QJM Advance Access originally published online on January 20, 2007
QJM 2007 100(2):93-96; doi:10.1093/qjmed/hcm003
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Liver unit admission following paracetamol overdose with concentrations below current UK treatment thresholds
From the 1Wolfson Unit of Clinical Pharmacology, School of Clinical and Laboratory Sciences, University of Newcastle, Newcastle upon Tyne, 2Liver Unit, Newcastle upon Tyne Hospitals NHS Trust, Freeman Hospital, Newcastle upon Tyne, and 3Scottish Poisons Information Bureau and 4Scottish Liver Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, UK
Address correspondence to S.H.L. Thomas, Wolfson Unit of Clinical Pharmacology, University of Newcastle, Newcastle upon Tyne NE2 4HH. email: simon.thomas{at}ncl.ac.uk
Received 16 June 2006 and in revised form 6 November 2006
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Summary |
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Background: It has been suggested that current UK thresholds for treating paracetamol overdose should be reduced, following case reports of patients developing fatal liver failure after presenting with paracetamol concentrations below these thresholds.
Aim: To determine the frequency of severe liver dysfunction following paracetamol overdose when paracetamol concentrations are below current UK antidote thresholds.
Design: Retrospective case note review.
Methods: Details were collected from all patients admitted to liver transplant units in Newcastle and Edinburgh with paracetamol-induced hepatotoxicity.
Results: Of 696 patients admitted to the two liver units following paracetamol overdose, 14 presented between 4 and 15 h after overdose with paracetamol concentrations below current UK treatment thresholds (estimated annual population rate 0.15/million person-years). Over the period of study, >100 000 presentations with paracetamol overdose would be expected in the catchment populations for these liver units.
Discussion: In view of the rarity of this event, this research does not suggest a need to lower the current thresholds for antidotal treatment.
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Introduction |
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Paracetamol overdose is a major public health problem in the UK, with the drug being implicated in about 40% of all overdose presentations. Paracetamol-induced hepatic necrosis has resulted in several hundred liver unit admissions and deaths each year.1,2
Patients at sufficient risk are treated with an antidote. In the UK, the treatment of choice is intravenous acetylcysteine.3 For patients presenting within 15 h, the need for treatment is determined on the basis of a nomogram relating plasma paracetamol concentration to the time since ingestion. Those without additional risk factors (e.g. chronic hepatic enzyme induction, cachexia) are treated if they have concentrations above a line starting at 200 mg/l at 4 h and subject to first-order decline with a 4 h half-life (the ‘200 line’). Those with risk factors for enhanced hepatotoxicity are treated at half these concentrations (the ‘100 line’).
In 1998, four cases of fatal hepatotoxicity were reported after presentation with paracetamol concentrations below the 200 line.4 None received acetylcysteine initially, and in three of the four this was consistent with current UK guidance. The authors proposed lowering treatment thresholds by 25% to bring them in line with nomograms used in some other countries, including the US (the ‘150 line’). However, the absolute risk of hepatotoxicity in patients with paracetamol concentrations between the 150 and 200 lines has not been determined accurately, and it remains unclear whether the benefits of treatment outweigh the risks, or if antidotal treatment is cost-effective in this group. Consequently, UK treatment guidance has not been changed.
This research was a systematic retrospective survey performed in defined geographic areas over specific time periods, to establish the numbers of patients admitted to two liver units with paracetamol-induced hepatic dysfunction who had initial paracetamol concentrations below the current nomogram levels at their original presentation.
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Methods |
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With ethical approval, the records of all patients admitted to the regional liver services in Newcastle (September 1996–March 2003) and Edinburgh (January 1992–June 2004) with paracetamol poisoning and severe liver dysfunction were reviewed. These two services cover the populations of north-east England and Scotland, totalling about 9.0 million people, and the periods of study encompassed about 95 million person-years. Clinical details were sought from the notes of the liver unit and, when necessary, the referring hospital (including the accident and emergency and clinical biochemistry departments). Data collected included the paracetamol concentration at the initial presentation, the timing of this following overdose, the presence of risk factors for enhanced hepatotoxicity, and the use and timing of acetylcysteine treatment. Information on the overall pattern of paracetamol poisoning was obtained from a survey of local hospitals performed in 1994, and from review of patients with paracetamol poisoning presenting to the Newcastle Hospitals NHS Trust during 2004.
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Results |
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During the periods of study, 696 patients with possible paracetamol hepatotoxicity were admitted to the two liver units. Of these, 553 (79%) presented >15 h after overdose and in 19 (2.7%) there was inadequate information available. Of the remaining 124 presenting within 15 h, 105 (81%) had paracetamol concentrations above the appropriate treatment line. Of the remainder, two were excluded because paracetamol concentrations had been taken <4 h after overdose, and three because liver function or clotting was already deranged at presentation, suggesting that the paracetamol overdose may have been taken earlier than stated.
Thus 14 patients were admitted to a liver unit after presenting within 15 h of overdose, with no evidence of abnormal liver function, and with paracetamol concentrations at presentation below the appropriate treatment line (Table 1). Eight of these patients had normal venous bicarbonate concentrations at initial presentation; results were not available in the other six. Ten had no recorded features to indicate high risk; of these, four were below the 100 line, four were between the 100 and 150 lines and two were between the 150 and 200 lines. Four patients were at high risk, all as a result of excess alcohol consumption, and all had paracetamol concentrations below the 100 line. Two patients were treated with acetylcysteine soon after presentation, but the remaining 12 were not treated until abnormal liver function or clotting had developed. Two patients died, one after undergoing liver transplantation, and the other from sepsis. The remainder recovered.
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In data collected from six A&E departments in the north-east of England in 1994 (n = 287), the proportions of all patients presenting with paracetamol poisoning who had paracetamol concentrations at presentation below the 100 line, between the 100 and 150 line and between the 150 and 200 lines were 64%, 13%, and 6.4%, respectively.1 Equivalent figures for 352 patients presenting during 2004 with paracetamol overdose to the Newcastle Clinical Toxicology Service, which admits all patients with drug overdose presenting in the city of Newcastle, were 71%, 15%, and 3.8%.
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Discussion |
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These data confirm the previous observation that some patients with relatively low paracetamol concentrations and normal clotting when apparently presenting within 15 h of overdose develop severe and occasionally fatal hepatic necrosis. In this systematic retrospective analysis, about 2% of those needing liver unit care following paracetamol poisoning fell into this category. This amounts to an annual presentation rate of 0.15 episodes per million population, or about nine UK cases. In the context of the frequency of paracetamol overdose, these cases appear very unusual. We cannot exclude the possibility that in some of these cases, unexpected hepatotoxicity developed because the interval between overdose and presentation was not given or recorded accurately.
Assuming an annual presentation rate of 750 cases/million population/year, consistent with previous reports,1,2 and that during the period of study the proportion of patients presenting with paracetamol concentrations in each concentration range was midway between the figures obtained in 1994 and 2004, which is a convenient estimate, the numbers of patients presenting in each paracetamol concentration range each year can be derived. Using data provided by this study on the numbers of patients requiring liver unit admission in each of these concentration ranges, it is possible to estimate the risk for each group. For patients with concentrations between the 150 and 200 lines, the 100 and 150 lines and below the 100 line, respectively, these risks would be approximately 1:1250, 1:1850 and 1:4400. However, these estimates should be interpreted with caution: proportions are based on limited patient numbers, and the data collection periods and geographic areas are not identical with the liver unit data. Furthermore, factors for enhanced hepatotoxicity are ignored, as there was inadequate information about presentation patterns in relation to them. The frequency of severe poisoning may have been reduced by legislation affecting pack sizes.5 Not all patients with severe hepatotoxicity will be referred to a liver unit. Finally, an unknown number of patients in each category will have been treated with acetylcysteine in spite of their low initial paracetamol concentration, especially following the Bridger4 publication. This may reduce the numbers of these patients needing liver unit admission, and thus result in an underestimation of risk. The proportion of patients treated with acetylcysteine increased from 25% to 76% for patients between the 150 and 200 lines, and from 2% to 15% for those between the 100 and 150 lines comparing the 19941 and 2004 north-east England data sets.
On the basis of these data, use of the 150 line for determining need for treatment would prevent only a few liver unit admissions; use of lower thresholds still would require treatment of very large patient numbers and would avoid only a few further episodes. These marginal benefits need to be offset against the inconvenience and costs of therapy and the risk of adverse reactions. Although usually not severe, anaphylactoid reactions to acetylcysteine appear more common in patients with lower plasma paracetamol concentrations.6 In a randomized controlled trial, drug-related adverse effects occurred in 45% and anaphylactoid reactions in 18% of recipients of the standard acetylcysteine infusion schedule.7 It is possible that lower doses of acetylcysteine may be effective and safer for patients with paracetamol concentrations below current UK thresholds. Clinical trials of these would be helpful, but are difficult to perform because of the very large numbers of participants that would be required to achieve adequate study power to demonstrate efficacy in this group.
Larger observational studies, which include the simultaneous collection of data on presentation patterns and risk factors, would be helpful in order to obtain more accurate estimates of risks without antidotal treatment in these patient groups. Abnormal clotting was present at presentation in some of the patients who go on to develop severe hepatic dysfunction, suggesting a longer interval between overdose and presentation than that suggested by the history. It may therefore be appropriate that a PT or INR should be performed on all patients at their original presentation; those with abnormal values should receive acetylcysteine irrespective of the plasma paracetamol concentration unless an alternative cause can be demonstrated.
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References |
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1. Thomas SHL, Horner JE, Chew K, et al. (1997) Paracetamol poisoning in the North East of England: presentation, early management and outcome. Hum Exp Toxicol 16 495–500.
2. Morgan O, Griffiths C, Majeed A. (2005) Impact of paracetamol pack size restrictions on poisoning from paracetamol in England and Wales; an observational study. J Public Health 27 19–24.
3. Prescott LF, Illingworth RN, Critchley JAJH, Stewart MJ, Adam RD, Proudfoot AT. (1979) Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J 2 1097–100.
4. Bridger S, Henderson K, Glucksman E, Ellis AJ, Henry JA, Williams R. (1998) Lesson of the week: Deaths from low dose paracetamol poisoning. Br Med J 316 1724–5.
5. Morgan O and Majeed A. (2005) Restricting paracetamol in the United Kingdom to reduce poisonings: a systematic review. J Public Health 27 12–18.
6. Schmidt LE and Dalhoff K. (2001) Risk factors for the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning. Br J Clin Pharmacol 51 87–91.[CrossRef][Web of Science][Medline]
7. Kerr F, Dawson A, Whyte IM, et al. (2005) The Australasian Clinical Toxicology Investigators Collaboration randomized trial of different loading infusion rates of N-acetylcysteine. Ann Emerg Med 45 402–8.[CrossRef][Web of Science][Medline]
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