allocation concealment, and

blinding.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Search results

We identified 861 references through the electronic searches of

The Cochrane Hepato-Biliary Group Controlled Trials Register (n =

11), The Cochrane Hepato-Biliary Group Miscellaneous database (n



= 21), The Cochrane Central Register of Controlled Trials in TheCochrane Library (n = 44), MEDLINE (n = 252), EMBASE (n =

318), and Science Citation Index Expanded (n = 215). Of these ref-

erences, we excluded 797 clearly irrelevant references and dupli-

cates. Accordingly, this review includes data from 64 references on

10 randomised clinical trials, one quasi-randomised study, 30 ob-

servational studies in patients with paracetamol overdose, and 18

trials including healthy human volunteers. Details of these studies

are given in the table ’Characteristics of included studies’.

Randomised clinical trials

Prevention of absorption

One trial randomised patients to no intervention, activated char-

coal, ipecacuanha, or gastric lavage (Underhill 1990). However,

there are doubts about the quality of the randomisation in this

trial (see ’Methodological quality of included studies’).

Charcoal haemoperfusion

Two trials randomised patients with paracetamol-induced fulmi-

nant hepatic failure (O’Grady 1988) or acute paracetamol over-

dose (Gazzard 1974a) to charcoal haemoperfusion or no interven-

tion.

Antidotes

Three trials randomised patients to different antidotes (me-

thionine, cysteine, cysteamine and dimercaprol) (Douglas 1976;

Hughes 1977; Hamlyn 1981). One trial randomised patients to

different infusion rates of N-acetylcysteine (Kerr 2005). One trial

randomised patients with paracetamol-induced fulminant hepatic

failure to N-acetylcysteine or placebo (Keays 1991).

Other interventions

Two trials randomised patients to heparin (Gazzard 1974) or fresh

frozen plasma (Gazzard 1975) compared to no intervention.

Non-randomised studies or studies including human volun-

teers


Five observational studies (Amitai 1987; Kirk 1991; Bond 1993;

Buckley 1999a; Montoya-Cabrera 1999), 15 randomised trials in-

cluding human volunteers (Levy 1976; Neuvonen 1983; Galinsky

1984; McNamara 1988; McNamara 1989; Rose 1991; Grierson

2000; Yeates 2000; Rangan 2001; Green 2001; Christophersen

2002; Saincher 1997; Sato 2003; Green 2004; Ly 2004), and two

non-randomised including human volunteers (Remmert 1990;

Hassig 1993) were identified. The interventions investigated were

activated charcoal, ipecacuanha, gastric lavage, or whole bowel ir-

rigation.


We identified one observational study (Silk 1978) that inves-

tigated charcoal haemoperfusion for patients with paracetamol-

induced fulminant hepatic failure. One observational study (

Higgens 1996) investigated the efficacy of haemoperfusion for

acute paracetamol poisoning.

Antidotes

We identified one quasi-randomised trial (Burkhart 1995), 13

observational studies (Crome 1976; Prescott 1976; Smith 1978;

Prescott 1979; Vale 1981; Smilkstein 1988; Harrison 1990; Parker

1990; Smilkstein 1991; Spiller 1994; Buckley 1999b; Woo 2000;

Ayonrinde 2005), and one randomised trial including human vol-

unteers (Chen 1985) examining different antidotes (cysteamine,

methionine, dimercaprol, N-acetylcysteine, or cimetidine) for

paracetamol overdose.

Liver transplantation

Ten observational studies (O’Grady 1991; Mutimer 1994; Schiodt

1996; Anand 1997; Bernal 1998; Shakil 2000; Brandsaeter 2002;

Chung 2003; Gow 2003; Larson 2005) describe the course of pa-

tients with severe paracetamol-induced fulminant hepatic failure

potentially eligible for liver transplantation.

Risk of bias in included studies


All ten included trials had unclear or insufficient control of bias.

Generation of the allocation sequence was described and was ad-

equate in three randomised trials (Douglas 1976; Hamlyn 1981;

O’Grady 1988), and allocation concealment was adequate in five

randomised trials (Gazzard 1974a; Gazzard 1975; Hamlyn 1981;

Keays 1991; Kerr 2005). All randomised trials were conducted un-

blinded except one (Keays 1991), which used placebo, but failed

to mask the aroma.

In one trial, the control group was given supportive treatment

in a different hospital, which may seriously affect the value of

this comparison group and questions how the randomisation was

carried out (Underhill 1990).

Quasi-randomised studies

One study (Burkhart 1995) used odd/even months at hospitalisa-

tion to allocate patients to different interventions.

Observational studies

Ten observational studies (Smith 1978; Smilkstein 1988; Parker

1990; O’Grady 1991; Smilkstein 1991; Spiller 1994; Schiodt

1996; Buckley 1999a; Buckley 1999b; Montoya-Cabrera 1999)

were prospective. Seven observational studies (Crome 1976;

Prescott 1976; Silk 1978; Prescott 1979; Vale 1981; Kirk 1991;

Higgens 1996) were likely to be retrospective. Fourteen observa-

tional studies (Amitai 1987; Harrison 1990; Bond 1993; Mutimer

1994; Anand 1997; Bernal 1998; Gee 1998; Shakil 2000; Woo

2000; Brandsaeter 2002; Chung 2003; Gow 2003; Ayonrinde

2005; Larson 2005) were clearly retrospective.

Randomised trials in human volunteers

In all 16 trials the allocation concealment and the generation of

allocation sequence was not described. None of the trials was con-

ducted blinded.

Effects of interventions



The few included randomised trials differed substantially in inclu-

sion criteria, interventions, and outcome measures. Therefore it

was only possible to perform one meta-analysis that had addressed

our outcome measures. Due to the amount of data from non-ran-

domised trials we have summarised the results under the heading

’Exploratory analyses of quasi-randomised studies, observational

studies, and randomised trials including human volunteers’. These

data should be interpreted with caution due to the increased risk

of bias.


Activated charcoal, gastric lavage and ipecacuanha

One trial (n = 60) found that activated charcoal was significantly

more effective in lowering the plasma paracetamol level than gas-

tric lavage (P = 0.013), ipecacuanha (P = 0.027), or supportive

treatment if given within four hours after ingestion (Underhill

1990). There was no significant difference (P = 0.081) between

gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha

were more effective than supportive treatment.


One trial (n = 16) found no clinically significant benefit of treat-

ment with charcoal haemoperfusion (Gazzard 1974a). The mean

cumulative amount of paracetamol removed was 1.4 g. One pa-

tient allocated to the haemoperfusion group died after ingesting

135 grams of paracetamol.

One trial found no significant difference in survival between 10

versus 5 hours of haemoperfusion in 53 patients with fulminant

hepatic failure (O’Grady 1988). Further, O’Grady et al found no

significant difference in survival between 10 hours of haemoper-

fusion versus no haemoperfusion in 32 patients with fulminant

hepatic failure and encephalopathy grade 4.

Cysteamine, methionine, and dimercaprol

Compared to no intervention, cysteamine had no significant effect

on mortality (Peto OR 0.53, 95% CI 0.05 to 5.22, two trials with

65 patients), but significantly decreased the risk of developing

hepatotoxicity (OR 0.17, 95% CI 0.06 to 0.53, two trials with 65

patients).

One trial (n = 40) found no significant difference between cys-

teamine, methionine, and no intervention in mortality (only one

patient died in the ’no intervention’ group) (Hamlyn 1981). Com-

pared to ’no intervention’, methionine significantly reduced the

number of patients with hepatotoxicity. No significant differ-

ence in hepatotoxicity was observed between methionine and cys-

teamine.

One trial (n = 52) found no significant difference between cys-

teamine and dimercaprol in mortality or hepatotoxicity (Hughes

1977). One patient receiving dimercaprol died.

All trials reported that most patients given cysteamine had nausea

and vomited during the therapy. Some patients also had severe

headaches, one had transient truncal rash, and one developed se-

vere malaise (Hamlyn 1981). One trial reported that 4/13 patients

given oral methionine needed additional metoclopramide to pre-

vent vomiting (Hamlyn 1981). Dimercaprol given as a deep in-

tramuscular injection was painful in all patients and 9/26 patients

developed severe abdominal pain (Hughes 1977).

N-acetylcysteine

One trial (n = 180) found no significant difference of initial in-

travenously dose of N-acetylcysteine over 60 min compared to 15

min on mortality (no deaths occurred) or hepatotoxicity (RR 0.75;

95% CI 0.22 to 2.56) (Kerr 2005). The 15 min infusion rate did

not significantly increase the risk of a specific adverse events (eg,

anaphylactoid reactions, gastrointestinal disorders, etc.) or drug-

related adverse events within two hours (RR 1.17; 95% CI 0.63

to 2.17), but significantly increased the number of patients with

occurrence of adverse events (RR 1.98; 95% CI 1.04 to 3.72).

One trial (n = 50) found that intravenous N-acetylcysteine com-

pared with placebo for paracetamol-induced fulminant hepatic

failure significantly reduced mortality (RR 0.65; 95% CI 0.43 to

0.99) (Keays 1991). No adverse events to N-acetylcysteine were

reported.

Other interventions

Two trials assessed heparin (Gazzard 1974) and fresh frozen plasma

therapy (Gazzard 1975) for patients with paracetamol overdose

without any finding of any significant clinical benefits.

Exploratory analyses of quasi-randomised studies

Cimetidine

One study (n = 107) found no significant effect of adding cime-

tidine to N-acetylcysteine on mortality (zero in both groups) and

hepatotoxicity (Burkhart 1995).

Exploratory analyses of observational studies

Activated charcoal

One study (n = 330) found that activated charcoal within 24 hours

significantly reduced the number of patients with paracetamol

concentration above the probable risk-line (Buckley 1999a). No

significant difference was observed in coma incidence and length

of hospital stay. Patients not receiving activated charcoal had a

significant longer time to presentation after ingestion. Subgroup

analyses indicate that activated charcoal is only beneficial if ad-

ministered within two hours.

One study (n = 122) found that activated charcoal within 16

hours significantly reduced the number of patients having a plasma

paracetamol concentration above the possible risk-line (Spiller

1994).

One study with 123 children found that activated charcoal within

two hours significantly reduced plasma paracetamol level (Kirk

1991).

On study with 14 children found that adding activated charcoal

to N-acetylcysteine significantly increased the half-life elimination

of paracetamol (Montoya-Cabrera 1999).

Ipecacuanha

One study with 455 children found that ipecacuanha significantly

reduced paracetamol concentration if vomiting occurred before 90

minutes. There was no significant reduction when ipecacuanha-

induced emesis occurred later than 90 minutes (Bond 1993).



One study with 123 children found that ipecacuanha within

one hour significantly reduced plasma paracetamol level (Kirk

1991). No significant difference on plasma paracetamol between

ipecacuanha and activated charcoal within two hours was ob-

served.

One study with 50 children found that ipecacuanha administered

early (at home) compared to late (at the hospital) decreased parac-

etamol concentration (Amitai 1987).

Gastric lavage

One study (n = 253) found that adding gastric lavage to activated

charcoal within 24 hours did not significantly reduce the number

of patients with paracetamol concentration above the possible risk

line or length of hospital stay (Buckley 1999a).

Haemoperfusion

One study (n = 79) found no significant difference on mortality

between charcoal haemoperfusion versus haemodialysis or versus

supportive therapy (Silk 1978).

One study found that charcoal haemoperfusion given within 42

hours compared to later than 42 hours after a paracetamol overdose

significantly reduced mortality (Higgens 1996).

Antidotes

We have presented the pooled results from all the studies (using

any of risk-line) (Table 1; Table 2; Table 3). We found that 21/107

(19%) on cysteamine, 31/197 (16%) on methionine, 418/2315

(18%) on N-acetylcysteine, and 52/90 (58%) given no interven-

tion developed hepatotoxicity. If any antidote was given within 10

hours, only 76/1153 (7%) developed hepatotoxicity compared to

392/1435 (27%) if antidotes were given later than 10 hours. A

total of 306/1614 (19%) given N-acetylcysteine orally developed

hepatotoxicity compared to 80/637 (13%) given N-acetylcysteine

intravenously. A total of 34/226 (15%) given N-acetylcysteine 980

mg/kg intravenously for 48 hours compared to 50/458 (11%) N-

acetylcysteine 300 mg/kg intravenously for 24 hours developed

hepatotoxicity. Pooling studies only using the 200 risk-line (prob-

able risk) did not change the above results significantly.

Table 1. Antidotes for paracetamol overdose

Cysteamine Methionine Dimercaprol N-acetylscysteine Supportive treatment

Treatment delay: 0 h

to 10 h

Mortality 0/97 (0%) 0/143 (0%) 1/26 (4%) 0/949 (0%) No data

Hepatotoxicity 4/61 (7%) 13/143 (9%) No data 58/949 (6%) No data



Table 1. Antidotes for paracetamol overdose (Continued)

Treatment delay: 10

h to 24 h

Mortality 2/24 (8%) 2/41 (5%) No data 16/1366 (1%) No data

Hepatotoxicity 16/28 (57%) 17/41 (38%) No data 359/1366 (25%) No data

All (0 h to 24 h):

Mortality 3/133 (2%) 2/197 (1%) 1/26 (4%) 16/2315 (0.7%) 5/90 (6%)

Hepatotoxicity 21/107 (20%) 31/197 (16%) No data 418/2315 (18%) 52/90 (58%)

Patients included

from:

Douglas 1976;

Smith 1978; Ham-

lyn 1981; Hughes

1977; Prescott 1976

Crome 1976; Ham-

lyn 1981; Prescott

1976; Vale 1981

Hughes 1977 Burkhar1 1990; Buck-

ley 1999b;

Parker 1990; Prescott

1979; Smilkstein 1989;

Smilkstein 1991; Woo

2000; Ayonrinde 2005

(0-12 h and 12-24 h):

Kerr 2005 (0-8 h and

8-24+ h)

Douglas 1976;

Hamlyn 1981; Prescott

1979

Table 2. Oral versus intravenous N-acetylcysteine (NAC)

Oral NAC intravenous NAC

Treatment delay: 0 h to 10 h

Mortality 0/634 (0%) 0/315 (0%)

Hepatotoxicity 45/634 (7%) 13/315 (4%)


Mortality 10/980 (1%) 6/322 (2%)

Hepatotoxicity 261/980 (27%) 67/322 (21%)

All (0 h to 24 h):

Mortality 10/1614 (0.6%) 6/637 (0.9%)

Hepatotoxicity 306/1614 (19%) 80/637 (13%)



Table 2. Oral versus intravenous N-acetylcysteine (NAC) (Continued)

Included patients from: Smilkstein 1988; Spiller 1990: Woo 2000 Buckley 1999b; Parker 1990; Prescott 1979; Smilkstein

1991; Ayonrinde 2005; Kerr 2005

Table 3. Intravenous N-acetylcysteine 980 mg/kg for 48 h versus to NAC 300 mg/kg for 24 h

NAC: 980 mg/kg 48 h NAC: 300 mg/kg 24 h


Mortality 0/106 (0%) 0/242 (0%)

Hepatotoxicity 7/106 (7%) 7/242 (1%)


Mortality 2/120 (2%) 4/216 (0.9%)

Hepatotoxicity 27/120 (23%) 43/216 (20%)


Mortality 2/226 (1%) 4/458 (0.9%)

Hepatotoxicity 34/226 (15%) 50/458 (11%)

Included patients from: Smilkstein 1991, Woo 2000 Prescott 1979; Parker 1990; Buckley 1999b; Ayonrinde 2005; Kerr

2005



One study (n = 98) in patients with paracetamol-induced fulmi-

nant hepatic failure found that N-acetylcysteine compared to no

intervention reduced mortality and the risk of coma significantly

(Harrison 1990).


Ten studies compared mortality among patients who had liver

transplantation to similar patients who did not. All studies used

almost the same criteria (Kings Hospital (O’Grady 1991)) for list-

ing patients for liver transplantation. The pooled results (Table 4)

show that 19/67 (28%) patients with transplantation and 121/180

(67%) patients without transplantation died.

Exploratory analyses of randomised trials including human

volunteers ingesting 1 g to 5 g of paracetamol

Activated charcoal

All trials, except one, found that activated charcoal given immedi-

ately, 30 min, or 60 min after a paracetamol ingestion, significantly

reduced the absorption. Two trials (Rose 1991; Christophersen

2002) found that activated charcoal given 120 min after ingestion

reduced absorption, but two trials (Yeates 2000; Green 2001) did

not support these findings (Table 5). One trial found activated

charcoal superior to ipecacuanha (Neuvonen 1983), and one study

found no significant difference (McNamara 1989).

Table 4. Liver transplantation for fulminant hepatic failure

Transplantation Supportive treatment Transpl. criteria Reference

2/6 (33%) mortality 7/8 (88%) mortality Kings College Hospital (KCH) and listed

for transplantation

O’Grady 1991

3/10 (30%) 6/7 (86%) Probably KCH and listed for transplan-

tation

Mutimer 1994

no data 6/10 (60%) KCH Schiodt 1996

no data 24/31 (77%) pH<7.3 Anand 1997

11/44 (25%) 20/24 (83%) KCH and listed for transplantation Bernal 1998

no data 10/14 (71%) KCH Shakil 2000

no data 16/32 (50%) KCH and listed for transplantation Brandsaeter 2002



Table 4. Liver transplantation for fulminant hepatic failure (Continued)

no data 4/6 (67%) KCH Chung 2003

1/1 (100%) 7/14 (50%) KCH Gow 2003

2/6 (33%) 19/34 (56%) KCH Larson 2005

19/67 (28%) 121/180 (67%) All

KCH: pH < 7.3 or prothrombin time >

100 (INR > 6.5), grade 3-4 encephalopa-

thy and serum creatinie > 300 umol/L

(17.5 mg/dl).

Table 5. Activated charcoal in volunteers (Outcome: bioavailability of paracetamol)

Paraceta-

mol dose

No of pa-

tients

Charcoal

(AC)

Form Delay

(min)

Control Charcoal Reduction

(%)

Study

1 g 8 5 g Carbo

adsorbens

from Norit

N.

0 39.9±7

(AUC (p) 0-

8 h,

mean ± SD)

19.5±4

(AUC (p) 0-

8 h,

mean ± SD)

51 (P <

0.05)

Remmert

1990

1 g 8 10 g 900 to 1500

mg/square

meters

0 90±11 (% of

dose) (AUC

(u) 0-48 h,

mean ± SD)

57± 24%

(AUC (u) 0-

48 h,

mean ± SD)

37 (P <

0.005)

Galinsky

1984

1 g

plus sodium

sulfate

8 10 g 900 to 1500

mg/square

meters

0 87±8 (% of

dose)

(AUC (u) 0-

48 h,

mean ± SD)

59± 15%

(AUC (u) 0-

48 h,

mean ± SD)

33 (P <

0.005)

Galinsky

1984

1 g 5 5 g 900 to 1500

mg/square

meters

0 83 ± 4 (% of

dose) (AUC

(u) 0-48 h,

mean ± SD)

44±7%

(AUC (u) 0-

48 h, mean ±

SD)

47 (P <

0.001)

Levy 1976

1 g 5 10 g 900 to 1500

mg/square

meters

0 83 ± 4 (% of

dose) (AUC

(u) 0-48 h,

mean ± SD)

32±9%

(AUC (u) 0-

48 mean ±

SD)

61 (P <

0.001)

Levy 1976



Table 5. Activated charcoal in volunteers (Outcome: bioavailability of paracetamol) (Continued)

5.6 g (80

mg/kg)

8 70 g (1g /kg)

plus cola

Char-

coAid 2000:

2000square

meters/g

0 298±83

mg*h/L

(AUC (u) 0-

6 h, mean ±

SD)

81±72

mg*h/L

(AUC (p) 0-

6 h, mean ±

SD)

73 (P <0.05) Rangan

2001

5.6 g (80

mg/kg)

8 70 g (1g /kg) Char-

coAid 2000:

2000square

meters/g

0 298±83

mg*h/L

(AUC (u) 0-

6 h, mean ±

SD)

77±85

mg*h/L

(AUC (p) 0-

6 h, mean ±

SD)

74 (P <0.05) Rangan

2001

1 g 6 50 g 1600 to

2000

mg/square

meters

5 100%

(AUC (p) 0-

24 h)

15% (range

1-30%)

85 (P <

0.01)

Neuvonen

1983

5 g 10 30g Super-

char: 3.150

square me-

ters/g

15 81±6%

(AUC (u) 0-

24 h, mean ±

SD)

42±10.2% 48 (P <

0.05)

Rose 1991

5 g 10 30 g Super-

char: 3.150

square me-

ters/g

30 81±6%

(AUC (u) 0-

24 h, mean ±

SD)

45±8% 44.1(P <

0.05)

Rose 1991

1 g 6 10 g 900 to 1500

mg/square

meters

30 100%

(AUC (u)0-

24 h)

40% (range

14-90%)

60 (P <

0.05)

Neuvonen

1983

1 g 5 10 g 900 to 1500

mg/square

meters

30 83 ± 4%

(AUC (u)0-

48 h, mean ±

SD)

57±7% 31.1 (P <

0.005)

Levy 1976

3 g 8 50 g Med Corp

Acta-Char:

950 square

meters/g

60 123

mg*h/ml

(AUC (p)0-

8 h) (A)

87 mg*h/ml

(AUC (p)0-

8 h) (A)

29 (A) (P <

0.05)

McNamara

1988

3.6 g (50

mg/kg)

12 50 g Carbomix:

2000 square

meters/g

60 190 mg*h/L

(95%

CI 119-235)

(AUC (p)0-

48 h)

539 mg*h/L

(95% CI

19.7-135)

66 (P <

0.05)

Christo-

phersen

2002




3 g 10 50 g Carbomix:

2000 square

meters/g

60 182 mg*h/L

(95% CI

143 to 221)

(AUC (b) 0-

48 h) SD:

19.5

92 mg*h/L

(95% CI 60

to 125) S.D:

16.3

43 (P <

0.05)

Yeates 2000

3 g 10 50 g 900 to1500

mg/square

me-

ters with ad-

ditional sor-

bitol

60 119

mg*h/ml

(AUC (p)0-

8 h) (A)

89 mg*h/ml

(A)

26 (A) (P <

0.05)

McNamara

1989

4 g 10 50g Charcodote:

?

60 221±122

mg*h/L

(AUC (p)0-

8 h)

154±71mg*h/L

67 (P <

0.001)

Green 2001


?

60 258±122

mg*h/L

(AUC (p)0-

48 h)

206±120

mg*h/L

20 (P <

0.10)

Green 2004


2000 square

meters/g

120 182 mg*h/L

(95% CI

143 to 221)

(AUC (p) 0-

48 h) SD:

19.5

164 mg*h/L

(95%

CI 122 to

2-205) S.D:

20.75

1 (P > 0.05) Yeates 2000

3.6 g (50

mg/kg)

12 50 g Carbomix:

2000 square

meters/g

120 190 mg*h/L

(95%

CI 119-235)

(AUC (p)0-

48 h)

152 mg*h/L

(95% CI

53.8-116.2)

23 (P <

0.05)

Christo-

phersen

2002


?

120 221±122

mg*h/L

(AUC (p)0-

8 h)

206±67

mg/l*h

15 (P >

0.05)

Green 2001

5 g 10 30 g Super-

char: 3.150

square me-

ters/g

120 81±6%

(AUC (u) 0-

24 h, mean ±

SD)

54±8% 33 (P <

0.05)

Rose 1991





?

180 221±122

mg*h/L

(AUC (p)0-

8 h)

204±58

mg/l*h

17 (P >

0.05)

Green 2001


2000 square

meters/g

240 182 mg*h/L

(95% CI

143 to 221)

(AUC (p) 0-

48 h) SD:

19.5

171 mg*h/L

(95% CI

135 to 207)

S.D: 18.0

-2 (P > 0.05) Yeates 2000

AUC

= area under

the paraceta-

mol plasma

(o) or urine

(u)versus

time curve.

A = cor-

rected mean

AUC

Gastric lavage

One trial found a significant reduction in absorption of parac-

etamol if gastric lavage was performed 60 min after ingestion (

Grierson 2000) (Table 6). One trial found no significant effect of

adding gastric lavage to activated charcoal one hour after ingesting

paracetamol (Christophersen 2002).

Table 6. Gastric lavage in volunteers (Outcome: bioavailability of paracetamol)

Paracetamol

dose

Number of pa-

tients

Delay (min) Control Lavage Reduction (%) Study

4 g 10 60 195 ± 31 mg*h/L 154 ± 52 mg*h/l 20 (P < 0.05) Grierson 2000

Ipecacuanha

One trial found that ipecacuanha one hour after ingestion signif-

icantly reduced paracetamol absorption (McNamara 1989). Two

trials found that ipecacuanha significantly reduced absorption five

minutes after ingestion, but not 30 min after ingestion (Neuvonen

1983; Saincher 1997) (Table 7).



Table 7. Ipecac in human volunteers (Outcome: bioavailability of paracetamol)

Paracetamol

dose

Number of

patients

Form Delay (min) Control Ipecacuanha Reduction (%) Study

3,9 g 10 30 mL 5 206 mg*h/L ±

48 (AUC (p)0-

6h, mean ± SD)

67 mg*h/L ± 37

(AUC (p)0-6h,

mean ± SD)

67 (P < 0.05) Saincher 1997

1 g 6 20 mL 5 55 mg*h/L 18 mg*h/L 65 (P < 0.01) Neuvonen 1983

1 g 6 20 ml 30 55 mg*h/L 54 mg*h/L 2 (P > 0.05) Neuvonen 1983

3,9 10 30 mL 30 206 mg*h/L ±

48 (AUC (p)0-

6h, mean ± SD)

183 mg*h/L ±

78 (AUC (p)0-

6h, mean ± SD)

11 (P > 0.05) Saincher 1997

3,9 10 30 mL 60 206 mg*h/L ±

48 (AUC (p)0-

6h, mean ± SD)

162 mg*h/L ±

47 (AUC (p)0-

6h, mean ± SD)

21 (P > 0.05) Saincher 1997

3 g 10 30 mL 60 120 (corrected

mean area under

the curve)

94 21 (P < 0.05) McNamara

1989

Whole bowel irrigation

One trial found that whole bowel irrigation (30 min after inges-

tion) had no significant reduction in absorption of paracetamol (

Ly 2004) (see Table 8). One trial found that whole bowel irrigation

(30 min after ingestion) had a significant reduction in absorption

of paracetamol if the ingested paracetamol dose was 4 g, but not

if the dose was 2 g (Hassig 1993).

Table 8. Whole bowel irrigation in volunteers (Outcome: bioavailability of paracetamol)

Dose Number of

patients

Type Delay (min) Control Bowel irriga-

tion

Reduction % Study

5 g (75

mg/kg)

10 ? 30 323 (95% CI

237-409)

(AUC (p) 0-6

h)

286 (95% CI

219-352)

(AUC (p) 0-6

h)

12 (P > 0.05) Ly 2004

Cimetidine

One trial found no statistical beneficial effect on plasma paraceta-

mol when ingesting cimetidine together with 750 mg paracetamol

(Chen 1985).

D I S C U S S I O N

Gastric lavage, activated charcoal, and ipecacuanha are able to re-

duce the absorption of paracetamol if given shortly after ingestion.

Activated charcoal seems to be the best choice to reduce parac-

etamol absorption but is less likely to be effective if given later

than two hours postingestion. N-acetylcysteine seems preferable to



placebo/supportive treatment, dimercaprol, and cysteamine, but

the superiority of N-acetylcysteine’s to methionine is unproven.

No N-acetylcysteine regimen has been shown to be more effective

than any other. Survival among patients with paracetamol-induced

fulminant hepatic failure seems higher if treated with N-acetyl-

cysteine; short-term survival is improved by liver transplantation

in those meeting transplant criteria, but long-term outcome data

are not available. There is no strong evidence supporting other

interventions for paracetamol overdose.

Our results highlight a lack of randomised trials on interventions

for paracetamol overdose, which is surprising as it is a very com-

mon type of drug poisoning. The included randomised trials were

small, the methodological quality was low, and most trials assessed

interventions not used today. Eg, no randomised trial has inves-

tigated the effect of the recommended antidote N-acetylcysteine

versus other antidotes or no intervention. More research to weight

up the benefits and risks of all interventions for paracetamol over-

dose are needed to confirm the established practice.

We included a several observational studies in explanatory analy-

ses, which raises some problems. There is no recommended search

strategy to identify observational studies within the Cochrane Col-

laboration. We tried to develop an extensive search strategy, but

we may not have been able to identify all relevant studies. Second,

there is no consensus within the Cochrane Collaboration on how

to assess the quality of observational studies. Furthermore, most

studies assessed surrogate outcomes indicating liver damage and

only few studies assessed important clinical outcomes. Accord-

ingly, the results of this review should be interpreted with caution.


Only one randomised trial found activated charcoal to be more

effective than gastric lavage, ipecacuanha, or no intervention in

preventing the absorption of paracetamol (Underhill 1990). How-

ever, the number of patients included was small and the time inter-

val between ingestion and intervention in the different groups was

not clearly reported. The control group was given supportive treat-

ment in a different hospital which questions how the randomisa-

tion was carried out. Furthermore, the supportive treatment was

stopped early due to ethical reasons that may seriously affect the

value of the comparison group. Therefore, the value of this trial is

limited.

All the observational studies and studies in volunteers found that

activated charcoal, gastric lavage, or ipecacuanha, shortly after in-

gestion, are able to reduce the absorption of paracetamol. Whether

this translates into clinical benefits is not clear. Two studies sug-

gested that activated charcoal reduces the need for N-acetylcysteine

treatment (Spiller 1994; Buckley 1999a). Some results indicate

that activated charcoal may prevent absorption up to two hours

postingestion (Rose 1991; Buckley 1999a), but it may vary, eg,

depending on the dose of paracetamol, the gastric environment,

and additionally taken drugs. Through passive diffusion, activated

charcoal may also absorb paracetamol from the bloodstream which

may favour protracted use of activated charcoal compared with

gastric lavage or ipecacuanha (Rose 1991; Spiller 1994). Two stud-

ies found no benefits of adding gastric lavage to activated charcoal

(Buckley 1999a; Christophersen 2002).

The risk of adverse events has barely been reported. One well-

known complication from all the three interventions is aspiration

pneumonia (Liisanantti 2003). We identified one randomised trial

(Cooper 2005), which reported no significant increase of adverse

events in patients receiving activated charcoal for any drug over-

dose. Position statements on drug poisonings indicate that serious

adverse events seem to be fewer in activated charcoal compared

to ipecacuanha and gastric lavage (Chyka 2005; Krenzelok 2004;

Vale 2004). Accordingly, weak evidence indicates that activated

charcoal is currently the best choice to prevent absorption of parac-

etamol.

Haemoperfusion

Haemoperfusion has only been studied superficially and we found

no evidence to support or refute haemoperfusion for paracetamol

overdose and fulminant hepatic failure. Given the availability of

cheap and more effective alternatives, any plausible benefits of

haemoperfusion are unlikely to be justifiable on economic or risk-

benefit grounds.

Antidotes

Cysteamine, methionine, and dimercaprol

Two randomised trials found hepatoprotective effect of methion-

ine and cysteamine compared to no intervention (Douglas 1976;

Hamlyn 1981). No significant difference was observed between

the two antidotes, but a third trial found cysteamine superior to

dimercaprol (Hughes 1977). Douglas et al (Douglas 1976) had a

control group with a significant higher paracetamol concentration

before treatment which may limit the value of this comparison

group. Further, it must also be noted that data from four patients

were used in two trials (Douglas 1976; Hamlyn 1981). One ob-

servational study supports the beneficial effects of methionine and

cysteamine on hepatotoxicity (Prescott 1976). Overall cysteamine

therapy was associated with a high rate of nausea and vomiting.

Few adverse events were noticed in patients given methionine and

dimercaprol. Accordingly, methionine probably seems to be the

best choice of antidote among the three.

N-acetylcysteine

One randomised trial found that N-acetylcysteine increases sur-

vival in patient with paracetamol-induced fulminant hepatic fail-

ure (Keays 1991). However, no randomised trials have assessed the

effect of N-acetylcysteine in the acute treatment of paracetamol

overdose. One observational study found that N-acetylcysteine



compared to supportive treatment decreased the risk of hepato-

toxicity (Prescott 1979). Compared with cysteamine or methio-

nine there was no statistical difference, but these antidotes were

considered to have more adverse events. The study was small (n

= 200) and the comparison antidote and supportive groups were

historical control groups treated three and ten years earlier, respec-

tively. Accordingly, the risk of biased findings in this study is sub-

stantial (Sacks 1982; Deeks 2003). However, since this study was

published, N-acetylcysteine has been recommended as the drug

of choice. Historical data show that the overall mortality rate has

dropped from 3% (all poisonings (Clark 1973)) or 5 % (all above

the probable risk-line (Prescott 1979)) to 0.7% (Table 1) after the

introduction of N-acetylcysteine.

Pooling (Table 1) the patients from all the studies indicates that

N-acetylcysteine should be preferred over supportive treatment

and that early treatment (0 h to 10 h) is preferable compared to

late treatment (10 h to 24 h) irrespective the type of antidote.

However, the risk-line used for treating patients in all studies was

not uniform.

No randomised trials have demonstrated the optimal way of ad-

ministration and most beneficial dose of N-acetylcysteine. Pool-

ing (Table 2; Table 3) the results from the all the studies indi-

cates no clear difference between oral and intravenous N-acetyl-

cysteine administration or different intravenous protocols. How-

ever, one randomised trials found that slow initial infusion (60

minutes) of the 300 mg/kg intravenous protocol did not cause a

clinical important decrease in the number of adverse events. N-

acetylcysteine has never been compared to supportive treatment

in randomised trials or large observational studies. Therefore it

is difficult to quantify the risk of adverse events. Intravenous N-

acetylcysteine may induce anaphylactoid reactions and delivered

doses of N-acetylcysteine often vary from the intended which may

lead to inadvertent overdose and death (Mant 1984; Appelboam

2002; Bailey 2004; Ferner 2004). Oral N-acetylcysteine adminis-

tration often results in rashes, nausea, vomiting, and abdominal

pain. Accordingly, intravenous N-acetylcysteine seems to be as-

sociated with fewer more severe adverse events compared to oral

N-acetylcysteine, which frequently is associated with less severe

adverse events.

Most recommendations advise to measure the plasma paraceta-

mol concentration. If the plasma paracetamol is above a chosen

risk-line, N-acetylcysteine is advocated. If it is not possible to ob-

tain a plasma paracetamol concentration, N-acetylcysteine treat-

ment should be given if a potentially toxic dose has been ingested

(150 mg/kg). Other recommendations advise to initiate treatment

based on reported dose and not wait for blood samples. However,

paracetamol concentrations correlates weakly with reported parac-

etamol dose (Thomas 1997).

Both the 200 risk-line and the 150 risk-line are used as a direc-

tion for continued N-acetylcysteine intervention. Many factors

like alcoholism, eating disorder, or use of enzyme-inducing agents

increase the risk of paracetamol hepatotoxicity, and these patient

groups may need a lower threshold for treatment. After treatment

liver biochemistry should be checked (Vale 1995). If these vari-

ables are normal and the patient is asymptomatic, then he/she may

be discharged. If the patient has developed or is at risk of develop-

ing fulminant hepatic failure, N-acetylcysteine treatment should

be continued until recovery. It should be noticed that N-acetylcys-

teine and/or paracetamol overdose itself without evidence of liver

injury may increase the international normalised ratio (INR), and

management decisions should be based on the entire liver bio-

chemistry (Whyte 2000; Schmidt 2002).


Pooling the results from ten observational studies with 247 pa-

tients, in which King’s College Hospital criteria for liver transplan-

tation were used, indicates that transplantation improves survival

(Table 4). Overall 28% (19/67) of the patients with transplanta-

tion and 67% (121/180) of the patients without transplantation

died, but long-term outcomes were not assessed. Furthermore, de-

spite fulfilling King’s Hospital criteria, a substantial difference in

mortality rates in patients without transplantation were identified.

This difference may be because some studies reported the out-

come of patients that fulfilled King’s Hospital criteria at admission

whereas other reported the outcome of patients that fulfilled these

criteria during hospital stay.

N-acetylcysteine administration improves survival in patients with

fulminant hepatic failure, but no study has demonstrated when it

is beneficial to switch from late N-acetylcysteine administration

to liver transplantation. It is, therefore, difficult to choose between

N-acetylcysteine treatment and the risk of delaying transplanta-

tion which increases the patients’ risk of developing multi-organ

failure. Furthermore, the decisions to proceed to transplantation

may be taken in the context of contraindication like alcohol or

drug abuse, other diseases, age, graft availability, other recipients,

and patient/relative compliance. The King’s Hospital criteria are

widely used to list patients for liver transplantation. These criteria

have some limitations, eg, in some studies 50% of the patients

fulfilling the criteria survived without transplantation. Future re-

search may identify criteria of higher sensitivity and specificity

(eg, APACHE II) in predicting patients mortality risks and need

for transplantation (Mitchell 1988; Larson 2005). Even in liver

transplanted patients we found that 28% had short-term mortal-

ity. Accordingly, randomised trials in selected patient groups seems

needed.

Children

Children who unintentionally ingest a paracetamol overdose rep-

resent a difficult group of patients. They are rarely able to tell how

much and when they have ingested the drug. Furthermore, the



applicability of the recommended treatment line in young chil-

dren has never been proven due to the paucity of data (Vale 1995).

Therefore, treatment of children should be carried out with great

caution and more research is needed.

A U T H O R S ’ C O N C L U S I O N SImplications for practice

Although the evidence for how to treat patients with paracetamol

overdose is weak, the following recommendations seem reasonable:

Activated charcoal, gastric lavage, and ipecacuanha are interven-

tions that seem able to reduce the absorption of paracetamol if

the patients are treated within one to two hours postingestion.

Whether this translates into clinical benefits is unclear. If the pa-

tient is compliant, activated charcoal seems the best choice.

N-acetylcysteine should be given promptly to patients with parac-

etamol overdose, but the selection criteria are not clear. A poten-

tially toxic dose could be based on ingested dose (150 mg/kg or

more) or plasma paracetamol concentration above a chosen risk-

line. Furthermore, N-acetylcysteine should be given to all patients

with abnormal liver biochemistry or fulminant hepatic failure af-

ter paracetamol overdose. No N-acetylcysteine treatment regime

(1330 mg/kg orally. (72 hours), 980 mg/kg intravenously (48

hours), or 300 mg/kg intravenously (24 hours)) has been shown

to be more effective than any other.

Liver transplantation reduces the short-term mortality in patients

selected according to Kings Hospital criteria. However, the short-

term mortality among transplanted patients is still around 28%

and the long-term survival is not known. Moreover, a substantial

proportion of patients listed for transplantation survive with con-

servative therapy. Furthermore, making a decision to proceed to

transplantation in patients who have attempted suicide is a diffi-

cult task which may limit this therapeutic option.

Implications for research

Patients with a paracetamol overdose need to be studied in large

multicentre randomised trials with adequate methodology and

with relevant clinical outcome measures. The substantial fall in

mortality rate from paracetamol overdose since the introduction

of N-acetylcysteine means that it is unlikely that it would be con-

sidered ethical to randomise to N-acetylcysteine versus no inter-

vention. This review has demonstrated a number of topics that

need assessment in randomised trials, eg, N-acetylcysteine admin-

istered intravenously versus orally; N-acetylcysteine in one dose

versus other doses; activated charcoal versus no decontamination

or other methods for reducing paracetamol absorption; long-term

outcome of N-acetylcysteine versus N-acetylcysteine plus liver

transplantation in patients with fulminant hepatic failure. Fur-

thermore, adverse events in relation to the different interventions

should be reported systematically. New trials should be registered

(http://www.icmje.org/clin_trialup.htm) and reported according

to the CONSORT guidelines (www.consort-statement.org).

A C K N O W L E D G E M E N T S

We are indebted to Dimitrinka Nikolova and Sarah Klingenberg

for their helpful assistance. We also want to express our gratitude

to the Contact Editor and peer reviewers as well as Ronald L Koretz

for many helpful comments.

R E F E R E N C E S

References to studies included in this review

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Higgens 1996 {published data only}

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Kirk 1991 {published data only}

Kirk M, Peterson J, Kulig K. Acetaminophen overdose in children:

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Levy 1976 {published data only}

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McNamara 1988 {published data only}

McNamara RM, Aaron CK, Gemborys M, Davidheiser S. Sorbitol

catharsis does not enhance efficacy if charcoal in a simulated ac-

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McNamara 1989 {published data only}

McNamara RM, Aaron CK, Gemborys M, Davidheiser S. Efficacy of

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934–8.

Montoya-Cabrera 1999 {published data only}

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Larios VM, Teran-Hernandez JA. Evaluation of the efficacy of N-

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Mutimer 1994 {published data only}

Mutimer DJ, Ayres RCS, Neuberger JM, Davies MH, Holguin J,

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Neuvonen 1983 {published data only}

Neuvonen PJ, Vartiainen M, Tokola O. Comparison of activated

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O’Grady 1988 {published data only}

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O’Grady 1991 {published data only}

O’Grady JG, Wendon J, Tan KC, Potter D, Cottam S, Cohen AT,

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Parker 1990 {published data only}

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Smith 1978 {published data only}

Smith JM, Roberts WO, Hall SM, White TA, Gilbertson AA. Late

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Spiller 1994 {published data only}

Spiller HA, Krenzelok EP, Grande GA, Safir EF, Diamond JJ. A

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Underhill 1990 {published data only}

Underhill TJ, Greene MK, Dove AF. A comparison of the afficacy

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Vale 1981 {published data only}

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etaminophen overdose: risk factors associated with hepatocellular

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Chamberlain 1993 {published data only}

Chamberlain JM, Gorman RL, Oderda GM, Klein-Schwartz W,

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Chan 1993 {published data only}

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Dordoni B, Willson RA, Thompson RPH, Williams R. Reduction of

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Read 1986 {published data only}

Read RB, Tredger JM, Williams R. Analysis of factors responsible for

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300–4.

Schiodt 1997 {published data only}

Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen tox-

icity in an urban county hospital. New England Journal of Medicine

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Schmidt 2002a {published data only}

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Singer 1995 {published data only}

Singer AJ, Carracio TR, Mofenson HC. The temporal profile of in-

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Dougherty 2000 {published data only}

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Amitai 1987

Methods A retrospective observational study.

Participants 50 children less than five years of age with paracetamol overdose; 27 were boys and 23 were girls.

Interventions Group 1:received ipecac syrup at home. Group 2:received ipecac syrup at the hospital.

Outcomes Plasma paracetamol and area under the concentration-time curve (AUC).

Notes

Risk of bias

Item Authors’ judgement Description

Allocation concealment? Unclear D - Not used

Anand 1997


Participants 31 patients with paracetamol induced fulminant hepatic failure and pH < 7.30.

Interventions Supportive care.

Outcomes Mortality

Notes

Risk of bias



Ayonrinde 2005


Participants 99 patients from medical records of 188 patients with a paracetamol overdose who had plasma levels above

the 200-line and received N-acetylcysteine..



Ayonrinde 2005 (Continued)

Interventions N-acetylcysteine.

Outcomes Aspartate aminotransferase.

Notes

Risk of bias



Bernal 1998


Participants 124 patients eligible for liver transplantation due to paracetamol overdose.

Transplant criteria were serum creatinine > 300 µmol/L, prothrombin time of > 100 seconds, and grade

3 or 4 encephalopathy in patients with normal pH, or the single finding of pH < 7.3.

Interventions Intervention group:

received liver transplantation.

Control group:

received only supportive treatment.

Outcomes Mortality.

Notes

Risk of bias



Bond 1993


Participants 644 paediatric patients (one to six years old) who ingested paracetamol and had high paracetamol con-

centration at four to 4.5 hours.

Interventions Patients received ipecac syrup.



Bond 1993 (Continued)

Outcomes Plasma paracetamol and time to emesis.

Notes

Risk of bias



Brandsaeter 2002


Participants 32 patients with paracetamol induced fulminant hepatic failure listed for liver transplantation and fulfilling

the Kings College criteria.

Interventions Supportive treatment.

Outcomes Mortality

Notes

Risk of bias



Buckley 1999a

Methods A prospective observational study.

Participants 981 patients with a potential paracetamol poisoning.

The same patients were included in Buckley 1999b.

Interventions Group 1:

patients treated with activated charcoal (1 to 2 g/kg) plus gastric lavage.

Group 2:

patients treated with activated charcoal (1 to 2 g/kg).

Control group:

no intervention to prevent the absorption of paracetamol.



Buckley 1999a (Continued)

Outcomes Mortality, plasma paracetamol concentration (ie, above the 150 and 200 risk-line).

Notes

Risk of bias



Buckley 1999b


Participants 981 patients with a potential paracetamol poisoning;

86 patients had a paracetamol concentration above the probable risk line.

The same patients were included in Buckley 1999a.


patients received activated charcoal (1 to 2 g/kg) if they arrived within four hours of ingestion.

Patients were given N-acetylcysteine. intravenously (300 mg/kg over 20 hours) if paracetamol concen-

tration was above the probable risk-line in the nomogram or if they had taken > 125 mg/kg and if the

serum concentration was not available within eight hours. Patients having a plasma concentration above

the possible risk-line in the nomogram were given NAC if the calculated half-life was > 4 hours.

Control group:

historical patients treated at other units given other doses of NAC.

Outcomes Mortality, acetaminophen plasma concentration (ie, above the 150 and 200 risk-line).

Notes

Risk of bias



Burkhart 1995

Methods A quasi-randomised study.

Used odd/even months at hospitalisation to allocate patients to different interventions.

Participants 107 patients with paracetamol overdose according to the 150 risk line.



Burkhart 1995 (Continued)


received intravenous N-acetylcysteine, a loading dose of 140 mg/kg followed by 12 intravenous or 17 oral

maintenance doses of 70 mg/kg.

Group 2:

received cimetidine given intravenously at a dose of 300 mg every six hours in addition to NAC as above.

Outcomes Mortality, aspartate aminotransferase, and alanine aminotransferase.

Notes Patients were having a plasma paracetamol above the 150 risk-line (possible risk). Therefore, this study

was not included in the meta-analysis.

Risk of bias



Chen 1985

Methods A randomised cross-over trial including human volunteers.

Participants Four healthy male volunteer aged 22 years and weighing between 62 and 70 kg.

Interventions All participants received 750 mg of paracetamol

Control group:

No intervention

Intervention group:

200 g of cimetidine.

Outcomes Paracetamol half-life, paracetamol clearance, and area under the plasma paracetamol concentration-time

curve (AUC).

Notes

Risk of bias





Christophersen 2002


Participants Twelve healthy volunteers. Seven women. Mean age 29 years (range 22-39). Mean weight 72 kg (range

55 to 104)

Interventions All participants ingested 50 mg/kg (average of 3.6 g) of paracetamol.

Intervention group 1:

one hour later the participants ingested

activated charcoal


one hour later the participants underwent gastric lavage plus ingested activated charcoal.


two hours later the participants ingested activated charcoal.

Control group:

no intervention

Outcomes Plasma paracetamol and area under the concentration-

time curve (AUC) in the blood.

Notes

Risk of bias



Chung 2003


Participants Six patients with paracetamol induced fulminant hepatic failure and fulfilling the Kings College criteria.


Outcomes Mortality.

Notes

Risk of bias





Crome 1976


Participants 30 patients at risk of hepatic damage from paracetamol ingestion according to patient history.


all patients received methionine (2.5 g orally every four hours up to a total dose of ten g).

Control group:

patients given supportive treatment at other units.

Outcomes Aspartate aminotransferase and bilirubin.

Notes

Risk of bias



Douglas 1976

Methods A randomised clinical trial.

Control of bias:

- Allocation sequence generated by table of random numbers

- Allocation concealed not described

- No double blinding.

Participants 38 patients who were admitted to the hospital within 17 hours of paracetamol ingestion, and those plasma-

paracetamol was above the 200-line (probable risk-line).

Interventions Cysteamine group:

cysteamine was given as described by Prescott et al. (1973) except that it was dissolved in 5% dextrose

and injected, or added to 5% dextrose infusion, using a Millipore filter attached to a syringe.

Control group:

received supportive treatment: 5% dextrose, 2-3 litres daily, with added vitamins and potassium if necessary.

Outcomes Mortality, maximum aspartate aminotransferase, maximum serum bilirubin, maximum prothrombin

time, liver biopsy findings, maximum serum-ferritin, maximum serum bile, and adverse events.

Notes Douglas et al did not provide the time interval between ingestion of paracetamol and treatment in either

groups.

Four of the patients were also included in Hamlyn 1981 study.

Risk of bias



Douglas 1976 (Continued)


Allocation concealment? Unclear B - Unclear

Galinsky 1984

Methods A randomised cross-over study including human volunteers.

Participants Eight healthy volunteers between 23 and 36 years weighing between 70 and 100 kg.

Interventions All participants ingested one gram of paracetamol

Intervention group:

ten grams of activated charcoal were consumed at the same time.

Control group:

no intervention.

Outcomes Plasma paracetamol and the area under the concentration-

time curve (AUC).

Notes

Risk of bias



Gazzard 1974


Control of bias:

- Generation of the allocation sequence: not described

- Allocation concealment: not described

- Blinding: no.

Participants 22 patients with a prothrombin time ratio of more than 2.2 after a paracetamol overdose.


All patients received 300 ml of fresh frozen plasma every six hour until the prothrombin time had returned

to 1.25 or less. They also received heparin, given intravenously by pump infusion, to maintain a blood

heparin equivalent of 0.5/100 ml/mg.

Control group:

They received the same as the first group but without the heparin.



Gazzard 1974 (Continued)

Outcomes Mortality, aspartate aminotransferase, prothrombin time ratio, bilirubin, clotting factors and encephalopa-

thy grade.

Notes

Risk of bias



Gazzard 1974a


Control of bias:


- Allocation concealment: by sealed envelopes

- Blinding: no.

Participants 16 patients with a plasma paracetamol level of greater than 200 µg/l at any time in the first 12 hours after

overdosage.

Interventions All patients were treated by gastric lavage when first seen and fresh frozen plasma and fluid were admin-

istrated as clinically indicated.

Haemoperfusion group: two catheters (14 French gauge 50 cm length) were positioned in the saphe-

nous vein and attached to a perfusion column. Charcoal used was covered with a thin coating of poly

hydroxyethylmethacrylate. This was done under X-ray control and in local anaesthesia. Patients were

heparinized before with an iv loading dose of 2000 units 10 min. before the procedure, and thereafter a

constant infusion pump delivered 1500-2000 heparin units/hour. Haemoperfusion was continued until

the patients paracetamol level was less than 30 µg/ml.

Outcomes Mortality, fall in paracetamol level versus time after ingestion, and

number of patients experiencing any adverse events.

Notes

Risk of bias


Allocation concealment? Yes A - Adequate



Gazzard 1975


Control of bias:



- Blinding: no.

Participants 20 patients who developed a severe coagulation defect, defined as prothrombin time ratio of more than

2.2 after a paracetamol overdose.


all patients received fresh frozen plasma (300 ml every six hour) until the prothrombin time ratio had

fallen to less than 1.4. If the prothrombin time ratio rose to 7.0 or more the dose of fresh frozen plasma

was increased to 600 ml.

Control group:

all patients received supportive treatment, but if prothrombin time ratio rose to more than 7.0 they

received 600 ml fresh frozen plasma every six hour.

Outcomes Mortality, aspartate aminotransferase, bilirubin, prothrombin time ratio, and levels of clotting factors.

Notes

Risk of bias



Gow 2003



Transplant criteria were finding of serum creatinine > 300 µmol/L, prothrombin time of > 100 s, and

grade 3 or 4 encephalopathy in patients with normal pH, or the single finding of pH < 7.3. Eight patients

fulfilled these criteria. Thirteen patients met the criteria of fulminant hepatic failure (ie, acute hepatic

failure and complicated by encephalopathy).



Control group:


Outcomes Mortality.

Notes



Gow 2003 (Continued)

Risk of bias



Green 2001


Participants 7 males and 3 females from 22 to 31 years old. Weight 77.4 ± 14.1 (mean ±SE).

Interventions All participants ingested four grams of acetaminophen with 250 ml water.

Intervention groups:

One, two, or three hours later the participant ingested 50 g of activated charcoal.

Control group:

no intervention.


time curve (AUC) and maximum level of paracetamol in the blood.

Notes

Risk of bias



Green 2004


Participants 6 males and 4 females from 23 to 37 years old.

Interventions All participants ingested four grams of paracetamol with 250 ml water.


one hour later the participant ingested 50 g of activated charcoal and atropine sulfate i.m. 0.01 mg/kg

prior to paracetamol.


one hour later the participant ingested 50 g of activated charcoal.

Control group:

no intervention.



Green 2004 (Continued)


time curve (AUC) and maximum level of paracetamol in the blood.

Notes

Risk of bias



Grierson 2000


Participants Eight healthy males and two females from 22 to 31 years old.

Interventions All participants ingested four grams of acetaminophen in a solution of 60 ml of water.

Intervention group:

one hour later the participant underwent gastric lavage.

Control group:

no intervention.


time curve (AUC).

Notes

Risk of bias





Hamlyn 1981


Control of bias:

- generation of the allocation sequence: not described


- Blinding: no

Used balanced block randomisation stratifying for age.

Participants 40 patients who had a plasma paracetamol level above the 200-line (probable risk line).

Exclusion criteria:

Minors, alcoholics, patients with other liver diseases, or pregnancy.

Interventions Group 1 (N):

Supportive therapy only in Newcastle.

Group 2 (N):

Supportive therapy and cysteamine in Newcastle.

Group 2 (L):

Supportive therapy and cysteamine in London.

Group 3 (N):

Supportive therapy and methionine in Newcastle.

Group 3 (L):

Supportive therapy and methionine in London.

They did not treat any patient with only supportive care in London.

All patients received gastric lavage.

Cysteamine was given intravenously as an immediate loading dose through a Millipore filter, followed by

slow intravenous infusion for 20 h up to a total base-equivalent dose of 3.6 grams.

Methionine was given orally, 2.5 g 4-hourly to a total dose of 10 grams.

Metoclopramide 10 mg. i.m. was administrated for severe or persistent vomiting.

Outcomes Aspartate aminotransferase, maximum serum bilirubin, maximum prothrombin time, liver biopsy find-

ings, number of patients experienced any adverse events, renal function, serum amylase, and myocardial

changes.

Notes Hamlyn et al. did not provide the SD of the mean in any of their results. Four of the patients were also

included in Douglas 1976.

Risk of bias





Harrison 1990


Participants 98 patients who developed paracetamol-induced fulminant hepatic failure.


received intravenous N-acetylcysteine between 10 to 36 hours after ingestion.

Control group:

received no antidote - only supportive treatment.

Outcomes Mortality, grade 3/4 coma, and prothrombin time.

Notes

Risk of bias



Hassig 1993

Methods A trial including human volunteers.

Participants 19 healthy males more than 18 years old. Seven and 12 participants, respectively, ingested 2 and 4 g of

paracetamol.


gut lavage with polyethylene glycol electrolyte sodium.

Control group.

no intervention.

Outcomes Plasma paracetamol

Notes

Risk of bias





Higgens 1996


Participants 73 patients with a severe paracetamol overdose. The inclusion criteria were:

1: NAC had not been administrated within 15 hours of the overdose.

2: a paracetamol level above the probable risk line.

3: peak AST/ALT above 5000 U/L.


received charcoal haemoperfusion and high-flux dialysis within 42 hours.

Group 2:

received charcoal haemoperfusion and high flux dialysis after 42 hours.

Outcomes Mortality.

Notes

Risk of bias



Hughes 1977


Control of bias:



- Blinding: no.

Participants 52 patients with a plasma paracetamol level that fell above a line on a semilog. graph joining values of 1.3

mmol/l (200 mg/ml) two hours after ingestion and 0.5 mol/l ( 80 mg/ml) 12 hours after ingestion.

Interventions Cysteamine group:

cysteamine were administered intravenously through a Millipore filter 0.22 mm in a dose of 2 grams in

20 ml water. A further 1.2 grams dissolved in 1500 ml 5% dextrose was given over the next 20 hours.

Dimercaprol group:

administered by intramuscular injection in a dose of 4 mg/kg body weight four-hourly for 24 hours, then

3 mg/kg four-hourly for 24 hours.

Outcomes Mortality, clinical symptoms, i. e., hepatic encephalopathy, fulminant hepatic failure,

maximum AST, maximum serum bilirubin (mmol/L), maximum prothrombin time, and liver biopsy

finding.

Notes



Hughes 1977 (Continued)

Risk of bias



Keays 1991


Control of bias:



- Blinding: The trial described the use of placebo, but treatment with acetylcysteine could not be given

blind because the solution has an easily identified pungent aroma.

Participants 50 patients with paracetamol induced fulminant hepatic failure.

Exclusion criteria:

patients who had not already received N-acetylcysteine.

Interventions N-acetylcysteine group:

N-acetylcysteine was given by intravenous infusion 150 mg/kg in 200 ml 5% dextrose over 15 minutes,

followed by 50 mg/kg in 500 ml 5% dextrose over four hours, then 100 mg/L over 16 hours. The final

infusion rate was continued until recovery from encephalopathy or death.

’Placebo’ group:

they received an equivalent amount of 5% dextrose without acetylcysteine.

If needed all patients received additional intensive liver care: maintenance of intravascular pressures, renal

support (haemodialysis), treatment (manitol, hyperventilation and thiopentone) for raised intracranial

pressure, elective ventilation, and muscle relaxant for grade four encephalopathy.

Outcomes Mortality, cerebral oedema, hypotension, and no. of patients needing renal support.

Notes

Risk of bias





Kerr 2005


Control of bias:


- Allocation concealment: by closed box

- Blinding: no.

Participants Patients that needed N-acetylcysteine after paracetamol overdose

N-acetylcysteine/15 min group:

No. of patients randomised: 109

Age in years (mean): 31

Males: 22.

Females: 87

mean weight: 70 kg

N-acetylcysteine /60 min group:

No. of patients randomised: 71

Age in years (mean): 28

Males: 26.

Females: 45

mean weight: 70 kg

Interventions N-acetylcysteine /15 min group:

150 mg/kg IV N-acetylcysteine in

200 mL of 5% glucose

over 15 min

N-acetylcysteine /60 min group:

150 mg/kg IV N-acetylcysteine in

200 mL of 5% glucose

over 60 min.

Both groups subsequently received 50 mg/kg IV N-acetylcysteine in 500 mL of 5% glucose over 4 hours

and 100 mg/kg IV N-acetylcysteine in 100 mL of 5% glucose over 16 hours.

Outcomes Adverse events and

alanine aminotransferase.

Notes 43 out of 223 patients were excluded from the analyses, after randomisation, due to incomplete study

data.

Risk of bias





Kirk 1991


Participants 123 children younger than six years old that ingested more than 150 mg/kg of paracetamol.


ipecac at home within one hour.

Group 2:

Activated charcoal within two hours at emergency department.

Group 3:

No intervention.

Outcomes Plasma paracetamol.

Notes

Risk of bias



Larson 2005


Participants 40 patients with fulminant hepatic failure and listed for transplantation according to Kings College

Criteria.

Interventions group 1:


group 2

No intervention

Outcomes Mortality.

Notes

Risk of bias





Levy 1976


Participants Five healthy male volunteers between 27 and 40 years old.

Interventions All participants ingested one gram of paracetamol.

Control group: no intervention.


additional activated

charcoal (five grams).


Additional activated charcoal (ten grams).


Additional activated charcoal (five grams) 30 min. after paracetamol ingestion.

Outcomes Bioavailability of paracetamol and its metabolites measured as area under the curve (AUC).

Notes

Risk of bias



Ly 2004


Participants Ten healthy volunteers between 21 and 45 years old. Six men and four Women

Interventions All participants received 75 mg/kg of paracetamol.


had whole bowel irrigation 30 min after ingestion.

Control group:

received no intervention.

Outcomes Plasma paracetamol and the area under the concentration-time curve (AUC).

Notes

Risk of bias





McNamara 1988


Participants Ten healthy male volunteers 18 to 35 years old.

Interventions All participants received three grams of paracetamol.


received 50 g of activated charcoal per 70% sorbitol solution (30 g activated charcoal/110 g sorbitol) one

hour after ingestion.


received 50 grams of activated charcoal one hour after ingestion.

Control group 3:



Notes

Risk of bias



McNamara 1989


Participants Ten healthy male volunteers 18 to 35 years old.

Interventions All received three grams of paracetamol.


received 30 ml syrup of ipecac one hour after ingestion.


received 50 grams of activated charcoal one hour after ingestion.

Control group:



Notes

Risk of bias




McNamara 1989 (Continued)


Montoya-Cabrera 1999


Participants 14 paediatric patients with a paracetamol overdose.

Interventions Control group:

received N-acetylcysteine.

Intervention group:

received N-acetylcysteine and activated charcoal.

Outcomes ACT-disappearance, half-life elimination of paracetamol, and exogenous body clearance of paracetamol.

Notes

Risk of bias



Mutimer 1994



Transplant criteria were serum creatinine > 300 µmol/L, prothrombin time of > 100 s, and grade 3 or 4

encephalopathy in patients with normal pH, or the single finding of pH < 7.3.



Control group: received only supportive treatment.

Outcomes Mortality.

Notes

Risk of bias




Mutimer 1994 (Continued)


Neuvonen 1983


Participants Six healthy volunteers aged 27 to 40 years old.

Interventions All participants ingested one gram of paracetamol.

Intervention groups 1:

all received activated charcoal (50 grams in suspension) given either five min. or 30 min. after ingestion

of paracetamol.

Intervention groups 2:

all received ipecacuanha given either five min. or 30 min. after ingestion of paracetamol.

Control group:

all received water (300 ml) five min. after ingestion of paracetamol.

Outcomes Area under the plasma paracetamol concentration-time curve (AUC).

Notes

Risk of bias



O’Grady 1988


Control of bias:

- Allocation sequence generation: by random numbers


- Blinding: no.

Participants Trial A:

53 patients with grade three encephalopathy or patients who developed grade tree encephalopathy within

four days after admission.

Trial B:

32 patients with established grade four encephalopathy.

All patients had paracetamol induced fulminant hepatic failure and encephalopathy had developed within

eight weeks of the onset of symptoms.



O’Grady 1988 (Continued)

Interventions Charcoal haemoperfusion:

The Smith and Nephew and the Gambro charcoal column was used. Blood flow was maintained at 150-

200 ml/min. Initial bolus of 5000 U of heparin was given and a continuous infusion to maintain the

clotting times (hemochron) between 250 and 300 seconds.

Trial A:

patients were randomised to five hours or ten hours of daily haemoperfusion.

Trial B:

patients were randomised to 10 hours of daily haemoperfusion or only supportive treatment.

Charcoal haemoperfusion intervention was continued until the patients regained consciousness or until

the onset of irreversible brainstem damage or preterminal refractory hypotension. Cerebral edema was

treated with manitol. Haemodialysis was performed if s-creatinine > 400 µmol/l, arterial pH < 7.20,

or fluid overload. Hypovolemia, haemorrhage, respiratory dysfunction, and blood glucose level were all

treated. All patients received cimetidine and lactulose.

Outcomes Mortality.

Notes

Risk of bias


Allocation concealment? No C - Inadequate

O’Grady 1991



Transplant criteria were serum creatinine > 300 µmol/L, prothrombin time of > 100 s, and grade 3 or 4

encephalopathy in patients with normal pH, or the single finding of pH < 7.3.

14 were registered for liver transplantation and six of these patients underwent transplantation.



Control group:


Outcomes Mortality.

Notes

Risk of bias



O’Grady 1991 (Continued)



Parker 1990


Participants 20 patients presenting between 12 and 24 hours after an overdose of paracetamol. All had a plasma

paracetamol concentration above the 200 risk line.

Interventions All patients received N-acetylcysteine (300 mg/kg in 20 hours). Gastric lavage was performed in five

patients.

Control group:

none.

Outcomes Mortality, aspartate aminotransferase, bilirubin, and prothrombin time.

Notes

Risk of bias



Prescott 1976


Participants 121 patients with paracetamol overdose. all patients receiving antidotes had plasma paracetamol level

above the 150 risk-line.

Interventions Intervention group 1:

received cysteamine given intravenously as an initial loading dose (2.0 g) followed by an infusion of 1.6

g for 20 hours.


received methionine given intravenously as an loading dose (2.0 g) followed by 15.0 g infused over 20

hours.

Control group:


Outcomes Aspartate aminotransferase, alanine aminotransferase, bilirubin, and prothrombin time ratio.



Prescott 1976 (Continued)

Notes Many of the patients also figure in Prescott 1979. However, in Prescott 1979 they do not compare

intervention between methionine and cysteamine.

Three patients treated with cysteamine and five patients treated with methionine had a four hour plasma

paracetamol between 150 and 250 mg/L. They were all included in the meta-analyses as having a four

hour plasma paracetamol above 200 mg/L.

Risk of bias



Prescott 1979


Participants 217 patients having a plasma paracetamol concentration above 200 risk-line.


received intravenous N-acetylcysteine (300 mg/kg for 20 hours).


received either intravenous methionine (total dose: 20 g) or cysteamine (total dose: 3.6 g).

Control group:


Outcomes Mortality, alanine aminotransferase, bilirubin, and prothrombin-time ratio.

Notes

Risk of bias



Rangan 2001


Participants Eight healthy adults volunteers from 18 to 44 years old. Seven men and one woman.



Rangan 2001 (Continued)

Interventions All participants ingested 80 mg/kg of paracetamol.


had superactivated charcoal 15 min after ingestion.


had superactivated charcoal and cola 15 min after ingestion.

Control group:



Notes

Risk of bias



Remmert 1990

Methods A cross-over trial including human volunteers.

Participants Eight healthy male volunteers from 20 to 25 years old.

Interventions All participants ingested 1 gram of paracetamol.


additional 5 grams of activated charcoal suspension 2 min. after ingestion of paracetamol.

Control group:

no intervention.


Notes

Risk of bias





Rose 1991


Participants Ten healthy, adult male volunteers from 21 to 39 years old.

Interventions All participants ingested five grams of paracetamol


additional 30 grams of activated charcoal either 15, 30, or 120 min. after ingestion of paracetamol.

Control group:

no intervention

Outcomes Bioavailability of paracetamol and its metabolites measured as area under the curve (AUC).

Notes We only included the trial with the maximal time between paracetamol ingestion and activated charcoal

in the meta-analysis because this is most relevant for the clinical situation.

Risk of bias



Saincher 1997


Participants Ten healthy adult volunteers.

Interventions All participants ingested 3.9 g of paracetamol.


had ipecac 5, 30, or 60 min after ingestion.

Control group:


Outcomes Plasma paracetamol and area under the concentration-time curve (AUC).

Notes

Risk of bias





Sato 2003


Participants 48 healthy volunteers.

Interventions All participants ingested 2 or 3 g of paracetamol.

Intervention group:

three hours later the participant ingested 50 g of superactivated charcoal.

Control group:

No intervention.

Outcomes Levels of paracetamol at four and seven hours.

Notes Two participants were unable to complete charcoal digestion and were excluded from the analyses.

Risk of bias



Schiodt 1996


Participants Ten patients with paracetamol induced fulminant hepatic failure and fulfilling the Kings College criteria.


Outcomes Mortality.

Notes

Risk of bias



Shakil 2000


Participants 14 patients with paracetamol induced fulminant hepatic failure and fulfilling the Kings College criteria.



Shakil 2000 (Continued)


Outcomes Mortality.

Notes

Risk of bias



Silk 1978


Participants Patients with fulminant hepatic failure and grade 4 coma.

Interventions All patients received glucose, lactulose, neomycin, magnesium, and vitamins. Hypotension was treated

with fresh frozen plasma.

Haemoperfusion:

the chromatography columns were filled with 220 - 300 grams of charcoal, produced by Smith and

Nephew Research Ltd. Blood from an arterio-venous shunt was pumped through the column at a rate of

between 100 and 300 ml/min, and the patients were heparinised so as to maintain the Lee-White clotting

time at between 10 and 20 min.

Outcomes Mortality.

Notes

Risk of bias



Smilkstein 1988


Participants 2540 patients with paracetamol overdose.

2023 patients had a plasma paracetamol concentration above 200 risk-line.



Smilkstein 1988 (Continued)

Interventions Intervention:

patients received a loading dose of 140 mg/kg oral N-acetylcysteine followed by 17 doses of 70 mg/kg.

Outcomes Mortality and aspartate aminotransferase.

Notes

Risk of bias



Smilkstein 1991


Participants 179 patients with a plasma paracetamol concentration above the 150 risk-line.


patients received 48 hours of intravenous N-acetylcysteine (loading dose of 140 mg/kg followed by 12

doses of 70 mg/kg).

Control group:

historical patients treated at other units given other doses of NAC.

Outcomes Mortality, alanine aminotransferase, and aspartate aminotransferase.

Notes

Risk of bias



Smith 1978





Smith 1978 (Continued)


patients received 3.2 g of cysteamine (mercaptamine) over 20 hours.

Control group:

received supportive care.

Outcomes Mortality, aspartate aminotransferase,bilirubin, and prothrombin.

Notes

Risk of bias



Spiller 1994




received standard oral N-acetylcysteine (1330 mg/kg over a 72 hours).


received activated charcoal followed by standard oral N-acetylcysteine therapy .


received activated charcoal followed by increased oral N-acetylcysteine (plus 40%).

Outcomes Paracetamol level and aspartate aminotransferase.

Notes

Risk of bias





Underhill 1990


Control of bias:



- Blinding: no.

The 12 patients taking additional drugs were spread throughout the treatment groups and the statistical

results were similar when these patients were excluded.

Participants 60 patients aged 16 and over who had ingested five or more grams of paracetamol within four hours of

admission.

Exclusion criteria:

not reported.


gastric lavage was carried out with a 36 FG tube.


administration of activated charcoal was carried out with Carbomix to drug ratio of 10:1.


ipecacuanha syrup 30 ml. This was repeated after 30 min. if there was no response.

Control group:

no intervention to limit absorption. (This group was treated in a different hospital in Derby).

Plasma paracetamol levels were measured on samples taken from an indwelling cannula prior to any

treatment, and following treatment at 60, 90, 150 minutes after the first sample.

Group 4 (no treatment) was stopped for ethical reasons after only five patients.

Outcomes Fall in plasma paracetamol concentration versus time.

Notes In the latter group, the plasma paracetamol concentration increased during treatment in 4/5 patients and

lead to cessation of the supportive treatment group.

Risk of bias



Vale 1981


Participants 132 patients with a plasma paracetamol concentration above a risk-line from 220 mg/L at four hours and

70 mg/L at 12 hours.


each patient received four doses of 2.5 gram of oral methionine over 12 hours.



Vale 1981 (Continued)

Outcomes Mortality, hepatotoxicity and serum creatinine.

Notes

Risk of bias



Woo 2000


Participants 75 patients with a plasma acetaminophen concentration above the a possible risk line from 140 mgL at 4

hours to 50 mg/l at 10 hours.


140 mg/kg of oral N-acetylcysteine as a loading dose followed by 70 mg/kg every four hours until the

serum paracetamol level was zero.

Outcomes Mortality, aspartate aminotransferase, and alanine aminotransferase.

Notes

Risk of bias



Yeates 2000


Participants Ten healthy volunteers between 20 to 41 years old. Six males and four females.

Interventions All participants ingested three grams of paracetamol.

Intervention group:

Additional 50 grams of activated charcoal 120 or 240 min after ingestion.

Control group:

no intervention.

Outcomes Area under the plasma paracetamol concentration-time curve (AUC).



Yeates 2000 (Continued)

Notes

Risk of bias



AUC: area under the plasma paracetamol concentration-time curve

g: grammes

h: hours

IU: international units

kg: kilogrammes

L: litre

mg: milligrammes

min.: minutes

ml: millilitre

SD: standard deviation

SE: standard error

µ: micro

Characteristics of excluded studies [ordered by study ID]

Alander 2000 Did not report hepatotoxicity as ALT > 1000 IU/L as defined in out protocol. Instead reported hepatotoxicity

as two times the normal upper limit.

Beckett 1989 Case series involving less than 20 patients.

Beckett 1990 Case series involving less than 20 patients.

Bond 1999 Included less than 20 patients ingesting single dose paracetamol.

Bray 1991 Not clearly consecutive, unreferred patients.

Brotodihardjo 1992 Contained insufficient information on hepatotoxicity, ingestion-treatment interval, and plasma paracetamol

concentration of each patient.

Chamberlain 1993 Assessed activated charcoal in human volunteers ingesting 3 g of paracetamol. However, the two comparison

groups ingested different doses on NAC.

Chan 1993 Case series involving less than 20 patients.



(Continued)

Chan 1994 Case series involving less than 20 patients.

Chan 1996 Case-control study.

Dordoni 1973 Not randomised. Study including human volunteers.

Gee 1998 No information on the time between ingestion and treatment with activated charcoal.

James 2002 A retrospective observational study. Contained insufficient information on hepatotoxicity, ingestion-treatment

interval, and NAC treatment protocol.

Levy 1985 A retrospective observational study. Contained insufficient information on hepatotoxicity, ingestion-treatment

interval, plasma paracetamol concentration, and NAC treatment protocol.

Makin 1995 Regarding N-acetylcysteine treatment:

- Selected patients transferred from other hospitals in high risk of liver failure..

Regarding transplantation:

- No clear data on mortality in patients listed for transplantation without a transplant.

Included the same patients as Bernal 1998 and O’Grady 1991 which are included.

Oh 1980 Case series involving less than 20 patients.

Oren 1992 A retrospective observational study. Contained insufficient information on hepatotoxicity, ingestion-treatment

interval, plasma paracetamol concentration, and N-acetylcysteine treatment protocol.

Perry 1998 Not clearly consecutive, unreferred patients.

Prescott 1989 Case series involving less than 20 patients.

Read 1986 Not clearly consecutive, unreferred patients. Less than 20 patients had paracetamol above the 200-line.

Riggs 1989 Not clearly consecutive, unreferred patients.

Rivera-Penera 1997 Did not clearly define transplantation criteria.

Schiodt 1997 A retrospective observational study. Contained insufficient information on hepatotoxicity and, ingestion-

treatment interval.

Schmidt 2002a Not clearly consecutive, unreferred patients.

Singer 1995 Not clearly consecutive, unreferred patients.



D A T A A N D A N A L Y S E S

Comparison 1. Charcoal haemoperfusion versus no intervention (randomised trials)

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Mortality 1 16 Peto Odds Ratio (Peto, Fixed, 95% CI) 7.39 [0.15, 372.38]

Comparison 2. Cysteamine versus no intervention (randomised trials)


studies

No. of



2 Hepatotoxicity (aspartate

aminotransferase > 1000 IU/L)

2 65 Odds Ratio (M-H, Fixed, 95% CI) 0.09 [0.02, 0.34]

Comparison 3. Cysteamine versus dimercaprol (randomised trials)


studies

No. of



2 Maximum alanine

aminotransferase (IU/L)

1 52 Mean Difference (IV, Fixed, 95% CI) -32.0 [-512.90,

448.90]

Comparison 4. Cysteamine versus methionine (randomised trials)


studies

No. of


1 Mortality 1 27 Peto Odds Ratio (Peto, Fixed, 95% CI) Not estimable


aminotransferase > 1000 U/L)




Comparison 5. Methionine and supportive treatment versus supportive treatment (randomised trials)


studies

No. of




aminotransferase > 1000 U/L)


Comparison 6. Initial dose over 15 min versus 60 min of intravenous N-acatylcysteine (randomised trials)


studies

No. of


1 Mortality 1 180 Peto Odds Ratio (Peto, Fixed, 95% CI) Not estimable

2 Hepatotoxicity 1 175 Odds Ratio (M-H, Fixed, 95% CI) 0.75 [0.22, 2.56]

3 Any adverse event 1 180 Odds Ratio (M-H, Fixed, 95% CI) 1.98 [1.04, 3.77]

Comparison 7. Charcoal haemoperfusion in patients with fulminant hepatic failure (randomised trials)


studies

No. of



Comparison 8. 5 h versus 10 h of charcoal haemoperfusion in patients with fulminant hepatic failure (randomised

trials)


studies

No. of





Comparison 9. Intravenous N-acatylcysteine versus ’placebo’ in patients with fulminant hepatic failure (ran-

domised trials)


studies

No. of



1.1 N-acetylcysteine given 36

h to 80 h after overdose versus

’placebo’

1 50 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.29 [0.09, 0.94]

Analysis 1.1. Comparison 1 Charcoal haemoperfusion versus no intervention (randomised trials), Outcome

1 Mortality.

Review: Interventions for paracetamol (acetaminophen) overdose

Comparison: 1 Charcoal haemoperfusion versus no intervention (randomised trials)

Outcome: 1 Mortality

Study or subgroup Char. haemoperfusion Control Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Gazzard 1974a 1/8 0/8 100.0 % 7.39 [ 0.15, 372.38 ]

Total (95% CI) 8 8 100.0 % 7.39 [ 0.15, 372.38 ]

Total events: 1 (Char. haemoperfusion), 0 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 1.00 (P = 0.32)

0.01 0.1 1 10 100

Favours treatment Favours control



Analysis 2.1. Comparison 2 Cysteamine versus no intervention (randomised trials), Outcome 1 Mortality.


Comparison: 2 Cysteamine versus no intervention (randomised trials)


Study or subgroup Cysteamine Control Peto Odds Ratio Weight Peto Odds Ratio


Douglas 1976 1/18 1/20 66.0 % 1.11 [ 0.07, 18.59 ]

Hamlyn 1981 0/14 1/13 34.0 % 0.13 [ 0.00, 6.33 ]

Total (95% CI) 32 33 100.0 % 0.53 [ 0.05, 5.22 ]

Total events: 1 (Cysteamine), 2 (Control)

Heterogeneity: Chi2 = 0.79, df = 1 (P = 0.37); I2 =0.0%


0.01 0.1 1 10 100

Favours cysteamine Favours control

Analysis 2.2. Comparison 2 Cysteamine versus no intervention (randomised trials), Outcome 2

Hepatotoxicity (aspartate aminotransferase > 1000 IU/L).


Comparison: 2 Cysteamine versus no intervention (randomised trials)

Outcome: 2 Hepatotoxicity (aspartate aminotransferase > 1000 IU/L)

Study or subgroup Cysteamine Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Douglas 1976 2/18 11/20 57.9 % 0.10 [ 0.02, 0.57 ]

Hamlyn 1981 1/14 7/13 42.1 % 0.07 [ 0.01, 0.66 ]

Total (95% CI) 32 33 100.0 % 0.09 [ 0.02, 0.34 ]

Total events: 3 (Cysteamine), 18 (Control)

Heterogeneity: Chi2 = 0.09, df = 1 (P = 0.76); I2 =0.0%


0.001 0.01 0.1 1 10 100 1000

Favours cysteamine Favours control



Analysis 3.1. Comparison 3 Cysteamine versus dimercaprol (randomised trials), Outcome 1 Mortality.


Comparison: 3 Cysteamine versus dimercaprol (randomised trials)


Study or subgroup Cysteamine Dimercaprol Peto Odds Ratio Weight Peto Odds Ratio


Hughes 1977 0/26 1/26 100.0 % 0.14 [ 0.00, 6.82 ]

Total (95% CI) 26 26 100.0 % 0.14 [ 0.00, 6.82 ]

Total events: 0 (Cysteamine), 1 (Dimercaprol)



0.01 0.1 1 10 100

Favours cysteamine Favours dimercaprol

Analysis 3.2. Comparison 3 Cysteamine versus dimercaprol (randomised trials), Outcome 2 Maximum

alanine aminotransferase (IU/L).


Comparison: 3 Cysteamine versus dimercaprol (randomised trials)

Outcome: 2 Maximum alanine aminotransferase (IU/L)

Study or subgroup Cysteamine Dimercaprol Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Hughes 1977 26 722 (902) 26 754 (867) 100.0 % -32.00 [ -512.90, 448.90 ]

Total (95% CI) 26 26 100.0 % -32.00 [ -512.90, 448.90 ]



-1000 -500 0 500 1000

Favours cysteamine Favours dimercaprol



Analysis 4.1. Comparison 4 Cysteamine versus methionine (randomised trials), Outcome 1 Mortality.


Comparison: 4 Cysteamine versus methionine (randomised trials)


Study or subgroup Cysteamine Methioninel Peto Odds Ratio Peto Odds Ratio


Hamlyn 1981 0/13 0/14 0.0 [ 0.0, 0.0 ]

Total (95% CI) 13 14 0.0 [ 0.0, 0.0 ]

Total events: 0 (Cysteamine), 0 (Methioninel)


Test for overall effect: Z = 0.0 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10

Favours cysteamine Favours methionine

Analysis 4.2. Comparison 4 Cysteamine versus methionine (randomised trials), Outcome 2 Hepatotoxicity

(aspartate aminotransferase > 1000 U/L).


Comparison: 4 Cysteamine versus methionine (randomised trials)

Outcome: 2 Hepatotoxicity (aspartate aminotransferase > 1000 U/L)

Study or subgroup Cysteamine Methionine Odds Ratio Weight Odds Ratio


Hamlyn 1981 1/14 1/13 100.0 % 0.92 [ 0.05, 16.46 ]

Total (95% CI) 14 13 100.0 % 0.92 [ 0.05, 16.46 ]

Total events: 1 (Cysteamine), 1 (Methionine)



0.001 0.01 0.1 1 10 100 1000

Favours cysteamine Favours methionine



Analysis 5.1. Comparison 5 Methionine and supportive treatment versus supportive treatment

(randomised trials), Outcome 1 Mortality.


Comparison: 5 Methionine and supportive treatment versus supportive treatment (randomised trials)


Study or subgroup Methionine Control Peto Odds Ratio Weight Peto Odds Ratio


Hamlyn 1981 0/13 1/13 100.0 % 0.14 [ 0.00, 6.82 ]

Total (95% CI) 13 13 100.0 % 0.14 [ 0.00, 6.82 ]

Total events: 0 (Methionine), 1 (Control)



0.001 0.01 0.1 1 10 100 1000

Favours methionine Favours control

Analysis 5.2. Comparison 5 Methionine and supportive treatment versus supportive treatment

(randomised trials), Outcome 2 Hepatotoxicity (aspartate aminotransferase > 1000 U/L).


Comparison: 5 Methionine and supportive treatment versus supportive treatment (randomised trials)

Outcome: 2 Hepatotoxicity (aspartate aminotransferase > 1000 U/L)

Study or subgroup Methionine Control Odds Ratio Weight Odds Ratio


Hamlyn 1981 1/13 7/13 100.0 % 0.07 [ 0.01, 0.72 ]

Total (95% CI) 13 13 100.0 % 0.07 [ 0.01, 0.72 ]

Total events: 1 (Methionine), 7 (Control)



0.001 0.01 0.1 1 10 100 1000

Favours methionine Favours control



Analysis 6.1. Comparison 6 Initial dose over 15 min versus 60 min of intravenous N-acatylcysteine



Comparison: 6 Initial dose over 15 min versus 60 min of intravenous N-acatylcysteine (randomised trials)


Study or subgroup 15 min 60 min Peto Odds Ratio Peto Odds Ratio


Kerr 2005 0/109 0/71 0.0 [ 0.0, 0.0 ]

Total (95% CI) 109 71 0.0 [ 0.0, 0.0 ]

Total events: 0 (15 min), 0 (60 min)


Test for overall effect: Z = 0.0 (P < 0.00001)

0.1 0.2 0.5 1 2 5 10

Favours 15 min Favours 60 min


(randomised trials), Outcome 2 Hepatotoxicity.



Outcome: 2 Hepatotoxicity

Study or subgroup 15 min 60 min Odds Ratio Weight Odds Ratio


Kerr 2005 6/107 5/68 100.0 % 0.75 [ 0.22, 2.56 ]

Total (95% CI) 107 68 100.0 % 0.75 [ 0.22, 2.56 ]




0.1 0.2 0.5 1 2 5 10





(randomised trials), Outcome 3 Any adverse event.



Outcome: 3 Any adverse event

Study or subgroup 15 min 60 min Odds Ratio Weight Odds Ratio


Kerr 2005 82/109 43/71 100.0 % 1.98 [ 1.04, 3.77 ]

Total (95% CI) 109 71 100.0 % 1.98 [ 1.04, 3.77 ]




0.1 0.2 0.5 1 2 5 10


Analysis 7.1. Comparison 7 Charcoal haemoperfusion in patients with fulminant hepatic failure



Comparison: 7 Charcoal haemoperfusion in patients with fulminant hepatic failure (randomised trials)


Study or subgroup Haemoperfusion Control Peto Odds Ratio Weight Peto Odds Ratio


O’Grady 1988 8/14 8/18 100.0 % 1.64 [ 0.41, 6.47 ]

Total (95% CI) 14 18 100.0 % 1.64 [ 0.41, 6.47 ]

Total events: 8 (Haemoperfusion), 8 (Control)



0.1 0.2 0.5 1 2 5 10

Favours haemoperfus. Favours control



Analysis 8.1. Comparison 8 5 h versus 10 h of charcoal haemoperfusion in patients with fulminant hepatic

failure (randomised trials), Outcome 1 Mortality.


Comparison: 8 5 h versus 10 h of charcoal haemoperfusion in patients with fulminant hepatic failure (randomised trials)


Study or subgroup H.-perfusion (5 h) H.-perfusion (10 Peto Odds Ratio Weight Peto Odds Ratio


O’Grady 1988 14/29 10/24 100.0 % 1.30 [ 0.44, 3.81 ]

Total (95% CI) 29 24 100.0 % 1.30 [ 0.44, 3.81 ]

Total events: 14 (H.-perfusion (5 h)), 10 (H.-perfusion (10)



0.1 0.2 0.5 1 2 5 10

Favours 5 h Favours 10 h

Analysis 9.1. Comparison 9 Intravenous N-acatylcysteine versus ’placebo’ in patients with fulminant hepatic

failure (randomised trials), Outcome 1 Mortality.


Comparison: 9 Intravenous N-acatylcysteine versus ’placebo’ in patients with fulminant hepatic failure (randomised trials)


Study or subgroup NAC ’lacebo/supportive Peto Odds Ratio Weight Peto Odds Ratio


1 N-acetylcysteine given 36 h to 80 h after overdose versus ’placebo’

Keays 1991 13/25 20/25 100.0 % 0.29 [ 0.09, 0.94 ]

Total (95% CI) 25 25 100.0 % 0.29 [ 0.09, 0.94 ]

Total events: 13 (NAC), 20 (’lacebo/supportive)



0.1 0.2 0.5 1 2 5 10

Favours NAC Favours ’placebo/sup



A P P E N D I C E SAppendix 1. Search strategies

Database Search strategy Time span

CHBG Controlled Trials Register (acetaminophen OR paracetamol) AND

(overdos* OR poison*) AND (methionin*

OR cystein* OR cysteamin* OR dimer-

caprol OR cimetidin* OR acetylcystein*

OR NAC OR ’gastric lavage*’ OR ’gas-

tric decontamination*’ OR charcoal OR

ipecacuanha OR ipecac OR hemoperfu-

sion* OR haemoperfusion*)

Last search performed 1 December 2005.

11 references were identified.

CHBG Miscellaneous database (acetaminophen OR paracetamol) AND

(overdos* OR poison*) AND (methionin*

OR cystein* OR cysteamin* OR dimer-

caprol OR cimetidin* OR acetylcystein*

OR NAC OR ’gastric lavage*’ OR ’gas-

tric decontamination*’ OR charcoal OR

ipecacuanha OR ipecac OR hemoperfu-

sion* OR haemoperfusion*)

Last search performed 1 December 2005.

21 references were identified.

Cochrane Central Register of Controlled

Trials (CENTRAL) in The Cochrane Li-

brary

#1 MeSH descriptor Acetaminophen ex-

plode all trees in MeSH products 1169

#2 acetaminophen* or paracetamol* in All

Fields in all products 2566

#3 (#1 OR #2) 2566

#4 MeSH descriptor Overdose explode all

trees in MeSH products 62

#5 overdos* or poison* in All Fields in all

products 986

#6 (#4 OR #5) 986

#7 methionin* OR cystein* OR cys-

teamin* OR dimercaprol OR cimetidin*

OR acetylcystein* OR NAC OR gastric

lavage* OR gastric decontamination* OR

charcoal OR ipecacuanha OR ipecac OR

hemoperfusion* OR haemoperfusion* in

All Fields in all products 4154

#8 (#3 AND #6 AND #7) 46

Issue 4, 2005. 44 references were identified.

MEDLINE #1 explode “Acetaminophen”/ all subhead-

ings

#2 (acetaminophen* or paracetamol*) in

TI

1950 to December 2005. 252 references

were identified.



(Continued)


AB

#4 #1 or #2 or #3

#5 explode “Overdose”/ all subheadings

#6 (overdos* or poison*) in TI

#7 (overdos* or poison*) in AB

#8 #5 or #6 or #7

#9 (methionin* or cystein* or cysteamin*

or dimercaprol or cimetidin* or acetyl-

cystein* or NAC or gastric lavage* or

gastric decontamination* or charcoal or

ipecacuanha or ipecac or hemoperfusion*

or haemoperfusion*) in TI






or haemoperfusion*) in AB

#11 #9 or #10

#12 #4 and #8 and #11

#13 ((random* or clinical or controlled or

observational) near (trial* or stud*)) in TI


observational) near (trial* or stud*)) in AB

#15 #13 or #14

#16 (human* or patient* or volunteer* or

healthy subject*) in TI


healthy subject*) in AB

#18 #16 or #17

#19 #12 and (#15 or #18)

#20 animal* in TG

#21 #19 not #20

EMBASE #1 explode “paracetamol”/ all subheadings


TI


AB

#4 #1 or #2 or #3

#5 explode “drug-intoxication”/ all sub-

headings

#6 explode “drug-overdose”/ all subhead-

ings

#7 (overdos* or poison*) in TI


were identified.



(Continued)

#8 (overdos* or poison*) in AB

#9 #5 or #6 or #7 or #8






or haemoperfusion*) in TI






or haemoperfusion*) in AB

#12 #10 or #11

#13 #4 and #9 and #12


observational) near (trial* or stud*)) in TI


observational) near (trial* or stud*)) in AB

#16 #14 or #15


healthy subject*) in TI


healthy subject*) in AB

#19 #17 or #18

#20 #13 and (#16 or #19)

#21 animal* in DER

#22 #20 not #21

Science Citation Index Expanded

(http://portal.isiknowledge.com/portal.cgi?DestApp=WOS&Func=Frame)

#19 #17 NOT #18

#18 (TS=animal*) OR (TI=animal*)

#17 #10 AND (#13 OR #16)

#16 #15 OR #14

#15 TI=(human* or patient* or volunteer*

or healthy subject*)

#14 TS=(human* or patient* or volunteer*

or healthy subject*)

#13 #12 OR #11

#12 TI=((random* or clinical or controlled

OR observational) AND (trial* or stud*))

#11 TS=((random* or clinical or controlled

OR observational) AND (trial* or stud*))

#10 #9 AND #6 AND #3

#9 #8 OR #7


were identified.



(Continued)

#8 TI=(methionin* or cystein* or cys-

teamin* or dimercaprol or cimetidin* or

acetylcystein* or NAC or gastric lavage*

or gastric decontamination* or charcoal or


or haemoperfusion*)

#7 TS=(methionin* or cystein* or cys-

teamin* or dimercaprol or cimetidin* or

acetylcystein* or NAC or gastric lavage*

or gastric decontamination* or charcoal or


or haemoperfusion*)

#6 #5 OR #4

#5 TI=(overdos* or poison*)

#4 TS=(overdos* or poison*)

#3 #2 OR #1

#2 TI=(acetaminophen* or paracetamol*)

#1 TS=(acetaminophen* or paracetamol*)

W H A T ’ S N E W

Last assessed as up-to-date: 21 February 2006.

9 November 2008 Amended Converted to new review format.

H I S T O R Y

Protocol first published: Issue 4, 2001

Review first published: Issue 3, 2002

C O N T R I B U T I O N S O F A U T H O R S

Jesper Brok designed, drafted, and revised the protocol; performed the searches; selected trials and studies; extracted data; and drafted

and revised the review.

Nick Buckley retrieved papers; extracted data; and revised the protocol and the review.

Christian Gluud revised the protocol and the review.



D E C L A R A T I O N S O F I N T E R E S T

None known.

S O U R C E S O F S U P P O R TInternal sources

• Copenhagen Trial Unit, Denmark.

External sources

• The 1991 Pharmacy Foundation, Denmark.

• Copenhagen Hospital Corporation’s Medical Research Council’s Grant on Getting Research into Practice (GRIP), Denmark.

• Danish Medical Research Council’s Grant on Getting Research into Practice (GRIP), Denmark.

• Copenhagen Hospital Corporation’s Medical Research Council, Denmark.

N O T E S

Since the publication of the protocol for this systematic Review, the following changes have been performed in the protocol part of the

Review:

The ’Objective’ section has been shortened and the more specific questions are now moved to ’Type of interventions’ .

Evidence from quasi-randomised studies, non-randomised studies, and randomised trials involving human volunteers has been placed

under ’Exploratory analysis’ at the end of the Result section. We caution readers that this evidence should be interpreted conservatively

due to the risk of systematic errors in non-randomised studies and the dangers of translating results from studies on human volunteers

into clinical practice.

Regarding ’The methods used to synthesize data’

We decided to analyse our data with both the fixed effect model as well as the random effects model. This was not included in the

primary protocol.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Acetaminophen [pharmacokinetics; ∗poisoning]; Analgesics, Non-Narcotic [pharmacokinetics; ∗poisoning]; Antidotes [therapeutic

use]; Charcoal [therapeutic use]; Gastric Lavage; Intestinal Absorption; Liver Failure, Acute [chemically induced; surgery]; Liver

Transplantation; Overdose [therapy]



MeSH check words

Humans



interventions for paracetamol (acetaminophen)...

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