QJM Advance Access originally published online on January 7, 2008
QJM 2008 101(2):121-125; doi:10.1093/qjmed/hcm139
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Does the patient history predict hepatotoxicity after acute paracetamol overdose?
From the Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh, 51 Little France Crescent Edinburgh, UK
Address correspondence to W.S. Waring, Scottish Poisons Information Bureau, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh, EH16 4TJ, UK. email: s.waring{at}ed.ac.uk
Received 8 August 2007 and in revised form 4 September 2007
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Summary |
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Background: Initial management of patients who were presented to hospital after acute paracetamol overdose depends on the suspected amount ingested and more than 12 g is potentially fatal. However, the validity of this approach has received comparatively little attention.
Methods: The present study is sought to establish whether the stated paracetamol dose might predict systemic exposure and risk of hepatotoxicity. A prospective observational study of consecutive patients presenting to the Emergency Department due to acute paracetamol overdose was performed. Serum paracetamol concentrations between 4 and 15 h post-ingestion were compared with the Rumack-Matthew ‘200-line’ nomogram, and hepatotoxicity was defined by prothrombin time ratio >1.3 or alanine transaminase 
1000 U/l.
Results: There were 987 patients, and the stated quantity of paracetamol ingested was 0–12 g in 475 (48.1%), >12 g in 349 (35.4%) and unknown in 163 (16.5%). Ingestion of >12 g was associated with paracetamol concentration above the ‘200-line’ in 31.8% (95% CI 27.1–36.9%) vs. 3.2% (1.9–5.2%), P < 0.0001 by 
2 proportional test, and associated with hepatotoxicity in 6.9% (4.6–10.1%) vs. 1.3% (0.5–2.8%), P = 0.0001.
Conclusions: Therefore, ingestion of >12 g predicted higher paracetamol exposure and increased risk of hepatotoxicity and supports the validity of patient history in this context.
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Introduction |
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Paracetamol (acetaminophen) is the most common means of deliberate self-poisoning in the United Kingdom and other European countries.1 For example, in the United Kingdom alone, paracetamol overdose gives rise to more than 70 000 emergency hospital attendances and causes around 18 deaths per million population annually.1–3 The need for N-acetylcysteine is normally determined from the suspected quantity of paracetamol ingested, interval between ingestion and presentation to hospital and factors that increase susceptibility to hepatotoxicity such as chronic heavy ethanol consumption, enzyme-inducing drugs and established liver disease.4 Risk may also be determined by the comparison of serum paracetamol concentrations to the Rumack-Matthew nomogram, which originally described an exponential decay between 200 mg/dl at 4 h and 30 mg/dl at 15 h.5 Several nomograms are used worldwide, all with minor modifications but based on the same principles, for example the ‘100-line’ represents 50% of the concentrations in the Rumack-Matthew nomogram and may be used as a lower threshold for antidote treatment in selected high-risk patients, and a ‘150-line’ is widely accepted in the United States.6 There are important limitations to the nomogram, and this method of risk stratification cannot be relied on if patients have taken a staggered overdose, co-ingested drugs capable of delaying gastrointestinal absorption, or presented late to hospital (>15 h post-ingestion).7 Therefore, N-acetylcysteine is normally administered if the patient is suspected of having ingested >12 g (or >150 mg/kg) in the previous 24 h.6,7
A common perception is that patient-reported dosages are unreliable in the context of acute overdose, but the validity of this approach has received comparatively little attention. A literature search using PubMed (www.pubmed.gov) for keywords {"paracetamol" OR "acetaminophen"} AND {"dose"} AND {"overdose" OR "ingestion" OR "toxicity" OR "poisoning"} revealed only a small number of English language articles concerning the validity of patient reported dose (Table 1).8–16 Limited data suggest that patients tend to over-estimate the quantity of paracetamol ingested, and that the stated amount ingested correlates poorly with the risk of hepatotoxicity.14,16 In contrast, others have found the reported dose of paracetamol to be sufficiently accurate to allow development of a predictive pharmacokinetic model and to determine those at highest risk of hepatotoxicity.15,17 However, these studies have included comparatively small patient numbers, some involving a retrospective design, and relate to acute overdose, staggered overdose and inadvertent supra-therapeutic administration. Therefore, the present study was designed to prospectively examine the significance of the patient history in a large group of patients who are managed in a consistent manner. The aim was to study whether the reported dose of ingested paracetamol might correspond to systemic exposure determined by serum paracetamol concentrations or the risk of subsequent hepatotoxicity.
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Methods |
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Study design
The protocol was reviewed and approved by the local research ethics committee. This was a prospective, observational study of consecutive patients presenting to the Emergency Department after acute paracetamol overdose between March 2005 and June 2006. Exclusion criteria were presentation >15 h after overdose, uncertainty about the timing of ingestion and ingestion staggered over 2 h or more. A standard operating procedure is used in management of paracetamol overdose patients to ensure consistency between the Emergency Department and Toxicology Unit, and is in accordance with TOXBASE®, the standard resource for poisoning management advice in the United Kingdom.18 In brief, intravenous N-acetylcysteine is indicated after acute ingestion if serum paracetamol concentration is above the Rumack-Matthew ‘200-line’ nomogram, or above the ‘100-line’ and the patient is considered at high risk due to chronic ethanol excess, enzyme inducing drugs (carbamazepine, phenobarbital, phenytoin, rifampicin, St John's Wort), chronic liver disease, or malnutrition. Chronic ethanol excess is defined by regular consumption of >21 U (168 g) per week in men or >14 U (112 g) in women.19 If more than 8 h have elapsed after ingestion and the patient is thought to have ingested >12 g or >150 mg/kg, then N-acetylcysteine may be initiated before paracetamol concentrations become available. Intravenous N-acetylcysteine 300 mg/kg is administered over 20.25h and serum creatinine, prothrombin time ratio, and liver biochemistry are monitored.
Measurements
A standardized data collection sheet was used to record patient age, gender, date and time of overdose, stated quantity ingested, risk factors for hepatotoxicity and serum paracetamol concentration. If the patient was unwilling or unable to give the amount ingested, then this was recorded as ‘unknown’. The primary outcome variables were serum paracetamol concentration above the ‘100-line’ or ‘200-line’ at 4–15 h post ingestion, administration of N-acetylcysteine and incidence of hepatotoxicity predefined by prothrombin time ratio >1.3 or alanine transaminase 1000 U/l.20
Data analyses
Where appropriate, data are presented as median, absolute values and proportions, with 95% confidence intervals constructed by the modified Wald method.21 The relationship between stated paracetamol dose and estimated 4 h acetaminophen concentration was determined in men and women separately using the Spearman rank correlation coefficient (rho), and compared by z-test. Convenience subgroups were created as multiples of the maximum daily therapeutic dose (4 g) and between-group comparisons were made using two-tailed Yate's corrected 2 proportional tests (MedCalc statistical software v.9.1.0.1, Mariakerke, Belgium). P-values <0.05 were accepted as statistically significant.
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Results |
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There were 987 patients (672 women, 68.1%) aged 30 years (ranged 14–93 years) and weight 65 kg (ranged 36–134 kg). The stated quantity of paracetamol ingested was 0–12 g in 475 (48.1%), >12 g in 349 (35.4%) and unknown in 163 (16.5%). Patients who reported ingestion of >12 g had paracetamol concentrations above the ‘200-line’ in 31.8% (27.1–36.9%), compared with only 3.2% (1.9–5.2%) after ingestion of 0–12 g (P < 0.0001). Patients who reported ingestion of >12 g were also more likely to require N-acetylcysteine, 62.5% (57.3–67.4%) vs. 13.5% (10.7–16.9%) (P < 0.0001) and suffered a higher incidence of hepatotoxicity, 6.9% (4.6–10.1%) vs. 1.3% (0.5–2.8%), P = 0.0001.
There was a positive correlation between stated dose ingested and estimated 4 h paracetamol concentration in men, rho = 0.654 (0.580–0.717) and women, rho = 0.667 (0.618–0.711) and no significant difference between men and women (z = 0.3096, P = 0.7569). Across the subgroups 0–4 g, 4.1–8 g, 8.1–12 g, 12.1–16 g, 16.1–24 g and >24 g, there was a positive dose-exposure relationship as determined by the proportion of patients with paracetamol concentrations higher than the ‘100-line’ and ‘200-line’, and the need for N-acetylcysteine administration (Figure 1). There was also a positive association between the stated dose ingested and the incidence of hepatotoxicity. Patients in whom the dose was unknown had serum paracetamol concentrations similar to those measured in the groups who reported ingestion of 8.1–12 g and 12.1–16 g.
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Discussion |
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In patients who were presented to hospital after acute paracetamol overdose, the reported quantities ingested are closely related to the extent of systemic exposure, as evidenced by serum paracetamol concentrations. The dosages reported by the patient informed both the extent of paracetamol exposure and also the likelihood of subsequent hepatotoxicity. This demonstrates the potential validity of the patient history in determining the quantity of drug ingested in poisoned patients who were presented to hospital. Furthermore, the data indicate a close correlation between the stated doses ingested and estimated 4 h paracetamol concentration for both men and women. It is rarely feasible to determine serum concentrations for a variety of drugs in the context of acute overdose and, therefore, the patient history might be an important surrogate for estimating overall drug exposure. Cautious interpretation is required for individual patients because of reporting variability, perhaps due to altered mental status, or the effects of co-ingested ethanol or sedative medications. Nonetheless, a correlation between stated dose and paracetamol concentrations higher than the ‘200-line’ has previously been found, irrespective of acute or chronic ethanol intake.11 The present data are directly applicable to clinical research in poisoned patients in whom conventional methods are rarely appropriate. Validity of the patient history for estimating overall exposure might allow dose-dependent effects to be studied in groups of poisoned patients, for example evaluation of dose-dependent QT prolongation.22
Patients who reported ingestion of more than 12 g of paracetamol showed a substantially higher risk of developing hepatotoxicity compared with ingestion of smaller quantities (6.9% vs. 1.3%), despite administration of N-acetylcysteine. The incidence of hepatotoxicity in patients who were unwilling or unable to state the dose ingested was comparatively low (1.2%), indicating that this subgroup is not exposed to additional risk. Overall, the incidence of hepatotoxicity across the whole study population (3.2%) was consistent with other studies involving young adults who were presented to hospital within 15 h of acute paracetamol overdose.7–9 Moreover, the higher incidence among those who ingested more than 12 g supports the use of this cut-off value when considering the need for N-acetylcysteine administration.
A limitation is that only patients who were presented to hospital early were included, because the risk nomogram was originally validated between 4 and 15 h after ingestion.5 Patient characteristics might conceivably differ between those who were presented to hospital early, late, or after a staggered overdose. Nonetheless, inclusion of these additional groups in an informal post hoc analysis did not alter the findings. Another potential concern is that data concerning paracetamol overdose might not be applicable to patients who have ingested other drugs. Nonetheless, a close correlation between the stated dose of quetiapine and serum concentrations has been reported elsewhere after deliberate overdose.23 Activated charcoal was rarely administered in this series, despite being recommended within 1 h of paracetamol ingestion.24 This might be due to specific contraindications, or limited opportunity to administer treatment within 1 h, or lack of awareness by Emergency Department staff. A further potential limitation is that reporting might have been enhanced if patients were aware that confirmatory paracetamol measurements would be made, but we do not believe that this would have had a significant effect here because the patient history was elicited before permission was sought for blood sampling.
In conclusion, it is possible to make comparisons between groups of patients stratified on the basis of self-reported quantities ingested. The patient history is sufficiently reliable to indicate both the extent of drug exposure and also the risk of subsequent toxicity. This approach merits further consideration in qualitative assessment of patients who were presented to hospital after deliberate overdose.
Conflict of interest: None declared.
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