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. 1998 Dec 12;317(7173):1654.

Deaths from low dose paracetamol poisoning

Executive action is needed to change national guidelines

John Barnes 1, Margaret Abban 1, Paul Howarth 1
PMCID: PMC1114447  PMID: 9848918

Editor—The lesson of the week by Bridger et al on deaths from low dose paracetamol poisoning was most welcome but probably titled incorrectly.1 None of the patients in the cases described took low doses of paracetamol. What did happen was that the current national guidelines for treating patients after poisoning with paracetamol failed to protect these patients.

We suspect that many doctors will have read these cases and dismissed them as poor management, assuming, for example, that the doctors concerned failed to establish the correct timing of the drug ingestion. We fear that complacency will persist with the belief that deaths will not happen if the current guidelines are adhered to properly.

One of the cases was managed in our hospital. The timing and circumstances of the poisoning seemed to be and still do seem to be clear cut. We know the time at which the paracetamol was purchased from a local shop and the time immediately after at which help was sought. These times concur with the history that was given. The concentrations of paracetamol at four hours were 22% below the national standard treatment line. We believe that the nomogram should allow for a safety margin of 22%.

We agree that there are many possible explanations for our patient’s death. Our patient may have been particularly susceptible to paracetamol but equally may have taken a sequential overdose. The key point is that a treatment strategy must allow a margin of safety that allows for some degree of inaccuracy in the history or an individual patient’s susceptibility to paracetamol.

We are from the hospital in the south west referred to in the article that has changed its treatment protocol to a lower treatment line. Since making this change in 1994 we have treated around an extra 60 patients each year with acetylcysteine who would not have been treated using the national guidelines. Of these extra patients treated, one third were considered to be at normal risk and two thirds at high risk of hepatotoxicity. We cannot know if any of these patients would otherwise have developed liver failure.

In 1994 we were indebted to Williams for reviewing the modifications that we had made to our local guidelines. These local guidelines are contrary to those in the British National Formulary and of the National Poisons Information Service. We therefore may be vulnerable to medicolegal problems if any patient has a reaction to acetylcysteine. We welcome the article by Bridger et al and strongly advocate that the national guidelines be changed to those now used in Truro. Executive action is clearly needed to review current practice and make appropriate changes to the national recommendations.

References

  • 1.Bridger S, Henderson K, Glucksman E, Ellis AJ, Henry JA, Williams R. Deaths from low dose paracetamol poisoning. BMJ. 1998;316:1724–1725. doi: 10.1136/bmj.316.7146.1724. . (6 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
BMJ. 1998 Dec 12;317(7173):1654.

Guidelines are under review

Geoffrey Brandon 1

Editor—The lesson of the week by Bridger et al is misleadingly titled.1-1 These case reports refer to serum paracetamol concentrations interpreted to be below the standard treatment line, not to low doses. Surely a crucial point is that in treating paracetamol overdoses, patient histories need to be relied on to interpret the clinical significance of serum paracetamol concentrations when deciding whether to treat with antidote, and such histories may be unreliable.

The guidelines agreed by the National Poisons Information Service on managing acute paracetamol overdosage advise that patients should be considered at risk of severe liver damage if 24 or more tablets have been ingested; in recognition of the uncertainties of patient histories or any other factors that do not seem to correlate they then say: “If there is doubt about timing or the need for treatment, treat.”1-2 The guidelines are currently under review, not only to update the management protocols but also to address the problem of the small number of patients who would benefit from treatment with an antidote but who, for a variety of reasons, do not receive it.

References

  • 1-1.Bridger S, Henderson K, Glucksman E, Ellis AJ, Henry JA, Williams R. Deaths from low dose paracetamol poisoning. BMJ. 1998;316:1724–1725. doi: 10.1136/bmj.316.7146.1724. . (6 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Management of acute paracetamol poisoning. Guidelines agreed by the UK National Poisons Information Service (1995). Supplied to accident and emergency centres in the United Kingdom by the Paracetamol Information Centre in collaboration with the British Association for Accident and Emergency Medicine.
BMJ. 1998 Dec 12;317(7173):1654.

Several issues were not considered in the article

D P McAliskey 1

Editor—Several important issues were not addressed by Bridger et al in their lesson of the week on deaths after allegedly low dose paracetamol poisoning.2-1

Firstly, the total dose ingested is important. The current national guidelines state: “Any patient should be considered at risk of severe liver damage if he/she has ingested more than 150 mg paracetamol/kg body weight or 12 g or more in total, whichever is the smaller.”2-2 Furthermore, the British National Formulary advises that “as little as 10-15 g of paracetamol may cause severe hepatocellular necrosis.”2-3 Thus, from the doses ingested each of the four fatal cases should have been considered on presentation to be at high risk of severe liver damage.

Secondly, although they suggested that timing errors were probably to blame for the “non-toxic” serum concentrations of paracetamol in cases 1, 3, and 4, Bridger et al did not emphasise the difficulties in assessing patients who present with deliberate self poisoning. Such patients are often uncooperative, manipulative, untruthful, and intoxicated with alcohol or other drugs. A low threshold for treating such patients therefore seems prudent, especially when potentially toxic injury may be attenuated by administration of a specific antidote such as acetylcysteine. This view is clearly advocated in the current national guidelines—namely, “If there is doubt about timing or the need for treatment, treat.”2-2

Thirdly, the authors did not mention the uselessness of the current treatment nomogram when paracetamol overdosage has occurred over several hours or more rather than as a single episode. In such cases, treatment with acetylcysteine is generally advisable.

Finally, Bridger et al recommend the adoption of a lower standard treatment line, as widely used in the United States. Interestingly, the Australian guidelines for paracetamol overdosage in adults use the same treatment nomogram as that used in the British guidelines.2-2,2-3 However, these recommendations include the advice that “some experts advocate that ALL cases above this lower line [high risk treatment line2-2,2-3] should be treated.”2-4

References

  • 2-1.Bridger S, Henderson K, Glucksman E, Ellis AJ, Henry JA, Williams R. Deaths from low dose paracetamol poisoning. BMJ. 1998;316:1724–1725. doi: 10.1136/bmj.316.7146.1724. . (6 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2-2.British Medical Association; Royal Pharmaceutical Society of Great Britain. British National Formulary. No 35. London: BMA, RPS; 1998. Emergency treatment of poisoning; pp. 20–21. [Google Scholar]
  • 2-3.Management of acute paracetamol poisoning. Guidelines agreed by the UK National Poisons Information Service (1995). Supplied to accident and emergency centres in the United Kingdom by the Paracetamol Information Centre in collaboration with the British Association for Accident and Emergency Medicine.
  • 2-4.Australian Working Group in conjunction with Australasian College for Emergency Medicine. Guidelines for the management of paracetamol overdose in adults (1997). Distributed by SmithKline Beecham International, Consumer Healthcare, Ermington, New South Wales, Australia.
BMJ. 1998 Dec 12;317(7173):1654.

Nomogram does not show absolute concentration for treatment

K S Aujla 1, V M Maclean 1, J R Richardson 1, E M Docherty 1

Editor—Bridger et al suggested that all patients presenting with a serum paracetamol concentration >150 mg/l should be treated with acetylcysteine, with a treatment threshold of 100 mg/l for patients with known risk factors for liver disease.3-1 Although we agree with this suggestion, we think that the four cases presented do not provide sufficient evidence to support a reduction in the threshold for treatment of paracetamol overdose.

For many years the policy in Aberdeen has been to admit all patients with overdose, checking paracetamol concentrations at four hours, or on admission, and again four hours later, thus reducing the effect of timing errors. We immediately start treatment with acetylcysteine in all patients who have ingested more than 150 mg/kg. We also check liver function and prothrombin time to identify those with underlying liver abnormality or early hepatic damage. These patients can then be treated earlier.

As pointed out by the authors, case 2 should have been treated according to the high risk threshold of existing guidelines. Under these same guidelines, cases 3 and 4 should have been treated on the basis of the amount ingested, if not also because the concentrations were close to the treatment line. (We always assume some degree of timing error.)

Case 1 may be an example of what happens when a patient reacts abnormally to paracetamol overdose. Other factors are, however, relevant. She had taken a significant overdose, the timing of which should always be viewed with suspicion. In addition, no mention is made of her weight; therefore, 10 g could have represented more than 150 mg/kg for her. With our current practice, deterioration would have been detected earlier and treatment started.

In conclusion, the current guidelines provide a sound basis for managing paracetamol overdose, provided that the nomogram is treated as a guide to risk assessment and not as showing the absolute concentration for treatment.

References

  • 3-1.Bridger S, Henderson K, Glucksman E, Ellis AJ, Henry JA, Williams R. Deaths from low dose paracetamol poisoning. BMJ. 1998;316:1724–1725. doi: 10.1136/bmj.316.7146.1724. . (6 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
BMJ. 1998 Dec 12;317(7173):1654.

If in doubt use the antidote

S H L Thomas 1

Editor—Bridger et al suggested changing the treatment line for use of antidotes in patients at standard risk from paracetamol poisoning from that currently recommended, which passes through 200 mg/l at four hours and 25 mg/l at 16 hours, to a lower line passing through 150 mg/l at four hours and 30 mg/l al 12 hours.4-1 This recommendation is based on the deaths of three patients who were apparently at standard risk and were not treated with an antidote after presenting with concentrations between these two lines. The fourth patient was at high risk of toxicity and would have been treated if current guidelines had been followed.

My colleagues and I recently collected data prospectively on patients presenting with paracetamol poisoning in north east England (43% of all overdoses).4-2 Extrapolating these data, which reflect the pattern in other parts of the country,4-3,4-4 we estimate that around 58 000 people take paracetamol overdoses each year in England and Wales. In 9% (5500) of them the associated paracetamol concentrations are above the currently recommended treatment line, while an additional 6% (3500) are above the lower line proposed by Bridger et al. The deaths of the three patients in this category show that this group are at some risk. However, the potentially large size of the denominator (which is unknown and depends on the geographical area and the time over which cases have been collected) suggests that the case fatality of this group may be low. They seem to be a small fraction of the patients who die each year of paracetamol poisoning, who may number as many as 200.4-5 It therefore remains uncertain whether their risk of paracetamol toxicity justifies the increased use of resources that would be needed to treat this potentially large group of patients. More information on the occurrence of death and liver failure in this group is needed.

An absolute cut off point between a non-toxic and a toxic paracetamol overdose does not exist. The timing of the blood sample in relation to the overdose is often uncertain and some of the differences in susceptibility to paracetamol are not well understood. In judging whether to use an antidote clinicians should always err on the side of caution. When using treatment nomograms they should assume the longest interval between poisoning and blood sampling that is consistent with the history. They should use the lower high risk line if there is any suggestion that a patient might be particularly susceptible—for example, because of alcoholism, use of enzyme inducing drugs, or poor nutrition and cachexia. If in doubt, an antidote should be used.

References

  • 4-1.Bridger S, Henderson K, Glucksman E, Ellis AJ, Henry JA, Williams R. Deaths from low dose paracetamol poisoning. BMJ. 1998;316:1724–1725. doi: 10.1136/bmj.316.7146.1724. . (6 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4-2.Thomas SHL, Homer JE, Chew K, Connolly J, Dorani B, Bevan L, et al. Paracetamol poisoning in the North East of England: presentation, early management and outcome. Hum Exper Toxicol. 1997;16:495–500. doi: 10.1177/096032719701600903. [DOI] [PubMed] [Google Scholar]
  • 4-3.Hawton K, Fagg J. Trends in deliberate self poisoning and self injury in Oxford, 1976-90. BMJ. 1992;304:1409–1411. doi: 10.1136/bmj.304.6839.1409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4-4.Bialas MC, Reid PG, Beck P, Lazarus JH, Smith PM, Scorer RC, et al. Changing patterns of self-poisoning in a UK health district. Q J Med. 1996;89:893–901. doi: 10.1093/qjmed/89.12.893. [DOI] [PubMed] [Google Scholar]
  • 4-5.Office of Population Censuses and Surveys. Mortality statistics: cause. London: HMSO; 1994. table 2. (Series DH2 No 20.) [Google Scholar]
BMJ. 1998 Dec 12;317(7173):1654.

More evidence needed to change recommendations

D F D’Costa 1

Editor—Bridger et al drove home the message of the toxicity of paracetamol overdoses, but they did not comment on whether the patients in cases 3 and 4 might have been helped if they had been given acetylcysteine despite their late presentation.5-1

The authors then recommend that the cut off point for treatment with acetylcysteine should be at a paracetamol concentration of 150 mg/l. It is not clear whether this refers to the concentration at four hours or any other time. Even if this new cut off point were adopted it would have made no difference in case 4. Furthermore, in the study that Bridger et al quote to endorse the lower concentration 1.4% (3 out of 214) of patients with concentrations below 150 mg/l developed hepatotoxicity.5-2 Does that mean that the treatment concentration should be lowered further?

In these enlightened days of evidence based medicine and cost effectiveness can the authors:

  • Calculate the increased number of people who will require treatment at the lower proposed concentration?

  • Predict the implications of treatment at the lower concentration on the great number of patients requiring admission, the cost entailed, and the likelihood of any accrued benefit—that is, the numbers needed to treat to save one complication or one death?

If there is no evidence to support the widespread adoption of this policy, should four anecdotal reports in which the management was suboptimal, as the authors acknowledge, be the basis of such a fundamental change? Perhaps not.

References

  • 5-1.Bridger S, Henderson K, Glucksman E, Ellis AJ, Henry JA, Williams R. Deaths from low dose paracetamol poisoning. BMJ. 1998;316:1724–1725. doi: 10.1136/bmj.316.7146.1724. . (6 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5-2.Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral acetylcysteine in the treatment of acetaminophen overdose. N Engl J Med. 1988;319:1557–1562. doi: 10.1056/NEJM198812153192401. [DOI] [PubMed] [Google Scholar]
BMJ. 1998 Dec 12;317(7173):1654.

Lower threshold has probably not overburdened hospital services in Gloucester

M G Cameron 1

Editor—I was heartened to read that Bridger et al have recommended a reduction in the threshold for treatment with acetylcysteine in cases of paracetamol poisoning.6-1

We have been using the lower threshold recommended by Bridger et al at this hospital since 1995. Two points may help to persuade others to adopt the lower threshold.

Firstly, immediately before the lower threshold was implemented a review of cases of paracetamol poisoning over six months (an average of one case per day presenting to the accident and emergency department) showed that only one additional admission would have resulted had the lower threshold been in place during these six months. This is reassuring to those who fear overburdening of already stretched inpatient services.

Secondly, having been asked to give evidence at an independent inquiry into one of the deaths reviewed in the case series by Bridger et al, I was astonished and disappointed to hear the inquiry panel criticise the junior doctor who followed the then existing guidelines and did not treat with acetylcysteine since the patient’s paracetamol concentration was significantly below the treatment line. It seems that the lesson revealed in the BMJ in 1998 was expected to have been intuitively grasped by a junior doctor several years before.

References

  • 6-1.Bridger S, Henderson K, Glucksman E, Ellis AJ, Henry JA, Williams R. Deaths from low dose paracetamol poisoning. BMJ. 1998;316:1724–1725. doi: 10.1136/bmj.316.7146.1724. . (6 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
BMJ. 1998 Dec 12;317(7173):1654.

Use of oral methionine for overdose below threshold for acetylcysteine

Ben Wright 1, Michael Crowe 1

Editor—Bridger et al suggested reducing the threshold for treatment with acetylcysteine after a paracetamol overdose to reduce the risk of hepatotoxicity.7-1 We would like to draw attention to oral methionine treatment, an effective antidote for paracetamol poisoning.7-2–7-4

Oral activated charcoal is often prescribed to patients who have taken paracetamol alone, and this prohibits the use of oral methionine.7-3 We treat patients who repeatedly use paracetamol to harm themselves. They often experience charcoal treatment as punishing and humiliating because the solution is difficult and unpleasant to swallow and stains clothes; this adds to their emotional distress. Were they to be allergic to intravenous acetylcysteine it would also seriously impair the absorption of oral methionine. In addition, patients may not be able to say when they took the overdose, partly because of their distress and partly because they may have taken paracetamol over several hours.

We immediately start treatment with oral methionine (2.5 g) before measuring blood paracetamol concentrations. We transfer all patients who do not have simple paracetamol poisoning to the local accident and emergency department (dose >150 mg/kg, body mass index <17.5 kg/m2, positive for HIV infection, alcohol misuse, prescribed drugs that induce liver enzymes). We initially manage patients with simple paracetamol poisoning in the psychiatric ward, where we measure blood concentrations. Three further doses of 2.5 g methionine are given every four hours if concentrations are >200 mg/l four hours after ingestion (or the equivalent at later times), the overdose started under 10 hours before, and patients have no significant nausea and are not vomiting. We always err on the side of caution in continuing methionine treatment.

Apart from occasional nausea and vomiting, our patients find this management acceptable and humane. We have used this conservative policy for the past three years without encountering any associated untoward events. Because of the problems identified by Bridger et al, we now plan to give methionine to all patients with simple paracetamol poisoning whatever their blood concentrations. We suggest that all patients presenting to accident and emergency departments with simple paracetamol poisoning should be prescribed oral methionine on presentation and that oral charcoal should not be used at all. Thus treatment with intravenous acetylcysteine could be started if necessary according to the recommendations of Bridger et al.7-1 Otherwise, oral methionine could be continued as an outpatient under the supervision of a responsible adult, who could also provide emotional support and encourage patients to return for psychiatric follow up.

References

  • 7-1.Bridger S, Henderson K, Glucksman E, Ellis AJ, Henry JA, Williams R. Deaths from low dose paracetamol poisoning. BMJ. 1998;316:1724–1725. doi: 10.1136/bmj.316.7146.1724. . (6 June.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7-2.Janes J, Routledge PA. Recent developments in the management of paracetamol (acetaminophen) poisoning. Drugs Safety. 1992;7:170–177. doi: 10.2165/00002018-199207030-00002. [DOI] [PubMed] [Google Scholar]
  • 7-3.Flanagan RJ, Meredith TJ. Use of N-acetylcysteine in clinical toxicology. Am J Med. 1991;91(3C):131–19S. doi: 10.1016/0002-9343(91)90296-a. [DOI] [PubMed] [Google Scholar]
  • 7-4.Vale JA, Meredith TJ, Goulding R. Treatment of acetaminophen poisoning. The use of oral methionine. Arch Intern Med. 1981;141:394–396. doi: 10.1001/archinte.141.3.394. [DOI] [PubMed] [Google Scholar]
BMJ. 1998 Dec 12;317(7173):1654.

Authors’ reply

S Bridger 1,2,3, K Henderson 1,2,3, A J Ellis 1,2,3, E Glucksman 1,2,3, Roger Williams 1,2,3, John Henry 1,2,3

Editor—We thank the correspondents for their constructive comments. With respect to the assertion of Barnes et al and Brandon that our lesson of the week was misleadingly titled, we would say that our title, “Fatal paracetamol overdose in patients not treated with an antidote” was submitted to the editorial process. It is a pity if this detracted from the intended message and led correspondents to concentrate on the issue of drug dosage.

Brandon, McAliskey, and Aujla et al emphasised the importance of total dosage ingested and referred to the current national guidelines.8-1 However, in clinical practice, the decision to treat with an antidote is universally determined by a single blood paracetamol concentration in conjunction with the type and timing of the overdose and the presence or absence of risk factors. As such, we agree with Barnes et al and Thomas that the current clinical guidelines failed for three of our four patients. The large studies analysing mortality after paracetamol overdose have not shown any correlation between the amount of paracetamol allegedly ingested and the blood concentration found.8-2 The principle of adopting a lower threshold for treatment using a nomogram which joins a paracetamol concentration of 150mg/l at four hours with a value of 30 mg/l at 12 hours has already been accepted by some of the respondents. In answer to D’Costa’s assertion that such a nomogram would have made no difference in the treatment of case 4, this patient’s concentration of 122 mg/l was measured six hours after ingestion.

Our audit findings, like those of Cameron, indicate that implementation of the lower threshold for a hospital accident and emergency department seeing 75 000 patients a year would result in the admission of one extra patient a month. Thomas suggests that this modification could lead to the treatment of an extra 3500 patients a year in England and Wales. However, we are aware that many physicians already err on the side of caution and treat a substantial number of these patients. Consequently the “denominator” may not be as large as Thomas assumes. The four cases we reported were referred over two years to one regional liver unit. Even if no other cases occurred in England and Wales during this time and if Thomas’s extrapolated figures are accurate, then the case fatality of this group could be one in 1000 or more. In view of the tragedy of a preventable death, the high medical and economic costs of treating patients with preventable liver failure, and the proved efficacy and safety of acetylcysteine or methionine, we reiterate our recommendation to treat all patients presenting with blood paracetamol concentrations greater than 150 mg/l at four hours.

References

  • 8-1.Management of acute paracetamol poisoning. Guidelines agreed by the UK National Poisons Information Service (1995). Supplied to accident and emergency centres in the United Kingdom by the Paracetamol Information Centre in collaboration with the British Association for Accident and Emergency Medicine.
  • 8-2.Read RB, Tredger JM, Williams R. Analysis of factors responsible for continuing mortality after paracetamol overdose. Hum Toxicol. 1986;5:201–206. doi: 10.1177/096032718600500309. [DOI] [PubMed] [Google Scholar]

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